UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, DC 20549
FORM 10‑K
(Mark One)
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ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 |
For the Fiscal Year Ended December 31, 2017
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TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 |
Commission File Number 001‑36668
DERMIRA, INC.
(Exact name of Registrant as specified in its charter)
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Delaware |
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27‑3267680 |
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(State or other jurisdiction of incorporation or organization) |
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(I.R.S. Employer Identification No.) |
275 Middlefield Road, Suite 150
Menlo Park, CA 94025
(Address of principal executive offices) (Zip Code)
(650) 421‑7200
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
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Title of Each Class: |
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Name of Each Exchange on which Registered |
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Common Stock, par value $0.001 per share |
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The NASDAQ Global Select Market |
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the Registrant is a well‑known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐
Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the Registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the Registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S‑T during the preceding 12 months (or for such shorter period that the Registrant was required to submit and post such files). Yes ☒ No ☐
Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S‑K is not contained herein, and will not be contained, to the best of Registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10‑K or any amendment to this Form 10‑K. ☒
Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non‑accelerated filer, or a smaller reporting company. See definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b‑2 of the Exchange Act.(Check one):
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Large accelerated filer |
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Accelerated filer |
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Non-accelerated filer |
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(Do not check if a smaller reporting company) |
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Smaller reporting company |
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Emerging growth company |
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If an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b‑2 of the Act). Yes ☐ No ☒
As of June 30, 2017, the last business day of the Registrant’s most recently completed second fiscal quarter, the aggregate market value of common stock held by non‑affiliates of the Registrant was approximately $945,328,205 (based on a closing price of $29.14 per share as reported by The NASDAQ Global Select Market on June 30, 2017). For purposes of this calculation, shares of common stock beneficially owned by the Registrant’s officers, directors and certain stockholders as of June 30, 2017 have been excluded in that such persons may be deemed to be affiliates. This determination of affiliate status is not necessarily a conclusive determination for other purposes. The Registrant has no non‑voting common equity.
As of February 12, 2018, the number of outstanding shares of the Registrant’s common stock, par value $0.001 per share, was 41,821,978.
DOCUMENTS INCORPORATED BY REFERENCE
Certain sections of the Registrant’s definitive Proxy Statement to be filed in connection with the Registrant’s 2018 Annual Meeting of Stockholders are incorporated by reference into Part III of this Form 10‑K where indicated. The Proxy Statement will be filed with the Securities and Exchange Commission pursuant to Regulation 14A within 120 days of the Registrant’s fiscal year ended December 31, 2017. Except with respect to information specifically incorporated by reference in this Form 10‑K, the Proxy Statement is not deemed to be filed as part of this Form 10‑K.
Form 10‑K
For the Fiscal Year Ended December 31, 2017
Table of Contents
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Item 1. |
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Item 1A. |
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Item 1B. |
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84 |
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Item 2. |
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Item 3. |
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Item 4. |
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Item 5. |
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Item 6. |
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Item 7. |
Management’s Discussion and Analysis of Financial Condition and Results of Operations |
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Item 7A. |
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Item 8. |
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Item 9. |
Changes in and Disagreements with Accountants on Accounting and Financial Disclosure |
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Item 9A. |
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Item 9B. |
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Item 10. |
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Item 11. |
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Item 12. |
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters |
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Item 13. |
Certain Relationships and Related Transactions, and Director Independence |
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Item 14. |
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Item 15. |
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Unless the context indicates otherwise, as used in this report, the terms “Company,” “Dermira,” “Registrant,” “we,” “us” and “our” refer to Dermira, Inc., a Delaware corporation, and its sole subsidiary taken as a whole.
“Dermira” is a registered trademark in Australia, Canada, the European Union, Japan, Mexico, Switzerland and the United States. A trademark application for “Dermira” and logo is pending in Canada, China, European Union, Hong Kong, Japan, Mexico and the United States. All other service marks, trademarks and tradenames appearing in this Annual Report on Form 10‑K are the property of their respective owners. Solely for convenience, the trademarks and tradenames referred to in this Annual Report on Form 10‑K appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.
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SPECIAL NOTE REGARDING FORWARD‑LOOKING STATEMENTS
This Annual Report on Form 10‑K, including the sections titled “Business,” “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” contains forward‑looking statements. All statements contained in this Annual Report on Form 10‑K other than statements of historical fact, including statements regarding our future consolidated results of operations and financial position, our business strategy and plans, market growth, and our objectives for future operations, are forward‑looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify these statements by forward‑looking words, such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “could,” “would,” “project,” “plan,” “potential,” “seek,” “expect,” “goal” or the negative or plural of these words or similar expressions.
These forward‑looking statements are subject to a number of risks, uncertainties and assumptions, including those described in “Risk Factors” and elsewhere in this Annual Report on Form 10‑K. Moreover, we operate in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward‑looking statements we may make. In light of these risks, uncertainties and assumptions, the forward‑looking events and circumstances discussed in this report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward‑looking statements.
You should not rely upon forward‑looking statements as predictions of future events. Although we believe that the expectations reflected in the forward‑looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward‑looking statements will be achieved or occur. Such forward‑looking statements speak only as of the date of this Annual Report on Form 10‑K. Except as may be required by law, we undertake no obligation to update publicly any forward‑looking statements for any reason after the date of this report to conform these statements to actual results or to changes in our expectations.
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Overview
We are a biopharmaceutical company dedicated to bringing biotech ingenuity to medical dermatology by delivering differentiated, new therapies to the millions of patients living with chronic skin conditions. We are committed to understanding the needs of both patients and physicians and using our insight to identify and develop leading-edge medical dermatology programs. Our pipeline includes three late-stage product candidates that could have a profound impact on the lives of patients: glycopyrronium tosylate (formerly DRM04), for which a New Drug Application (“NDA”) is under review by the U.S. Food and Drug Administration (“FDA”) for the treatment of primary axillary hyperhidrosis (underarm sweating beyond what is needed for normal body temperature regulation); olumacostat glasaretil (formerly DRM01), in Phase 3 development for the treatment of acne vulgaris; and lebrikizumab, in Phase 2b development for the treatment of moderate-to-severe atopic dermatitis. We are headquartered in Menlo Park, California.
We are focused on the development of therapeutic solutions in medical dermatology to treat skin conditions, such as hyperhidrosis, acne vulgaris and atopic dermatitis. These diseases impact millions of people worldwide and can have significant, multidimensional effects on patients’ quality of life, including their physical, functional and emotional well‑being. According to multiple published studies, patients report that medical dermatology conditions affect quality of life in ways comparable to other serious diseases, such as cancer, heart disease, diabetes, epilepsy, asthma and arthritis.
Our three late‑stage product candidates are:
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Glycopyrronium tosylate, a novel, small-molecule investigational agent formulated as a topical, once-daily anticholinergic wipe that we are developing for the treatment of primary axillary hyperhidrosis (excessive underarm sweating), a medical condition that results in sweating beyond what is needed for normal body temperature regulation. Anticholinergics are a class of pharmaceutical products that exert their effect by blocking the action of acetylcholine, a neurotransmitter that transmits signals within the nervous system that are responsible for a range of bodily functions, including the activation of sweat glands. Glycopyrronium tosylate is a novel form of an anticholinergic agent that has been approved for systemic administration in other indications, and is designed to block sweat production by inhibiting the interaction between acetylcholine and the cholinergic receptors responsible for sweat gland activation. In July 2015, we commenced a Phase 3 clinical program for glycopyrronium tosylate in patients with primary axillary hyperhidrosis that comprised three clinical trials – the ATMOS-1 and ATMOS-2 pivotal trials and the ARIDO open-label safety trial. In June 2016, we announced positive topline results from the ATMOS-1 and ATMOS-2 trials, which enrolled a total of 697 adult and adolescent patients (ages nine and older) with primary axillary hyperhidrosis. Based on the overall dataset from the intent-to-treat (“ITT”) populations, glycopyrronium tosylate demonstrated statistically significant improvements compared to vehicle for both co-primary endpoints and both secondary endpoints in the ATMOS-2 trial and one of the co-primary endpoints and both secondary endpoints compared in the ATMOS-1 trial. For the second co-primary endpoint in the ATMOS-1 trial, when extreme outlier data from one analysis center were excluded in accordance with the pre-specified statistical analysis plan submitted to the FDA, glycopyrronium tosylate demonstrated statistically significant results compared to vehicle. Consistent with the results of an earlier Phase 2b trial, glycopyrronium tosylate was well-tolerated with side effects that were primarily mild to moderate in severity. In December 2016, the treatment period for ARIDO, the open-label Phase 3 trial assessing the long-term safety of glycopyrronium tosylate, was completed. The safety and tolerability profile for glycopyrronium tosylate in the ARIDO trial was consistent with what was observed in the ATMOS-1 and ATMOS-2 trials. Based on the results of the glycopyrronium tosylate Phase 3 program and a pre-NDA meeting with the FDA in February 2017, we submitted an NDA for glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis to the FDA. The FDA has accepted our NDA for substantive review with a Prescription Drug User Fee Act target date (“PDUFA date”) for the completion of the FDA’s review of the NDA by June 30, 2018. |
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Lebrikizumab, a novel, injectable, humanized monoclonal antibody targeting interleukin 13 (“IL-13”) that we are developing for the treatment of moderate-to-severe atopic dermatitis. IL-13 is a naturally occurring cytokine that is thought to play an important role in mediating effects of inflammation on bodily tissues, including in patients with atopic dermatitis. Lebrikizumab is designed to bind to IL-13 with high affinity, specifically preventing formation of the IL-13 receptor/interleukin 4 (“IL-4”) receptor complex and subsequent signaling. In August 2017, we entered into a license agreement (the “Roche Agreement”) with F. Hoffmann-La Roche Ltd and Genentech, Inc. (together, “Roche”) pursuant to which we obtained exclusive, worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications, except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab for interstitial lung diseases, such as idiopathic pulmonary fibrosis (the “Retained Field”), and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. Based on the results of two exploratory Phase 2 clinical trials conducted by Roche in atopic dermatitis patients, we initiated a Phase 2b clinical trial in January 2018 to evaluate the safety and efficacy of lebrikizumab as a monotherapy compared with placebo and to establish the dosing regimen for a potential Phase 3 program in patients with moderate-to-severe atopic dermatitis. The study is expected to enroll approximately 275 patients ages 18 years and older. We expect topline results from the Phase 2b clinical trial in the first half of 2019. |
Our Strategy
Our strategy is to develop and commercialize innovative and differentiated therapies that we believe can advance the standard of care for patients with dermatologic diseases. The key components of our strategy are to:
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Rapidly develop our late‑stage product candidates. We produced positive clinical trial results within 10 months of initiating our Phase 3 clinical program for glycopyrronium tosylate and produced positive clinical trial results within 14 months of initiating our Phase 2b dose-ranging trial of olumacostat glasaretil. We believe that our team’s expertise in designing and executing product development programs in medical dermatology, combined with the relative efficiencies of dermatology product development, will enable us to rapidly develop our late‑stage product candidates. |
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Maximize the value of our portfolio by commercializing our approved products ourselves where we can effectively do so and partnering with other companies to help us reach new markets. We currently plan to commercialize our approved products, if any, in the United States by deploying a specialized sales force targeting primarily dermatologists as well as other healthcare practitioners. We may partner with other third parties to help us reach additional geographic markets or medical specialties. For our glycopyrronium tosylate product candidate, we have granted an exclusive license to Maruho Co., Ltd. (“Maruho”) to develop and commercialize glycopyrronium tosylate for the treatment of hyperhidrosis in Japan. For our lebrikizumab product candidate, Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field. |
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Continue to build a team of committed, experienced employees and engage with patients and members of the dermatology community. We believe that the field of medical dermatology offers a unique opportunity to build relationships with medical practitioners, opinion leaders, patients and advocacy groups. We believe that consolidation in the medical dermatology industry has resulted in an enhanced opportunity for a medical dermatology‑focused company to build relationships with these stakeholders and has made available a large and growing talent pool of experienced employees who can make significant contributions to our company. |
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Efficiently establish proof‑of‑concept for early‑stage product candidates and advance promising candidates into late‑stage development. In developing early‑stage product candidates, we focus on translating advances in the understanding of skin disease biology into innovative solutions for unmet needs in dermatology. We seek to rapidly and efficiently establish proof‑of‑concept for these product candidates. Using this approach, our experienced management team is able to efficiently determine whether and how to advance product candidates into the next stages of development, which we believe increases our ability to direct resources to promising programs and enhances our likelihood of successfully developing and commercializing our product candidates. |
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In‑license and acquire new product candidates. Since our founding in 2010, we have executed multiple transactions resulting in our portfolio of product candidates. In August 2011, we acquired Valocor Therapeutics, Inc., which gave us rights to a portfolio of intellectual property and product candidates to treat acne vulgaris and inflammatory skin diseases. In April 2013, we entered into agreements with Rose U LLC (“Rose U”) and Stiefel Laboratories, Inc., a GSK company (“Stiefel”), to obtain rights to intellectual property related to our hyperhidrosis program. In August 2017, we entered into the Roche Agreement pursuant to which we obtained exclusive, worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications, except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. We intend to continue to identify, evaluate, in‑license and acquire product candidates from a number of sources by leveraging the insights, network and experience of our management team. Our objective is to maintain a well‑balanced portfolio by in‑licensing or acquiring additional product candidates across various stages of development. |
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Our portfolio of product candidates is summarized in the following figure:
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Pursuant to the Roche Agreement, Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. |
Glycopyrronium Tosylate
Overview
Glycopyrronium tosylate is our late‑stage product candidate for the treatment of primary axillary hyperhidrosis (excessive underarm sweating). Glycopyrronium tosylate, a novel form of a small‑molecule anticholinergic agent that has been approved for systemic administration in other indications, is designed to block sweat production by inhibiting the interaction between acetylcholine and the cholinergic receptors responsible for sweat gland activation.
Hyperhidrosis is a condition of sweating beyond what is physiologically required to maintain normal thermal regulation. Sweat is produced by glands in the skin and released to the skin surface through ducts. Sweat gland activity is controlled by the nervous system. The nervous system transmits signals to the sweat glands by a neurotransmitter called acetylcholine. Primary hyperhidrosis, which is excessive sweating without a known cause, can affect the underarms, palms of the hands, soles of the feet, face and other areas. Several studies have demonstrated that excessive sweating often impedes normal daily activities and can result in occupational, emotional, psychological, social and physical impairment. Studies also suggest that the negative impact caused by excessive sweating has been reported to be similar to, if not greater than, the negative impact caused by conditions such as psoriasis and other chronic diseases. There are very few approved treatments for hyperhidrosis and the unmet medical need remains high.
According to a study published in 2016, the prevalence of hyperhidrosis in the United States is estimated to be 4.8% of the population, or approximately 15.3 million people. According to this published study, 65% of hyperhidrosis sufferers in the United States have axillary hyperhidrosis.
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The market for products to control sweating is large and highly underpenetrated by prescription pharmaceutical products. Despite the limited efficacy of over‑the‑counter (“OTC”) antiperspirants for the alleviation of hyperhidrosis symptoms, according to the 2016 study, only 51% of patients suffering from hyperhidrosis have discussed their condition with a healthcare professional (“HCP”). The reasons most commonly cited by hyperhidrosis sufferers for not discussing their excessive sweating with an HCP are lack of awareness that hyperhidrosis is a medical condition and belief that nothing can be done to treat their condition. Of those who do see an HCP about their hyperhidrosis, 53% were diagnosed with the condition. In addition, patients may suffer from excessive sweating for years before seeking treatment. One study analyzing data from 1993‑2005 indicated that patients experienced an average duration of untreated symptoms of 8.9 years. We believe that this is largely a result of the lack of effective, well‑tolerated and convenient prescription treatment options. For example, according to a recent Dermira survey of a sample of axillary hyperhidrosis sufferers in the United States, approximately half indicated they are not at all satisfied or only slightly satisfied with the products they are currently using to treat their condition. Patients who seek treatment from a physician most commonly receive prescription topical antiperspirants. According to data provided by IQVIA NPA, these topical antiperspirants generated approximately 410,000 prescriptions in the United States in 2017. However, their use is limited by modest efficacy, particularly in patients with more severe disease and skin irritation. We believe that the market opportunity for a new, effective, well‑tolerated and self-administered prescription topical hyperhidrosis treatment is substantially larger than the current market for prescription topical antiperspirants because such a therapy could further penetrate the segment of patients who seek treatment from a physician and encourage more patients to seek treatment. Therapeutic options for patients who are unsatisfied with topical antiperspirants are largely limited to more cumbersome or invasive strategies directed to blocking the activation of, destroying or removing the sweat glands by injectable, systemic, surgical or other means. These treatment options, which include injectable botulinum toxin (“Botox”) and off‑label use of oral anticholinergic agents, are often poorly tolerated and are used much less frequently than topical therapies.
Based on the results of our Phase 2 program described below and an end‑of‑Phase 2 meeting with the FDA in April 2015, we commenced a Phase 3 clinical program for glycopyrronium tosylate in patients with primary axillary hyperhidrosis in July 2015 that comprised three trials – the ATMOS-1 and ATMOS-2 pivotal trials and the ARIDO open-label safety trial. We completed patient enrollment in the ATMOS-1 and ATMOS-2 trials in February 2016 and announced positive topline results in June 2016. The treatment period for the ARIDO trial was completed in December 2016. Based on the results of these trials and a pre-NDA meeting with the FDA in February 2017, we submitted an NDA to the FDA for approval of glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis. The FDA has accepted our NDA for substantive review with a PDUFA date for the completion of the FDA’s review of the NDA by June 30, 2018. If approved, glycopyrronium tosylate is expected to be the first FDA-approved topical wipe medication specifically indicated to treat patients with primary axillary hyperhidrosis.
Clinical Development
Our initial target indication for glycopyrronium tosylate (referred to as “G.T.” in the following charts) is primary axillary hyperhidrosis. Three Phase 2 clinical trials and three Phase 3 clinical trials to evaluate efficacy and safety have been completed.
Phase 2a Clinical Trial. The Phase 2a clinical trial was a randomized, double‑blind study in 38 patients with severe, primary axillary hyperhidrosis. A topical formulation of a reference agent, a different form of the anticholinergic agent in glycopyrronium tosylate that has been approved for systemic administration in other indications, was administered to establish proof of concept for the treatment of hyperhidrosis. In six cohorts of six or seven patients each, two concentrations of the reference agent in each of two topical formulations were compared with their respective vehicles, which contain no active ingredient. Based on the positive results of this trial, we selected the formulation for further development and commenced our Phase 2b clinical program.
Phase 2b Clinical Program. Our Phase 2b clinical program comprised two randomized, multi‑center, double‑blind, vehicle‑controlled clinical trials that assessed the safety, efficacy and pharmacokinetics of glycopyrronium tosylate, the topical formulation of the reference agent, and vehicle only in a total of 303 patients with primary axillary hyperhidrosis. In these studies, patients were instructed to apply the study product to each axilla once daily for four weeks using wipes containing either drug product or vehicle only, and efficacy was evaluated based on axillary sweat production, as well as disease severity as reported by patients using the widely-used Hyperhidrosis Disease Severity Scale (“HDSS”), the Axillary Hyperhidrosis Patient Measures (“AHPM”), or
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both. The AHPM was developed in connection with the second Phase 2b trial according to current regulatory standards and includes three separate patient-reported outcome (“PRO”) assessments: the four-item Axillary Sweating Daily Diary (“ASDD”) for use in patients 16 years of age and older (or the two-item ASDD-C for use in patients nine to 15 years of age); six Weekly Impact Items; and a single-item Patient Global Impression of Change. The four-item ASDD was initially validated in this second Phase 2b trial and confirmed using data obtained in the Phase 3 trials described below, with Item 2 being validated for use in regulatory decision making. Validation was performed in accordance with FDA Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, December 2009.
Phase 3 Clinical Program. Based on the results of the three Phase 2 clinical trials, we conducted an end‑of‑Phase 2 meeting with the FDA in April 2015 during which we requested and received feedback from the FDA regarding certain elements of our proposed development plan for glycopyrronium tosylate in primary axillary hyperhidrosis, including the design and size of our Phase 3 program, which we initiated in July 2015. The Phase 3 program comprised two pivotal clinical trials named ATMOS-1 and ATMOS-2 that were designed to assess the safety and efficacy of glycopyrronium tosylate relative to vehicle and one clinical trial named ARIDO that was designed to assess the long-term safety of glycopyrronium tosylate.
ATMOS-1 and ATMOS-2 Trials. The ATMOS-1 and ATMOS-2 clinical trials were designed as identical, multi-center, randomized, double-blind, vehicle-controlled trials to assess the safety and efficacy of glycopyrronium tosylate at a concentration of 3.75% compared to vehicle in adult and adolescent patients (ages nine and older) with primary axillary hyperhidrosis. A total of 697 patients were enrolled in the two trials. The co-primary endpoints were the proportion of patients who achieved at least a four-point improvement from baseline in sweating severity as measured by Item 2 of the 11-point ASDD scale and the average absolute change from baseline in gravimetrically-measured sweat production. For the purpose of the sweat production endpoint, sweat production was assessed in each patient as the average of the amounts of sweat produced in each underarm during a five-minute period. The two secondary endpoints in the trials measured the proportion of patients who had at least a two-grade improvement from baseline as measured by the HDSS and the proportion of patients with at least a 50% reduction from baseline in gravimetrically-measured sweat production. Patients were instructed to apply the study product to each underarm once daily for four weeks using topical wipes containing either glycopyrronium tosylate or vehicle only. Both the primary and secondary endpoints were assessed at the end of the four-week treatment period. Inclusion criteria required that, prior to the start of treatment, all patients produced at least 50 mg of sweat in each underarm over a five-minute period and rated the severity of their sweating as a four or higher on Item 2 of the ASDD (an 11-point scale) and as a three or a four on the four-grade HDSS.
The ATMOS-1 trial enrolled 344 patients at 29 sites in the United States and Germany. In the trial, 229 patients were randomized to receive glycopyrronium tosylate, and 115 patients were randomized to receive vehicle. In this trial:
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The proportion of patients who achieved at least a four-point improvement in sweating severity, as measured by Item 2 of the ASDD, was 52.8% in glycopyrronium tosylate-treated patients, compared to 28.3% in patients who received the vehicle only (p<0.001). |
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The average reduction in sweat production was 104.9 mg in patients treated with glycopyrronium tosylate as compared to 91.9 mg in vehicle-treated patients based on the overall dataset from the ITT population (p=0.065). As outlined in the pre-specified statistical analysis plan submitted to the FDA, a sensitivity analysis was conducted that led to the exclusion of an analysis center with extreme outlier data for the gravimetric measurement of sweat. This analysis center consisted of 14 patients, of whom nine were treated with glycopyrronium tosylate and five received vehicle only. Following the exclusion of this analysis center, patients treated with glycopyrronium tosylate demonstrated an average reduction in sweat production of 96.2 mg as compared to 90.6 mg in patients who received the vehicle only (p=0.001). |
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The proportion of patients who achieved at least a two-grade improvement in HDSS score, a secondary endpoint, was 56.5% in patients treated with glycopyrronium tosylate as compared to 23.7% in patients who received the vehicle only (p<0.001). |
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The ATMOS-2 trial enrolled 353 patients at 20 sites in the United States. In the trial, 234 patients were randomized to receive glycopyrronium tosylate and 119 patients were randomized to receive vehicle. In this trial:
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The proportion of patients who achieved at least a four-point improvement in sweating severity, as measured by Item 2 of the ASDD, was 66.1% in glycopyrronium tosylate-treated patients, compared to 26.9% in patients who received the vehicle only (p<0.001). |
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The average reduction in sweat production was 110.3 mg in patients treated with glycopyrronium tosylate as compared to 92.2 mg in patients who received the vehicle only (p<0.001). |
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The proportion of patients who achieved at least a two-grade improvement in HDSS score, a secondary endpoint, was 61.6% in patients treated with glycopyrronium tosylate as compared to 27.8% in patients who received the vehicle only (p<0.001). |
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The proportion of patients with at least a 50% reduction from baseline in gravimetrically-measured sweat production, a secondary endpoint, was 77.3% in patients treated with glycopyrronium tosylate as compared to 53.3% in patients who received the vehicle only (p<0.001). |
Efficacy Results for Co-Primary and Secondary Endpoints
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Co-Primary Endpoints: |
Secondary Endpoints: |
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ASDD Response Rate at Week Four (% of patients with ≥4-point improvement from baseline) |
HDSS Response Rate at Week Four (% of patients with ≥2-point improvement from baseline) |
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Change in Sweat Production at Week Four (average change from baseline, mg per 5 min.) |
Sweat Production Response Rate at Week Four (% of patients with 50% reduction from baseline) |
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Data are presented from the ITT population (all randomized patients dispensed study medication) except for the ATMOS-1 ITT (Ex-AC) population, which represents results of a pre-specified sensitivity analysis that led to exclusion of an analysis center (“AC”), consisting of 14 patients (9 and 5 of whom received glycopyrronium tosylate and vehicle only, respectively), with extreme outlier data in the gravimetric measurement of sweat. ASDD response rate refers to subjects’ rating the severity of their sweating on a scale from 0-10 (Item 2 of the four-item ASDD PRO instrument). P-values reflect the probability of an observation occurring due to chance alone. P-values of less than 0.05 (denoted by *) typically represent statistically significant results. The P-values shown above represent comparisons to corresponding data observed in patients who received vehicle only.
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Consistent with the results from the Phase 2 clinical program, glycopyrronium tosylate was generally well-tolerated with side effects that were primarily mild to moderate in severity.
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In ATMOS-1, the most frequently reported adverse events were dry mouth (18.9% and 3.5% for glycopyrronium tosylate and the vehicle only, respectively), application site pain (8.8% and 9.6%), dilated pupil (mydriasis; 6.6% and 0.0%), headache (4.4% and 2.6%), sore throat (oropharyngeal pain; 4.0% and 1.8%), upper respiratory tract infection (4.0% and 0.9%), blurred vision (3.5% and 0.0%), urinary hesitation (2.2% and 0.0%) and dry eye (0.9% and 0.0%). In this trial, 3.5% (8/229) of patients treated with glycopyrronium tosylate withdrew from the trial due to adverse events, compared to 0.9% (1/115) of patients who received vehicle only. There was one treatment-related serious adverse event reported in this trial for a patient treated with glycopyrronium tosylate who reported a dilated pupil. |
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In ATMOS-2, the most frequently reported adverse events were dry mouth (29.3% and 7.6% for glycopyrronium tosylate and the vehicle only, respectively), application site pain (8.6% and 9.3%), dilated pupil (mydriasis; 6.9% and 0.0%), headache (5.6% and 1.7%), sore throat (oropharyngeal pain; 7.3% and 0.8%), upper respiratory tract infection (2.2% and 4.2%), blurred vision (3.4% and 0.0%), urinary hesitation (4.7% and 0.0%) and dry eye (3.9% and 0.8%). In this trial, 3.8% (9/234) of patients treated with glycopyrronium tosylate withdrew from the trial due to adverse events, compared to 0.0% (0/119) who received vehicle only. There were no treatment-related serious adverse events reported in the ATMOS-2 trial. |
Dry mouth, dilated pupil, blurred vision, urinary hesitation and dry eye are well-known side effects of anticholinergic agents.
ARIDO Trial. In addition to the ATMOS-1 and ATMOS-2 trials, we also conducted ARIDO, an open-label trial assessing the long-term safety of glycopyrronium tosylate, as part of our Phase 3 program to provide safety data for a minimum of 100 patients who had received glycopyrronium tosylate for at least 12 months per the International Council for Harmonisation guidelines. Patients from the ATMOS-1 and ATMOS-2 trials were permitted to enroll in the ARIDO trial and continued to receive glycopyrronium tosylate (active treatment) for up to an additional 44 weeks from the end of the four-week treatment periods in the ATMOS-1 or ATMOS-2 trials. A total of 564 patients, more than 80% of those enrolled in the ATMOS-1 and ATMOS-2 trials, elected to enroll in ARIDO. In December 2016, the treatment period for ARIDO was completed. The safety and tolerability profile of glycopyrronium tosylate in the ARIDO study was consistent with what was observed in the ATMOS-1 and ATMOS-2 Phase 3 clinical trials.
Regulatory Pathway. Based on these results and a pre-NDA meeting with the FDA in February 2017, we submitted an NDA to the FDA for approval of glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis. We are seeking FDA approval of glycopyrronium tosylate through Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the “505(b)(2) pathway”). Under the 505(b)(2) pathway, we may be allowed to leverage certain findings made by the FDA in approving the anticholinergic agent we intend to reference in our NDA, which could expedite the glycopyrronium tosylate development program by potentially decreasing the amount of non-clinical or clinical data that we would need to generate to obtain FDA approval. The degree to which we will be permitted to leverage such findings, if at all, will be dependent upon our ability to demonstrate an acceptable clinical bridge through comparative pharmacokinetic data between glycopyrronium tosylate and the approved product, which have different chemical structures, routes of administration, dosage forms and indications. We cannot provide assurances that we will be able to utilize the Section 505(b)(2) pathway or that use of the Section 505(b)(2) pathway would lead to faster product development or earlier approval. The FDA has accepted our NDA for substantive review with a PDUFA date for the completion of the FDA’s review of the NDA by June 30, 2018.
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Overview
Olumacostat glasaretil is our late-stage product for the treatment of acne vulgaris. It is a novel, small molecule designed to target sebum production following topical application. Sebum is an oily substance made up of lipids produced by glands in the skin called sebaceous glands, and excessive sebum production is an important aspect of acne that is not addressed by available topical therapies. Olumacostat glasaretil is designed to exert its effect by inhibiting acetyl coenzyme‑A carboxylase, an enzyme that plays an important role in the synthesis of fatty acids, a type of lipid that represents an essential component of the majority of sebum lipids.
Acne is one of the most common skin diseases. It is characterized by clogging of the pores and associated local skin lesions that usually appear on the face, chest or back. Acne lesions are believed to result from an interaction of four primary pathogenic, or contributing, factors: (1) excessive production of sebum; (2) alterations in skin cells that, in concert with excess sebum production, contribute to clogging of pores through which sebum is normally released to the skin surface; (3) colonization of the area in and around the sebaceous glands by bacteria that are nourished by sebum; and (4) inflammation often associated with colonization by bacteria and their breakdown of sebum into irritating breakdown products. Clogged pores can become enlarged and inflamed as sebum and its breakdown products accumulate, resulting in visible lesions that can be unsightly and cause permanent scarring.
Acne can significantly impact patients’ quality of life, resulting in social, psychological and emotional impairments that are comparable to those reported by patients with epilepsy, asthma, diabetes or arthritis. According to widely‑cited data, acne vulgaris is one of the most common skin conditions, affecting up to 50 million people in the United States. It is estimated that approximately 85% of people in the United States between the ages of 12 and 24 experience acne, and acne is the reason most cited for visits to the dermatologists by patients 14 to 45 years old. According to GfK Custom Research, LLC, acne represented nearly one‑fourth of U.S. dermatologists’ patient volume in 2015.
Based on US IQVIA data, the annual market for acne products in the United States was approximately $3.5 billion in 2017, with topical products accounting for approximately $2.2 billion. These IQVIA data also indicate that there were 25.1 million acne product prescriptions in the United States in 2017, nearly 60% of which were for topical products. The major product classes predominantly used to treat acne have been available for over 30 years, and we believe that growth in this market recently has been significantly limited by a lack of innovation in new product development.
We believe that there is a substantial unmet need and commercial opportunity for a topical acne therapy that targets sebum production. Acne treatment guidelines published by the Global Alliance to Improve Outcomes in Acne recommend that acne treatment be directed toward as many pathogenic factors as possible. Accordingly, patients are often treated with regimens that incorporate agents with complementary mechanisms of action targeting different pathogenic factors. The vast majority of acne patients are treated with topical therapies, and all of the four primary pathogenic factors except for excessive sebum production can be targeted with available topical treatments. While systemic therapies may affect sebum production, their use is limited by significant, systemic side effects. As a result, we believe that the introduction of a topical acne treatment that is designed to target sebum production could establish a new product class and expand the market for acne treatment.
Based on the results of our Phase 2 program described below and an end-of-Phase 2 meeting with the FDA, in December 2016 we commenced a Phase 3 clinical program for olumacostat glasaretil as a potential treatment for acne vulgaris in adult and adolescent patients (ages nine and older) that comprises the CLAREOS-1 and CLAREOS-2 pivotal trials and the CLARITIUDE open-label safety trial. We announced the completion of patient enrollment in the CLAREOS-1 and CLAREOS-2 trials in October 2017 and expect to announce topline results from both of these trials in the first quarter of 2018.
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We are developing olumacostat glasaretil (referred to as “O.G.” in the following charts) in accordance with published FDA draft guidance regarding the development of acne drugs. Established in 2005, this draft guidance has been widely used in the design, conduct and analysis of clinical trials intended to support marketing approval for new acne products. We have completed Phase 1, Phase 2a and Phase 2b clinical trials to assess the efficacy, safety and tolerability of olumacostat glasaretil.
Phase 1 Clinical Trial. In the Phase 1 clinical trial, six healthy volunteers applied topical olumacostat glasaretil gel to the face for seven days. All subjects completed dosing, and no adverse events were reported.
Phase 2a Clinical Trial. The FDA recommends that the principal clinical trials used to demonstrate safety and efficacy of acne therapies in support of marketing approval be randomized, multi‑center, blinded trials designed to demonstrate superiority of the investigational product relative to a vehicle or placebo control following a treatment duration of at least 12 weeks. Our Phase 2a clinical trial was a randomized, multi‑center, double‑blind, vehicle‑controlled study designed in accordance with the published FDA draft guidance. In this trial, 108 patients with moderate or severe acne vulgaris were instructed to apply either olumacostat glasaretil gel or vehicle gel to the face twice daily for 12 weeks. Olumacostat glasaretil gel was formulated at a concentration of 7.5%. Of the 108 patients enrolled in the trial, 53 were randomized to receive olumacostat glasaretil, and the other 55 were randomized to receive vehicle only.
Three primary efficacy endpoints recommended in the published FDA draft guidance were used as primary efficacy endpoints in this trial:
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Inflammatory lesion count, assessed as the absolute change from baseline in the number of inflammatory acne lesions; |
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Non‑inflammatory lesion count, assessed as the absolute change from baseline in the number of non‑inflammatory acne lesions; and |
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Investigator’s Global Assessment (“IGA”) assessed as the proportion of patients who achieve a successful improvement in the investigator’s assessment of disease severity, as assessed on a five‑point scale that ranges from a score of zero, representing clear skin, to a score of four, representing severe disease. |
In our trial, lesions were counted by the investigators, and a successful improvement in IGA score was defined as a reduction from baseline of at least two points on the IGA scale. As is standard practice in acne clinical trials, the primary efficacy endpoints were assessed on the face at the end of the 12‑week treatment period. In addition to evaluating the primary efficacy endpoints, we conducted several non‑primary efficacy analyses, including an evaluation of the percent change from baseline in the number of inflammatory lesions and an evaluation of the percent change from baseline in the number of non‑inflammatory lesions, each as assessed on the face at the end of the 12‑week treatment period.
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As outlined below, olumacostat glasaretil demonstrated statistically significant improvements relative to vehicle in all three primary efficacy endpoints. The following chart summarizes the impact of olumacostat glasaretil on acne lesion counts. Based on these results, patients treated with olumacostat glasaretil achieved a 45% greater average absolute reduction in inflammatory lesion count and a 78% greater average absolute reduction in non‑inflammatory lesion count than patients who received vehicle only.
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Changes in Lesion Counts at Week 12 |
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P < 0.01 vs. placebo. The P-values shown above represent comparisons to corresponding data in patients who received vehicle only. |
Data represent average changes from baseline. As recommended in the published FDA draft guidance regarding the development of acne drugs, data are presented from the ITT population, defined as all randomized patients who were dispensed study product, and the last available on‑treatment observation is used to estimate missing data points. The average lesion count at baseline includes all 108 patients in the ITT population. Missing data for one patient in the vehicle cohort for whom no on‑treatment efficacy assessment was available are excluded from the patient population observed at the end of the 12‑week treatment period.
When analyzing the Phase 2a study data looking at per‑protocol patients, a population that is smaller in size and thus has lower statistical power, although the IGA and inflammatory lesion count results are statistically significant (p=0.0314 and p=0.0048, respectively), the non‑inflammatory lesion count results do not reach statistical significance (p=0.0566).
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The following chart summarizes the impact of olumacostat glasaretil on the third primary efficacy endpoint: the proportion of patients who achieved a successful improvement in the severity of their disease, as assessed using the IGA. Based on these results, patients treated with olumacostat glasaretil were more than three times more likely than patients who received vehicle only to achieve a successful improvement in IGA score.
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IGA Response Rate at Week 12 |
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P < 0.01 vs. placebo. The P-values shown above represent comparisons to corresponding data in patients who received vehicle only. |
As recommended in the published FDA draft guidance regarding the development of acne drugs, data are presented from the ITT population, defined as all randomized patients who were dispensed study product. In this analysis, patients with missing data points were considered non‑responders.
The most common adverse events observed in this clinical trial were upper respiratory tract infections, which were considered unrelated to treatment, and application‑site conditions, which are frequently observed in most clinical trials of topical products. No treatment‑related serious adverse events were reported.
Phase 2b Clinical Trial. Based on the efficacy, safety and tolerability profile observed in the Phase 2a clinical trial, we commenced a Phase 2b dose-ranging clinical trial in April 2015. The Phase 2b trial was a randomized, multi-center, double-blind, parallel-group, vehicle-controlled study designed to assess the safety and efficacy of olumacostat glasaretil compared to vehicle in adult patients 18 years and older with moderate-to-severe acne vulgaris. A total of 420 patients were enrolled in the study at 34 sites in the United States and Canada. Consistent with the previous Phase 2a trial, the primary endpoints were absolute changes from baseline in inflammatory and non-inflammatory lesion counts and the proportion of patients achieving at least a two-point improvement from baseline in the five-point IGA scale. Each endpoint was measured on the face at the end of the 12-week treatment period. Inclusion criteria required a minimum of 20 inflammatory lesions and 20 non-inflammatory lesions and an IGA score of three or four on a five-point scale that ranges from a score of zero, representing clear skin, to a score of four, representing severe disease, in all cases measured on the face.
Patients were randomized into five separate arms and instructed to apply olumacostat glasaretil at concentrations of 4.0% once daily (n=106), 7.5% once daily (n=110) or 7.5% twice daily (n=101), or to apply vehicle once or twice daily (n=53 and n=50, respectively), in all cases for 12 weeks.
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In the Phase 2b trial, olumacostat glasaretil demonstrated statistically significant improvements from baseline to week 12 relative to vehicle in all primary efficacy endpoints at the highest dose of olumacostat glasaretil tested and in most primary endpoints at the two lower doses tested.
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At the 7.5% twice daily dose, olumacostat glasaretil demonstrated statistically significant improvements from baseline to week 12 relative to vehicle in all primary efficacy endpoints. This highest dose of olumacostat glasaretil also demonstrated the highest efficacy in all primary endpoints compared to the two lower doses. Following 12 weeks of treatment, the number of inflammatory lesions in patients treated with this highest dose of olumacostat glasaretil was reduced by an average of 15.0 compared to 10.7 in patients in the combined vehicle group (p=0.001), or an average percentage reduction of 55.6% compared to 40.0% (p<0.001). The number of non-inflammatory lesions in patients treated with this same dose of olumacostat glasaretil was reduced by an average of 17.5 compared to 9.3 in patients in the combined vehicle group (p<0.001), or an average percentage reduction of 47.8% compared to 28.7% (p<0.001). At the end of the 12-week treatment period, 25.9% of patients treated with this highest dose of olumacostat glasaretil achieved a successful improvement in the IGA score (minimum two-grade improvement) compared to 9.8% of patients in the combined vehicle group (p=0.004). |
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At the 7.5% once daily dose, olumacostat glasaretil demonstrated statistically significant improvements in the inflammatory and non-inflammatory lesion count endpoints compared to the combined vehicle group, and approached but did not reach statistical significance in the IGA improvement endpoint. Following 12 weeks of treatment, the number of inflammatory lesions in patients treated with this dose of olumacostat glasaretil was reduced by an average of 14.5 compared to 10.7 in patients in the combined vehicle group (p=0.004), or an average percentage reduction of 53.3% compared to 40.0% (p=0.004). The number of non-inflammatory lesions in patients treated with olumacostat glasaretil at the 7.5% dose once daily was reduced by an average of 13.4 compared to 9.3 in patients in the combined vehicle group (p=0.050), or an average percentage reduction of 36.6% compared to 28.7% (p=0.152). At the end of the same 12-week treatment period, 19.2% of patients achieved a successful improvement in the IGA score (minimum two-grade improvement) compared to 9.8% of patients in the combined vehicle group (p=0.063). |
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At the 4.0% once daily dose, olumacostat glasaretil demonstrated statistically significant improvements in all three primary endpoints compared to the combined vehicle group. Following 12 weeks of treatment, the number of inflammatory lesions in patients treated with this dose of olumacostat glasaretil was reduced by an average of 14.6 compared to 10.7 in patients in the combined vehicle group (p=0.003), or an average percentage reduction of 54.8% compared to 40.0% (p=0.002). The number of non-inflammatory lesions in patients treated with olumacostat glasaretil at the 4.0% dose once daily was reduced by an average of 15.3 compared to 9.3 in patients in the combined vehicle group (p=0.004), or an average percentage reduction of 42.1% compared to 28.7% (p=0.014). At the end of the same 12-week treatment period, 21.6% of patients achieved a successful improvement in the IGA score (minimum two-grade improvement) compared to 9.8% of patients in the combined vehicle group (p=0.024). |
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Lesion count data represent average changes from baseline. As recommended in the published FDA guidance, data are presented from the ITT population, defined as all randomized patients dispensed study product. The vehicle group represents all patients who received vehicle once daily (“qd”) or twice daily (“bid”). Missing values were handled using the Markov Chain Monte Carlo multiple imputation. IGA response rate reflects the percentage of patients achieving at least a two-point improvement in IGA score from baseline. The P-values shown above represent comparisons to corresponding data observed in the combined vehicle group. P-values of less than 0.05 are denoted by *. |
Consistent with the Phase 2a trial, olumacostat glasaretil was well-tolerated. Adverse events were primarily mild or moderate in severity. The most frequently reported adverse events across all three olumacostat glasaretil treatment groups were common cold (nasopharyngitis; 5.4%), upper respiratory tract infection (2.5%) and application site itching (pruritus; 2.5%). All of the cases of common cold and upper respiratory tract infection were considered unrelated to treatment. No treatment-related serious adverse events were reported.
Phase 3 Clinical Program. Based on the results of these two Phase 2 clinical trials, we conducted an end‑of‑Phase 2 meeting with the FDA in September 2016 during which we requested and received feedback from the FDA regarding certain elements of our proposed development plan for olumacostat glasaretil in acne vulgaris, including the design and size of Phase 3 clinical trials. We initiated our Phase 3 clinical program in December 2016.
The Phase 3 clinical program consists of two randomized, multi-center, double-blind, parallel-group, vehicle-controlled trials, CLAREOS-1 and CLAREOS-2, designed to assess the safety and efficacy of olumacostat glasaretil compared to vehicle to support a potential NDA submission to the FDA. In October 2017, we announced the completion of the enrollment of 1,503 patients ages nine and older (759 in CLAREOS-1 and 744 in CLAREOS-2) with moderate-to-severe acne vulgaris at 94 sites in the United States, Canada and Australia. In each trial, patients were randomized in a 2:1 fashion and instructed to apply either olumacostat glasaretil at a concentration of 5.0% or vehicle twice daily for 12 weeks.
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Consistent with the two earlier Phase 2 trials, inclusion criteria require a minimum of 20 inflammatory lesions and 20 non-inflammatory lesions and an IGA score of three or four on a five-point scale that ranges from a score of zero, representing clear skin, to a score of four, representing severe disease, in all cases measured on the face. The primary endpoints of both trials will evaluate the absolute changes from baseline in inflammatory and non-inflammatory lesion counts and the proportion of patients achieving at least a two-grade improvement from baseline to a final grade of 0 or 1 on the five-point IGA scale. Secondary endpoints will evaluate the percentage change from baseline in inflammatory and non-inflammatory lesion counts and the proportion of patients achieving at least a two-grade improvement from baseline on the five-point IGA scale. All efficacy endpoints will be measured on the face at the end of the 12-week treatment period. Safety will also be assessed.
The Phase 3 program also includes an open-label study, CLARITUDE, assessing the long-term safety of olumacostat glasaretil, in which approximately 700 patients from either of the two Phase 3 studies will be permitted to continue to receive treatment for up to an additional 36 weeks.
We expect to announce topline results from the CLAREOS-1 and CLAREOS-2 trials in the first quarter of 2018.
Lebrikizumab
Overview
Lebrikizumab is our late-stage product candidate for the treatment of moderate-to-severe atopic dermatitis. IL-13 is a naturally occurring molecule that is thought to play an important role in mediating effects of inflammation on bodily tissues, including in patients with atopic dermatitis. Lebrikizumab is designed to bind IL-13 with high affinity, specifically preventing formation of the IL-13 receptor/IL-4 receptor complex and subsequent signaling. Roche has studied lebrikizumab in clinical trials involving more than 4,000 subjects across a range of conditions, such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, including two exploratory Phase 2 clinical trials in moderate-to-severe atopic dermatitis patients. In August 2017, we entered into a licensing agreement with Roche pursuant to which we obtained exclusive, worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications, except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes.
Atopic dermatitis is the most common and severe form of eczema, a chronic inflammatory condition that can present as early as childhood and continue into adulthood. It is estimated to affect 12% of children and 10% of adults. A complex disorder involving an interplay of immune system dysfunction, skin barrier compromise and environmental exposures, atopic dermatitis is characterized by dry, itchy, red, swollen and/or cracked skin, often accompanied by increased risk of infection, as well as intense, persistent itching that exacerbates skin barrier disruption and other clinical symptoms. Moderate-to-severe disease can cover much of the body and have a profound, negative impact on patients’ mental and physical functioning, limiting their sleep quality, activities and health-related quality of life.
Atopic dermatitis is commonly treated with topical products, including moisturizing emollients, corticosteroids and calcineurin inhibitors, as well as topical and oral antimicrobial therapies to manage skin infections and antihistamines to aid in the management of itch. Moderate-to-severe disease is often treated with systemic, immunomodulatory therapy, most commonly oral corticosteroids and less frequently other immunosuppressants, such as methotrexate, cyclosporine, azathioprine and mycophenolate mofetil, which carry risks of well-documented side effects, including kidney, liver and blood toxicity, that require intensive monitoring by the prescribing physician during long-term use. In March 2017, Dupixent, a monoclonal antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4 receptor subunit, became the first systemic therapy specifically approved by the FDA for the treatment of atopic dermatitis, offering a significant advance in treatment based on its efficacy and lack of systemic side effects associated with oral corticosteroids and other immunosuppressants.
The introduction of new, targeted therapies, such as Dupixent, is projected to transform the treatment of moderate-to-severe atopic dermatitis in much the same way that the advent of biologic therapies transformed the treatment of moderate-to-severe psoriasis over the past 14 years. Prior to FDA approval of the first biologic therapy
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for psoriasis in 2003, moderate-to-severe psoriasis was treated with many of the same oral immunosuppressants used to treat atopic dermatitis today, with moderate efficacy and well-documented side effects. According to Decision Resources, since the FDA approved the first biologic therapy for psoriasis in 2003, and with the subsequent introduction of systemic, biologic and small-molecule therapies targeting a range of inflammatory mediators, the market for psoriasis therapies in the United States has grown approximately tenfold and was projected to total more than $8 billion in sales in 2017.
In comparison with psoriasis, which Decision Resources estimates currently affects approximately 8.6 million people in the United States, of whom approximately 1.7 million suffer from moderate-to-severe disease, atopic dermatitis is estimated to affect 33 million people in the United States, of whom approximately 7 million suffer from moderate-to-severe disease. With the introduction of new, targeted therapies, such as Dupixent, EvaluatePharma estimates that worldwide sales of atopic dermatitis medications will grow from $0.9 billion in 2016 to $6.0 billion in 2022.
IL-13 and Lebrikizumab. IL-13 is thought to play an important role in mediating effects of inflammation on bodily tissues in atopic dermatitis and other allergic diseases. In atopic dermatitis, IL-13 is highly expressed in skin lesions, where expression levels appear to correlate with lesion severity and chronicity. It is hypothesized that dysregulation of IL-13 disrupts the skin’s ability to serve as an effective barrier to environmental exposures, and it has been established that IL-13 down-regulates production of structural proteins that are important for maintenance of skin barrier integrity. Blocking IL-13 has been shown to increase production of these proteins and reduce inflammation in preclinical models of atopic dermatitis. Successful treatment of atopic dermatitis normalizes both IL-13 expression and IL-13-mediated signaling. Recent clinical studies have demonstrated improvements in signs and symptoms in atopic dermatitis patients treated with monoclonal antibodies targeting IL-13.
We believe that lebrikizumab offers an attractive approach to the treatment of atopic dermatitis based on its ability to bind IL-13 with high affinity, specifically disrupting formation of the IL-13 receptor/IL-4 receptor complex and subsequent downstream signaling. Whereas many antibodies that bind receptor proteins are rapidly cleared from the body following binding to their targets, lebrikizumab, like many antibodies that bind circulating proteins, such as IL-13, is cleared from the body more slowly. Relative to other antibodies targeting IL-13, lebrikizumab has high affinity for its target, as well as a differentiated mechanism of action that does not involve inhibition of the binding of IL-13 to an alternate IL-13 receptor that serves as a natural regulator of IL-13 activity. These characteristics may enable lebrikizumab to be more effective and/or less frequently administered than many other antibodies.
Roche has studied lebrikizumab in clinical trials involving more than 4,000 subjects across a range of conditions, including two exploratory Phase 2 clinical trials in moderate-to-severe atopic dermatitis patients. In addition to the initial efficacy results generated in atopic dermatitis patients, we believe the substantial safety experience accumulated across the lebrikizumab program to date is supportive of the development of lebrikizumab in atopic dermatitis.
Additionally, the potentially important role of IL-13 in mediating the effects of inflammation across multiple bodily tissues suggests that lebrikizumab may have applicability in conditions beyond atopic dermatitis. In clinical trials conducted to date, lebrikizumab has usually been administered once every four weeks (“q4w”).
Clinical Development in Atopic Dermatitis
Phase 2a Clinical Trials. In addition to a number of studies in other potential indications, Roche has completed two exploratory Phase 2 clinical trials evaluating lebrikizumab in adults with moderate-to-severe atopic dermatitis.
TREBLE Phase 2 Exploratory Clinical Study. The TREBLE study was a randomized, placebo-controlled, double-blind, Phase 2, proof-of-concept study designed and conducted by Roche to assess the efficacy and safety of lebrikizumab, administered via subcutaneous injection as add-on therapy to twice-daily topical corticosteroids (“TCS”) in 209 adult patients with moderate-to-severe atopic dermatitis. Dosing in this study was largely based on experience with lebrikizumab in asthma clinical trials and the objective of characterizing both dose-response relationships and dosing frequency requirements in atopic dermatitis.
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After two weeks of twice daily TCS therapy, patients in the TREBLE study were randomized 1:1:1:1 to receive either a single dose of 125 milligrams (“mg”) of lebrikizumab plus continued TCS (n=52), a single, 250-mg dose of lebrikizumab plus TCS (n=53), 125 mg of lebrikizumab q4w plus TCS (n=51), or placebo q4w plus TCS (n=53), for up to 12 weeks. The primary endpoint was the percentage of patients achieving a 50% reduction from baseline in the 72-point clinical grading scale called the Eczema Area and Severity Index (“EASI-50”), an endpoint that has been widely used to measure treatment success in clinical atopic dermatitis trials, at the end of the 12-week treatment period. In addition, the time course of response to lebrikizumab treatment was assessed via a range of other measures, including EASI-50, as well as the proportion of patients achieving a 75% reduction from baseline in EASI score (“EASI-75”), the proportion of patients achieving a 90% reduction from baseline in EASI score (“EASI-90”), and the proportion of patients achieving clearing or near clearing of atopic dermatitis, as rated by the investigator on a five-point scale called the Investigator Global Assessment that ranges from zero, representing clear skin, to four, representing severe disease (“IGA0/1”). Inclusion criteria required that patients had an inadequate response to TCS and a regular emollient, and at both screening and the end of the initial two weeks of TCS treatment prior to the initiation of lebrikizumab treatment, had an EASI score of at least 14 and an IGA score of at least three.
The results of the TREBLE study provided proof-of-concept for the treatment of atopic dermatitis with lebrikizumab, including information we believe that we can use to optimize the clinical profile of lebrikizumab in future clinical trials. Across a number of key efficacy measures employed in this study, lebrikizumab provided clinically meaningful placebo-corrected improvements, generally in a dose-dependent manner. These improvements were observed on top of intensive TCS application that was associated with substantial responses in the placebo group.
Efficacy across Key Measures over 12 Weeks
P-values shown above are as of the end of the 12-week treatment period and represent comparisons to corresponding data in patients who received placebo only. P-values of less than 0.05 are denoted by *.
After 12 weeks of treatment, relative to patients who received placebo, the group of patients who received 125 mg of lebrikizumab q4w achieved statistically significant improvements in the primary endpoint, EASI-50 (82.4% vs. 62.3%, p=0.03). Improvements were also seen in the EASI-75 (54.9% vs. 34.0%, p=0.04) and EASI-90 (25.5% vs. 9.4%, p=0.03). The percentage of subjects achieving IGA0/1 was 33.3% in the 125 mg lebrikizumab group and 18.9% in the placebo group (p=0.10). In these patients, placebo-adjusted efficacy across these measures did not appear to plateau at the end of the 12-week treatment period, consistent with the fact that in the absence of a loading dose, circulating lebrikizumab concentrations likely did not reach a steady state during this period. While the groups of patients who received single, 125- or 250-mg doses of lebrikizumab generally did not achieve statistically significant improvements relative to those who received placebo after 12 weeks of observation in this study, results in these patients showed that placebo-adjusted effects on disease severity appeared to peak several weeks following the administration of a single lebrikizumab injection.
We believe that the dose-response relationships observed across multiple endpoints, as well as trends toward improved efficacy with increasing dose and duration, suggest that increasing the dose and/or duration of repeated administration of lebrikizumab may result in improved efficacy in future clinical atopic dermatitis trials, an effect that may be further improved by the introduction of a loading dose to achieve steady-state circulating lebrikizumab concentrations shortly after the start of therapy. Additionally, we believe that the time course of the responses
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observed in the TREBLE study, including following single doses of lebrikizumab, suggest that it may be feasible to administer lebrikizumab q4w, if not less frequently, in atopic dermatitis.
ARBAN Phase 2 Exploratory Clinical Study. ARBAN was an open-label study designed to assess the safety of lebrikizumab as a monotherapy, with an exploratory assessment of efficacy, in adult patients with moderate-to-severe atopic dermatitis. Clinical improvements were observed in patients treated with lebrikizumab.
Safety and Tolerability. Consistent with results observed across the lebrikizumab program to date, lebrikizumab was generally well-tolerated in these exploratory clinical studies in atopic dermatitis. There were no imbalances in proportions of patients reporting adverse events, serious adverse events, events leading to discontinuation, or overall infections when comparing all lebrikizumab-treated patients with controls. Four patients (2.2%) in the lebrikizumab groups (all doses combined) and two control patients (2.5%) experienced an adverse event that led to withdrawal from the studies. Injection-site reactions occurred infrequently (in 1.2% of patients in all lebrikizumab groups and 1.3% of control patients).
Phase 2b Clinical Program. Based on the results of the exploratory clinical trials conducted by Roche in atopic dermatitis, in January 2018 we initiated a randomized, double-blind, placebo-controlled, parallel-group, Phase 2b dose-ranging study designed to evaluate the safety and efficacy of lebrikizumab as a monotherapy compared with placebo, and to establish the dosing regimen for a potential Phase 3 program. The study is designed to evaluate our hypothesis that the efficacy of lebrikizumab in atopic dermatitis may be improved by increasing the dose and duration of repeated administration, together with the introduction of a loading dose. The study is expected to enroll approximately 275 patients ages 18 years and older with moderate-to-severe atopic dermatitis at sites in the United States. The study will evaluate three active treatment groups compared to a placebo treatment group, for 16 weeks, with patients randomized in a 3:3:3:2 fashion:
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Treatment Group 1: A loading dose of 250 mg of lebrikizumab at week zero, followed by 125 mg of lebrikizumab every four weeks. |
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Treatment Group 2: A loading dose of 500 mg of lebrikizumab at week zero, followed by 250 mg of lebrikizumab every four weeks. |
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Treatment Group 3: A loading dose of 500 mg of lebrikizumab at weeks zero and two, followed by 250 mg of lebrikizumab every two weeks. |
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Treatment Group 4: Placebo at week zero and every two weeks thereafter. |
The primary endpoint of the study is the percent change in the EASI score from baseline to week 16. Key secondary endpoints that will be evaluated during the 16-week treatment period include EASI-50, EASI-75 and EASI-90; the proportion of patients with an IGA score of zero (clear) or one (almost clear) and a reduction of two or more points (on a five-point scale) from baseline; and changes in pruritus (itch) and sleep loss and scores from baseline, both scored using 11-point numerical rating scales. Key inclusion criteria for patients enrolled in this study include chronic atopic dermatitis for at least one year, an EASI score of 16 or greater, an IGA score of three or four, and involvement of at least 10% of body surface area at screening and baseline. Following the end of the 16-week treatment period, patients will be followed for an additional 16 weeks.
We expect topline results from this Phase 2b clinical trial in the first half of 2019.
Research Programs
We continue to work on other compounds in early stages of development. In August 2016, we entered into an exclusive option and license agreement with Takeda Pharmaceutical Company Limited (“Takeda”) pursuant to which we acquired an option to license exclusive worldwide rights for three early-stage programs with undisclosed mechanisms of action as potential topical treatment options for dermatologic diseases. In December 2017, we acquired from Takeda an option to license exclusive worldwide rights for an additional early-stage program. If we exercise our option for any program, we would obtain an exclusive, worldwide license to develop and commercialize selected compounds from that program and be solely responsible for further research, development and commercialization costs related to these compounds.
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Our industry is highly competitive and subject to rapid and significant change. While we believe that our development and commercialization experience, scientific knowledge and industry relationships provide us with competitive advantages, we face competition from pharmaceutical and biotechnology companies, including specialty pharmaceutical companies, generic drug companies, academic institutions, government agencies and research institutions.
Many of our competitors have significantly greater financial, technical and human resources than we have. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Our commercial opportunity could be reduced if our competitors develop or market products or other novel therapies that are more effective, safer or less costly than our current or future product candidates, or obtain regulatory approval for their products more rapidly than we may obtain approval for our product candidates. Our success will be based in part on our ability to identify, develop and manage a portfolio of product candidates that are safer and/or more effective than competing products.
Hyperhidrosis
If approved for the treatment of primary axillary hyperhidrosis, we anticipate that glycopyrronium tosylate would compete with other therapies used for hyperhidrosis, including:
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Self‑Administered Treatments. Self‑administered treatments include OTC and prescription topical antiperspirants. Oral and compounded topical anticholinergics may also be used off‑label. |
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Non‑Surgical Office‑Based Procedures. Office‑based procedures have been approved for the treatment of hyperhidrosis, including Botox intradermal injections marketed by Allergan plc (“Allergan”), and device-based treatments, such as MiraDry, a microwave treatment marketed by Miramar Labs, Inc., and PrecisionTx, a laser procedure from Cynosure, Inc. |
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Surgical Treatments. Surgical treatments include techniques for the removal of sweat glands, such as excision, curettage and liposuction. Surgical procedures, such as endoscopic thoracic sympathectomy, also are used to destroy nerves that transmit activating signals to sweat glands. |
In addition, there are several treatments under development that could potentially be approved and used to treat hyperhidrosis and compete with glycopyrronium tosylate, including: an ultrasound device from Ulthera, Inc., a subsidiary of Merz Pharma GmbH & Co. KGaA; topical forms of botulinum toxin from Allergan and Eirion Therapeutics, Inc.; topical anticholinergic product candidates from Brickell Biotech, Inc. and GlaxoSmithKline LLC (“GSK”); and oral anticholinergic product candidates from TheraVida, Inc. and Atacama Therapeutics, Inc.
Acne
If approved for the treatment of acne vulgaris, we anticipate that olumacostat glasaretil would compete with other approved prescription acne products, including:
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Topical Retinoids. Single‑agent topical retinoid products prescribed for the treatment of acne include: Differin, marketed by Galderma S.A., a division of Nestle Skin Health (“Galderma”) S.A.; Tazorac, marketed by Allergan; Fabior, marketed by GSK; and branded and generic tretinoin products, such as Retin‑A Micro, marketed by Valeant Pharmaceuticals International, Inc. (“Valeant”). Topical retinoids are also used in branded and generic combination products that include an antimicrobial, such as benzoyl peroxide, as in Epiduo, marketed by Galderma, and a generic version of Epiduo marketed by Perrigo Company plc; or clindamycin phosphate, as in Ziana, marketed by Medicis Pharmaceutical Corporation, a division of Valeant, and Veltin, marketed by Aqua Pharmaceuticals, LLC, a division of Almirall, S.A. |
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Oral Isotretinoin. Several branded and generic oral isotretinoin products are prescribed for the treatment of acne, including: Absorica, marketed by Ranbaxy Laboratories Limited, a division of Sun Pharmaceutical Industries Ltd. (“Sun”), and by Cipher Pharmaceuticals Inc.; Amnesteem, marketed by Mylan N.V. (“Mylan”); Claravis, marketed by Teva Pharmaceutical Industries Ltd. (“Teva”); Myorisan, marketed by Akorn, Inc.; and Zenatane, marketed by Promius Pharma, LLC, a division of Dr.Reddy’s Laboratories Ltd (“Dr.Reddy”). |
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Oral Hormonal Therapies. Several branded and generic oral hormonal therapies are prescribed for the treatment of acne, including: branded and generic combinations of drospirenone and ethinyl estradiol, such as Yaz and Ocella, marketed by Bayer HealthCare AG (formerly Intendis, Inc.) and by Teva, respectively; and branded and generic combinations of norgestimate and ethinyl estradiol, such as Ortho Tri‑Cyclen, marketed by Janssen Pharmaceuticals, Inc., a division of Johnson & Johnson, Tri‑Sprintec, marketed by Teva, and Diane-35, cyproterone acetate with ethinylestradol, marketed by Bayer. |
In addition to approved prescription acne therapies, a number of prescription products are used off‑label for the treatment of acne, including branded and generic products containing the oral hormonal therapy spironolactone, such as Aldactone, marketed by G.D. Searle LLC, a division of Pfizer Inc. (“Pfizer”). A wide range of OTC and device products are also used to treat acne, including: OTC Differin, marketed by Galderma; OTC benzoyl peroxide products and skin cleansers, such as Proactiv, marketed by Guthy‑Renker LLC; and light‑based therapies, such as Blu‑U and Acne Clearing Blue Light, marketed by Dusa Pharmaceuticals, Inc., a division of Sun and Tria Beauty, Inc., respectively.
Furthermore, there are several product candidates in development that could potentially be used to treat acne and compete with olumacostat glasaretil. Product candidates in Phase 3 development or registration include: topical retinoids by Galderma, Valeant, Dr. Reddy and Phosphagenics Limited; topical antimicrobials by Galderma, Maruho, Allergan and Foamix Pharmaceuticals Ltd.; a topical hormonal therapy by Cassiopea SpA, a subsidiary of Cosmo Pharmaceuticals S.A. (“Cassiopea”); an oral antibiotic by Allergan; a topical nitric oxide‑based therapy by Novan, Inc.; and light‑based therapies by LEO Pharma A/S (“LEO Pharma”) and KLOX Technologies, Inc. There are also product candidates in earlier stages of development that could potentially be used to treat acne and compete with olumacostat glasaretil, including products currently being developed by AndroScience Corporation, Anterios, Inc. a subsidiary of Allergan, AOBiome, LLC, BioPharmX Corporation, Braintree Laboratories, Inc, Cassiopea, Celtaxsys Inc, Cutanea Life Sciences, Inc, LEO Pharma, Melinta Therapeutics, Inc., Mimetica Pty Limited, Sol-Gel Technologies Ltd., Therapeutics, Inc., Thesan Pharmaceutical Inc., Valeant, Vyome Biosciences Pvt Ltd and XBiotech Inc.
Atopic Dermatitis
If approved for the treatment of moderate-to-severe atopic dermatitis, we anticipate that lebrikizumab would compete with other approved and marketed prescription atopic dermatitis products, including:
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Other Systemic Treatments. Other systemic treatments are prescribed for the treatment of moderate-to-severe atopic dermatitis, including branded and generic oral corticosteroids, generic injectable and oral methotrexate products marketed by Sandoz International GmbH, a division of Novartis (“Sandoz”), Mylan, Teva and Hospira, Inc., a subsidiary of Pfizer; branded oral cyclosporine products such as Neoral, marketed by Novartis AG, and Gengraf, marketed by AbbVie Inc. (“AbbVie”); generic oral cyclosporine products marketed by Sandoz and IVAX Corporation, a subsidiary of Teva; branded oral mycophenolate products, such as CellCept, marketed by Roche, and Myfortic, marketed by Novartis; and generic oral mycophenolate products marketed by Mylan, Sandoz and Teva. |
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Other Therapies. Oral antibiotics and antihistamines are often used to manage comorbidities of atopic dermatitis, such as skin infections, and symptoms of atopic dermatitis, such as itch, respectively. There are also several prescription, non-prescription and OTC topical products utilized to treat atopic dermatitis, including Eucrisa, marketed by Pfizer, topical corticosteroids and topical calcineurin inhibitors, as well as bath solutions and moisturizers. |
In addition to moderate-to-severe atopic dermatitis treatments that are currently available for commercial use, there are several pharmaceutical product candidates that are under development and could potentially be used to treat atopic dermatitis and compete with lebrikizumab. Product candidates in or about to begin Phase 3 development include tralokinumab from LEO Pharma, baricitinib from Eli Lilly and Company (“Eli Lilly”), PF-04945842 from Pfizer and upadacitinib from AbbVie. There are also product candidates in earlier stages of development that could potentially be used to treat atopic dermatitis and compete with lebrikizumab, including products currently being developed by Asana Biosciences, LLC; AnaptysBio, Inc.; Amgen Inc. (“Amgen”) and MedImmune, LLC, a division of AstraZeneca PLC; Chugai Pharmaceutical Co., Galderma and Maruho; DS BioPharma Limited; Galapagos NV and MorphoSys AG; GSK; Glenmark Pharmaceuticals Limited; Menlo Therapeutics Inc.; Novartis; Pfizer; and Vanda Pharmaceuticals Inc.
Commercial Operations
We are building a commercial infrastructure to support the potential commercialization of our product candidates in the United States. We intend to build a targeted sales force to establish relationships with dermatologists as well as other healthcare practitioners and other prescribers. We expect that our sales force will be supported by sales management, an internal marketing group, market access and payer efforts and supply chain management. In addition to our efforts with physicians, we are committing and will continue to commit financial and management resources to engage patients directly. To develop the appropriate commercial infrastructure, we will have to invest significant financial and management resources, some of which will be committed prior to any confirmation that our product candidates will be approved, and we could invest resources and then later learn that a particular product candidate is not being approved. We may also partner with third parties to help us reach other geographic markets or therapeutic specialties.
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Total research and development expenses were $104.4 million, $83.2 million and $66.8 million for the years ended December 31, 2017, 2016 and 2015, respectively.
Intellectual Property
Our success depends in large part upon our ability to obtain and maintain proprietary protection for our products and technologies, and to operate without infringing the proprietary rights of others. With respect to the former, our policy is to protect our proprietary position by, among other methods, filing patent applications on inventions that are important to the development and conduct of our business with the U.S. Patent and Trademark Office (“USPTO”) and its foreign counterparts. We seek to avoid the latter by monitoring patents and publications that may affect our business, and to the extent we identify such developments, evaluate and take appropriate courses of action.
As of December 31, 2017, we own or have an exclusive license to 27 issued U.S. patents and 50 issued foreign patents, which include granted European patent rights that have been validated in various EU member states, and 10 pending U.S. patent applications and 50 pending foreign patent applications.
Issued U.S. and foreign patents and pending U.S. and foreign patent applications, if issued, for our lead product candidates, glycopyrronium tosylate, olumacostat glasaretil and lebrikizumab, will expire between 2020 and 2037.
We also use other forms of protection, such as trademark, copyright and trade secret protection, to protect our intellectual property, particularly where we do not believe patent protection is appropriate or obtainable. We aim to take advantage of all of the intellectual property rights that are available to us and believe that this comprehensive approach will provide us with proprietary positions for our product candidates, where available.
Patents extend for varying periods according to the date of patent filing or grant and the legal term of patents in various countries where patent protection is obtained. The actual protection afforded by a patent, which can vary from country to country, depends on the type of patent, the scope of its coverage and the availability of legal remedies in the country.
We also protect our proprietary information by requiring our employees, consultants, contractors and other advisors to execute nondisclosure and assignment of invention agreements upon commencement of their respective employment or engagement. Agreements with our employees also prevent them from bringing the proprietary rights of third parties to us. In addition, we also require confidentiality or service agreements from third parties that receive our confidential information or materials.
Collaboration and License Agreements
Agreements with Rose U and Stiefel
In April 2013, we entered into an exclusive license agreement with Rose U pursuant to which we obtained a worldwide exclusive license within a field of use including hyperhidrosis to practice, enforce and otherwise exploit certain patent rights, know‑how and data related to our hyperhidrosis program. The license agreement with Rose U included a sublicense of certain data and an assignment of certain regulatory filings which Rose U had obtained from Stiefel. In connection with the license agreement, we entered into a letter agreement with Stiefel pursuant to which we assumed Rose U’s obligation to pay Stiefel approximately $2.5 million in connection with the commercialization of products developed using the licensed data and to indemnify Stiefel for claims arising from the use, development or commercialization of products developed using the Stiefel data. The agreements require us to use commercially reasonable efforts to develop and commercialize products using the licensed patent rights, know‑how and data.
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Pursuant to these agreements with Rose U and the related agreement with Stiefel with respect to our hyperhidrosis program, we have paid license and other fees of $0.8 million to Rose U and are required to pay additional amounts totaling up to $4.1 million upon the achievement of specified regulatory, commercialization and other milestones under these agreements to Rose U and Stiefel. In addition, we are obligated to pay Rose U low‑to‑mid single‑digit royalties on net product sales and low double‑digit royalties on sublicense fees and certain milestone, royalty and other contingent payments received from sublicensees, to the extent such amounts are in excess of the milestone and royalty payments we are obligated to pay Rose U directly upon the events or sales triggering such payments.
We are permitted to grant sublicenses to the licensed rights and may assign the agreements upon an acquisition of us or our assets that relate to the license agreement, provided that in the event of an acquisition of our assets we must first pay to Stiefel the commercialization payment we are obligated to make on behalf of Rose U, if such amount has not already been paid. We may terminate the license agreement if Rose U experiences certain insolvency events or if Rose U commits a material breach of the license agreement, subject to applicable cure provisions. We may also terminate the license agreement if we determine that development results or market dynamics do not justify further development or commercialization of licensed products, in which case, all patent and technology rights shall revert to Rose U and we will (1) grant Rose U a perpetual nonexclusive license to any improvements owned by us related to the Rose U intellectual property that have been applied to or used with our hyperhidrosis program, at a royalty rate to be mutually agreed through good faith negotiation, and (2) for 120 days after such termination, assist and cooperate with Rose U (at Rose U’s expense) in connection with the license of such improvements to Rose U. Rose U may terminate the license in certain circumstances if we experience certain insolvency events or if we commit a material breach of the license agreement or if we cause Rose U to be in material breach of its license agreement with Stiefel, subject in each case to applicable cure provisions. Subject to earlier termination, the license agreement remains in effect until 15 years following the first commercial sale of a licensed product have elapsed or, if later, the date that the last patent or patent application in the licensed patent rights has expired or been revoked, invalidated or abandoned. The last‑to‑expire issued patent that we licensed under the license agreement with Rose U expires in 2029.
Agreements with Maruho
In March 2013, we entered into a Right of First Negotiation Agreement with Maruho (“Maruho Right of First Negotiation Agreement”), pursuant to which we provided Maruho with certain information and the right to negotiate an exclusive license to develop and commercialize certain of our products in specified territories. In connection with the entry into this agreement, Maruho paid us $10.0 million (“Maruho Payment”), which will be credited against certain payments payable by Maruho to us if we enter into a license agreement for any of our products with Maruho. Maruho’s right of first negotiation expired in December 2016 but the right to credit the Maruho Payment against certain payments under any future license agreement for our products remains.
In connection with the execution of the Maruho Right of First Negotiation Agreement, Maruho purchased 1,187,014 shares of our Series B convertible preferred stock in March 2013 for an aggregate purchase price of $10.0 million. As of December 31, 2017, Maruho owned approximately 2.8% of our outstanding capital stock.
In September 2016, we entered into an Exclusive License Agreement with Maruho, which grants Maruho an exclusive license to develop and commercialize glycopyrronium tosylate for the treatment of hyperhidrosis in Japan (“Maruho G.T. Agreement”). Pursuant to the terms of the Maruho G.T. Agreement, we received an upfront payment of $25.0 million from Maruho in October 2016 and are eligible to receive additional payments totaling up to $70.0 million, contingent upon the achievement of certain milestones associated with submission and approval of a marketing application in Japan and certain sales thresholds, as well as royalty payments based on a percentage of net product sales in Japan. The Maruho G.T. Agreement further provides that Maruho will be responsible for funding all development and commercial costs for the program in Japan and, until such time, if any, as Maruho elects to establish its own source of supply of drug product, Maruho will purchase product supply from us for development and, if applicable, commercial purposes at cost. The Maruho G.T. Agreement is unrelated to, and the exclusive license of glycopyrronium tosylate in Japan to Maruho was not subject to the terms of, the Maruho Right of First Negotiation Agreement.
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Unless earlier terminated, the Maruho G.T. Agreement will remain in effect until the later of: (1) expiration or abandonment of the last valid claim of the applicable patent rights in Japan; (2) expiration of any market exclusivity in Japan granted by the applicable regulatory authority; and (3) 15 years following the date of the first commercial sale of the drug product in Japan.
Agreement with Roche
In August 2017, we entered into the Roche Agreement pursuant to which we obtained exclusive, worldwide rights to develop and commercialize lebrikizumab, an injectable, humanized antibody targeting IL-13, for atopic dermatitis and all other indications, except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. The Roche Agreement became effective in September 2017 upon the early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended. Unless earlier terminated, the Roche Agreement will remain in effect until no royalty or other payment obligations are or may become due.
Under the terms of the Roche Agreement, we made an initial payment of $80.0 million to Roche in October 2017 and will make additional payments to Roche in 2018 totaling $55.0 million. We will also be obligated to make payments upon the achievement of certain milestones, comprising $40.0 million upon the initiation of the first Phase 3 clinical study, up to $210.0 million upon the achievement of regulatory and first commercial sale milestones in certain territories and up to $1.0 billion based on the achievement of certain thresholds for net sales of lebrikizumab for indications other than interstitial lung diseases. Upon regulatory approval, if obtained, we will make royalty payments representing percentages of net sales that range from the high single-digits to the high teens. Royalty payments will be made from the first commercial sale date in a country (other than for the Retained Field) in such country and end on the later of the date that is (a) ten years after the date of the first commercial sale of lebrikizumab (other than for the Retained Field) in such country, (b) the expiration of the last to expire valid claim of the applicable licensed compound patent rights, Dermira patent rights or joint patent rights in such country covering the use, manufacturing, import, offering for sale, or sale of lebrikizumab (other than for the Retained Field) in such country, (c) the expiration of the last to expire valid claim of the applicable licensed non-compound patent rights in such country covering the use, import, offering for sale, or sale of the product in such country, or (d) the expiration of the last to expire regulatory exclusivity conferred by the applicable regulatory authority in such country for lebrikizumab (other than for the Retained Field).
Collaboration with UCB
In March 2014, we and UCB Pharma S.A. (“UCB”), entered into a Development and Commercialisation Agreement, dated March 21, 2014 (“UCB Agreement”), which provided that we would (a) develop Cimzia (certolizumab pegol) for the treatment of psoriasis in order for UCB to seek regulatory approval from the FDA, the European Medicines Agency and the Canadian federal department for health, and (b) upon the grant of regulatory approval in the United States and Canada, promote sales of Cimzia to dermatologists and conduct related medical affairs activities in the United States and Canada.
The UCB Agreement also provided either party with the right to terminate the agreement under certain terms. We expressed our intent to terminate the UCB Agreement in accordance with its terms. As a result, we and UCB entered into an agreement on November 6, 2017 to effect the termination of the UCB Agreement and an orderly transition of the development and commercialization activities under the UCB Agreement from us to UCB (“Transition Agreement”). The Transition Agreement, among other things, (a) terminated the UCB Agreement on February 15, 2018, (b) provided for the repurchase by UCB of all product rights, licenses and intellectual property relating to Cimzia, (c) specified the responsibilities and obligations of us and UCB in connection with the transition of certain activities under the UCB Agreement from us to UCB as a result of the termination of the UCB Agreement, (d) terminated UCB’s right to designate a director nominee to our board of directors and (e) provided for the resignation of UCB’s designee from our board of directors.
Pursuant to the UCB Agreement, there were no termination or penalty payments required by either party. In consideration for the repurchase of all product rights, licenses and intellectual property relating to Cimzia, UCB paid us $11.0 million in November 2017 and, upon approval of Cimzia in psoriasis in the United States, will pay us an
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additional $39.0 million within 30 days of such approval. We are obligated to reimburse UCB for up to $10.0 million of development costs incurred by UCB in connection with the development of Cimzia between January 1, 2018 and June 30, 2018. If the aggregate development costs reimbursed by us to UCB during this six-month period are less than $10.0 million, we will pay UCB the difference between such aggregate costs and $10.0 million. These terms replace the provisions of the UCB Agreement pursuant to which we would have been eligible to recoup our external development costs incurred related to the Cimzia program, net of milestones received, through a royalty on future net sales of Cimzia. The $10.0 million payable to UCB is recorded on our consolidated balance sheets as refund liability. The $1.0 million net consideration from the $11.0 million payment received from UCB and the $10.0 million refund liability due to UCB will be recognized as revenue over the period in which we are obligated to perform transition services pursuant to the Transition Agreement.
Government Regulation
FDA Drug Approval Process
In the United States, pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug, and Cosmetic Act (“FDC Act”) and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post‑approval monitoring and reporting, sampling and import and export of pharmaceutical products. Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending NDAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution. As a result of these regulations, pharmaceutical product development and approval are very expensive and time consuming.
Pharmaceutical product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND, which must become effective before clinical testing may commence, and adequate and well‑ controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought. Satisfaction of FDA pre‑market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity and novelty of the product or disease.
Clinical trials to support NDAs for marketing approval are typically conducted in three sequential phases, but the phases may overlap. In Phase 1, the initial introduction of the drug into healthy human subjects or patients, the drug is tested to assess pharmacological actions, side effects associated with increasing doses and, if possible, early evidence on effectiveness. For dermatology products, Phase 2 usually involves trials in a limited patient population to determine metabolism, pharmacokinetics, the effectiveness of the drug for a particular indication, dosage tolerance and optimum dosage, and to identify common adverse effects and safety risks. If a compound demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations, Phase 3 clinical trials are undertaken to obtain the additional information about clinical efficacy and safety in a larger number of patients, typically at geographically dispersed clinical trial sites, to permit the FDA to evaluate the overall benefit‑risk relationship of the drug and to provide adequate information for the labeling of the drug. In most cases the FDA requires two adequate and well‑controlled Phase 3 clinical trials with statistically significant results to demonstrate the efficacy of the drug. A single Phase 3 clinical trial with other confirmatory evidence may be sufficient in rare instances where the study is a large multicenter trial demonstrating internal consistency and a statistically very persuasive finding of an effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.
After completion of the required activities, including clinical testing, an NDA is prepared and submitted to the FDA. FDA approval of the NDA is required before marketing of the product may begin in the United States.
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The FDA also may refer applications for novel drug products, or drug products that present difficult questions of safety or efficacy, to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved. The FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations. Before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with the FDA’s good clinical practice requirements. Additionally, the FDA typically inspects the facility or the facilities at which the drug is manufactured, and may inspect the sponsor company and investigator sites that participated in the clinical trials. The FDA will not approve the product unless compliance with current good manufacturing practice (“cGMP”) is satisfactory and the NDA contains data that provide substantial evidence that the drug is safe and effective for the stated indication.
After the FDA evaluates the NDA and the manufacturing facilities, it issues either an approval letter or a complete response letter. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing, or information, in order for the FDA to reconsider the application. If, or when, those deficiencies have been addressed to the FDA’s satisfaction following FDA review of a resubmission of the NDA, the FDA will issue an approval letter.
An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. As a condition of NDA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”), to help ensure that the benefits of the drug outweigh the potential risks. REMS can include medication guides, communication plans for healthcare professionals and elements to assure safe use (“ETASU”). ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring and the use of patient registries. The requirement for a REMS can materially affect the potential market and profitability of the drug. Moreover, product approval may require substantial post‑approval testing and surveillance to monitor the drug’s safety or efficacy. Once granted, product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.
Changes to some of the conditions established in an approved application, including changes in indications, labeling, or manufacturing processes or facilities, require submission and FDA approval of a new NDA or NDA supplement before the change can be implemented. An NDA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA generally uses the same procedures and actions in reviewing NDA supplements as it does in reviewing NDAs.
Section 505(b)(2) New Drug Applications
Most drug products obtain FDA marketing approval pursuant to an NDA filed under section 505(b)(1) of the FDC Act. An alternative is a special type of NDA, commonly referred to as a Section 505(b)(2) NDA (“505(b)(2) NDA”), which enables the applicant to rely, in part, on the FDA’s previous approval of a similar product, or published literature, in support of its application.
505(b)(2) NDAs often provide an alternate path to FDA approval for new or improved formulations or new uses of previously approved products. Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference. If the 505(b)(2) NDA applicant can establish that reliance on the FDA’s previous approval is scientifically appropriate, it may eliminate the need to conduct certain preclinical or clinical studies of the new product. The FDA may also require companies to perform additional studies or measurements to support the change from the approved product. The FDA may then approve the new product candidate for all, or some, of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) NDA applicant.
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Biological products used for the prevention, treatment or cure of a disease or condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of NDAs. Biological products are approved for marketing under provisions of the Public Health Service Act (“PHSA”), via a Biologics License Application (“BLA”). However, the application process and requirements for approval of BLAs and BLA supplements, including review timelines, are very similar to those for NDAs and NDA supplements, and biologics are associated with similar approval risks and costs as other drugs.
Post‑Approval Requirements
Once an NDA is approved, a product will be subject to certain post‑approval requirements. For instance, the FDA closely regulates the post‑approval marketing and promotion of drugs, including standards and regulations for direct‑to‑consumer advertising, off‑label promotion, industry‑sponsored scientific and educational activities and promotional activities involving the internet. Drugs may be marketed only for the approved indications and in accordance with the provisions of the approved labeling.
Adverse event reporting and submission of periodic safety reports is required following FDA approval of an NDA. The FDA also may require post‑marketing testing, known as Phase 4 testing, REMS and surveillance to monitor the effects of an approved product, or the FDA may place conditions on an approval that could restrict the distribution or use of the product. In addition, quality‑control, drug manufacture, packaging and labeling procedures must continue to conform to cGMPs after approval. Drug manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies. Registration with the FDA subjects entities to periodic unannounced inspections by the FDA, during which the agency inspects manufacturing facilities to assess compliance with cGMPs. Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality‑control to maintain compliance with cGMPs. Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.
Pediatric Information
Under the Pediatric Research Equity Act, NDAs or supplements to NDAs must contain data to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective. The FDA may grant full or partial waivers, or deferrals, for submission of data.
The Best Pharmaceuticals for Children Act (“BPCA”) provides NDA holders a six‑month extension of any exclusivity, patent or non‑patent, for a drug if certain conditions are met. Conditions for exclusivity include the FDA’s determination that information relating to the use of a new drug in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric studies and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe. Applications under the BPCA are treated as priority applications, with all of the benefits that designation confers.
Disclosure of Clinical Trial Information
Sponsors of clinical trials of FDA‑regulated products, including drugs, are required to register and disclose certain clinical trial information. Information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is then made public as part of the registration. Sponsors are also obligated to disclose the results of their clinical trials after completion. Competitors may use this publicly available information to gain knowledge regarding the progress of our programs.
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Regulation Outside of the United States
In addition to regulations in the United States, we will be subject to regulations of other countries in which our clinical trials or commercial sales are conducted. Whether or not we obtain FDA approval for a product, we must obtain approval by the comparable regulatory authorities of countries outside of the United States before we can commence clinical trials in such countries and approval of the regulators of such countries or economic areas, such as the European Union, before we may market products in those countries or areas. Regulatory authorities in certain countries outside of the United States have a process similar to the FDA’s that requires the submission of a clinical trial application (“CTA”), much like the IND prior to the commencement of human clinical trials. In the European Union, for example, a CTA must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and institutional review board, respectively. Once the CTA is approved in accordance with a country’s requirements, clinical trial development may proceed. The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country, and the time may be longer or shorter than that required for FDA approval.
Under European Union regulatory systems, a company may submit marketing authorization applications either under a centralized or decentralized procedure. The centralized procedure, which is compulsory for medicines produced by biotechnology or those medicines intended to treat HIV, AIDS, cancer, neurodegenerative diseases, auto-immune and other immune dysfunctions, orphan (rare) diseases, viral diseases or diabetes and is optional for those medicines which are highly innovative, provides for the grant of a single marketing authorization that is valid for all European Union member states. The decentralized procedure provides for mutual recognition of national approval decisions. Under this procedure, the holder of a national marketing authorization from one state may submit an application to the remaining member states. Within 90 days of receiving the applications and assessments report, each member state must decide whether to recognize approval. If a member state does not recognize the marketing authorization, the disputed points are eventually referred to the European Commission, whose decision is binding on all member states.
Anti‑Kickback, False Claims Laws
In addition to FDA restrictions on marketing of pharmaceutical products, several other types of state and federal laws have been applied to restrict certain marketing practices in the pharmaceutical industry. These laws include, among others, anti‑kickback statutes, false claims statutes and other statutes pertaining to healthcare fraud and abuse. The federal healthcare program anti‑kickback statute prohibits, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration to induce, or in return for, purchasing, leasing, ordering or arranging for the purchase, lease or order of any healthcare item or service reimbursable under Medicare, Medicaid or other federally financed healthcare programs. The Patient Protection and Affordable Care Act, as amended (“PPACA”), amended the intent element of the federal anti‑kickback statute so that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it. This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary managers on the other. Although there are a number of statutory exceptions and regulatory safe harbors protecting certain common activities from prosecution or other regulatory sanctions, the exceptions and safe harbors are drawn narrowly, and practices that involve remuneration intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.
Other Federal and State Regulatory Requirements
The Centers for Medicare & Medicaid Services (“CMS”) has issued a final rule pursuant to PPACA that requires certain manufacturers of prescription drugs to annually collect and report information on payments or transfers of value to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Manufacturers were required to begin collecting information on August 1, 2013, with the first reports due March 31, 2014. The reported data is posted in searchable form on a public website maintained by CMS. Failure to submit required information may result in civil monetary penalties.
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In addition, several states now require prescription drug companies to report expenses relating to the marketing and promotion of drug products and to report gifts and payments to individual healthcare practitioners and entities in these states. Other states prohibit various other marketing‑related activities. Still other states require the posting of information relating to clinical studies and their outcomes. In addition, California, Connecticut, Nevada and Massachusetts require pharmaceutical companies to implement compliance programs and marketing codes. Several additional states are considering similar proposals. Some of the state laws are broader in scope than federal laws. Compliance with these laws is difficult and time consuming, and companies that do not comply with these state laws face civil penalties.
Reimbursement
Sales of any of our product candidates that are approved will depend, in part, on how our products are managed by third‑party payers, such as commercial insurance companies, pharmacy benefit managers and government health programs. Third‑party payers are responsible for managing overall pharmaceutical drug spending for their client membership and can employ a variety of means – including excluding a medicine from a formulary – to help control patient utilization. Third-party payers and their employer clients may also require patients to pay a high percentage of the list price of a medicine, which has been shown to negatively impact adherence to chronic medicines.
Additionally, the containment of healthcare costs has become a priority of the federal and state governments, and efforts to manage the prices of drugs have been a component of this effort. The U.S. federal government (including Congress), state legislatures and foreign governments have shown significant interest in implementing cost‑containment programs, including price controls, demonstration of cost effectiveness versus standard of care with specified models, restrictions on reimbursement and requirements for mandatory substitution of therapeutically similar generic products. Adoption of price controls and cost‑containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could limit our net revenue and results of operation. If any of our products are approved and these third‑party payers do not consider our approved products to be clinically superior or cost‑effective compared to therapeutically similar therapies, they may not cover our approved products in their formularies, or, if covered, the amount of patient cost-sharing could deter initiation and/or subsequent adherence, which would affect our net profitability.
The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”) imposed new requirements for the distribution and pricing of prescription drugs for Medicare beneficiaries. Under Part D of the MMA, Medicare beneficiaries may enroll in prescription drug plans offered by private entities which will provide coverage of outpatient prescription drugs. Part D plans include both stand‑alone prescription drug benefit plans and prescription drug coverage as a supplement to Medicare Advantage plans. Unlike Medicare Part A and B, Part D coverage is not standardized. Part D prescription drug plan sponsors are not required to pay for all covered Part D drugs, and each drug plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level. However, Part D prescription drug formularies must include drugs within each therapeutic category and class of covered Part D drugs, though not necessarily all the drugs in each category or class. Any formulary used by a Part D prescription drug plan must be developed and reviewed by a pharmacy and therapeutic committee. Government payment for some of the costs of prescription drugs may increase demand for our products for which we receive marketing approval. However, any negotiated prices for our approved products covered by a Part D prescription drug plan will likely be lower than the prices we might otherwise obtain. Moreover, while the MMA applies only to drug benefits for Medicare beneficiaries, private payers may follow Medicare coverage policy and payment limitations in setting their own coverage policies. Any denials in coverage or high beneficiary cost-sharing that results from the MMA may result in similar treatment from non‑governmental payers.
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The PPACA, as amended by the Health Care and Education Affordability Reconciliation Act of 2010 (collectively “ACA”), enacted in March 2010, had a significant impact on the health care industry. The ACA expanded coverage for the uninsured, while at the same time implementing measures to contain overall healthcare costs. We cannot predict the impact of the ACA on pharmaceutical companies, as many of the ACA reforms require the promulgation of detailed regulations implementing the statutory provisions, which has not yet occurred. Moreover, although the U.S. Supreme Court upheld the constitutionality of most of the ACA, some states have indicated that they intend to not implement certain sections of the ACA and the current presidential administration and certain members of the majority of the U.S. Congress have sought to repeal all or part of the ACA and implement a replacement program. For example, the so-called “individual mandate” was repealed as part of tax reform legislation adopted in December 2017, such that the shared responsibility payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, as amended, will be eliminated beginning in 2019.
In addition, in some non‑U.S. jurisdictions, the proposed pricing for a product candidate must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Historically, product candidates launched in the European Union do not follow price structures of the United States, and prices in the European Union generally tend to be significantly lower.
Manufacturing and Supply
We currently contract with third parties for the manufacture of our drug substances and drug products for preclinical studies and clinical trials and intend to continue doing so in the future. We have assembled a team of experienced employees and consultants to provide the necessary technical, quality and regulatory oversight over the contract manufacturing organizations (“CMOs”) with which we contract. We rely on third‑party manufacturers for scale‑up and process development work and to produce sufficient quantities of development product candidates for use in clinical and preclinical trials. We currently have development contracts and quality agreements with several CMOs for the manufacturing of our drug substances and drug products. We anticipate that these CMOs will have capacity to support commercial scale, but we do not have any formal agreements at this time with any of these CMOs to cover commercial production. We also may elect to pursue other CMOs for manufacturing supplies for later‑stage trials and for commercialization. Pursuant to the terms of the Roche Agreement, Roche is responsible for the manufacture and supply to us of lebrikizumab drug substance. Subject to certain requirements, Roche has the right to transfer its manufacture and supply responsibilities to us at any time.
Employees
As of December 31, 2017, we had 162 regular full‑time employees, including 79 in research and development. From time to time, we also retain independent contractors to support our organization. Our employees are not represented by a labor union or covered by a collective bargaining agreement. We have not experienced any work stoppages, and we consider our relations with our employees to be good.
Corporate Information
We were incorporated in the State of Delaware in August 2010 under the name Skintelligence, Inc. We changed our name to Dermira, Inc. in September 2011. Our principal executive offices are located at 275 Middlefield Road, Suite 150, Menlo Park, CA 94025, and our telephone number is (650) 421‑7200. Our website address is www.dermira.com. The information contained on, or that can be accessed through, our website is not a part of this Annual Report on Form 10‑K.
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Our website address is www.dermira.com. The information contained on, or that can be accessed through, our website is not a part of this report. Investors should not rely on any such information in deciding whether to purchase our common stock. Our Annual Report on Form 10‑K, Quarterly Reports on Form 10‑Q, Current Reports on Form 8‑K, reports filed pursuant to Section 16 under the Securities Exchange Act of 1934, as amended (“Exchange Act”), proxy and information statements and amendments to items filed pursuant to Sections 13(a), 14, 15(d) and 16 of the Exchange Act are filed with the U.S. Securities and Exchange Commission (“SEC”). We are subject to the informational requirements of the Exchange Act and file or furnish reports, proxy statements and other information with the SEC. Such documents and other information filed by the Company with the SEC are available free of charge on the Investor section of our website when such reports are available on the SEC’s website.
The public may read and copy any materials filed with the SEC at the SEC’s Public Reference Room at 100 F Street, NE, Room 1580, Washington, D.C. 20549. The public may obtain information on the operation of the Public Reference Room by calling the SEC at 1‑800‑SEC‑0330. The SEC maintains an Internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with the SEC at www.sec.gov.
We webcast our earnings calls and certain events we participate in or host with members of the investment community on the “Investors” page of our website. Corporate governance information, including the charters for the committees of our board of directors, codes of business conduct and ethics and corporate governance guidelines, is also available on the “Investors” page of our website located at http://investor.dermira.com.
In addition to SEC filings, press releases, public conference calls and webcasts, we use our website (www.dermira.com), LinkedIn page (https://www.linkedin.com/company/dermira‑inc‑) and corporate Twitter account (@DermiraInc) as channels of distribution of information about our company, our product candidates, our planned financial and other announcements, our attendance at upcoming investor and industry conferences, and other matters. It is possible that the information we post on our website, LinkedIn page and our corporate Twitter account could be deemed material information. We may use these channels to comply with our disclosure obligations under Regulation FD. Therefore, investors should monitor our website, LinkedIn page and corporate Twitter account in addition to following our press releases, SEC filings, public conference calls and webcasts.
The contents of the websites referred to above are not incorporated into this report. Further, our references to the URLs for these websites are intended to be inactive textual references only.
Executive Officers
The following table sets forth the names, ages as of February 22, 2018, and positions of our executive officers:
|
Name |
|
Age |
|
Position |
|
Thomas G. Wiggans |
|
66 |
|
Chief Executive Officer and Chairman of the Board |
|
Eugene A. Bauer, M.D. |
|
75 |
|
Chief Medical Officer and Director |
|
Christopher M. Griffith |
|
41 |
|
Senior Vice President, Corporate Development & Strategy |
|
Andrew L. Guggenhime |
|
49 |
|
Chief Operating Officer and Chief Financial Officer |
|
Lori Lyons-Williams |
|
40 |
|
Chief Commercial Officer |
|
Luis C. Peña |
|
55 |
|
Chief Development Officer |
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Thomas G. Wiggans. Mr. Wiggans founded our company in August 2010, has served as our Chief Executive Officer and a member of our board of directors since August 2010 and has served as the Chairman of our board of directors since April 2014. He currently serves on the board of directors of Annexon Biosciences, Inc., a privately-held biotechnology company. Mr. Wiggans has also served on the boards of various industry organizations, educational institutions and private and public companies, including service on the boards of directors of Onyx from March 2005 until its acquisition by Amgen in October 2013, Sangamo Biosciences from June 2008 until June 2012, Somaxon Pharmaceuticals, Inc. from June 2008 until May 2012 and as Chairman of the board of directors of Excaliard Pharmaceuticals, Inc. from October 2010 until its acquisition by Pfizer in December 2011. From October 2007, Mr. Wiggans served as Chairman of the board of directors of Peplin and in August 2008, he became its Chief Executive Officer, serving in these positions until Peplin’s acquisition by LEO Pharma in November 2009. Previously, Mr. Wiggans served as Chief Executive Officer of Connetics from 1994, and as Chairman of the board of directors of Connetics from January 2006, and he served in these positions until December 2006 when Connetics was acquired by Stiefel Laboratories. From 1992 to 1994, Mr. Wiggans served as President and Chief Operating Officer of CytoTherapeutics Inc., a biotechnology company. From 1980 to 1992, Mr. Wiggans served at Ares‑Serono S.A. in various management positions including President of its U.S. pharmaceutical operations and Managing Director of its U.K. pharmaceutical operations. Mr. Wiggans began his career with Eli Lilly. In addition, Mr. Wiggans is a member of the board of directors of the Biotechnology Innovation Organization and is a member of the board of trustees of the University of Kansas Endowment Association. Mr. Wiggans holds a B.S. in pharmacy from the University of Kansas and an M.B.A. from Southern Methodist University.
Eugene A. Bauer, M.D. Dr. Bauer founded our company in August 2010, has served as a member of our board of directors since August 2010 and has served as our Chief Medical Officer since October 2011. From February 2010 to June 2012, Dr. Bauer served on the board of directors of Vyteris, Inc. From June 2006, Dr. Bauer served as a member of board of directors of Peplin, Inc., a biotechnology company, and in October 2008, he became its President and Chief Medical Officer, and he served in these positions until Peplin’s acquisition by LEO Pharma A/S in November 2009. From November 2004 to October 2008, Dr. Bauer was Chief Executive Officer of Neosil Inc., a dermatology company that was acquired by Peplin in October 2008. In 1993, Dr. Bauer co‑founded Connetics Corporation, a biotechnology company, where he served as a member of the board of directors until October 2005. Dr. Bauer served as Dean of the Stanford University School of Medicine from 1995 to 2001 and as Chair of the Department of Dermatology at the Stanford University School of Medicine from 1988 to 1995. Dr. Bauer is a Lucy Becker Professor, Emeritus, in the School of Medicine at Stanford University, a position he has held since 2002. In addition, he is a member of the boards of directors of Aevi Genomic Medicine, Inc. (formerly Medgenics, Inc.), First Wave Technologies, Inc. and Kadmon Corporation, LLC. Dr. Bauer also previously served as a member of the boards of directors of Cerecor, Inc., Dr. Tattoff, Inc., Protalex, Inc., PetDRx, Inc., Arbor Vita Corp., Patient Safety Technologies, Inc., MediSync Bioservices and Modigene Inc. (later re‑named PROLOR Biotech, Inc.). Dr. Bauer was a U.S. National Institutes of Health (“NIH”) funded investigator for 25 years and has served on review groups for the NIH. Dr. Bauer has been elected to several societies, including the National Academy of Medicine of the United States, and currently serves as a director of the American Dermatological Association, Inc. Dr. Bauer received a B.S. in medicine and an M.D. from Northwestern University.
Christopher M. Griffith founded our company in August 2010 and has served as our Senior Vice President of Corporate Development and Strategy since January 2017, after previously serving as our Vice President of Corporate Development and Strategy since August 2011 and Head of Corporate Development and Strategy since September 2010. From July 2005 to September 2010, Mr. Griffith worked in corporate development at Gilead Sciences, Inc., most recently as Associate Director of Corporate Development. From May 2004 to August 2004, Mr. Griffith worked in the bio‑oncology strategy group at Genentech, Inc., a biotechnology company. From 2001 to 2003, Mr. Griffith worked at Bay City Capital. Mr. Griffith received B.S. and M.S. degrees in biological sciences from Stanford University and an M.B.A. degree from Harvard Business School.
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Andrew L. Guggenhime has served as our Chief Operating Officer and Chief Financial Officer since April 2014. From September 2011 to April 2014, Mr. Guggenhime served as Chief Financial Officer for CardioDx, Inc., a molecular diagnostics life sciences company, and as a member of the CardioDx board of directors from April 2014 until July 2016. From September 2010 to April 2011, Mr. Guggenhime served as Chief Financial Officer for Calistoga Pharmaceuticals, Inc., a biotechnology company acquired in April 2011 by Gilead. From December 2008 to June 2010, Mr. Guggenhime served as Senior Vice President and Chief Financial Officer for Facet Biotech Corporation, a biotechnology company acquired in April 2010 by Abbott Laboratories. Facet Biotech Corporation was spun off from PDL BioPharma, Inc., a biopharmaceutical company, at which Mr. Guggenhime served as Chief Financial Officer from April 2006 to December 2008. From October 2000 to March 2006, Mr. Guggenhime served as Senior Vice President and Chief Financial Officer for Neoforma, Inc., a provider of supply‑chain management solutions for the healthcare industry, and from January to October 2000 he served as its Vice President, Corporate Development. Mr. Guggenhime began his career in financial services at Merrill Lynch & Co. and Wells Fargo & Company. Mr. Guggenhime holds an M.B.A. from the J.L. Kellogg Graduate School of Management at Northwestern University and a B.A. in international politics and economics from Middlebury College.
Lori Lyons-Williams has served as our Chief Commercial Officer since December 2016. Prior to joining Dermira, Ms. Lyons-Williams served 15 years in various positions within the sales and marketing organization at Allergan plc, most recently as Vice President, Sales & Marketing for the Urology franchise from January 2014 to August 2016. In previous roles within Allergan, she served as Product Director for Allergan’s medical dermatology brands and also held senior-level positions on the Aczone and Botox marketing teams. Ms. Lyons-Williams began her career as a pharmaceutical sales representative at Johnson & Johnson. She is currently involved with certain non-profit organizations, including serving as a director and Vice Chair of the National Association for Continence and as a director of Girls, Inc. Orange County. She holds an M.B.A. from the Carlson School of Management of the University of Minnesota and a B.A. in interdisciplinary studies from Virginia Polytechnic Institute and State University.
Luis C. Peña is a co‑founder and has served as our Chief Development Officer since February 2016, after previously serving as our Executive Vice President of Product Development from July 2013 to February 2016 and our Vice President of Product Development from June 2011 to July 2013. From November 2010 to June 2011, Mr. Peña served as a consultant to our company. Mr. Peña served as Vice President, Head of Global Prescription Development at Stiefel, a GSK company, from January 2010 to March 2011 and, from January 2007 to December 2009, Mr. Peña served as Senior Vice President Portfolio Planning and Management at Stiefel, prior to its acquisition by GlaxoSmithKline LLC. From 2005 to 2007, Mr. Peña served as Vice President of Portfolio Planning and Management of Connetics. From 2001 to 2005, Mr. Peña served as Vice President of Product Development of Nuvelo, Inc., a biopharmaceutical company. Previously, Mr. Peña served as Senior Director of Project Planning and Management for Theravance, Incorporated, a pharmaceutical company, and held various positions in manufacturing, research and development at Genentech. Mr. Peña currently serves as an advisor to the SPARK program for the Stanford University School of Medicine where he has been an advisor since 2012. Mr. Peña holds a B.S. in biochemistry from San Francisco State University.
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RISK FACTORS
Our operations and financial results are subject to numerous risks and uncertainties, including those described below, which may have a material and adverse effect on our business, results of operations, cash flows, financial conditions, and the trading price of our common stock. The risks and uncertainties described below are not the only ones facing us. Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may impair our business operations. You should consider these risks and uncertainties carefully, together with all of the other information included or incorporated by reference in this Annual Report on Form 10‑K. If any of the following risks actually occur, our business, financial condition, results of operations and future prospects could be materially and adversely affected. In that event, the market price of our stock could decline, and you could lose part or all of your investment.
Risks Related to Development, Regulatory Approval and Commercialization
Our business is dependent on the successful development, regulatory approval and commercialization of our product candidates.
Our pipeline includes three late-stage product candidates that could have a profound impact on the lives of patients: glycopyrronium tosylate (formerly DRM04), for which a New Drug Application (“NDA”) is under review by the U.S. Food and Drug Administration (“FDA”) for the treatment of primary axillary hyperhidrosis (underarm sweating beyond what is needed for normal body temperature regulation); olumacostat glasaretil (formerly DRM01), in Phase 3 development for the treatment of acne vulgaris; and lebrikizumab, in Phase 2b development for the treatment of moderate-to-severe atopic dermatitis. The success of our business, including our ability to finance our company and generate any revenue in the future, will primarily depend on the successful development, regulatory approval and commercialization of our late-stage product candidates. In the future, we may also become dependent on other product candidates that we may in-license, acquire or develop. The clinical and commercial success of our product candidates will depend on a number of factors, including the following:
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• |
the ability to raise additional capital on acceptable terms, or at all; |
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• |
whether we are required by the FDA or similar foreign regulatory agencies to conduct additional clinical trials or other studies beyond those planned to support the approval and commercialization of our product candidates or any future product candidates; |
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• |
acceptance of our proposed indications and primary endpoint assessments relating to the proposed indications of our product candidates by the FDA and similar foreign regulatory authorities; |
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• |
our ability to demonstrate to the satisfaction of the FDA and similar foreign regulatory authorities the safety, efficacy and acceptable risk to benefit profile of our product candidates or any future product candidates; |
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• |
the prevalence, duration and severity of potential side effects experienced with our product candidates or future product candidates or approved products, if any; |
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• |
the timely receipt of necessary marketing approvals from the FDA and similar foreign regulatory authorities; |
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• |
achieving and maintaining, and, where applicable, ensuring that our third-party contractors achieve and maintain, compliance with our contractual obligations and with all regulatory requirements applicable to our product candidates or any future product candidates or approved products, if any; |
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|
• |
the ability of third parties with whom we contract to manufacture clinical trial and commercial supplies of our product candidates or any future product candidates, remain in good standing with regulatory agencies and develop, validate and maintain commercially viable manufacturing processes that are compliant with current good manufacturing practices (“cGMP”); |
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• |
a continued acceptable safety profile during clinical development and following approval of our product candidates or any future product candidates; |
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• |
our ability to successfully commercialize our product candidates or any future product candidates in the United States and internationally, if approved for marketing, reimbursement, sale and distribution in such countries and territories, whether alone or in collaboration with others; |
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• |
acceptance by physicians, payers and patients of the benefits, safety and efficacy of our product candidates or any future product candidates, if approved, including relative to alternative and competing treatments; |
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• |
our and our partners’ ability to establish and enforce intellectual property rights in and to our product candidates or any future product candidates; |
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• |
our and our partners’ ability to avoid third-party patent interference or intellectual property infringement claims; and |
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• |
our ability to in-license or acquire additional product candidates that we believe can be successfully developed and commercialized. |
If we do not achieve one or more of these factors, many of which are beyond our control, in a timely manner or at all, we could experience significant delays or an inability to obtain regulatory approvals or commercialize our product candidates. Even if regulatory approvals are obtained, we may never be able to successfully commercialize any of our product candidates. Accordingly, we cannot provide assurances that we will be able to generate sufficient revenue through the sale of our product candidates or any future product candidates to continue our business.
We have had significant and increasing operating expenses and we will require substantial additional financing to achieve our goals, which we may not be able to obtain when needed and on acceptable terms, or at all. We have a history of losses and may not be able to achieve or maintain profitability, which could cause our business and operating results to suffer.
We are a clinical-stage biopharmaceutical company with a limited operating history upon which investors can evaluate our business and prospects. We are not profitable and have incurred losses in each year since we commenced operations in August 2010. We have incurred net losses of $303.3 million, $89.1 million and $78.4 million for the years ended December 31, 2017, 2016 and 2015, respectively. As of December 31, 2017, we had an accumulated deficit of $553.4 million.
We have financed our operations primarily through the sale of equity securities and convertible debt securities. Since our inception, most of our resources have been dedicated to the development of our product candidates. The size of our future net losses will depend, in part, on our future expenses and our ability to generate revenue, if any. Revenue from our current and potential future collaborations is uncertain because milestones or other contingent payments under our agreements may not be achieved or received.
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As of December 31, 2017, we had capital resources consisting of cash and cash equivalents and investments of $551.0 million. We will continue to expend substantial cash resources for the foreseeable future for the clinical development and potential commercialization of our product candidates and development of any other indications and product candidates we may choose to pursue. These expenditures will include costs associated with any acquisition or in-license of products and product candidates, technologies or businesses, research and development, conducting preclinical studies, non-clinical studies and clinical trials, manufacturing and supply, regulatory submissions, preparing for potential commercial approvals and product launches, as well as marketing and selling any products approved for sale. In addition, other unanticipated costs may arise. Because the conduct and results of any clinical trial are highly uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of our current and any future product candidates.
We believe that our existing cash and cash equivalents and investments as of December 31, 2017 are sufficient to meet our anticipated cash requirements into the second half of 2019 and to: complete and generate topline results from our ongoing Phase 3 pivotal clinical trials for olumacostat glasaretil and Phase 2b dose-ranging study for lebrikizumab; commercialize our glycopyrronium tosylate product candidate, assuming that we receive the necessary regulatory approvals; complete registration-enabling activities and submit an NDA to the FDA for potential approval related to olumacostat glasaretil assuming the data from our Phase 3 clinical trials are positive; and continue potential lifecycle management activities related to our product candidates. We have based these estimates, however, on assumptions that may prove to be wrong, and we could spend our available capital resources much faster than we currently expect or require more capital to fund our operations than we currently expect. Our currently anticipated expenditures for the development and potential commercialization of all of our current product candidates, glycopyrronium tosylate, olumacostat glasaretil and lebrikizumab, exceed our existing cash and cash equivalents and investments. We will need to raise additional capital to fund our operations and continue to support our planned research and development and commercialization activities.
The amount and timing of our future funding requirements will depend on many factors, including:
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• |
the timing, rate of progress and cost of any preclinical and clinical trials and other product development activities for our current and any future product candidates that we develop, in-license or acquire; |
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• |
the results of the clinical trials for our product candidates in the United States and any foreign countries; |
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• |
the timing of, and the costs involved in, FDA approval and any foreign regulatory approval of our product candidates, if at all; |
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• |
the number and characteristics of any additional future product candidates we develop or acquire; |
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our ability to establish and maintain strategic collaborations, licensing, co-promotion or other arrangements and the terms and timing of such arrangements; |
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costs relating to building our infrastructure to prepare for potential commercial launch of our products, which will be incurred even if our product candidates are not ultimately approved for sale; |
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the cost of commercialization activities if our current or any future product candidates are approved for sale, including manufacturing, marketing, sales and distribution costs; |
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the degree and rate of market acceptance of any approved products; |
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costs under our third-party manufacturing and supply arrangements for our current and any future product candidates and any products we commercialize; |
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costs and timing of completion of any additional outsourced commercial manufacturing or supply arrangements that we may establish; |
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whether we are required to assume manufacture and supply responsibilities for lebrikizumab drug substance (see “—We are dependent on Roche for the manufacture and supply of lebrikizumab drug substance. If Roche elects to transfer its manufacture and supply responsibilities to us, we may not be able to engage a qualified contract manufacturer to manufacture and supply the drug substance in a timely manner, if at all. Any interruption in our supply may cause serious delays in the timing of our clinical studies, increase our costs and adversely impact our financial results.”); |
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costs associated with prosecuting or defending any litigation that we may become involved in and any damages payable by us that result from such litigation; |
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costs associated with defending any government investigations or enforcement actions including legal costs and fines; |
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costs associated with any product recall that could occur; |
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costs of operating as a public company; |
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the emergence, approval, availability, perceived advantages, relative cost, relative safety and relative efficacy of alternative and competing products or treatments; |
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costs associated with any acquisition or in-license of products and product candidates, technologies or businesses; and |
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personnel, facilities and equipment requirements. |
We cannot be certain that additional funding will be available on acceptable terms, or at all. Any future debt financing into which we enter may impose upon us covenants that restrict our operations, including limitations on our ability to incur liens or additional debt, pay dividends, redeem our stock, make certain investments and engage in certain merger, consolidation or asset sale transactions. In addition, we may seek additional capital due to favorable market conditions or strategic considerations even if we believe that we have sufficient funds for our current or future operating plans.
In order to fund the development and potential commercialization of our product candidates, we may also need to enter into collaboration agreements with pharmaceutical and biotechnology companies. Our ability to establish and maintain these collaborations is highly uncertain and subject to a number of variables. Under these arrangements, we may be responsible for substantial costs in connection with the clinical development, regulatory approval or the commercialization of a partnered product candidate. Furthermore, the payments we could receive from our potential collaboration partners may be subject to numerous conditions and may ultimately be insufficient to cover the cost of this development and commercialization.
If we are unable to raise additional capital when required or on acceptable terms, we may be required to significantly delay, scale back or discontinue one or more of our product development programs or our commercialization efforts, or other aspects of our business plan. In addition, our ability to achieve profitability or to respond to competitive pressures would be significantly limited.
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Clinical drug development for our product candidates is very expensive, time-consuming and uncertain. Our clinical trials may fail to adequately demonstrate the safety and efficacy of our product candidates, which could prevent or delay regulatory approval and commercialization.
Clinical drug development for our product candidates is very expensive, time-consuming and difficult to design and implement, and its outcome is inherently uncertain. Before obtaining regulatory approval for the commercial sale of a product candidate, we must demonstrate through clinical trials that a product candidate is both safe and effective for use in the target indication. Most product candidates that commence clinical trials are never approved by regulatory authorities for commercialization. The clinical trials for these product candidates may take significantly longer than expected to complete. In addition, we, any partner with which we currently or may in the future collaborate, the FDA, an institutional review board (“IRB”) or other regulatory authorities, including state and local agencies and counterpart agencies in foreign countries, may suspend, delay, require modifications to or terminate our clinical trials at any time, for various reasons, including:
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discovery of serious or unexpected toxicities or side effects experienced by study participants or other safety issues; |
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lack of effectiveness of any product candidate during clinical trials or the failure of our product candidates to meet specified endpoints; |
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slower than expected rates of subject recruitment and enrollment rates in clinical trials resulting from numerous factors, including the prevalence of other companies’ clinical trials for their product candidates for the same indication, such as acne; |
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difficulty in retaining subjects who have initiated participation in a clinical trial but may withdraw at any time due to adverse side effects from the therapy, insufficient efficacy, fatigue with the clinical trial process or for any other reason; |
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difficulty in obtaining IRB approval for studies to be conducted at each site; |
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delays in manufacturing or obtaining, or inability to manufacture or obtain, sufficient quantities of materials for use in clinical trials; |
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inadequacy of or changes in our manufacturing process or the product formulation or method of delivery; |
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changes in applicable laws, regulations and regulatory policies; |
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delays or failure in reaching agreement on acceptable terms in clinical trial contracts or protocols with prospective CROs, clinical trial sites and other third-party contractors; |
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inability to add a sufficient number of clinical trial sites; |
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uncertainty regarding proper dosing; |
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failure of our CROs or other third-party contractors to comply with contractual and regulatory requirements or to perform their services in a timely or acceptable manner; |
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failure by us, our employees, our CROs or their employees or any partner with which we may collaborate or their employees to comply with applicable FDA or other regulatory requirements relating to the conduct of clinical trials or the handling, storage, security and recordkeeping for drug and biologic products; |
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scheduling conflicts with participating clinicians and clinical institutions; |
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failure to design appropriate clinical trial protocols; |
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inability or unwillingness of medical investigators to follow our clinical protocols; |
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difficulty in maintaining contact with subjects during or after treatment, which may result in incomplete data; or |
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insufficient data to support regulatory approval. |
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In the case of our topical product candidates, we are seeking to deliver sufficient concentrations of the active pharmaceutical ingredient (“API”) through the skin barrier to the targeted dermal tissue to achieve the intended therapeutic effect. As a result, safety and efficacy can be difficult to establish. The topical route of administration may involve new dosage forms, which can be difficult to develop and manufacture and may raise novel regulatory issues and result in development or review delays. For example, the dosage form for glycopyrronium tosylate is an API-saturated wipe, and we are not aware of previous FDA approvals of prescription drug wipes. In addition, it is possible that the FDA may require more exposure of individuals to glycopyrronium tosylate than we have collected in our safety database. If we are required to expose additional individuals to glycopyrronium tosylate in order to establish a safety database sufficient for approval, approval of glycopyrronium tosylate, if at all, could be delayed and our costs could increase.
We or any partner with which we may collaborate may suffer significant setbacks in our clinical trials similar to the experience of a number of other companies in the pharmaceutical and biotechnology industries, even after receiving promising results in earlier trials. In the event that we or our potential partners abandon or are delayed in the clinical development efforts related to our product candidates, we may not be able to execute on our business plan effectively and our business, financial condition, operating results and prospects would be harmed. For example, if additional clinical trials of glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis are required, and we experience delays in the completion of, or if we terminate, the clinical trials, our business, financial condition, operating results and prospects would be adversely affected.
We may be unable to obtain regulatory approval for any of our product candidates under applicable regulatory requirements. The FDA and foreign regulatory bodies have substantial discretion in the approval process, including the ability to delay, limit or deny approval of product candidates. The delay, limitation or denial of any regulatory approval would adversely impact commercialization, our potential to generate revenue, our business and our operating results.
We currently have no products approved for sale, and we may never obtain regulatory approval to commercialize any of our current or future product candidates. The research, testing, manufacturing, safety surveillance, efficacy, quality control, recordkeeping, labeling, packaging, storage, approval, sale, marketing, distribution, import, export and reporting of safety and other post-market information related to our product candidates are subject to extensive regulation by the FDA and other regulatory authorities in the United States and in foreign countries, and such regulations differ from country to country. We are not permitted to market any of our current product candidates in the United States until we receive approval of an NDA, biologics license application (“BLA”) or other applicable regulatory filing from the FDA. We are also not permitted to market any of our current product candidates in any foreign countries until we receive the requisite approval from the applicable regulatory authorities of such countries.
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To gain approval to market a new drug such as glycopyrronium tosylate or olumacostat glasaretil or a biologic product such as lebrikizumab, the FDA and foreign regulatory authorities must receive preclinical, clinical and chemistry, manufacturing and controls data that adequately demonstrate the safety, purity, potency, efficacy and compliant manufacturing of the product for the intended indication applied for in an NDA, BLA or other applicable regulatory filing. The development and approval of new drug products and biologic products involves a long, expensive and uncertain process. A delay or failure can occur at any stage in the process. A number of companies in the pharmaceutical and biopharmaceutical industry have suffered significant setbacks in clinical trials, including in Phase 3 clinical development, even after promising results in earlier preclinical studies or clinical trials. These setbacks have been caused by, among other things, findings made while clinical trials were underway and safety or efficacy observations made in clinical trials, including previously unreported adverse events. Success in preclinical testing and early clinical trials does not ensure that later clinical trials will be successful, and the results of clinical trials by other parties may not be indicative of the results in trials we or our partners may conduct. For example, in one of the two glycopyrronium tosylate Phase 3 trials, glycopyrronium tosylate demonstrated statistically significant results compared to vehicle for the objective measurement of sweat production only following exclusion of extreme outlier data from one analysis center in accordance with the pre-specified statistical analysis plan submitted to the FDA. The FDA may determine that we did not achieve statistically significant results for this objective measurement in this trial and may require us to conduct an additional Phase 3 study as a result of the extreme outlier data, and approval of glycopyrronium tosylate, if at all, could be delayed and our costs would increase. Further, as one of the primary assessments of efficacy in our glycopyrronium tosylate Phase 3 trials, we used a new patient-reported outcome assessment (“PRO”), the Axillary Sweating Daily Diary, the sweating severity item of which was validated in our Phase 2 clinical program to assess efficacy in a subjective manner. This PRO has not been previously used in an NDA filing to support potential approval of a product and the FDA may determine that is not sufficient to support approval.
The FDA and foreign regulatory bodies have substantial discretion in the drug approval process, including the ability to delay, limit or deny approval of product candidates for many reasons, including:
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the FDA or the applicable foreign regulatory body may disagree with the design, implementation, choice of dose, analysis plans, or interpretation of the outcome of one or more clinical trials; |
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the FDA or the applicable foreign regulatory body may not deem a product candidate safe and effective for its proposed indication, or may deem a product candidate’s safety or other perceived risks to outweigh its clinical or other benefits; |
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the FDA or the applicable foreign regulatory body may not find the data from preclinical studies and clinical trials, including the number of subjects in the safety database, sufficient to support approval, or the results of clinical trials may not meet the level of statistical or clinical significance required by the FDA or the applicable foreign regulatory body for approval; |
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the FDA or the applicable foreign regulatory body may disagree with our interpretation of data from preclinical studies or clinical trials performed by us or third parties, or with the interpretation of any partner with which we may collaborate; |
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the data collected from clinical trials may not be sufficient to support the submission and approval of an NDA, BLA or other applicable regulatory filing; |
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the FDA or the applicable foreign regulatory body may require additional preclinical studies or clinical trials; |
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the FDA or the applicable foreign regulatory agency may identify deficiencies in the formulation, manufacturing, quality control, labeling or specifications of our current or future product candidates; |
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the FDA or the applicable foreign regulatory agency may require clinical trials in pediatric patients in order to establish pharmacokinetics or safety for this more drug-sensitive population; |
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the FDA or the applicable foreign regulatory agency may grant approval contingent on the performance of costly additional post-approval clinical trials; |
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the FDA or the applicable foreign regulatory agency may grant approval but impose substantial and costly post-approval requirements; |
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the FDA or applicable foreign regulatory agency may not approve the labeling that we believe is necessary or desirable for the successful commercialization of our product candidates; |
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the FDA or the applicable foreign regulatory body may not approve of the manufacturing processes, controls or facilities of third-party manufacturers or testing labs with which we contract; or |
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the FDA or the applicable foreign regulatory body may change its approval policies or adopt new regulations in a manner rendering our clinical data or regulatory filings insufficient for approval. |
Of the large number of drugs, including biologics, in development, only a small percentage successfully complete the FDA or other regulatory approval processes and are commercialized. For example, the FDA may not agree with our Phase 3 clinical trial protocols for our product candidates. In addition, our product candidates may not be approved by the FDA or applicable foreign regulatory agencies even though they meet specified endpoints in our clinical trials. The FDA or applicable foreign regulatory agencies may ask us to conduct additional costly and time-consuming clinical trials in order to obtain marketing approval or approval to enter into an advanced phase of development, or may change the requirements for approval even after such agency has reviewed and commented on the design for the clinical trials. Any delay in obtaining, or inability to obtain, applicable regulatory approval for any of our product candidates would delay or prevent commercialization of our product candidates and would harm our business, financial condition, operating results and prospects.
We have never prepared a BLA or obtained approval of a BLA or NDA submission or equivalent foreign filing, and we may be unable to successfully do so for any of our product candidates. Failure to successfully prepare or obtain approval of a BLA or NDA submission or equivalent foreign filing in a timely manner for any of our product candidates could have a material adverse impact on our business and financial performance.
Preparing and obtaining approval of a BLA or NDA submission or equivalent foreign filing are complicated processes. Although our employees have prepared BLAs, and obtained approvals of BLAs, NDAs and equivalent foreign filings in the past while employed at other companies, we as a company have not done so. As a result, such activities may require more time and cost more than we anticipate. Failure to complete or obtain, or delays in completing or obtaining, approval of our NDA and BLA submissions for glycopyrronium tosylate, olumacostat glasaretil or lebrikizumab, respectively, would prevent us from or delay us in commercializing our product candidates in the United States. The occurrence of any of the foregoing could have a material adverse impact on our business and financial performance.
Even if our current product candidates or any future product candidates obtain regulatory approval, they may fail to achieve the broad degree of physician and patient adoption and use necessary for commercial success.
The commercial success of any of our current or future product candidates, if approved, will depend significantly on the broad adoption and use of the resulting product by physicians and patients for approved indications. Our product candidates may not be commercially successful. The degree and rate of physician and patient adoption of our current or future product candidates, if approved, will depend on a number of factors, including:
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the clinical indications for which the product is approved and patient demand for approved products that treat those indications; |
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our ability to successfully compete with existing therapies, some of which are widely known and accepted by physicians and patients, including demonstrating that the relative cost, safety and efficacy of our product provides an attractive alternative to the existing therapies; |
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the availability of formulary coverage and adequate reimbursement from private third-party payers for any of our product candidates that may be approved; |
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the cost of treatment with our product candidates in relation to alternative treatments and willingness to pay for the product, if approved, on the part of patients; |
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acceptance by physicians, major operators of clinics and patients of the product as a safe and effective treatment; |
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physician and patient willingness to adopt a new therapy over other available therapies to treat approved indications; |
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in the case of hyperhidrosis, patients’ perception of the condition as one for which medical treatment may be appropriate and a prescription therapy may be available; |
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overcoming any biases physicians or patients may have toward particular therapies for the treatment of approved indications; |
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proper training and administration of our product candidates by physicians and medical staff; |
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patient satisfaction with the results and administration of our product candidates and overall treatment experience; |
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the willingness of patients to pay for certain of our product candidates relative to other discretionary items, especially during economically challenging times; |
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the revenue and profitability that our product candidate may offer a physician as compared to alternative therapies; |
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the prevalence and severity of side effects; |
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limitations or warnings contained in the FDA-approved labeling for our product candidates; |
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any FDA requirement to undertake a risk evaluation and mitigation strategy (“REMS”); |
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the effectiveness of our sales, marketing and distribution efforts; |
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adverse publicity about our product candidates or favorable publicity about competitive products; |
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potential product liability claims; |
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our ability to effectively manage our third-party supply and manufacturing operations while increasing production capabilities for our current product candidates to commercial levels; and |
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our ability to manage our growth and operations to effectively support our commercialization activities. |
If any of our current or future product candidates are approved for use but fail to achieve the broad degree of physician, patient and payer adoption necessary for commercial success, our operating results and financial condition will be adversely affected, which may delay, prevent or limit our ability to generate revenue and continue our business.
Our product candidates, if approved, will face significant competition and our failure to effectively compete may prevent us from achieving significant market penetration.
The pharmaceutical industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on developing proprietary therapeutics. Numerous companies are engaged in the development, patenting, manufacturing and marketing of healthcare products competitive with those that we are developing. We face competition from a number of sources, such as pharmaceutical companies, generic drug companies, biotechnology companies and academic and research institutions, many of which have greater financial resources, marketing capabilities, sales forces, manufacturing capabilities, research and development capabilities, clinical trial expertise, intellectual property portfolios, experience in obtaining patents and regulatory approvals for product candidates and other resources than we do. Some of the companies that offer competing products also have a broad range of other product offerings, large direct sales forces and long-term customer relationships with our target physicians, which could inhibit our market penetration efforts. In addition, certain of our product candidates, if approved, may compete with other dermatological products, including over-the-counter (“OTC”) treatments, for a share of some patients’ discretionary budgets and for physicians’ attention within their clinical practices.
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Many pharmaceutical companies currently offer products or are developing alternative product candidates and technologies, for indications similar to those targeted by our product candidates, including: AbbVie Inc., Akaal Pharma Pty Ltd., Allergan plc, Almirall, S.A., Amgen Inc., AnaptysBio, Inc., Asana BioSciences, LLC, Astellas Pharma US, Inc., Bayer HealthCare AG (formerly Intendis, Inc.), BioPharmX Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., Brickell Biotech, Inc., Can-Fite BioPharma Ltd., Cassiopea S.p.A., a subsidiary of Cosmo Pharmaceuticals S.A., Celgene Corporation, Dermavant Sciences Ltd., DS Biopharma Limited, Eirion Therapeutics, Inc., Eli Lilly and Company, Foamix Pharmaceuticals Ltd., Galapagos NV, Galderma S.A., GlaxoSmithKline LLC, Glenmark Pharmaceuticals Limited, Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson), Johnson & Johnson, LEO Pharma A/S, Maruho Co., Ltd., Medimetriks Pharmaceuticals, Inc., MedImmune, LLC (a wholly-owned subsidiary of AstraZeneca plc), Miramar Labs, Inc., Momenta Pharmaceuticals, Inc., MorphoSys AG, Mylan Inc., Novan, Inc., Novartis AG, Pfizer Inc., Qurient Co., Ltd., Ralexar Therapeutics, Inc., Ranbaxy Laboratories Limited, a division of Sun Pharmaceutical Industries Ltd., Regeneron Pharmaceuticals, Inc., Sandoz International GmbH (a division of Novartis), Sanofi-Aventis GroupeS.A., Shire plc, Teva Pharmaceutical Industries Ltd., TheraVida, Inc., Torii Pharmaceutical Co. Ltd., Ulthera, Inc. (a subsidiary of Merz Pharma GmbH & Co. KGaA) and Valeant Pharmaceuticals International, Inc.
The markets for dermatological therapies are competitive and are characterized by significant technological development and new product introduction. We anticipate that, if we obtain regulatory approval of our product candidates, we will face significant competition from other approved therapies. If approved, our product candidates may also compete with unregulated, unapproved and off-label treatments. Certain of our product candidates, if approved, would present novel therapeutic approaches for the approved indications and would have to compete with existing therapies, some of which are widely known and accepted by physicians and patients. To compete successfully in this market, we will have to demonstrate that the relative cost, safety and efficacy of our approved products, if any, provide an attractive alternative to existing and other new therapies. The competition we face could lead to reduced market share for our product candidates and contribute to downward pressure on the pricing of our product candidates, which could harm our business, financial condition, operating results and prospects.
Due to less stringent regulatory requirements in certain foreign countries, there are many more dermatological products and procedures available for use in those international markets than are approved for use in the United States. In certain international markets, there are also fewer limitations on the claims that our competitors can make about the effectiveness of their products and the manner in which they can market their products. As a result, we expect to face more competition in these markets than in the United States.
We expect to face generic competition for our product candidates and may face competition from biosimilars, which could adversely affect our business, financial condition, operating results and prospects.
Upon the expiration or loss of any patent protection for any of our product candidates that are approved, or upon the “at-risk” launch, despite pending patent infringement litigation against the generic product, by a generic competitor of a generic version of any of our product candidates that are approved, which may be sold at significantly lower prices than our approved product candidates, we could lose a significant portion of sales of that product in a short period of time, which would adversely affect our business, financial condition, operating results and prospects. In particular, our glycopyrronium tosylate product candidate faces competition from currently marketed generic oral and compounded topical anticholinergic agents. In addition, we may be subject to additional competition from third parties pursuing topical formulations of other anticholinergic agents for hyperhidrosis.
We may also face competition from biosimilars. In the United States, the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) created an abbreviated approval pathway for biological products that are demonstrated to be “highly similar,” or “biosimilar,” to or “interchangeable” with an FDA-approved biological product. This pathway allows competitors to reference the FDA’s prior determinations regarding innovative biological products and to obtain approval of a biosimilar application 12 years after the time of approval of the innovative biological product. The 12-year exclusivity period runs from the initial approval of the innovator product and not from approval of a new indication. In addition, the 12-year exclusivity period does not prevent another company from developing a product that is highly similar to the innovative product, generating all the data necessary for a full BLA and seeking approval. Exclusivity only assures that another company cannot rely on the FDA’s prior determinations in approving a BLA for an innovator’s biological product to support the biosimilar product’s approval. Further, under the FDA’s current interpretation, it is possible that a biosimilar applicant could
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obtain approval for one or more of the indications approved for the innovator product by extrapolating clinical data from one indication to support approval for the other indications. We cannot predict to what extent the entry of biosimilars or other competing products will impact our business, financial condition, operating results and prospects.
Any product candidates that we commercialize, or that any partner with which we may collaborate commercializes, will be subject to ongoing and continued regulatory review. Failure to comply with applicable regulatory requirements could have a material adverse impact on our business.
Even after we or our partners achieve U.S. regulatory approval for a product candidate, if any, we or our partners will be subject to continued regulatory review and compliance obligations. For example, with respect to our product candidates, the FDA may impose significant restrictions on the approved indicated uses for which the product may be marketed or on the conditions of approval. A product candidate’s approval may contain requirements for potentially costly post-approval studies and surveillance, including Phase 4 clinical trials or other REMS, to monitor the safety and efficacy of the product. We will also be subject to ongoing FDA obligations and continued regulatory review with respect to, among other things, the manufacturing, processing, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion and recordkeeping for our product candidates. These requirements include submissions of safety and other post-marketing information and reports and registration, as well as continued compliance with cGMP requirements and with the FDA’s good clinical practice (“GCP”) requirements and good laboratory practice (“GLP”) requirements, which are regulations and guidelines enforced by the FDA for all of our product candidates in clinical development, and for any clinical trials that we conduct post-approval. To the extent that a product candidate is approved for sale in other countries, we may be subject to similar restrictions and requirements imposed by laws and government regulators in those countries.
In addition, manufacturers of drug and biologic products and their facilities are subject to continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMP regulations. If we or a regulatory agency discovers previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facility where, or processes by which, the product is manufactured, a regulatory agency may impose restrictions on that product or us, including requesting that we initiate a product recall, or requiring notice to physicians, withdrawal of the product from the market or suspension of manufacturing.
If we, our product candidates or the manufacturing facilities for our product candidates fail to comply with applicable regulatory requirements, a regulatory agency may:
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impose restrictions on the marketing or manufacturing of the product, suspend or withdraw product approvals or revoke necessary licenses; |
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mandate modifications to promotional materials or require us to provide corrective information to healthcare practitioners; |
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require us or our partners to enter into a consent decree, which can include imposition of various fines, reimbursements for inspection costs, required due dates for specific actions and penalties for noncompliance; |
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issue warning letters, show cause notices or untitled letters describing alleged violations, which may be publicly available; |
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commence criminal investigations and prosecutions; |
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impose injunctions, suspensions or revocations of necessary approvals or other licenses; |
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impose other civil or criminal penalties; |
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suspend any ongoing clinical trials; |
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delay or refuse to approve pending applications or supplements to approved applications filed by us or our potential partners; |
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refuse to permit drugs or precursor chemicals to be imported or exported to or from the United States; |
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seize or detain products or require us or our partners to initiate a product recall. |
The regulations, policies or guidance of the FDA and other applicable government agencies may change and new or additional statutes or government regulations may be enacted that could prevent or delay regulatory approval of our product candidates or further restrict or regulate post-approval activities. We cannot predict the likelihood, nature or extent of adverse government regulations that may arise from future legislation or administrative action, either in the United States or abroad. If we are not able to achieve and maintain regulatory compliance, we may not be permitted to market our product candidates, which would adversely affect our ability to generate revenue and achieve or maintain profitability.
We have conducted, are conducting and may in the future conduct clinical trials for our product candidates outside the United States and the FDA and applicable foreign regulatory authorities may not accept data from such trials, which would likely result in additional costs to us and delay our business plan.
We have conducted, are conducting and may in the future choose to conduct, one or more of our clinical trials outside the United States, including in Australia, Canada and Europe. For example, our Phase 3 clinical program for olumacostat glasaretil is being conducted in multiple countries. Although the FDA or applicable foreign regulatory authority may accept data from clinical trials conducted outside the United States or the applicable jurisdiction, acceptance of such study data by the FDA or applicable foreign regulatory authority may be subject to certain conditions. Where data from foreign clinical trials are intended to serve as the basis for marketing approval in the United States, the FDA will not approve the application on the basis of foreign data alone unless those data are applicable to the U.S. population and U.S. medical practice; the studies were performed by clinical investigators of recognized competence; and the data are considered valid without the need for an on-site inspection by the FDA or, if the FDA considers such an inspection to be necessary, the FDA is able to validate the data through an on-site inspection or other appropriate means. Many foreign regulatory bodies have similar requirements. In addition, such foreign studies would be subject to the applicable local laws of the foreign jurisdictions where the studies are conducted. There can be no assurance the FDA or applicable foreign regulatory authority will accept data from trials conducted outside of the United States or the applicable jurisdiction. If the FDA or applicable foreign regulatory authority does not accept such data, it would likely result in the need for additional trials, which would be costly and time-consuming and delay aspects of our business plan.
Our product candidates may cause undesirable side effects or have other unexpected properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label or result in post-approval regulatory action, any of which may adversely impact our business, financial condition, operating results and prospects.
Unforeseen side effects from any of our product candidates could arise either during clinical development or, if approved, after the approved product has been marketed. Undesirable side effects caused by product candidates could cause us, any partners with which we may collaborate or regulatory authorities to interrupt, modify, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or comparable foreign regulatory authorities. Results of clinical trials could reveal a high and unacceptable severity and prevalence of one or more of these side effects. In such an event, trials could be suspended or terminated and the FDA or comparable foreign regulatory authorities could order us, or our potential partners, to cease further development of or deny approval of product candidates for any or all targeted indications. Any drug-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial or result in product liability claims. Any of these occurrences may harm our business, financial condition, operating results and prospects.
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Additionally, if we or others identify undesirable side effects, or other previously unknown problems, caused by our product candidates after obtaining U.S. or foreign regulatory approval or other products with the same or related active ingredients, a number of potentially negative consequences could result, including:
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regulatory authorities may withdraw their approval of the product; |
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regulatory authorities may require a recall of the product or we or our potential partners may voluntarily recall a product; |
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regulatory authorities may require the addition of warnings or contraindications in the product labeling, narrowing of the indication in the product label or field alerts to physicians and pharmacies; |
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we may be required to create a medication guide outlining the risks of such side effects for distribution to patients or institute a REMS; |
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we may have limitations on how we promote the product; |
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we may be required to change the way the product is administered or modify the product in some other way; |
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the FDA or applicable foreign regulatory authority may require additional clinical trials or costly post-marketing testing and surveillance to monitor the safety or efficacy of the product; |
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sales of the product may decrease significantly; |
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we could be sued and held liable for harm caused to patients; and |
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our brand and reputation may suffer. |
Any of the above events resulting from undesirable side effects or other previously unknown problems could prevent us or our potential partners from achieving or maintaining market acceptance of the affected product candidate and could substantially increase the costs of commercializing our product candidates.
We may face product liability exposure, and if successful claims are brought against us, we may incur substantial liability if our insurance coverage for those claims is inadequate.
We face an inherent risk of product liability as a result of the clinical testing of our product candidates and will face an even greater risk if we commercialize any products. This risk exists even if a product is approved for commercial sale by the FDA and manufactured in facilities licensed and regulated by the FDA or an applicable foreign regulatory authority. Our product candidates are designed to affect important bodily functions and processes. Any side effects, manufacturing defects, failure to follow instructions, misuse or abuse associated with our product candidates could result in injury to a patient or even death. We cannot offer any assurance that we will not face product liability suits in the future, nor can we provide assurances that our insurance coverage will be sufficient to cover our liability under any such cases.
In addition, a liability claim may be brought against us even if our product candidates merely appear to have caused an injury. Product liability claims may be brought against us by consumers, healthcare providers, pharmaceutical companies or others selling or otherwise coming into contact with our product candidates, among others. If we cannot successfully defend ourselves against product liability claims, we will incur substantial liabilities and reputational harm. In addition, regardless of merit or eventual outcome, product liability claims may result in:
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withdrawal of clinical trial participants; |
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decreased enrollment rates of clinical trial participants; |
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termination of clinical trial sites or entire clinical trial programs; |
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the inability to commercialize our product candidates; |
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decreased demand for our product candidates; |
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product recall or withdrawal from the market or labeling, marketing or promotional restrictions; |
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substantial costs of any related litigation or similar disputes; |
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distraction of management’s attention and other resources from our primary business; |
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substantial monetary awards to patients or other claimants against us that may not be covered by insurance; or |
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loss of revenue. |
Large judgments have been awarded in class action or individual lawsuits based on drugs that had anticipated or unanticipated side effects. Although we have obtained product liability insurance coverage for clinical trials, our insurance coverage may not be sufficient to cover all of our product liability related expenses or losses and may not cover us for any expenses or losses we may suffer. Moreover, insurance coverage is becoming increasingly expensive and, in the future, we may not be able to maintain insurance coverage at a reasonable cost, in sufficient amounts or upon adequate terms to protect us against losses due to product liability. We will need to increase our product liability coverage if any of our product candidates receive regulatory approval, which will be costly, and we may be unable to obtain this increased product liability insurance on commercially reasonable terms, or at all. A successful product liability claim or series of claims brought against us could cause our stock price to decline and, if judgments exceed our insurance coverage, could decrease our cash and could harm our business, financial condition, operating results and prospects.
If any of our product candidates are approved for marketing and we are found to have improperly promoted off-label uses, or if physicians misuse our products or use our products off-label, we may become subject to prohibitions on the sale or marketing of our products, product liability claims and significant fines, penalties and sanctions, and our brand and reputation could be harmed.
The FDA and other regulatory agencies strictly regulate the marketing and promotional claims that are made about drug and biologic products. In particular, a product may not be promoted for uses or indications that are not approved by the FDA or such other regulatory agencies as reflected in the product’s approved labeling and comparative safety or efficacy claims cannot be made without direct comparative clinical data. For example, although our glycopyrronium tosylate product candidate, if approved, may appeal to individuals who have not been diagnosed with hyperhidrosis, we will only be able to promote glycopyrronium tosylate for its approved indication. If we are found to have promoted off-label uses of any of our product candidates, we may receive warning or untitled letters and become subject to significant criminal and civil liability, which would materially harm our business. Both federal and state governments have levied large civil and criminal fines against companies for alleged improper off-label promotion and have enjoined several companies from engaging in off-label promotion.
If we become the target of such an investigation or prosecution based on our marketing and promotional practices, we could face similar sanctions, which would materially harm our business. In addition, management’s attention could be diverted from our business operations, significant legal expenses could be incurred and our brand and reputation could be damaged. The FDA has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. If we are deemed by the FDA to have engaged in the promotion of our products for off-label uses, we could be subject to FDA regulatory or enforcement actions, including the issuance of an untitled letter, a warning letter, injunction, seizure, civil fine or criminal penalties. It is also possible that other federal, state or foreign enforcement authorities might take action if they consider our business activities to constitute promotion of an off-label use, which could result in significant penalties, including criminal, civil or administrative penalties, damages, fines, disgorgement, exclusion from participation in government healthcare programs and the curtailment or restructuring of our operations.
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We cannot, however, prevent a physician from using our product candidates outside of those indications for use when in the physician’s independent professional medical judgment he or she deems appropriate. Physicians may also misuse our product candidates or use improper techniques, potentially leading to adverse results, side effects or injury, which may lead to product liability claims. If our product candidates are misused or used with improper technique, we may become subject to costly litigation by physicians or their patients. Furthermore, the use of our product candidates for indications other than those approved by the FDA may not effectively treat such conditions, which could harm our reputation among physicians and patients.
We may choose not to continue developing or commercializing any of our product candidates at any time during development or after approval, which would reduce or eliminate our potential return on investment for those product candidates.
At any time, we may decide to discontinue the development of any of our product candidates or not to continue commercializing one or more of our approved product candidates for a variety of reasons, such as the appearance of new technologies that make our product obsolete, competition from a competing product, changes in or failure to comply with applicable regulatory requirements, the discovery of unforeseen side effects after the approved product has been marketed or the occurrence of adverse events at a rate or severity level that is greater than experienced in our clinical trials. If we terminate a program in which we have invested significant resources, we will not receive any return on our investment and we will have missed the opportunity to have allocated those resources to potentially more productive uses. See also “—Our product candidates may cause undesirable side effects or have other unexpected properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label or result in post-approval regulatory action, any of which may adversely impact our business, financial condition, operating results and prospects.”
We or our current and prospective partners may be subject to product recalls in the future that could harm our brand and reputation and could negatively affect our business.
We or our current and prospective partners may be subject to product recalls, withdrawals or seizures if any of our product candidates, if approved for marketing, fail to meet specifications or are believed to cause injury or illness or if we are alleged to have violated governmental regulations including those related to manufacturing, labeling, promotion, sale or distribution. Any recall, withdrawal or seizure in the future could materially and adversely affect consumer confidence in our brand and lead to decreased demand for our approved products. In addition, a recall, withdrawal or seizure of any of our approved products would require significant management attention, would likely result in substantial and unexpected expenditures and would harm our business, financial condition and operating results.
If the FDA concludes that our glycopyrronium tosylate product candidate does not satisfy the requirements under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (“Section 505(b)(2)” pathway), or if the requirements for our glycopyrronium tosylate product candidate under the Section 505(b)(2) pathway are not as we expect, the approval pathway for our glycopyrronium tosylate product candidate will likely take significantly longer, cost significantly more and entail significantly greater complications and risks than anticipated, any of which may adversely impact our business, financial condition, operating results and prospects.
We are seeking FDA approval of our glycopyrronium tosylate product candidate for the treatment of primary axillary hyperhidrosis through the Section 505(b)(2) pathway. Glycopyrronium tosylate is a novel form of an anticholinergic agent that has been approved for systemic administration in other indications. The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments, added Section 505(b)(2) to the Federal Food, Drug, and Cosmetic Act. The Section 505(b)(2) pathway permits the submission of an NDA where at least some of the information required for approval comes from studies that were not conducted by or for the applicant, and for which the applicant either does not own or has not obtained a right of reference. Reliance on certain findings made by the FDA in approving the anticholinergic agent referenced in our NDA could expedite the glycopyrronium tosylate development program by potentially decreasing the amount of non-clinical or clinical data that we would need to generate in order to obtain FDA approval.
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Glycopyrronium tosylate differs from the approved product we referenced in chemical structure, route of administration, dosage form and indication, and if we are unable to demonstrate an acceptable clinical bridge through comparative pharmacokinetic data between glycopyrronium tosylate and the approved product, the FDA may not permit us to use the Section 505(b)(2) pathway for regulatory approval. If the FDA does not allow us to pursue the Section 505(b)(2) pathway as anticipated or determines that our clinical bridge is not adequate, or if the Section 505(b)(2) pathway fails to significantly decrease the amount of testing we must conduct, we may need to conduct additional non-clinical or clinical trials, provide additional data and information and meet additional standards for regulatory approval, which would substantially increase the time and financial resources required to obtain FDA approval for glycopyrronium tosylate and entail significantly greater complications and risks than anticipated. If this were to occur, our business, financial condition, operating results and prospects may be adversely impacted.
Moreover, inability to pursue the Section 505(b)(2) pathway could result in new competitive products reaching the market more quickly than our product candidate, which would likely harm our competitive position and prospects. Even if we are allowed to pursue the Section 505(b)(2) pathway, we cannot provide assurances that our product candidate will receive the requisite approvals for commercialization.
Notwithstanding the approval of a number of products by the FDA under Section 505(b)(2) over the last few years, certain competitors and others have objected to the FDA’s interpretation of Section 505(b)(2). If the FDA’s interpretation of Section 505(b)(2) is successfully challenged, the FDA may be required to change its Section 505(b)(2) policies and practices, which could delay or even prevent the FDA from approving any NDA that we submit under the Section 505(b)(2) pathway. In addition, the pharmaceutical industry is highly competitive, and Section 505(b)(2) NDAs are subject to special requirements designed to protect the patent rights of sponsors of previously approved drugs that are referenced in a Section 505(b)(2) NDA. These requirements may give rise to patent litigation and mandatory delays in approval of our NDAs for up to 30 months depending on the outcome of any litigation. In addition, Section 505(b)(2) NDAs are subject to potential data or marketing exclusivity rights that reward certain research performed by the sponsors of previously approved drugs. The exercise of such exclusivity rights can delay FDA approval of a Section 505(b)(2) NDA, or certain proposed product uses, for a period ranging from three to seven years, depending on the type of exclusivity earned. It is not uncommon for a manufacturer of an approved referenced product to file a citizen petition with the FDA seeking to delay approval of, or impose additional approval requirements for, pending competing products. If successful, such petitions can significantly delay, or even prevent, the approval of the new product. However, even if the FDA ultimately denies such a petition, the FDA may substantially delay approval while it considers and responds to the petition. In addition, even if we are able to utilize the Section 505(b)(2) pathway, there is no guarantee this would ultimately lead to faster product development or earlier approval.
Our commercial success may be severely hindered if patients do not have access to our approved products, if any, from their insurers without undue restriction.
The availability of formulary coverage and adequate reimbursement from private third-party payers such as pharmacy benefit managers and commercial insurers, and to a lesser degree, governmental healthcare programs, such as Medicare and Medicaid, is critical to market acceptance and commercial success of any of our product candidates, if approved, that become available only by prescription. Timely coverage and acceptable patient cost-sharing tiers for our products, if approved, may be adversely affected by a number of factors, including but not limited to, increasing and intense pressure from political, social, competitive and other sources to reduce drug unit costs or limit changes in list price; changes in federal, state or foreign government regulations or private third-party payers’ reimbursement policies; consolidation and increasing assertiveness of commercial payers seeking net price reduction via drug rebates and other forms of discounts linked to the placement of our products, if approved, on their formularies; and the imposition of restrictions on access or coverage of particular drugs or pricing determined based on perceived pharmacoeconomic value.
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A primary trend in the healthcare industry is cost containment. Third-party payers are developing increasingly sophisticated methods of controlling healthcare costs by, among other methods, limiting or preventing (via formulary exclusion) coverage for particular medications, requiring drug companies to provide them with varying levels of discounts from list prices and/or challenging the value of list prices charged for medical products. Coverage decisions may depend upon the size of a patient population, perceptions of clinical efficacy and economic standards that may disfavor new drug products when more established or lower cost therapeutic alternatives are already available or subsequently become available.
Although private third-party payers in the United States tend to follow Medicare reimbursement policies for products which are administered in a hospital or physician office setting, no uniform policy of pharmacy benefit coverage and reimbursement for drug products exists among third-party payers. Therefore, coverage and reimbursement for drug products adjudicated in a pharmacy benefit setting can differ significantly across payers. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates, if approved, to each third-party payer separately, with no assurance that coverage will be obtained.
In addition, the market for our product candidates will depend significantly on access to third-party payers’ drug formularies, or lists of medications for which third-party payers provide coverage and impose patient out-of-pocket cost sharing limits. The industry competition to be included in such formularies often leads to downward pricing pressures on pharmaceutical companies. Also, third-party payers may refuse to include a particular branded drug in their formularies or otherwise restrict patient access to a branded drug when a less costly generic equivalent or other therapeutically similar alternative is available.
Third-party payers may also seek additional clinical evidence, beyond the data required to obtain regulatory approval, demonstrating clinical benefits and value in specific patient populations before covering our products for those patients. If any of our product candidates do not demonstrate attractive efficacy profiles, they may not qualify for coverage and reimbursement.
Patients who are prescribed medicine for the treatment of their conditions generally rely on third-party payers to reimburse all or part of the costs of their prescription drugs. Even if we obtain favorable coverage for a given product, the patient may be required to pay co-payments or co-insurance they find unacceptably high. Patients may be unlikely to use our products, if approved, unless coverage is established and reimbursement for their medicine from their insurer adequately covers a significant portion of the cost of our products.
Our inability to promptly obtain insurance coverage, profitable reimbursement rates or access to third-party payers’ drug formularies from private payers and, to a smaller degree, government-funded health insurance for any approved products that we develop could have a material adverse effect on our business, financial condition, operating results and prospects.
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Healthcare reform measures could hinder or prevent the commercial success of our products and product candidates.
In the United States, there have been, and we expect there will continue to be, a number of legislative and regulatory changes to the healthcare system that could affect our future revenue and profitability and the future revenue and profitability of any partner with which we may collaborate. Federal and state lawmakers regularly propose and, at times, enact legislation that results in significant changes to the healthcare system, some of which are intended to contain or reduce the costs of medical products and services. For example, in March 2010, former President Obama signed one of the most significant healthcare reform measures in decades, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, “Affordable Care Act”). It contains a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement changes and fraud and abuse measures, all of which have impacted and are expected to continue to impact existing government healthcare programs and result in the development of new programs. The Affordable Care Act, among other things, (1) increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to certain individuals enrolled in Medicaid managed care organizations, (2) established annual fees on manufacturers of certain branded prescription drugs and (3) enacted a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.
The current presidential administration and certain members of the majority of the U.S. Congress have sought to repeal all or part of the Affordable Care Act and implement a replacement program. For example, the so-called “individual mandate” was repealed as part of tax reform legislation adopted in December 2017, such that the shared responsibility payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, as amended (the “Code”) will be eliminated beginning in 2019. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products once approved or additional pricing pressures.
We may also be subject to healthcare laws, regulation and enforcement and our failure to comply with those laws could adversely affect our business, operations and financial condition.
Certain federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’ rights, among other topics, are and will be applicable to our business. We are subject to regulation by both the federal government and the states in which we or our partners conduct our business. The healthcare laws and regulations that may affect our ability to operate include:
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the federal Anti-Kickback Statute, which prohibits, among other things, any person or entity from knowingly and willfully offering, soliciting, receiving or providing any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce either the referral of an individual or in return for the purchase, lease, or order of any good, facility item or service, for which payment may be made, in whole or in part, under federal healthcare programs such as the Medicare and Medicaid programs; |
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federal civil and criminal false claims laws and civil monetary penalty laws, including, for example, the federal civil False Claims Act, which impose criminal and civil penalties, including civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, to the federal government, including the Medicare and Medicaid programs, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government; |
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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their implementing regulations, which impose obligations on covered entities, including certain healthcare providers, health plans, and healthcare clearinghouses, as well as their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information; |
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the federal physician sunshine requirements under the Affordable Care Act, which require certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value provided to physicians and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members; and |
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state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws, which may apply to items or services reimbursed by any third-party payer, including commercial insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government, or otherwise restrict payments that may be provided to healthcare providers and other potential referral sources; state laws that require drug manufacturers to report information related to payments and other transfers of value to healthcare providers or marketing expenditures; and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts. |
Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws. In addition, recent healthcare reform legislation has strengthened these laws. For example, the Affordable Care Act, among other things, amended the intent requirement of the federal Anti-Kickback Statute and certain criminal healthcare fraud statutes. A person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. In addition, the Affordable Care Act codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.
Achieving and sustaining compliance with these laws may prove costly. In addition, any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. If our operations are found to be in violation of any of the laws described above or any other governmental laws or regulations that apply to us, we may be subject to penalties, including administrative, civil and criminal penalties, damages, fines, disgorgement, the exclusion from participation in federal and state healthcare programs, individual imprisonment or the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our financial results.
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Our business involves the use of hazardous materials and we and our third-party suppliers and manufacturers must comply with environmental laws and regulations, which can be expensive and restrict how we do business.
The manufacturing activities of our third-party suppliers and manufacturers involve the controlled storage, use and disposal of hazardous materials owned by us, including the components of our product candidates and other hazardous compounds. We and our manufacturers and suppliers are subject to laws and regulations governing the use, manufacture, storage, handling and disposal of these hazardous materials. In some cases, these hazardous materials and various wastes resulting from their use are stored at our suppliers’ or manufacturers’ facilities pending use and disposal. We and our suppliers and manufacturers cannot completely eliminate the risk of contamination, which could cause an interruption of our commercialization efforts, research and development efforts and business operations, injury to our service providers and others and environmental damage resulting in costly clean-up and liabilities under applicable laws and regulations governing the use, storage, handling and disposal of these materials and specified waste products. Although we believe that the safety procedures utilized by our third-party suppliers and manufacturers for handling and disposing of these materials generally comply with the standards prescribed by these laws and regulations, we cannot guarantee that this is the case or eliminate the risk of accidental contamination or injury from these materials. In such an event, we may be held liable for any resulting damages and such liability could exceed our resources. We do not currently carry biological or hazardous waste insurance coverage.
Our employees, independent contractors, principal investigators, consultants, vendors, CROs and any partners with which we may collaborate may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could have an adverse effect on our business.
We are exposed to the risk that our employees, independent contractors, principal investigators, consultants, vendors, CROs and any partners with which we may collaborate may engage in fraudulent or other illegal activity. Misconduct by these persons could include intentional, reckless or negligent conduct or unauthorized activity that violates: laws or regulations, including those laws requiring the reporting of true, complete and accurate information to the FDA or foreign regulatory authorities; manufacturing standards; federal, state and foreign healthcare fraud and abuse laws and data privacy; or laws that require the true, complete and accurate reporting of financial information or data. In particular, sales, marketing and other business arrangements in the healthcare industry are subject to extensive laws intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws may restrict or prohibit a wide range of business activities, including research, manufacturing, distribution, pricing, discounting, marketing and promotion, sales commissions, customer incentive programs and other business arrangements. Activities subject to these laws also involve the improper use of information obtained in the course of clinical trials, or illegal misappropriation of drug product, which could result in regulatory sanctions or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations, and serious harm to our reputation. In addition, federal procurement laws impose substantial penalties for misconduct in connection with government contracts and require certain contractors to maintain a code of business ethics and conduct. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of our operations, any of which could adversely affect our ability to operate our business and our operating results.
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Risks Related to Our Dependence on Third Parties
We have in the past relied and expect to continue to rely on third-party CROs and other third parties to conduct and oversee our clinical trials, other aspects of our product development and our regulatory submission process. If these third parties do not meet our requirements, conduct the trials as required or otherwise provide services as anticipated, we may not be able to satisfy our contractual obligations or obtain regulatory approval for, or commercialize, our product candidates when expected or at all.
We have in the past relied and expect to continue to rely on third-party CROs and other third parties to conduct and oversee our clinical trials, other aspects of our product development and our regulatory submission process. We also rely upon various medical institutions, clinical investigators and contract laboratories to conduct our trials in accordance with our clinical protocols and all applicable regulatory requirements, including the FDA’s regulations and GCPs, which are an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors, and state regulations governing the handling, storage, security and recordkeeping for drug and biologic products. These CROs and other third parties play a significant role in the conduct of our clinical trials, the subsequent collection and analysis of data from the clinical trials and the preparation for and submission of our filings with the FDA and comparable foreign regulatory authorities. See also “—We rely completely on third parties to supply, manufacture and distribute clinical drug supplies for our product candidates, including certain sole-source suppliers and manufacturers, we intend to rely on third parties for commercial supply, manufacturing and distribution if any of our product candidates receive regulatory approval and we expect to rely on third parties for supply, manufacturing and distribution of preclinical, clinical and commercial supplies of any future product candidates.”
We rely heavily on third parties for the execution of our clinical trials and preclinical studies, and control only certain aspects of their activities. We and our CROs and other third-party contractors are required to comply with GCP and GLP requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for products in clinical development. Regulatory authorities enforce these GCP and GLP requirements through periodic inspections of trial sponsors, principal investigators and trial sites. If we or any of these third parties fail to comply with applicable GCP and GLP requirements, the clinical data generated in our clinical trials may be deemed unreliable and the FDA or other regulatory authority may require us to perform additional clinical trials before approving our or our partners’ marketing applications. We cannot provide assurances that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical or preclinical trials complies with applicable GCP and GLP requirements. In addition, our clinical trials must generally be conducted with products produced under cGMP regulations. Our failure to comply with these regulations and policies may require us to repeat clinical trials, which would delay the regulatory approval process.
If any of our CROs or clinical trial sites terminate their involvement in one of our clinical trials for any reason, we may not be able to enter into arrangements with alternative CROs or clinical trial sites in a timely manner, or do so on commercially reasonable terms or at all. In addition, if our relationship with clinical trial sites is terminated, we may experience the loss of follow-up information on patients enrolled in our ongoing clinical trials unless we are able to transfer the care of those patients to another qualified clinical trial site. In addition, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and could receive cash compensation in connection with such services. If these relationships and any related compensation result in perceived or actual conflicts of interest, the integrity of the data generated at the applicable clinical trial site may be questioned by the FDA and comparable foreign regulatory authorities.
Additionally, the regulatory submission process for our product candidates is complex. We expect to rely on a third-party service provider for the preparation and submission of filings with the FDA and comparable foreign regulatory authorities for approval of our product candidates. If our relationship with such service provider is terminated prior to completion of our regulatory submission process, we may not be able to enter into an arrangement with an alternative service provider in a timely manner, or do so on commercially reasonable terms, and our submission may be substantially delayed.
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We rely completely on third parties to supply, manufacture and distribute clinical drug supplies for our product candidates, including certain sole-source suppliers and manufacturers, we intend to rely on third parties for commercial supply, manufacturing and distribution if any of our product candidates receive regulatory approval and we expect to rely on third parties for supply, manufacturing and distribution of preclinical, clinical and commercial supplies of any future product candidates.
We do not currently have, nor do we plan to acquire, the infrastructure or capability to supply, manufacture or distribute preclinical, clinical or commercial quantities of drug substances or products. Our ability to develop our product candidates depends, and our ability to commercially supply our products will depend, in part, on our ability to successfully obtain the APIs and other substances and materials used in our product candidates from third parties and to have finished products manufactured by third parties in accordance with regulatory requirements and in sufficient quantities for preclinical and clinical testing and commercialization. If we fail to develop and maintain supply relationships with these third parties, we may be unable to continue to develop or commercialize our product candidates. See also “—We are dependent on Roche for the manufacture and supply of lebrikizumab drug substance. If Roche elects to transfer its manufacture and supply responsibilities to us, we may not be able to engage a qualified contract manufacturer to manufacture and supply the drug substance in a timely manner, if at all. Any interruption in our supply may cause serious delays in the timing of our clinical studies, increase our costs and adversely impact our financial results.”)
We rely and will continue to rely on certain third parties as the sole source of the materials they supply or the finished products they manufacture. The drug substances and other materials used in our product candidates are currently available only from one domestic or foreign supplier and foreign manufacturer and certain of our finished product candidates are manufactured by one or a limited number of contract manufacturers. For example, we are dependent on our current suppliers of the nonwoven material and pouchstock in our glycopyrronium tosylate finished product. Any of our existing suppliers or manufacturers may:
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fail to supply us with product on a timely basis or in the requested amount due to unexpected damage to or destruction of facilities or equipment or otherwise; |
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be unable to meet our production demands due to issues related to their reliance on sole-source suppliers and manufacturers; |
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supply us with product that fails to meet regulatory requirements; |
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become unavailable through business interruption or financial insolvency; |
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lose regulatory status as an approved source; |
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be unable or unwilling to renew current supply agreements when such agreements expire on a timely basis, on acceptable terms or at all; or |
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discontinue production or manufacturing of necessary drug substances or products. |
In the event of any of the foregoing, if we do not have an alternative supplier or manufacturer in place, we would be required to expend substantial management time and expense to identify, qualify and transfer processes to alternative suppliers or manufacturers. Transferring technology to other sites may require additional processes, technologies and validation studies, which are costly, may take considerable amounts of time, may not be successful and, in some cases, require review and approval by the FDA and foreign regulatory authorities. Any need to find and qualify new suppliers or manufacturers could delay production of our products or development of product candidates indefinitely, adversely impact our ability to develop, obtain regulatory approval of or market our product candidates, if approved, and adversely affect our business. There can be no assurance that replacements would be available to us on a timely basis, on acceptable terms or at all. Additionally, we and our manufacturers do not currently maintain significant inventory of drug substances and other materials. Any interruption in the supply of a drug substance or other material or in the manufacture of a finished product could have a material adverse effect on our business, financial condition, operating results and prospects.
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We expect to continue to depend on third-party contract suppliers and manufacturers for the foreseeable future. Our supply and manufacturing agreements, if any, do not guarantee that a contract supplier or manufacturer will provide services adequate for our needs. We and our contract suppliers and manufacturers continue to improve production processes, certain aspects of which are complex and unique, and we may encounter difficulties with new or existing processes. While we attempt to build in certain contractual obligations on such third-party suppliers and manufacturers, we may not be able to ensure that such third parties comply with these obligations. Depending on the extent of any difficulties encountered, we could experience an interruption in clinical or commercial supply, with the result that the development, regulatory approval or commercialization of our product candidates may be delayed or interrupted. Third-party suppliers and manufacturers may have the ability to increase the price payable by us for the supply of the APIs and other substances and materials used in our product candidates, in some cases without our consent. In addition, our reliance on contract manufacturers and suppliers further exposes us to the possibility that they, or third parties with access to their facilities, will have access to and may misappropriate our trade secrets or other proprietary information.
To date, some of our drug substances and product candidates have been manufactured in relatively small quantities for clinical trials. As we prepare for potential commercialization, we have completed the scale-up of production of some of our drug substances and product candidates, but may consider further scale-up and transferring production to new third-party suppliers or manufacturers. If any of our product candidates is approved for sale, our contract manufacturers and suppliers will need to produce the resulting drug product and its components reliably in large quantities, cost effectively and, in certain cases, at higher yields than they currently achieve. These third-party contractors may not be able to successfully increase the manufacturing capacity for any products in a timely or cost-effective manner or at all. In addition, quality issues may arise during those scale-up activities because of the inherent properties of a product candidate itself or of a product candidate in combination with other components added during the manufacturing and packaging process, or during shipping and storage of the drug substance or the finished product. If our third-party contractors are unable to successfully scale up the manufacture of any of our product candidates in sufficient quality and quantity and at commercially reasonable prices, and we are unable to find one or more replacement suppliers or manufacturers capable of production at a substantially equivalent cost in substantially equivalent volumes and quality or we are unable to successfully transfer the processes on a timely basis, the commercial launch for any resulting products may be delayed, or there may be a shortage in supply, either of which could significantly harm our business, financial condition, operating results and prospects.
We do not have direct control over the ability of our contract suppliers and manufacturers to maintain adequate capacity and capabilities to serve our needs, including quality control, quality assurance and qualified personnel. Although we are ultimately responsible for ensuring compliance with regulatory requirements such as cGMPs, we are dependent on our contract suppliers and manufacturers for day-to-day compliance with cGMPs for production of both APIs and finished products. Facilities used by our contract suppliers and manufacturers to produce the drug substances and materials or finished products for commercial sale must pass inspection and be approved by the FDA and other relevant regulatory authorities. Our contract suppliers and manufacturers must comply with cGMP requirements enforced by the FDA through its facilities inspection program and review of submitted technical information. If the safety of any product or product candidate is compromised due to a failure to adhere to applicable laws or for other reasons, we may not be able to successfully commercialize or obtain regulatory approval for the affected product or product candidate, and we may be held liable for injuries sustained as a result. In addition, the manufacturing facilities of certain of our suppliers are located outside of the United States. This may give rise to difficulties in importing our products or product candidates or their components into the United States or other countries as a result of, among other things, regulatory agency approval requirements, taxes, tariffs, local import requirements such as import duties or inspections, incomplete or inaccurate import documentation or defective packaging. Any of these factors could cause a delay or termination of preclinical studies, clinical trials or regulatory submissions or approvals of our product candidates, and could entail higher costs or result in our being unable to effectively commercialize our approved products on a timely basis, or at all.
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We are dependent on Roche for the manufacture and supply of lebrikizumab drug substance. If Roche elects to transfer its manufacture and supply responsibilities to us, we may not be able to engage a qualified contract manufacturer to manufacture and supply the drug substance in a timely manner, if at all. Any interruption in our supply may cause serious delays in the timing of our clinical studies, increase our costs and adversely impact our financial results.
Pursuant to the terms of our license agreement with F. Hoffmann-La Roche Ltd and Genentech, Inc. (together, “Roche”) for the exclusive, worldwide rights to develop and commercialize lebrikizumab for, among other indications, atopic dermatitis (the “Roche Agreement”), Roche is responsible for the manufacture and supply to us of lebrikizumab drug substance and we are completely reliant upon Roche to provide us with adequate supply for our use. We may experience an interruption in supply if, among other reasons, we incorrectly forecast our supply requirements, Roche allocates supply to its own development programs, Roche incorrectly plans its manufacturing production or Roche is unable to manufacture lebrikizumab drug substance in a timely manner to match our development or commercial needs.
Additionally, the Roche Agreement provides that, subject to certain requirements, Roche has the right to transfer its drug substance manufacture and supply responsibilities to us at any time. We do not currently have, nor do we plan to acquire, the infrastructure or capability to supply, manufacture or distribute clinical or commercial quantities of lebrikizumab drug substances. If Roche elects to transfer its manufacture and supply responsibilities to us, we will incur added costs in qualifying a contract manufacturer to manufacture and supply the drug substance and there can be no assurance that a qualified contract manufacturer would be available to us on a timely basis, on acceptable terms or at all.
If we experience any interruption in the supply of lebrikizumab drug substance, our ability to timely supply our clinical sites would be adversely impacted, causing potentially serious delays in the timing of our clinical studies and substantially increased costs if studies need to be adjusted or re-performed. See also “—We rely completely on third parties to supply, manufacture and distribute clinical drug supplies for our product candidates, including certain sole-source suppliers and manufacturers, we intend to rely on third parties for commercial supply, manufacturing and distribution if any of our product candidates receive regulatory approval and we expect to rely on third parties for supply, manufacturing and distribution of preclinical, clinical and commercial supplies of any future product candidates.”
Manufacturing and supply of the APIs and other substances and materials used in our product candidates and finished drug products is a complex and technically challenging undertaking, and there is potential for failure at many points in the manufacturing, testing, quality assurance and distribution supply chain, as well as the potential for latent defects after products have been manufactured and distributed.
Manufacturing and supply of APIs, other substances and materials and finished drug products is technically challenging. Changes beyond our direct control can impact the quality, volume, price and successful delivery of our product candidates and can impede, delay, limit or prevent the successful development and commercialization of our product candidates. Mistakes and mishandling are not uncommon and can affect successful production and supply. Some of these risks include:
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failure of our manufacturers to follow cGMP requirements or mishandling of product while in production or in preparation for transit; |
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inability of our contract suppliers and manufacturers to efficiently and cost-effectively increase and maintain high yields and batch quality, consistency and stability; |
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inability of our suppliers and manufacturers to meet our production demands due to issues related to their reliance on sole-source suppliers and manufacturers; |
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difficulty in establishing optimal production, storage, packaging and shipment methods and processes; |
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challenges in designing effective drug delivery substances and techniques; |
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transportation and import/export risk, particularly given the global nature of our supply chain; |
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delays in analytical results or failure of analytical techniques that we depend on for quality control and release of product; |
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natural disasters, labor disputes, financial distress, lack of raw material supply, issues with facilities and equipment or other forms of disruption to the business operations of our contract manufacturers and suppliers; and |
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latent defects that may become apparent after product has been released and which may result in recall and destruction of product. |
Any of these factors could result in delays or higher costs in connection with our clinical trials, regulatory submissions, required approvals or commercialization of our products, which could harm our business, financial condition, operating results and prospects.
If we are not able to establish and maintain collaborations, we may have to alter our development and commercialization plans.
The development and potential commercialization of our product candidates will require substantial additional cash to fund expenses. In order to fund further development of our product candidates, we may collaborate with pharmaceutical and biotechnology companies for the development and potential commercialization of those product candidates. We face significant competition in seeking appropriate partners. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the partner’s resources and experience, the terms and conditions of the proposed collaboration and the proposed partner’s evaluation of a number of factors. Those factors may include the design or results of clinical trials; the likelihood of approval by the FDA or other regulatory authorities; the potential market for the subject product candidate; the costs and complexities of manufacturing and delivering such product candidate to patients; the potential of competing products; any uncertainty with respect to our ownership of our intellectual property; and industry and market conditions generally. The partner may also consider alternative product candidates or technologies for similar indications that may be available for collaboration and whether such a collaboration could be more attractive than the one with us for our product candidate. We may also be restricted under future license agreements from entering into agreements on certain terms with potential partners. Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future partners.
Collaborations typically impose detailed obligations on each party, such as those required under the Roche Agreement. If we were to breach our obligations, we may face substantial consequences, including potential termination of the collaboration, and our rights to product candidates, in which we have invested substantial time and money, would be lost.
We may not be successful in our efforts to implement collaborations or other alternative arrangements for the development of our product candidates. When we partner with a third party for development and commercialization of a product candidate, we can expect to relinquish to the third party some of the control over the future success of that product candidate. Our collaboration partner may not devote sufficient resources to the commercialization of our product candidates or may otherwise fail in their commercialization. The terms of any collaboration or other arrangement that we establish may not be favorable to us. In addition, any collaboration that we enter into may be unsuccessful in the development and commercialization of our product candidates. In some cases, we may be responsible for continuing preclinical and initial clinical development of a partnered product candidate or research program, and the payment we receive from our collaboration partner may be insufficient to cover the cost of this development.
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We may not be able to negotiate collaborations on a timely basis, on acceptable terms or at all. If we are unable to do so, we may have to curtail the development of a product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further develop our product candidates or bring them to market and generate product revenue.
Our plans for the development and commercialization of lebrikizumab for the treatment of moderate-to-severe atopic dermatitis may be adversely impacted by Roche’s decisions and actions regarding product development, regulatory strategy and commercialization of lebrikizumab for interstitial lung diseases (the “Retained Field”).
Pursuant to the terms of the Roche Agreement, we obtained the exclusive, worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications except Roche retained certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. Roche’s rights in the Retained Field will be relinquished to us (the “Roche Reversion”): (a) at Roche’s election at any time following 30 days’ prior written notice to us; or (b) automatically if at any time in a period of 18 consecutive months Roche is not conducting an active clinical study of lebrikizumab or recurring, bona fide activities aimed at receiving regulatory approval for the compound in the Retained Field, provided that such automatic reversion may not occur within three years of the effective date of the Roche Agreement or following regulatory approval for the compound in the Retained Field. Until the occurrence of the Roche Reversion, if at all, Roche has the sole right to develop lebrikizumab in the Retained Field and, if regulatory approval is obtained, will be responsible for promotion, market access, reimbursement, funding and listing activities relating to lebrikizumab in the Retained Field. In exercising its rights in the Retained Field, Roche may make decisions and take actions with respect to the development and promotion of lebrikizumab which may not align with and may adversely impact our efforts for the development and commercialization lebrikizumab for the treatment of moderate-to-severe atopic dermatitis. See also “—If any of our product candidates are approved for marketing and we are found to have improperly promoted off-label uses, or if physicians misuse our products or use our products off-label, we may become subject to prohibitions on the sale or marketing of our products, product liability claims and significant fines, penalties and sanctions, and our brand and reputation could be harmed.”
Risks Related to Our Business and Financial Operations
We need to further increase the size and complexity of our organization, and we may experience difficulties in executing our growth strategy and managing any growth.
Our management, personnel, systems and facilities currently in place are not adequate to support our business plan and future growth. As of December 31, 2017, we had 162 full-time employees. We expect to experience significant growth in the number of our employees and the scope of our operations as we prepare for potential commercialization of our product candidates. We will need to further expand our scientific, medical affairs, sales and marketing, managerial, operational, financial and other resources to support our planned research, development and commercialization activities.
Our need to manage our operations, growth and various projects effectively requires that we:
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continue to improve our operational, financial, management and regulatory compliance controls and reporting systems and procedures; |
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identify, recruit, maintain, motivate and integrate additional talented employees; |
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develop a marketing, sales and distribution capability; |
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manage our commercialization activities for our product candidates effectively and in a cost-effective manner; |
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establish and maintain relationships with development and commercialization partners; |
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manage our preclinical and clinical trials effectively; |
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expand our facilities; and |
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manage our development efforts effectively while carrying out our contractual obligations to partners and other third parties. |
In addition, historically, we have utilized and continue to utilize the services of part-time outside consultants to perform a number of tasks for us, including tasks related to preclinical and clinical testing. Our growth strategy may also entail expanding our use of consultants to implement these and other tasks going forward. We rely on consultants for certain functions of our business and will need to effectively manage these consultants to ensure that they successfully carry out their contractual obligations and meet expected deadlines. There can be no assurance that we will be able to manage our existing consultants or find other competent outside consultants, as needed, on economically reasonable terms, or at all.
To effectively manage our growth and expand our organization, we may incur significant costs and our management and business development resources may be diverted. If we are unable to successfully implement the tasks necessary to effectively execute our growth strategy and manage our growth, our ability to achieve our research, development and commercialization goals may be materially adversely impacted.
If we fail to attract and retain management and other key personnel, we may be unable to continue to successfully develop or commercialize our product candidates or otherwise implement our business plan.
Our ability to compete in the highly competitive pharmaceuticals industry depends upon our ability to attract and retain highly qualified managerial, scientific, medical, sales and marketing and other personnel. We are highly dependent on our management and scientific personnel, including: our Chief Executive Officer and Chairman of our board of directors, Thomas G. Wiggans; our Chief Medical Officer and a member of our board of directors, Eugene A. Bauer, M.D.; our Chief Operating Officer and Chief Financial Officer, Andrew L. Guggenhime; our Chief Development Officer, Luis C. Peña; our Chief Commercial Officer, Lori Lyons-Williams; and our Senior Vice President, Corporate Development and Strategy, Christopher M. Griffith. The loss of the services of any of these individuals could impede, delay or prevent the successful development of our product pipeline, completion of our planned clinical trials, commercialization of our product candidates or in-licensing or acquisition of new assets and could negatively impact our ability to successfully implement our business plan. If we lose the services of any of these individuals, we might not be able to find suitable replacements on a timely basis or at all, and our business could be harmed as a result. We do not maintain “key man” insurance policies on the lives of these individuals or the lives of any of our other employees. We employ all of our executive officers and key personnel on an at-will basis and their employment can be terminated by us or them at any time, for any reason and without notice. In order to retain valuable employees at our company, in addition to salary and cash incentives, we provide stock options and restricted stock units that vest over time. The value to employees of stock options and restricted stock units that vest over time will be significantly affected by movements in our stock price that are beyond our control, and may at any time be insufficient to counteract offers from other companies.
We might not be able to attract or retain qualified management and other key personnel in the future due to the intense competition for qualified personnel among biotechnology, pharmaceutical and other businesses, particularly in the San Francisco Bay Area where we are headquartered. We could have difficulty attracting experienced personnel to our company and may be required to expend significant financial resources in our employee recruitment and retention efforts. Many of the other pharmaceutical companies with whom we compete for qualified personnel have greater financial and other resources, different risk profiles and longer histories in the industry than we do. They also may provide more diverse opportunities and better chances for career advancement. If we are not able to attract and retain the necessary personnel to accomplish our business objectives, we may experience constraints that will harm our ability to implement our business strategy and achieve our business objectives.
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In addition, we have scientific and clinical advisors who assist us in formulating our development and clinical strategies. These advisors are not our employees and may have commitments to, or consulting or advisory contracts with, other entities that may limit their availability to us. In addition, our advisors may have arrangements with other companies to assist those companies in developing products or technologies that may compete with ours.
We currently have no sales representatives and limited marketing and distribution capabilities. If we are unable to establish sales, marketing and distribution capabilities on our own or through third parties, we will be unable to successfully commercialize our product candidates, if approved, or generate product revenue.
Although our employees have experience in the marketing, sale and distribution of pharmaceutical products from prior employment at other companies, we as a company have no prior experience in the marketing, sale and distribution of pharmaceutical products. To achieve commercial success, we must continue to effectively build our commercial infrastructure, including our marketing, sales, distribution, managerial and other non-technical capabilities, as well as substantially expand our organization cross-functionally to enable us to execute on our commercialization goals. Factors that may inhibit our efforts to commercialize our products through our own sales organization include:
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our inability to recruit, train and retain adequate numbers of effective sales and marketing personnel; |
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the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future drugs; |
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the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; |
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unforeseen costs and expenses associated with creating an independent sales and marketing organization; and |
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inability to ensure adequate access to our products via agreements with payers. |
There are significant risks involved in building and managing a sales organization, including our ability to hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel and effectively manage a geographically dispersed sales and marketing team. Recruiting and training a sales force is expensive and time consuming and could delay a product launch. If the commercial launch of a product candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred significant commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel. See also —“We need to further increase the size and complexity of our organization, and we may experience difficulties in executing our growth strategy and managing any growth.”
We may also choose to collaborate with third parties that have direct sales forces and established distribution systems, either to augment our own sales force and distribution systems or in lieu of our own sales force and distribution systems. If we are unable to enter into such arrangements on acceptable terms or at all, we may not be able to successfully commercialize our product candidates. Even if we are able to enter into such arrangements, we will likely have little control over these third parties, and any such third party may fail to devote the necessary resources and attention to sell and market our products effectively.
Any failure or delay in the development of our commercial infrastructure and sales, marketing and distribution capabilities would adversely impact the commercialization of our product candidates. The inability to successfully commercialize our product candidates, either on our own or through collaborations with one or more third parties, would harm our business, financial condition, operating results and prospects.
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Our failure to successfully in-license, acquire, develop and market additional product candidates or approved products would impair our ability to grow our business.
We intend to in-license, acquire, develop and market additional products and product candidates. Because our internal research and development capabilities are limited, we may be dependent upon pharmaceutical companies, academic scientists and other researchers to sell or license products or technology to us. The success of this strategy depends partly upon our ability to identify and select promising pharmaceutical product candidates and products, negotiate licensing or acquisition agreements with their current owners and finance these arrangements.
The process of proposing, negotiating and implementing a license or acquisition of a product candidate or approved product is lengthy and complex. Other companies, including some with substantially greater financial, marketing, sales and other resources, may compete with us for the license or acquisition of product candidates and approved products. We have limited resources to identify and execute the acquisition or in-licensing of third-party products, businesses and technologies and integrate them into our current infrastructure. Moreover, we may devote resources to potential acquisitions or licensing opportunities that are never completed, or we may fail to realize the anticipated benefits of such efforts. We may not be able to acquire the rights to additional product candidates on terms that we find acceptable, or at all.
Further, any product candidate that we acquire may require additional development efforts prior to commercial sale, including preclinical or clinical testing and approval by the FDA and applicable foreign regulatory authorities. All product candidates are prone to risks of failure typical of pharmaceutical product development, including the possibility that a product candidate will not be shown to be sufficiently safe and effective for approval by regulatory authorities. In addition, we cannot provide assurance that any approved products that we acquire will be manufactured or sold profitably or achieve market acceptance.
We intend to in-license and acquire product candidates or engage in other strategic transactions, which could impact our liquidity, increase our expenses and present significant distractions to our management.
Our strategy is to in-license and acquire product candidates or engage in other strategic transactions. Additional potential transactions that we may consider include a variety of different business arrangements, including spin-offs, strategic partnerships, joint ventures, restructurings, divestitures, business combinations and investments. Any such transaction may require us to incur non-recurring or other charges, may increase our near- and long-term expenditures and may pose significant integration challenges or disrupt our management or business, which could adversely affect our operations and financial results. For example, these transactions entail numerous potential operational and financial risks, including:
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exposure to unknown liabilities; |
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disruption of our business and diversion of our management’s time and attention in order to develop acquired products, product candidates or technologies; |
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incurrence of substantial debt or dilutive issuances of equity securities to pay for acquisitions; |
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substantial acquisition and integration costs; |
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write-downs of assets or impairment charges; |
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increased amortization expenses; |
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difficulty and cost in combining the operations and personnel of any acquired businesses with our operations and personnel; |
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impairment of relationships with key suppliers, partners or customers of any acquired businesses due to changes in management and ownership; and |
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inability to retain our key employees or those of any acquired businesses. |
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Accordingly, there can be no assurance that we will undertake or successfully complete any transactions of the nature described above, and any transaction that we do complete could harm our business, financial condition, operating results and prospects. We have no current plan, commitment or obligation to enter into any transaction described above.
Our operating results may fluctuate significantly, which makes our future operating results difficult to predict and could cause our operating results to fall below expectations, adversely impacting our stock price.
Our operations to date have been primarily limited to researching and developing our product candidates and undertaking preclinical studies and clinical trials of our product candidates. We have not yet obtained regulatory approvals for any of our product candidates. Consequently, any predictions made about our future success or viability may not be as accurate as they could be if we had a longer operating history or approved products on the market. From time to time, we may enter into collaboration agreements and license agreements with other companies that include development funding and significant upfront and milestone expenditures and payments, and we expect that amounts earned from or paid pursuant to these agreements will be a significant source of our capital expenditures and an important source of our revenue. Accordingly, our revenue and profitability will depend on the achievement of milestones under a license agreement with Maruho Co., Ltd. pursuant to which we granted Maruho an exclusive license to develop and commercialize glycopyrronium tosylate for the treatment of hyperhidrosis in Japan, as well as any potential future collaboration and license agreements and sales of our products, if approved. These upfront and milestone payments may vary significantly from period to period and any such variance could cause a significant fluctuation in our operating results from one period to the next. In addition, we measure compensation cost for stock-based awards made to employees at the grant date of the award, based on the fair value of the award as determined by our board of directors, and recognize the cost as an expense over the employee’s requisite service period. As the variables that we use as a basis for valuing these awards change over time, including our underlying stock price and stock price volatility, the magnitude of the expense that we must recognize may vary significantly. Furthermore, our operating results may fluctuate due to a variety of other factors, many of which are outside of our control and may be difficult to predict, including the following:
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delays in the commencement, patient enrollment and the timing of clinical testing for our product candidates; |
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the timing and success or failure of clinical trials for our product candidates or competing product candidates, or any other change in the competitive landscape of our industry, including consolidation among our competitors or partners; |
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any delays in regulatory review and approval of product candidates in clinical development; |
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the timing and cost of, and level of investment in, research and development activities relating to our product candidates, which may change from time to time; |
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the cost of manufacturing our product candidates, which may vary depending on FDA guidelines and requirements, and the quantity of production; |
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our ability to obtain additional funding to develop our product candidates; |
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expenditures that we will or may incur to acquire or develop additional product candidates and technologies; |
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the level of demand for our product candidates, should they receive approval, which may vary significantly; |
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potential side effects of our product candidates that could delay or prevent commercialization or cause an approved drug to be taken off the market; |
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the availability of formulary coverage and adequate reimbursement from private third-party payers for any of our product candidates that may be approved; |
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our dependency on third-party manufacturers to supply or manufacture our product candidates; |
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our ability to establish an effective sales, marketing and distribution infrastructure in a timely manner; |
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market acceptance of our product candidates, if approved, and our ability to forecast demand for those product candidates; |
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our ability to receive regulatory approval and commercialize our product candidates; |
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our ability to establish and maintain collaborations, licensing or other arrangements; |
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our ability and third parties’ abilities to protect intellectual property rights; |
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costs related to and outcomes of potential litigation or other disputes; |
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our ability to adequately support future growth; |
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our ability to attract and retain key personnel to manage our business effectively; |
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potential liabilities associated with hazardous materials; |
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our ability to maintain adequate insurance policies; and |
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future accounting pronouncements or changes in our accounting policies. |
Our operating results and liquidity needs could be negatively affected by market fluctuations and economic downturn.
Our operating results and liquidity could be negatively affected by economic conditions generally, both in the United States and elsewhere around the world. The market for discretionary medical products and procedures may be particularly vulnerable to unfavorable economic conditions. Some patients may consider certain of our product candidates to be discretionary, and if full reimbursement for such products is not available, demand for these products may be tied to the discretionary spending levels of our targeted patient populations. Domestic and international equity and debt markets have experienced and may continue to experience heightened volatility and turmoil based on domestic and international economic conditions and concerns. In the event these economic conditions and concerns continue or worsen and the markets continue to remain volatile, our operating results and liquidity could be adversely affected by those factors in many ways, including weakening demand for certain of our approved products, if any, and making it more difficult for us to raise funds if necessary, and our stock price may decline. Additionally, although we plan to market our products primarily in the United States, our partners have extensive global operations, indirectly exposing us to additional risk.
Our ability to utilize our net operating loss (“NOL”) carryforwards and research and development income tax credit carryforwards may be limited.
As of December 31, 2017, we had NOL carryforwards available to reduce future taxable income, if any, for federal, California and Canadian income tax purposes. If not utilized, the federal and California NOL carryforwards will begin expiring during the year ending December 31, 2030 and the Canadian NOL carryforwards will begin expiring during the year ending December 31, 2028. Under Section 382 of the Code, if a corporation undergoes an “ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period, the corporation’s ability to use its pre-change NOL carryforwards and other pre-change tax attributes (such as research tax credits) to offset its post-change income may be limited. We have experienced at least one ownership change since inception and our utilization of NOL carryforwards will therefore be subject to annual limitation. We may also experience ownership changes in the future as a result of subsequent shifts in our stock ownership. As a result, if we earn net taxable income, our ability to use our pre-change NOL carryforwards to offset U.S. federal taxable income may be subject to limitations, which could potentially result in increased future tax liability to us. In addition, at the state level, there may be periods during which the use of NOL carryforwards is suspended or otherwise limited, which could accelerate or permanently increase state taxes owed.
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We may be adversely affected by natural disasters and other catastrophic events, and by man-made problems such as terrorism, that could disrupt our business operations and our business continuity and disaster recovery plans may not adequately protect us from a serious disaster.
Our corporate headquarters are located in Menlo Park, California, near major earthquake and fire zones. If a disaster, power outage or other event occurred that prevented us from using all or a significant portion of our headquarters, that damaged critical infrastructure, such as enterprise financial systems, manufacturing resource planning or enterprise quality systems, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for us to continue our business for a substantial period of time. Our contract manufacturers’ and suppliers’ facilities are located in multiple locations, where other natural disasters or similar events, such as blizzards, tornadoes, fires, explosions or large-scale accidents or power outages, could severely disrupt our operations and have a material adverse effect on our business, financial condition, operating results and prospects. In addition, acts of terrorism and other geo-political unrest could cause disruptions in our business or the businesses of our partners, manufacturers or the economy as a whole. All of the aforementioned risks may be further increased if we do not implement a disaster recovery plan or our partners’ or manufacturers’ disaster recovery plans prove to be inadequate. To the extent that any of the above should result in delays in the regulatory approval, manufacture, distribution or commercialization of our product candidates, our business, financial condition, operating results and prospects would suffer.
Our business and operations would suffer in the event of failure, invasion, corruption, destruction or interruption of our or our partners’ critical information technology systems or infrastructure.
Despite the implementation of security measures, our information technology systems and infrastructure, and those of our current and any future partners, contractors and consultants, are vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. The ever-increasing use and evolution of technology, including cloud-based computing, creates opportunities for the unintentional dissemination or intentional destruction of confidential information stored in our systems or in non-encrypted portable media or storage devices. We could also experience a business interruption, intentional theft of confidential information, or reputational damage from espionage attacks, malware or other cyber-attacks, which may compromise our system infrastructure or lead to data leakage, either internally or at our third-party providers. While we have not experienced any such material system failure, accident or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our manufacturing activities, development programs and our business operations. For example, the loss of manufacturing records or clinical trial data from completed or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability and the further commercialization and development of our product candidates could be delayed.
Risks Related to Our Intellectual Property
We may not be able to obtain or enforce patent rights or other intellectual property rights that cover our product candidates and technologies that are of sufficient breadth to prevent third parties from competing against us.
Our success with respect to our product candidates and technologies will depend in part on our ability to obtain and maintain patent protection in both the United States and other countries, to preserve our trade secrets and to prevent third parties from infringing upon our proprietary rights. Our ability to protect any of our product candidates from unauthorized or infringing use by third parties depends in substantial part on our ability to obtain and maintain valid and enforceable patents.
Our patent portfolio includes patents and patent applications in the United States and foreign jurisdictions where we believe there is a market opportunity for our products. The covered technology and the scope of coverage vary from country to country. For those countries where we do not have granted patents, we may not have any ability to prevent the unauthorized use of our technologies. Any patents that we may obtain may be narrow in scope and thus easily circumvented by competitors. Further, in countries where we do not have granted patents, third parties may be able to make, use or sell products identical to or substantially similar to, our product candidates.
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The patent application process, also known as patent prosecution, is expensive and time-consuming, and we and our current or future licensors and licensees may not be able to prepare, file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we or our current licensors or licensees, or any future licensors or licensees, will fail to identify patentable aspects of inventions made in the course of development and commercialization activities before it is too late to obtain patent protection on them. Therefore, these and any of our patents and applications may not be prosecuted and enforced in a manner consistent with the best interests of our business. It is possible that defects of form in the preparation or filing of our patents or patent applications may exist, or may arise in the future, such as with respect to proper priority claims, inventorship, claim scope or patent term adjustments. If our current licensors or licensees, or any future licensors or licensees, are not fully cooperative or disagree with us as to the prosecution, maintenance or enforcement of any patent rights, such patent rights could be compromised and we might not be able to prevent third parties from making, using and selling competing products. If there are material defects in the form or preparation of our patents or patent applications, such patents or applications may be invalid and unenforceable. Moreover, our competitors may independently develop equivalent knowledge, methods and know-how. Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business, financial condition and operating results.
Due to legal standards relating to patentability, validity, enforceability and claim scope of patents covering pharmaceutical inventions, our ability to obtain, maintain and enforce patents is uncertain and involves complex legal and factual questions. Accordingly, rights under any existing patents or any patents we might obtain or license may not cover our product candidates, or may not provide us with sufficient protection for our product candidates to afford a commercial advantage against competitive products or processes, including those from branded and generic pharmaceutical companies. In addition, we cannot guarantee that any patents will issue from any pending or future patent applications owned by or licensed to us. Even if patents have issued or will issue, we cannot guarantee that the claims of these patents are or will be held valid or enforceable if challenged in post-grant proceedings or by the courts or will provide us with any significant protection against competitive products or otherwise be commercially valuable to us.
Competitors in the field of dermatologic therapeutics have created a substantial amount of prior art, including scientific publications, patents and patent applications. Our ability to obtain and maintain valid and enforceable patents depends on whether the differences between our technology and the prior art allow our technology to be patentable over the prior art. Although we believe that our technology includes certain inventions that are unique and not duplicative of any prior art, we do not have outstanding issued patents covering all of the recent developments in our technology and we are unsure of the patent protection that we will be successful in obtaining, if any. Even if the patents do successfully issue, third parties may design around or challenge the validity, enforceability or scope of such issued patents or any other issued patents we own or license, which may result in such patents being narrowed, invalidated or held unenforceable. In particular, due to the extensive prior art relating to anticholinergic agents to control hyperhidrosis and because glycopyrronium tosylate is a form of a generic anticholinergic agent, the patent protection available for glycopyrronium tosylate may not prevent competitors from developing and commercializing similar products. If the breadth or strength of protection provided by the patents we hold or pursue with respect to our product candidates is challenged, it could dissuade companies from collaborating with us to develop, or threaten our ability to commercialize, our product candidates.
The laws of some foreign jurisdictions do not provide intellectual property rights to the same extent as in the United States and many companies have encountered significant difficulties in protecting and defending such rights in foreign jurisdictions. If we encounter such difficulties in protecting or are otherwise precluded from effectively protecting our intellectual property in foreign jurisdictions, our business prospects could be substantially harmed.
The degree of future protection of our proprietary rights is uncertain. Patent protection may be unavailable or severely limited in some cases and may not adequately protect our rights or permit us to gain or keep our competitive advantage. For example:
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we might not have been the first to invent or the first to file the inventions covered by each of our pending patent applications and issued patents; |
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others may independently develop similar or alternative technologies or duplicate any of our technologies; |
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any patents we obtain or our licensors’ issued patents may not encompass commercially viable products, may not provide us with any competitive advantages or may be challenged by third parties; |
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any patents we obtain or our in-licensed issued patents may not be valid or enforceable; and |
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we may not develop additional proprietary technologies that are patentable or provide us with a competitive advantage. |
Patents have a limited lifespan. In the United States, the natural expiration of a patent is generally 20 years after it is filed. Various extensions may be available; however, the life of a patent, and the protection it affords, is limited. Without patent protection for our product candidates, we may be open to competition from generic versions of our product candidates. Further, the extensive period of time between patent filing and regulatory approval for a product candidate limits the time during which we can market a product candidate under patent protection, which may particularly affect the profitability of our early-stage product candidates. The issued U.S. patents relating to olumacostat glasaretil, glycopyrronium tosylate and lebrikizumab will expire between 2020 and 2037.
Proprietary trade secrets and unpatented know-how are also very important to our business. Although we have taken steps to protect our trade secrets and unpatented know-how by entering into confidentiality agreements with third parties, and intellectual property protection agreements with certain employees, consultants and advisors, third parties may still obtain this information or we may be unable to protect our rights. We also have limited control over the protection of trade secrets used by our suppliers, manufacturers and other third parties. There can be no assurance that binding agreements will not be breached, that we would have adequate remedies for any breach or that our trade secrets and unpatented know-how will not otherwise become known or be independently discovered by our competitors. If trade secrets are independently discovered, we would not be able to prevent their use. Enforcing a claim that a third party illegally obtained and is using our trade secrets or unpatented know-how is expensive and time-consuming, and the outcome is unpredictable. In addition, courts outside the United States may be less willing to protect trade secret information.
Changes in patent laws or the interpretations of patent laws could diminish the value of patents in general, thereby impairing our ability to protect our product candidates.
The patent positions of pharmaceutical and biotechnology companies can be highly uncertain and involve complex legal and factual questions for which important legal principles remain unresolved. Changes in either the patent laws or in the interpretations of patent laws in the United States and other countries may diminish the value of our intellectual property. We cannot predict the breadth of claims that may be allowed or enforced in our patents or in third-party patents. The United States has recently enacted and is currently implementing wide-ranging patent reform legislation. Further, recent U.S. Supreme Court rulings have either narrowed the scope of patent protection available in certain circumstances or weakened the rights of patent owners in certain situations. In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the scope and value of patents, once obtained.
For our U.S. patent applications containing a priority claim after March 16, 2013, there is a greater level of uncertainty in the patent law. In September 2011, the Leahy-Smith America Invents Act, also known as the America Invents Act (“AIA”) was signed into law. The AIA includes a number of significant changes to U.S. patent law, including provisions that affect the way patent applications will be prosecuted and may also affect patent litigation. The AIA and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have an adverse effect on our business. An important change introduced by the AIA is that, as of March 16, 2013, the United States transitioned to a “first-to-file” system for deciding which party should be granted a patent when two or more patent applications are filed by different parties claiming the same invention. A third party that files a patent application in the U.S. Patent and Trademark Office (“USPTO”) after that date but before us could therefore be awarded a patent covering an invention of ours even if we had made the invention before it was made by the third party. This will require us to be cognizant going forward of the time from invention to filing of a patent application.
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Among some of the other changes introduced by the AIA are changes that limit where a patentee may file a patent infringement suit and provide opportunities for third parties to challenge any issued patent in the USPTO. This applies to all of our U.S. patents, even those issued before March 16, 2013. Because of a lower evidentiary standard in USPTO proceedings compared to the evidentiary standard in United States federal court necessary to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action. Accordingly, a third party may attempt to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged by the third party as a defendant in a district court action.
Depending on decisions by the U.S. Congress, the U.S. federal courts, the USPTO or similar authorities in foreign jurisdictions, the laws and regulations governing patents could change in unpredictable ways that may weaken our and our licensors’ ability to obtain new patents or to enforce existing patents we and our licensors or partners may obtain in the future.
We may not be able to protect our intellectual property rights throughout the world.
Filing, prosecuting and defending patents on our product candidates in all countries throughout the world would be prohibitively expensive. The requirements for patentability may differ in certain countries, particularly developing countries. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as laws in the United States. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent protection, but enforcement on infringing activities is inadequate. These products may compete with our products, and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.
Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents and other intellectual property protection, particularly those relating to pharmaceuticals, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our proprietary rights generally. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful. In addition, certain countries in Europe and certain developing countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In those countries, we may have limited remedies if our patents are infringed or if we are compelled to grant a license to our patents to a third party, which could materially diminish the value of those patents. This could limit our potential revenue opportunities. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we own or license. Finally, our ability to protect and enforce our intellectual property rights may be adversely affected by unforeseen changes in foreign intellectual property laws.
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Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
Periodic maintenance and annuity fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. If we or our licensors fail to maintain the patents and patent applications covering our product candidates, our competitors might be able to enter the market, which would have an adverse effect on our business.
If we fail to comply with our obligations under our intellectual property license agreements, we could lose license rights that are important to our business.
We are a party to certain license agreements that impose various diligence, milestone, royalty, insurance and other obligations on us. If we fail to comply with these obligations, the respective licensors may have the right to terminate the license, in which event we may not be able to develop or market the affected product candidate. The loss of such rights could materially adversely affect our business, financial condition, operating results and prospects. For example, any dispute with Roche relating to compliance with the terms of the Roche Agreement could lead to delays in, or termination of, the development and commercialization of lebrikizumab for the treatment of atopic dermatitis and time consuming and expensive arbitration.
If we are sued for infringing intellectual property rights of third parties, it will be costly and time-consuming, and an unfavorable outcome in that litigation could have a material adverse effect on our business.
Our commercial success depends upon our ability to develop, manufacture, market and sell our product candidates and use our proprietary technologies without infringing the proprietary rights of third parties. We cannot provide assurances that marketing and selling such candidates and using such technologies will not infringe existing or future patents. Numerous U.S. and foreign issued patents and pending patent applications owned by third parties exist in the fields relating to our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that others may assert that our product candidates, technologies or methods of delivery or use infringe their patent rights. Moreover, it is not always clear to industry participants, including us, which patents cover various drugs, biologics, drug delivery systems or their methods of use, and which of these patents may be valid and enforceable. Thus, because of the large number of patents issued and patent applications filed in our fields, there may be a risk that third parties may allege they have patent rights encompassing our product candidates, technologies or methods.
In addition, there may be issued patents of third parties that are infringed or are alleged to be infringed by our product candidates or proprietary technologies. Because some patent applications in the United States may be maintained in secrecy until the patents are issued, because patent applications in the United States and many foreign jurisdictions are typically not published until eighteen months after filing and because publications in the scientific literature often lag behind actual discoveries, we cannot be certain that others have not filed patent applications for technology covered by our own and in-licensed issued patents or our pending applications. Our competitors may have filed, and may in the future file, patent applications covering our product candidates or technology similar to ours. Any such patent application may have priority over our own and in-licensed patent applications or patents, which could further require us to obtain rights to issued patents covering such technologies. If another party has filed a U.S. patent application on inventions similar to those owned or in-licensed to us, we or, in the case of in-licensed technology, the licensor may have to participate, in the United States, in an interference proceeding to determine priority of invention.
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We may be exposed to, or threatened with, future litigation by third parties having patent or other intellectual property rights alleging that our product candidates or proprietary technologies infringe such third parties’ intellectual property rights, including litigation resulting from filing under Paragraph IV of the Hatch-Waxman Act. These lawsuits could claim that there are existing patent rights for such drug and this type of litigation can be costly and could adversely affect our operating results and divert the attention of managerial and technical personnel, even if we do not infringe such patents or the patents asserted against us are ultimately established as invalid. There is a risk that a court would decide that we are infringing the third party’s patents and would order us to stop the activities covered by the patents. In addition, there is a risk that a court will order us to pay the other party damages for having violated the other party’s patents.
There is a substantial amount of litigation involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries generally. To date, no litigation asserting infringement claims has ever been brought against us. If a third party claims that we infringe its intellectual property rights, we may face a number of issues, including:
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infringement and other intellectual property claims which, regardless of merit, may be expensive and time-consuming to litigate and may divert our management’s attention from our core business; |
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substantial damages for infringement, which we may have to pay if a court decides that the product or technology at issue infringes or violates the third party’s rights, and if the court finds that the infringement was willful, we could be ordered to pay treble damages and the patent owner’s attorneys’ fees; |
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a court prohibiting us from selling or licensing the product or using the technology at issue unless the third party licenses its intellectual property rights to us, which it is not required to do; |
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if a license is available from a third party, we may have to pay substantial royalties or upfront fees or grant cross-licenses to intellectual property rights for our products or technologies; and |
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redesigning our products or processes so they do not infringe, which may not be possible or may require substantial monetary expenditures and time. |
Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources. In addition, any uncertainties resulting from the initiation and continuation of any litigation could harm our ability to raise additional funds or otherwise adversely affect our business, financial condition, operating results and prospects.
Because we rely on certain third-party licensors, licensees and partners, and will continue to do so in the future, if one of our licensors, licensees or partners is sued for infringing a third party’s intellectual property rights, our business, financial condition, operating results and prospects could suffer in the same manner as if we were sued directly. In addition to facing litigation risks, we have agreed to indemnify certain third-party licensors, licensees and partners against claims of infringement caused by our proprietary technologies, and we have entered or may enter into cost-sharing agreements with some our licensors, licensees and partners that could require us to pay some of the costs of patent litigation brought against those third parties whether or not the alleged infringement is caused by our proprietary technologies. In certain instances, these cost-sharing agreements could also require us to assume greater responsibility for infringement damages than would be assumed just on the basis of our technology.
The occurrence of any of the foregoing could adversely affect our business, financial condition or operating results.
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We may become involved in lawsuits or other adverse proceedings to protect or enforce our patents or other intellectual property or the patents of our licensors, which could be expensive and time-consuming.
Competitors may infringe our intellectual property, including our patents or the patents of our licensors. As a result, we may be required to file infringement claims to stop third-party infringement or unauthorized use. This can be expensive, particularly for a company of our size, and time-consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours is not valid or is unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patent claims do not cover its technology or that the factors necessary to grant an injunction against an infringer are not satisfied. An adverse determination of any litigation or other proceedings could put one or more of our patents at risk of being invalidated, interpreted narrowly or amended such that they do not cover our product candidates. Moreover, such adverse determinations could put our patent applications at risk of not issuing, or issuing with limited and potentially inadequate scope to cover our product candidates or to prevent others from marketing similar products.
Interference, derivation or other proceedings such as inter partes review, post-grant review and reexamination brought at the USPTO may be necessary to determine the priority or patentability of inventions with respect to our patent applications or those of our licensors or potential partners. Litigation or USPTO proceedings brought by us may fail or may be invoked against us by third parties. Even if we are successful, domestic or foreign litigation or USPTO or foreign patent office proceedings may result in substantial costs and distraction to our management. We may not be able, alone or with our licensors or potential partners, to prevent misappropriation of our proprietary rights, particularly in countries where the laws may not protect such rights as fully as in the United States.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation or other proceedings, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation or other proceedings. In addition, during the course of this kind of litigation or proceedings, there could be public announcements of the results of hearings, motions or other interim proceedings or developments or public access to related documents. If investors perceive these results to be negative, the market price for our common stock could be significantly harmed.
We may be subject to claims that our employees, consultants or independent contractors have wrongfully used or disclosed to us alleged trade secrets of their former employers or their former or current customers.
As is common in the biotechnology and pharmaceutical industries, certain of our employees were formerly employed by other biotechnology or pharmaceutical companies, including our competitors or potential competitors. Moreover, we engage the services of consultants to assist us in the development of our product candidates, many of whom were previously employed at or may have previously been or are currently providing consulting services to, other biotechnology or pharmaceutical companies, including our competitors or potential competitors. We may be subject to claims that these employees and consultants or we have inadvertently or otherwise used or disclosed trade secrets or other proprietary information of their former employers or their former or current customers. Although we have no knowledge of any such claims being alleged to date, if such claims were to arise, litigation may be necessary to defend against any such claims. Even if we are successful in defending against any such claims, any such litigation could be protracted, expensive, a distraction to our management team, not viewed favorably by investors and other third parties and may potentially result in an unfavorable outcome.
Risks Related to the Securities Markets and Ownership of Our Common Stock
The stock price of our common stock has been, and is likely to continue to be, volatile and may decline and stockholders may not be able to resell their shares at or above the price at which they purchased the shares.
Prior to our initial public offering (“IPO”) in October 2014, there had not been a public market for our common stock. The market price of our common stock may fluctuate significantly in response to numerous factors, many of which are beyond our control, including:
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the development status of our product candidates, including whether any of our product candidates receive regulatory approval; |
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regulatory or legal developments in the United States and foreign countries; |
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the clinical results of our competitors or potential competitors; |
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the success of, and fluctuations in, the commercial sales of products approved for commercialization, if any; |
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the execution of our partnering and manufacturing arrangements; |
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our execution of collaboration, co-promotion, licensing or other arrangements, and the timing of payments we may make or receive under these arrangements; |
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variations in the level of expenses related to our preclinical and clinical development programs, including relating to the timing of invoices from, and other billing practices of, our CROs and clinical trial sites; |
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variations in the level of expenses related to our commercialization activities, if any product candidates are approved; |
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the performance of third parties on whom we rely for clinical trials, manufacturing, marketing, sales and distribution, including their ability to comply with regulatory requirements; |
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overall performance of the equity markets; |
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changes in operating performance and stock market valuations of other pharmaceutical companies; |
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market conditions or trends in our industry or the economy as a whole; |
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the public’s response to press releases or other public announcements by us or third parties, including our filings with the Securities and Exchange Commission (“SEC”) and announcements relating to acquisitions, strategic transactions, licenses, joint ventures, capital commitments, intellectual property, litigation or other disputes impacting us or our business; |
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developments with respect to intellectual property rights; |
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our commencement of, or involvement in, litigation; |
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FDA or foreign regulatory actions affecting us or our industry; |
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changes in the structure of healthcare payment systems; |
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changes to laws affecting our industry, including full or partial repeal of the Affordable Care Act; |
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the financial projections we may provide to the public, any changes in these projections or our failure to meet these projections; |
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changes in financial estimates by any securities analysts who follow our common stock, our failure to meet these estimates or failure of those analysts to initiate or maintain coverage of our common stock; |
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ratings downgrades by any securities analysts who follow our common stock; |
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the development and sustainability of an active trading market for our common stock; |
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the size of our market float; |
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future sales of our common stock by our officers, directors and significant stockholders; |
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future sales and purchases of any shares of our common stock issued upon conversion of the 3.00% Convertible Senior Notes due 2022 (“Notes”); |
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recruitment or departure of key personnel; |
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changes in accounting principles; |
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other events or factors, including those resulting from war, incidents of terrorism, natural disasters or responses to these events; and |
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any other factors discussed herein. |
In addition, the stock markets, and in particular The NASDAQ Global Select Market, have experienced extreme price and volume fluctuations that have affected and continue to affect the market prices of equity securities of many pharmaceutical companies. Stock prices of many pharmaceutical companies have fluctuated in a manner unrelated or disproportionate to the operating performance of those companies. In the past, stockholders have instituted securities class action litigation following periods of market volatility. If we were involved in securities litigation, we could incur substantial costs and our resources and the attention of management could be diverted from our business.
During the period between January 1, 2016 and December 31, 2017, the closing sale price of our common stock on The NASDAQ Global Select Market ranged from $18.67 to $38.03 per share. Because our stock price has been volatile, investing in our common stock is risky.
If a large number of shares of our common stock are sold in the public market, the sales could reduce the trading price of our common stock, impede our ability to raise future capital and holders may have difficulty selling their shares based on current trading volumes of our stock.
Our stock is currently traded on The NASDAQ Global Select Market, but we can provide no assurance that we will be able to maintain an active trading market on The NASDAQ Global Select Market or any other exchange in the future. The trading volume of our stock tends to be low and we have several stockholders who hold a significant number of shares. If there is no active trading market or if the volume of trading is limited, holders of our common stock may have difficulty selling their shares.
As of December 31, 2017, we had 41,797,561 shares of common stock outstanding, and stockholders holding 5% or more of our stock, individually or with affiliated persons or entities, collectively beneficially owned or controlled approximately 48% of such shares. If stockholders holding a significant number of our shares sell, indicate an intention to sell, or if it is perceived that they will sell, substantial amounts of our common stock in the public market, the trading price of our common stock could decline and our ability to raise future capital may be adversely affected.
Furthermore, we completed a sale of $287.5 million aggregate principal amount of Notes in May 2017 in a private placement in reliance on Section 4(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”), to qualified institutional buyers pursuant to Rule 144A promulgated under the Securities Act. The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms. Holders of the Notes may convert all or a portion of their Notes at their option at any time prior to the close of business on the business day immediately prior to May 15, 2022, in multiples of $1,000 principal amount. The Notes are convertible into shares of our common stock at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock. As of December 31, 2017, the Notes were convertible into 8,109,771 shares of our common stock. The conversion rate and the corresponding conversion price will be subject to adjustment upon the occurrence of certain events. Any sales in the public market of the common stock issuable upon such conversion could adversely affect prevailing market prices of our common stock. In addition, the existence of the Notes may encourage short selling by market participants because the conversion of the Notes could be used to satisfy short positions, or anticipated conversion of the Notes into shares of our common stock could depress our stock price.
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If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our common stock.
The Sarbanes-Oxley Act requires us, among other things, to assess and report on the effectiveness of our internal control over financial reporting annually and disclosure controls and procedures quarterly. In addition, our independent registered public accounting firm is required to audit the effectiveness of our internal control over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act annually.
Effective internal control over financial reporting is necessary for us to provide reliable financial reports and, together with adequate disclosure controls and procedures, are designed to prevent fraud. To maintain and improve the effectiveness of our disclosure controls and procedures and internal control over financial reporting, we have expended and will continue to expend significant resources, including accounting and professional services fees related costs and in providing diligent management oversight.
Any failure to implement required new or improved controls, or difficulties encountered in their implementation, could cause us to fail to meet our reporting obligations. Moreover, our independent registered public accounting firm could issue a report that is adverse in the event it is not satisfied with the level at which our controls are documented, designed or operating. Ineffective internal control could also cause investors to lose confidence in our reported financial information, which could have a negative effect on the trading price of our common stock. In addition, any future testing by us conducted in connection with Section 404 of the Sarbanes-Oxley Act, or the subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our consolidated financial statements, which could lead to financial statement restatements and require us to incur the expense of remediation.
Risks associated with use of our company-wide enterprise resource planning (“ERP”) system may adversely affect our business and results of operations or the effectiveness of internal control over financial reporting.
We completed implementation of a company-wide ERP system in 2016 to handle the business and financial processes within our operations and corporate functions. To reap the benefits of our ERP system, we were required to change certain business and financial processes. Our business and results of operations may be adversely affected if we experience operating problems with the ERP system, or if the ERP system and the associated process changes do not give rise to the benefits that we expect. If the ERP system does not operate as intended, our business, results of operations and internal controls over financial reporting may be adversely affected.
If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our stock price and trading volume could decline.
The trading market for our common stock depends in part on the research and reports that securities or industry analysts publish about us or our business. Prior to our IPO in October 2014, there had not been a public market for our common stock and we did not have research coverage by securities and industry analysts. If one or more of the analysts who covers us downgrades our stock or publishes inaccurate or unfavorable research about our business, our stock price would likely decline. If one or more of these analysts ceases coverage of us or fails to publish reports on us regularly, demand for our stock could decrease, which could cause our stock price and trading volume to decline.
77
If we sell or issue additional shares of our common stock or securities convertible into our common stock in the future, the percentage ownership of our stockholders will be diluted.
On November 2, 2015, we filed a shelf registration statement on Form S-3 for the potential offering, issuance and sale by us of up to $300.0 million of our common stock, preferred stock, debt securities, warrants to purchase our common stock, preferred stock and debt securities, subscription rights to purchase our common stock, preferred stock and debt securities, and units consisting of all or some of these securities. Our shelf registration statement was declared effective by the SEC on November 24, 2015. In June 2016, we sold 5,175,000 shares of our common stock in an underwritten public offering pursuant to the shelf registration statement for aggregate gross proceeds of $144.9 million. Furthermore, pursuant to a sales agreement between us and Cowen and Company, LLC (“Cowen”), common stock with an aggregate offering price of up to $75.0 million may be issued and sold pursuant to an “at-the-market” offering for sales of our common stock. Subject to certain limitations in the sales agreement and compliance with applicable law, we have the discretion to deliver a sales notice to Cowen at any time throughout the term of the sales agreement, which has a term equal to the term of the registration statement on Form S-3 unless otherwise terminated earlier by us or Cowen pursuant to the terms of the sales agreement. The number of shares that are sold by Cowen after delivering a sales notice will fluctuate based on the market price of our common stock during the sales period and limits we set with Cowen. Because the price per share of each share sold will fluctuate based on the market price of our common stock during the sales period, it is not possible at this stage to predict the number of shares that will be ultimately issued. As of the date hereof, no shares of our common stock have been sold pursuant to the sales agreement.
In addition, in February 2017, we filed an automatic shelf registration statement on Form S-3, which immediately became effective. In March 2017, we sold 5,750,000 shares of our common stock in an underwritten public offering pursuant to the automatic shelf registration statement for aggregate gross proceeds of $193.8 million. As long as we continue to satisfy the requirements to be deemed a “well-known seasoned issuer” under SEC rules, and subject to certain other requirements, we will be eligible to file automatic shelf registration statements that become immediately effective upon filing and allow us to issue registered shares of common stock and other securities in one or more offerings, in amounts, at prices and on the terms that we will determine at the time of the offering. If we sell additional common stock, preferred stock, convertible securities and other equity securities in future transactions pursuant to our shelf registration statements or otherwise, existing investors may be materially diluted by such subsequent sales and new investors could gain rights superior to our existing stockholders.
Furthermore, we completed a sale of the Notes in May 2017 in a private placement in reliance on Section 4(a)(2) of the Securities Act. The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms. Holders of the Notes may convert all or a portion of their Notes at their option at any time prior to the close of business on the business day immediately prior to May 15, 2022, in multiples of $1,000 principal amount. The Notes are convertible into shares of our common stock at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock. As of December 31, 2017, the Notes were convertible into 8,109,771 shares of our common stock. The conversion rate and the corresponding conversion price will be subject to adjustment upon the occurrence of certain events. The conversion of some or all of the Notes into shares of our common stock will dilute the ownership interests of existing stockholders.
78
Our directors and executive officers, together with their affiliates, will be able to exert significant influence over us and could impede a change of corporate control.
As of December 31, 2017, our directors and executive officers beneficially owned (determined in accordance with the rules of the SEC), in the aggregate, approximately 15% of our outstanding common stock. As a result, these stockholders, acting together, would have the ability to exert significant influence on matters submitted to our stockholders for approval, including the election of directors and any merger, consolidation or sale of all or substantially all of our assets. In addition, these stockholders, acting together, have the ability to significantly influence the management and affairs of our company. Accordingly, this concentration of ownership could harm the market price of our common stock by:
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• |
delaying, deferring or preventing a change of control of us; |
|
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• |
impeding a merger, consolidation, takeover or other business combination involving us; or |
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• |
discouraging a potential acquiror from making a tender offer or otherwise attempting to obtain control of us. |
Delaware law and provisions in our restated certificate of incorporation and restated bylaws could make a merger, tender offer or proxy contest difficult, thereby depressing the trading price of our common stock.
The anti-takeover provisions of the Delaware General Corporation Law may discourage, delay or prevent a change of control by prohibiting us from engaging in a business combination with stockholders owning in excess of 15% of our outstanding voting stock for a period of three years after the person becomes an interested stockholder, even if a change of control would be beneficial to our existing stockholders. In addition, our restated certificate of incorporation and restated bylaws contain provisions that may make the acquisition of our company more difficult, including the following:
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• |
our board of directors is classified into three classes of directors with staggered three-year terms, with directors removable from office only for cause, so that not all members of our board of directors are elected at one time; |
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• |
only our board of directors has the right to fill a vacancy created by the expansion of our board of directors or the resignation, death or removal of a director, which prevents stockholders from being able to fill vacancies on our board of directors; |
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• |
only our chairman of our board of directors, our chief executive officer, our president or a majority of our board of directors are authorized to call a special meeting of stockholders; |
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• |
certain litigation against us can only be brought in Delaware; |
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• |
our restated certificate of incorporation authorizes the issuance of undesignated preferred stock, the terms of which may be established and shares of which may be issued without stockholder approval, and which may include rights superior to the rights of the holders of common stock; |
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• |
all stockholder actions must be taken at meetings of our stockholders, and may not be taken by written consent; |
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• |
our board of directors is expressly authorized to make, alter or repeal our bylaws; and |
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• |
advance notice requirements apply for stockholders to nominate candidates for elections to our board of directors or to bring matters that can be acted upon by stockholders at stockholder meetings. |
These provisions could also discourage proxy contests and make it more difficult for stockholders to elect directors of their choosing so as to cause us to take certain corporate actions they desire.
79
Because management has broad discretion as to the use of the net proceeds from our previous and future sales of securities, stockholders may not agree with how we use them, and such proceeds may not be applied successfully.
Our management will have considerable discretion over the use of proceeds from our previous and future sales of securities and could spend the proceeds in ways that do not necessarily improve our operating results or enhance the value of our common stock, or with which our stockholders otherwise disagree. The failure of our management to apply these funds effectively could, among other things, result in unfavorable returns and uncertainty about our prospects, each of which could cause the price of our common stock to decline. Pending their use, we may invest the net proceeds from our previous and future sales of securities in a manner that does not produce income or that loses value. These investments may not yield a favorable return to our investors.
We have never paid dividends on our capital stock, and we do not anticipate paying any cash dividends in the foreseeable future.
We have never declared nor paid cash dividends on our capital stock. We currently intend to retain any future earnings to finance the operation and expansion of our business, and we do not expect to declare or pay any dividends in the foreseeable future. Consequently, stockholders must rely on sales of their common stock after price appreciation, which may never occur, as the only way to realize any future gains on their investment.
Risks Related to the Notes
We have indebtedness in the form of convertible senior notes, which could adversely affect our financial health and our ability to respond to changes in our business.
In May 2017, we completed an offering of the Notes in a private placement in reliance on Section 4(a)(2) of the Securities Act (the “Notes Offering”). The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms. Holders of the Notes may convert all or a portion of their Notes at their option at any time prior to the close of business on the business day immediately prior to May 15, 2022, in multiples of $1,000 principal amount. The Notes are convertible into shares of our common stock at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock. As of December 31, 2017, the Notes were convertible into 8,109,771 shares of our common stock. The conversion rate and the corresponding conversion price will be subject to adjustment upon the occurrence of certain events. The conversion of some or all of the Notes into shares of our common stock will dilute the ownership interests of existing stockholders. In addition, the indenture for the Notes provides that we are required to repay amounts due under the indenture in the event that there is an event of default for the Notes that results in the principal, premium, if any, and interest, if any, becoming due prior to maturity date for the Notes. There can be no assurance that we will be able to repay this indebtedness when due, or that we will be able to refinance this indebtedness on acceptable terms or at all.
As a result of our level of increased debt after the completion of the Notes Offering:
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• |
our vulnerability to adverse general economic conditions and competitive pressures is heightened; |
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• |
we are required to dedicate a larger portion of our cash flow from operations to interest payments, limiting the availability of cash for other purposes; |
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• |
our flexibility in planning for, or reacting to, changes in our business and industry may be more limited; and |
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• |
our ability to obtain additional financing in the future for working capital, capital expenditures, acquisitions, general corporate purposes or other purposes may be impaired. |
We cannot be sure that our leverage resulting from the level of increased debt due to the Notes Offering will not materially and adversely affect our ability to finance our operations or capital needs or to engage in other business activities. In addition, we cannot be sure that additional financing will be available when required or, if available, will be on terms satisfactory to us. Further, even if we are able to obtain additional financing, we may be required to use such proceeds to repay a portion of our debt.
80
We may be unable to repurchase the Notes upon a fundamental change when required by the holders or repay prior to maturity any accelerated amounts due under the Notes upon an event of default, and our future debt agreements may contain limitations on our ability to pay cash upon conversion, repurchase or repayment of the Notes.
Holders of the Notes have the right to require us to repurchase their Notes upon the occurrence of a fundamental change at a fundamental change repurchase price equal to 100% of the principal amount of the Notes to be purchased, plus accrued and unpaid interest, if any, to, but not including, the fundamental change repurchase date. In addition, the indenture for the Notes provides that we are required to repay amounts due under the indenture in the event that there is an event of default for the Notes that results in the principal, premium, if any, and interest, if any, becoming due prior to the maturity date for the Notes. However, we may not have enough available cash or be able to obtain financing at the time we are required to repurchase Notes surrendered upon a fundamental change or repay prior to maturity any accelerated amounts.
In addition, our ability to purchase the Notes or repay prior to maturity any accelerated amounts under the Notes upon an event of default or redeem the Notes may be limited by law, by regulatory authority or by agreements governing our future indebtedness. Our failure to repurchase Notes at a time when the repurchase is required by the indenture (whether upon a fundamental change or otherwise under the indenture) would constitute a default under the indenture. A default under the indenture or the fundamental change itself could also lead to a default under agreements governing any of our future indebtedness. If the repayment of the related indebtedness were to be accelerated after any applicable notice or grace periods, we may not have sufficient funds to repay the indebtedness or repurchase the Notes.
Servicing debt requires a significant amount of cash, and we may not have sufficient cash flow from our business to pay our debt.
Our ability to make scheduled payments of the principal of, to pay interest on or to refinance our indebtedness, including the Notes, depends on our future financial condition and operating performance, which is subject to economic, financial, competitive and other factors beyond our control. Our business may not generate cash flow from operations in the future sufficient to satisfy our obligations under the Notes and any future indebtedness we may incur and to make necessary capital expenditures. We cannot assure you that we will have in the future a level of cash flows from operating activities sufficient to permit us to pay the principal, premium, if any, and interest on our debt, including the Notes.
If we are unable to generate such cash flow, we may be required to adopt one or more alternatives, such as reducing or delaying investments or capital expenditures, selling assets, refinancing or obtaining additional equity capital on terms that may be onerous or highly dilutive. These alternative measures may not be successful and may not permit us to meet our schedule debt servicing obligations. Further, we may need to refinance all or a portion of our debt on our before maturity, and our ability to refinance the Notes or future indebtedness will depend on the capital markets and our financial condition at such time. We may not be able to engage in any of these activities on commercially reasonable terms or at all, which could result in a default on the Notes or future indebtedness.
We may still incur substantially more debt or take other actions which would intensify the risks discussed above.
We and our subsidiaries may incur substantial additional debt in the future, subject to the restrictions contained in our future debt instruments. We are not restricted under the terms of the indenture governing the Notes from incurring additional debt, securing existing or future debt, recapitalizing our debt, repurchasing our stock, pledging our assets, making investments, paying dividends, guaranteeing debt or taking a number of other actions that are not limited by the terms of the indenture governing the Notes that could have the effect of diminishing our ability to make payments on the Notes when due.
81
Conversion of the Notes will dilute the ownership interest of existing stockholders, including holders who had previously converted their Notes, or may otherwise depress our stock price.
The conversion of some or all of the Notes will dilute the ownership interests of existing stockholders. Any sales in the public market of the common stock issuable upon such conversion could adversely affect prevailing market prices of our common stock. In addition, the existence of the Notes may encourage short selling by market participants because the conversion of the Notes could be used to satisfy short positions, or anticipated conversion of the Notes into shares of our common stock could depress our stock price.
Our indebtedness could adversely affect our financial health and our ability to respond to changes in our business.
As a result of our level of debt following the completion of our sale of the Notes:
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• |
our vulnerability to adverse general economic conditions and competitive pressures will be heightened; |
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|
• |
we will be required to dedicate a larger portion of our capital resources to interest payments, limiting the availability of cash for other purposes; |
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|
• |
our flexibility in planning for, or reacting to, changes in our business and industry may be more limited; and |
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|
• |
our ability to obtain additional financing in the future for working capital, capital expenditures, acquisitions, general corporate purposes or other purposes may be impaired. |
We cannot be sure that our leverage resulting from the level of debt after the completion of our sale of the Notes will not materially and adversely affect our ability to finance our operations or capital needs or to engage in other business activities. In addition, we cannot be sure that additional financing will be available when required or, if available, will be on terms satisfactory to us. Further, even if we are able to obtain additional financing, we may be required to use such proceeds to repay a portion of our debt.
The Notes are effectively junior to any secured debt we may incur and structurally subordinated to any liabilities of our subsidiary.
The Notes are our unsecured obligations exclusively and are not guaranteed by our subsidiary. Our subsidiary is a separate and distinct legal entity and has no obligation, contingent or otherwise, to make payments on the Notes or to make any funds available for that purpose. In addition, the indenture for the Notes will not restrict us or our subsidiary from incurring additional debt or other liabilities. Accordingly, the Notes rank senior in right of payment to any of our indebtedness that is expressly subordinated in right of payment to the Notes; will rank equally in right of payment with any of our unsecured indebtedness that is not so subordinated; will be effectively junior in right of payment to any secured indebtedness we may incur to the extent of the value of the assets securing such indebtedness; and will be structurally junior to any indebtedness and other liabilities (including trade payables) of our subsidiaries. In the event of our bankruptcy, liquidation, reorganization or other winding up, our assets that secure any of our debt will be available to pay obligations on the Notes only after such secured debt we may incur has been repaid in full. There may not be sufficient assets remaining to pay amounts due on any or all of the Notes then outstanding.
Our right to receive assets from our subsidiary upon its liquidation or reorganization, and the right of holders of the Notes to participate in those assets, is structurally subordinated to claims of the subsidiary’s creditors, including trade creditors. Even if we were a creditor of our subsidiary, our rights as a creditor would be subordinate to any security interest in the assets of the subsidiary and any indebtedness of the subsidiary senior to that held by us. Furthermore, our subsidiary is not under any obligation to make payments to us, and any payments to us would depend on the earnings or financial condition of our subsidiary and various business considerations. Statutory, contractual or other restrictions may also limit our subsidiary’s ability to pay dividends or make distributions, loans or advances to us. For these reasons, we may not have access to any assets or cash flows of our subsidiary to make payments on the Notes.
82
The fundamental change repurchase feature of the Notes may delay or prevent an otherwise beneficial attempt to take over our company.
The terms of the Notes require us to repurchase the Notes in the event of a fundamental change. Under certain circumstances, a takeover of our company would trigger an option of the holders of the Notes to require us to repurchase the Notes. In addition, if a make-whole fundamental change occurs prior to the maturity date of the Notes, we will in some cases be required to increase the conversion rate for a holder that elects to convert its Notes in connection with such make-whole fundamental change. Furthermore, the indenture for the Notes prohibits us from engaging in certain mergers or acquisitions unless, among other things, the surviving entity assumes our obligations under the Notes. These and other provisions of the indenture may have the effect of delaying or preventing a takeover of our company that would otherwise be beneficial to investors in the Notes.
83
None.
We lease approximately 68,990 square feet of office space in Menlo Park, California under a lease and a sublease that expires in December 2021 and April 2024, respectively. We have an option to renew the lease for an additional five‑year term to 2026. We use our current facilities for our research and development and general and administrative personnel. We believe that our existing facilities are sufficient for our current and near‑term needs, and that our facilities are in good condition and are adequate and suitable for their purposes.
From time to time, we may become involved in legal proceedings arising in the ordinary course of our business. We are not presently a party to any legal proceedings that, if determined adversely to us, would individually or taken together have a material adverse effect on our business, operating results, financial condition or cash flows.
None.
84
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ITEM 5. |
MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES |
Market Price of Our Common Stock
Our common stock is listed on The NASDAQ Global Select Market under the symbol “DERM.” The following table sets forth for the periods indicated the high and low sales prices per share of our common stock as reported on The NASDAQ Global Select Market:
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Low |
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High |
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||
|
Fiscal Year Ended December 31, 2017 |
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|
|
|
|
|
|
|
|
Fourth Quarter |
|
$ |
23.23 |
|
|
$ |
30.62 |
|
|
Third Quarter |
|
|
21.35 |
|
|
|
30.49 |
|
|
Second Quarter |
|
|
25.63 |
|
|
|
35.76 |
|
|
First Quarter |
|
|
27.32 |
|
|
|
38.75 |
|
|
Fiscal Year Ended December 31, 2016 |
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|
|
|
|
|
|
|
|
Fourth Quarter |
|
$ |
27.92 |
|
|
$ |
36.34 |
|
|
Third Quarter |
|
|
28.51 |
|
|
|
36.16 |
|
|
Second Quarter |
|
|
20.13 |
|
|
|
34.00 |
|
|
First Quarter |
|
|
17.42 |
|
|
|
34.31 |
|
On February 12, 2018, the last reported sale price of our common stock as reported on The NASDAQ Global Select Market was $27.69 per share.
Holders of our Common Shares
As of February 12, 2018, there were 41,821,978 shares of our common stock issued and outstanding with 19 holders of record of our common stock. The actual number of stockholders is greater than this number of record holders, and includes stockholders who are beneficial owners, but whose shares are held in street name by brokers and other nominees. This number of holders of record also does not include stockholders whose shares may be held in trust by other entities.
Dividend Policy
We have never declared or paid cash dividends on our capital stock. We do not expect to pay dividends on our common stock for the foreseeable future. Instead, we anticipate that all of our available funds and future earnings, if any, will be used for the operation and growth of our business. Any future determination to declare cash dividends would be subject to the discretion of our board of directors and would depend upon various factors, including our results of operations, financial condition and capital requirements, restrictions that may be imposed by applicable law and our contracts and other factors deemed relevant by our board of directors.
Securities Authorized for Issuance under Equity Compensation Plans
The information concerning our equity compensation plans required by this item is incorporated by reference herein to the section in the definitive Proxy Statement for our 2018 Annual Meeting of Stockholders entitled “Equity Compensation Plan Information.”
85
Unregistered Sales of Equity Securities
During the three months ended December 31, 2017, we did not make any sales of unregistered securities other than the sale of 19,715 shares of our common stock to Takeda Pharmaceutical Company Limited (“Takeda”) pursuant to the terms of an exclusive option and license agreement dated August 29, 2016, as amended, in exchange for the right to evaluate and conduct research on Takeda compounds directed to an additional biological target and an option to license exclusive worldwide rights to selected compounds from the additional program. The shares were sold in reliance on the exemption from the registration requirements of the Securities Act of 1933, as amended (“Securities Act”), set forth in Rule 506(b) of Regulation D promulgated under the Securities Act, based on the sale of securities to an accredited investor in a transaction not involving any public offering.
Issuer Purchases of Equity Securities
None.
86
The following stock performance graph compares our total stock return with the total return for (1) The NASDAQ Composite Index and (2) The NASDAQ Biotechnology Index for the period from October 3, 2014 (the date our common stock commenced trading on The NASDAQ Global Select Market) through December 31, 2017. The figures represented below assume an investment of $100 in our common stock at the closing price of $15.55 on October 3, 2014 and in The NASDAQ Composite Index and The NASDAQ Biotechnology Index on October 3, 2014 and the reinvestment of dividends into shares of common stock; however, no dividends have been declared on our common stock to date. The comparisons in the table are required by the SEC, and are not intended to forecast or be indicative of possible future performance of our common stock. This graph shall not be deemed “soliciting material” or be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (“Exchange Act”), or otherwise subject to the liabilities under that Section, and shall not be deemed to be incorporated by reference into any of our filings under the Securities Act of 1933, as amended (the “Securities Act”), whether made before or after the date hereof and irrespective of any general incorporation language in any such filing, except to the extent we specifically incorporate it by reference into such filing.
87
You should read the following selected consolidated financial data together with the section of this report entitled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our consolidated financial statements and the related notes included in this Annual Report on Form 10‑K. The consolidated statement of operations data for the years ended December 31, 2017, 2016 and 2015 and the consolidated balance sheet data as of December 31, 2017 and 2016 are derived from our audited financial statements included elsewhere in this report. The selected consolidated statement of operations data for the years ended December 31, 2014 and 2013 and the selected consolidated balance sheet data as of December 31, 2015, 2014 and 2013 have been derived from our audited consolidated financial statements and accompanying notes that are not included in this Annual Report on Form 10‑K.
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|
Year Ended December 31, |
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|||||||||||||||||
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|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|
2014 |
|
|
2013 |
|
|||||
|
|
|
(in thousands, except per share amounts) |
|
|||||||||||||||||
|
Consolidated Statements of Operations Data: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Revenue: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Collaboration and license revenue |
|
$ |
4,541 |
|
|
$ |
22,585 |
|
|
$ |
7,300 |
|
|
$ |
7,300 |
|
|
$ |
— |
|
|
Operating expenses: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Research and development |
|
|
104,409 |
|
|
|
83,166 |
|
|
|
66,831 |
|
|
|
30,710 |
|
|
|
17,937 |
|
|
Acquired in-process research and development |
|
|
128,555 |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
General and administrative |
|
|
71,903 |
|
|
|
30,043 |
|
|
|
17,721 |
|
|
|
8,288 |
|
|
|
4,366 |
|
|
Impairment of intangible assets |
|
|
— |
|
|
|
— |
|
|
|
2,394 |
|
|
|
— |
|
|
|
— |
|
|
Total operating expenses |
|
|
304,867 |
|
|
|
113,209 |
|
|
|
86,946 |
|
|
|
38,998 |
|
|
|
22,303 |
|
|
Loss from operations |
|
|
(300,326 |
) |
|
|
(90,624 |
) |
|
|
(79,646 |
) |
|
|
(31,698 |
) |
|
|
(22,303 |
) |
|
Interest and other income (expense), net |
|
|
5,205 |
|
|
|
1,540 |
|
|
|
896 |
|
|
|
7 |
|
|
|
(38 |
) |
|
Interest expense |
|
|
(8,140 |
) |
|
|
— |
|
|
|
(147 |
) |
|
|
(153 |
) |
|
|
(9 |
) |
|
Loss on extinguishment of debt |
|
|
— |
|
|
|
— |
|
|
|
(124 |
) |
|
|
— |
|
|
|
— |
|
|
Loss before taxes |
|
|
(303,261 |
) |
|
|
(89,084 |
) |
|
|
(79,021 |
) |
|
|
(31,844 |
) |
|
|
(22,350 |
) |
|
(Benefit) provision for income taxes |
|
|
— |
|
|
|
— |
|
|
|
(622 |
) |
|
|
31 |
|
|
|
— |
|
|
Net loss |
|
$ |
(303,261 |
) |
|
$ |
(89,084 |
) |
|
$ |
(78,399 |
) |
|
$ |
(31,875 |
) |
|
$ |
(22,350 |
) |
|
Net loss per share, basic and diluted |
|
$ |
(7.48 |
) |
|
$ |
(2.70 |
) |
|
$ |
(2.93 |
) |
|
$ |
(4.96 |
) |
|
$ |
(27.03 |
) |
|
Weighted-average common shares used to compute net loss per share, basic and diluted |
|
|
40,562 |
|
|
|
33,045 |
|
|
|
26,727 |
|
|
|
6,426 |
|
|
|
827 |
|
|
|
|
As of December 31, |
|
|||||||||||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|
2014 |
|
|
2013 |
|
|||||
|
|
|
(in thousands) |
|
|||||||||||||||||
|
Consolidated Balance Sheets Data: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cash and cash equivalents and investments |
|
$ |
550,993 |
|
|
$ |
251,942 |
|
|
$ |
214,693 |
|
|
$ |
97,151 |
|
|
$ |
22,144 |
|
|
Working capital |
|
|
451,256 |
|
|
|
248,999 |
|
|
|
191,337 |
|
|
|
93,573 |
|
|
|
17,973 |
|
|
Long–term investments |
|
|
— |
|
|
|
24,551 |
|
|
|
1,019 |
|
|
|
66,483 |
|
|
|
— |
|
|
Total assets |
|
|
560,794 |
|
|
|
312,601 |
|
|
|
221,932 |
|
|
|
178,221 |
|
|
|
26,871 |
|
|
Convertible notes, net |
|
|
279,389 |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
Convertible preferred stock |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
59,588 |
|
|
Accumulated deficit |
|
|
(553,393 |
) |
|
|
(250,132 |
) |
|
|
(161,048 |
) |
|
|
(82,649 |
) |
|
|
(50,774 |
) |
|
Total stockholders’ equity (deficit) |
|
|
149,649 |
|
|
|
247,370 |
|
|
|
185,475 |
|
|
|
153,579 |
|
|
|
(49,803 |
) |
88
This Management’s Discussion and Analysis of Financial Condition and Results of Operations should be read in conjunction with the consolidated financial statements and notes thereto for the year ended December 31, 2017, included elsewhere in this Form 10‑K for the year ended December 31, 2017 and other disclosures (including the disclosures under “Part I Item 1A. Risk Factors”) included in this Annual Report on Form 10‑K. In addition to historical information, this discussion and analysis contains forward‑looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act. These statements are often identified by the use of words such as “may,” “will,” “expect,” “believe,” “anticipate,” “intend,” “could,” “should,” “potential,” “predict,” “project,” “estimate,” or “continue,” and similar expressions or variations. Forward‑looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward‑looking statements. Factors that could cause or contribute to these differences include those set forth elsewhere in this report, particularly in Part I Item 1A. Risk Factors, that could cause actual results to differ materially from historical results or anticipated results. Except as may be required by law, we disclaim any obligation to update any forward‑looking statements to reflect events or circumstances after the date of such statements.
Overview
We are a biopharmaceutical company dedicated to bringing biotech ingenuity to medical dermatology by delivering differentiated, new therapies to the millions of patients living with chronic skin conditions. We are committed to understanding the needs of both patients and physicians and using our insight to identify and develop leading-edge medical dermatology programs. Our pipeline includes three late-stage product candidates that could have a profound impact on the lives of patients: glycopyrronium tosylate (formerly DRM04), for which a New Drug Application (“NDA”) is under review by the U.S. Food and Drug Administration (“FDA”) for the treatment of primary axillary hyperhidrosis (underarm sweating beyond what is needed for normal body temperature regulation); olumacostat glasaretil (formerly DRM01), in Phase 3 development for the treatment of acne vulgaris; and lebrikizumab, in Phase 2b development for the treatment of moderate-to-severe atopic dermatitis. We are headquartered in Menlo Park, California.
89
Our three late‑stage product candidates are:
|
|
• |
Glycopyrronium tosylate, a novel, small-molecule investigational agent formulated as a topical, once-daily anticholinergic wipe that we are developing for the treatment of primary axillary hyperhidrosis (excessive underarm sweating), a medical condition that results in sweating beyond what is needed for normal body temperature regulation. Anticholinergics are a class of pharmaceutical products that exert their effect by blocking the action of acetylcholine, a neurotransmitter that transmits signals within the nervous system that are responsible for a range of bodily functions, including the activation of sweat glands. Glycopyrronium tosylate is a novel form of an anticholinergic agent that has been approved for systemic administration in other indications, and is designed to block sweat production by inhibiting the interaction between acetylcholine and the cholinergic receptors responsible for sweat gland activation. In July 2015, we commenced a Phase 3 clinical program for glycopyrronium tosylate in patients with primary axillary hyperhidrosis that comprised three clinical trials – the ATMOS-1 and ATMOS-2 pivotal trials and the ARIDO open-label safety trial. In June 2016, we announced positive topline results from the ATMOS-1 and ATMOS-2 trials, which enrolled a total of 697 adult and adolescent patients (ages nine and older) with primary axillary hyperhidrosis. Based on the overall dataset from the intent-to-treat populations, glycopyrronium tosylate demonstrated statistically significant improvements compared to vehicle for both co-primary endpoints and both secondary endpoints in the ATMOS-2 trial and one of the co-primary endpoints and both secondary endpoints compared in the ATMOS-1 trial. For the second co-primary endpoint in the ATMOS-1 trial, when extreme outlier data from one analysis center were excluded in accordance with the pre-specified statistical analysis plan submitted to the FDA, glycopyrronium tosylate demonstrated statistically significant results compared to vehicle. Consistent with the results of an earlier Phase 2b trial, glycopyrronium tosylate was well-tolerated with side effects that were primarily mild to moderate in severity. In December 2016, the treatment period for ARIDO, the open-label Phase 3 trial assessing the long-term safety of glycopyrronium tosylate, was completed. The safety and tolerability profile for glycopyrronium tosylate in the ARIDO trial was consistent with what was observed in the ATMOS-1 and ATMOS-2 trials. Based on the results of the glycopyrronium tosylate Phase 3 program and a pre-NDA meeting with the FDA in February 2017, we submitted an NDA for glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis to the FDA. The FDA has accepted our NDA for substantive review with a Prescription Drug User Fee Act target date (“PDUFA date”) for the completion of the FDA’s review of the NDA by June 30, 2018. |
|
|
• |
Olumacostat glasaretil, a novel, small molecule designed to target sebum production following topical application that we are developing for the treatment of acne vulgaris. Sebum is an oily substance made up of lipids produced by glands in the skin called sebaceous glands, and excessive sebum production is an important aspect of acne vulgaris that is not addressed by available topical therapies. Olumacostat glasaretil is designed to exert its effect by inhibiting acetyl coenzyme-A carboxylase, an enzyme that plays an important role in the synthesis of fatty acids, a type of lipid that represents an essential component of the majority of sebum lipids. In April 2015, we commenced a Phase 2b dose-ranging clinical trial to evaluate the safety and efficacy of olumacostat glasaretil in adult patients with moderate-to-severe acne vulgaris, and in May 2016, we announced positive topline results. In the Phase 2b dose-ranging trial, which enrolled a total of 420 patients, olumacostat glasaretil demonstrated statistically significant improvements in all primary endpoints compared to vehicle at the highest dose and in most primary endpoints at the other doses. Olumacostat glasaretil was well-tolerated with adverse events primarily mild or moderate in severity. Based on these results, in December 2016, we initiated a Phase 3 program to evaluate the safety and efficacy of olumacostat glasaretil as a potential treatment for acne vulgaris to support a potential NDA submission to the FDA. The Phase 3 program comprises three clinical trials – the CLAREOS-1 and CLAREOS-2 pivotal trials and the CLARITUDE open-label safety trial. In October 2017, we announced the completion of patient enrollment in CLAREOS-1 and CLAREOS-2 with a total of 1,503 adult and adolescent patients (ages nine and older) with moderate-to-severe acne vulgaris. We expect to announce topline results from the CLAREOS-1 and CLAREOS-2 trials in the first quarter of 2018. |
90
91
Following is a summary of selected key developments affecting our business that have occurred since December 31, 2016.
Glycopyrronium Tosylate
|
|
• |
Announced in November 2017 that the FDA had accepted our NDA for glycopyrronium tosylate for substantive review with a PDUFA date for the completion of the FDA’s review of the NDA by June 30, 2018. |
|
|
• |
Completed a meeting with the FDA in February 2017 to discuss our planned submission of an NDA for glycopyrronium tosylate. |
Olumacostat Glasaretil
|
|
• |
Announced in October 2017 the completion of patient enrollment in the CLAREOS-1 and CLAREOS-2 pivotal trials investigating the safety and efficacy of olumacostat glasaretil in patients with acne vulgaris. The two pivotal trials enrolled a total of 1,503 patients. |
|
|
• |
Announced in January 2017 the initiation of a Phase 3 program to evaluate the safety and efficacy of olumacostat glasaretil as a potential treatment for acne vulgaris to support a potential NDA submission to the FDA. The Phase 3 program comprises three clinical trials – the CLAREOS-1 and CLAREOS-2 pivotal trials and the CLARITUDE open-label safety trial. |
Lebrikizumab
|
|
• |
Announced in January 2018 the initiation of a Phase 2b dose-ranging study to evaluate the safety and efficacy of lebrikizumab as a monotherapy and to establish the dosing regimen for a potential Phase 3 program in patients with moderate-to-severe atopic dermatitis. The study is expected to enroll approximately 275 patients ages 18 years and older with moderate-to-severe atopic dermatitis at sites in the United States. |
|
|
• |
Acquired exclusive, worldwide rights pursuant to the Roche Agreement, which became effective in September 2017, to develop and commercialize lebrikizumab for atopic dermatitis and all other indications except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. |
Non-Program Developments
|
|
• |
Closed a private placement of 3.00% Convertible Senior Notes due 2022 (“Notes”) in May 2017, which generated net proceeds to us of $278.3 million. |
|
|
• |
Closed an underwritten public offering in March 2017 (“2017 Public Offering”), which generated net proceeds to us of $181.5 million. |
Other
|
|
• |
In November 2017, we announced that following our expressed intent to exercise our right to terminate the development and commercialisation agreement between us and UCB Pharma S.A. (“UCB”), dated March 21, 2014 (“UCB Agreement”), which provided for the development and commercialization of Cimzia, an injectable biologic tumor necrosis factor-alpha inhibitor, for the treatment of psoriasis, we and UCB entered into a transition agreement (“Transition Agreement”). The Transition Agreement provided for an orderly transition of the development and commercialization activities under the UCB Agreement from us to UCB and terminated the collaboration on February 15, 2018. |
92
For the year ended December 31, 2017, net loss increased 240% to $303.3 million from $89.1 million for the same period in 2016. The increase is primarily due to our recognition in 2017 of acquired in-process research and development expenses of $128.6 million related to the costs to acquire exclusive worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. Excluding the charge for the in-process research and development, our research and development expenses increased 26% to $104.4 million for the year ended December 31, 2017 compared to the same period in 2016, driven primarily by growth in clinical trial activities for our olumacostat glasaretil product candidate and by headcount growth and associated expenses, partially offset by a reduction in clinical trial activities for Cimzia and our glycopyrronium tosylate product candidates. General and administrative expenses increased 139% to $71.9 million compared to the same period in 2016, driven primarily by headcount growth and associated expenses, as well as expenses incurred to build out our infrastructure and prepare for our first product launch.
As of December 31, 2017, we had cash and cash equivalents and investments of $551.0 million.
Since our inception, we have devoted substantially all of our efforts to developing our product candidates, including conducting preclinical and clinical trials and manufacturing activities, and providing general and administrative support for our operations. We have financed our operations primarily through the sale of equity securities and convertible debt securities. We do not have any approved products and have never generated any revenue from product sales. Other than the revenue we may generate in connection with our agreements with UCB and Maruho Co., Ltd (“Maruho”), we do not expect to generate any revenue from any product candidates that we develop unless and until we obtain regulatory approval and commercialize our products or enter into other collaboration or license agreements with third parties for the development or license of those product candidates.
We have never been profitable and may never be profitable. As of December 31, 2017, we had an accumulated deficit of $553.4 million. We incurred net losses of $303.3 million, $89.1 million and $78.4 million for the years ended December 31, 2017, 2016 and 2015, respectively. We expect to incur significant costs to build out our infrastructure and prepare for our first product launch in advance of any of our product candidates receiving regulatory approval. As a result, we will need substantial additional funding to support our operating activities. Adequate funding may not be available to us on acceptable terms, or at all. We currently anticipate that we will seek to fund our operations through public or private equity or debt financings or other sources, such as potential collaboration or license agreements. Our failure to obtain sufficient funds on acceptable terms as and when needed could have a material adverse effect on our business, results of operations and financial condition.
Critical Accounting Polices and Significant Estimates
Our consolidated financial statements are prepared in accordance with U.S. generally accepted accounting principles. The preparation of these consolidated financial statements requires us to make estimates and assumptions that affect the reported amounts of assets, liabilities, revenue, costs and expenses and related disclosures. We base our estimates on our historical experience and on various other assumptions that we believe to be reasonable under the circumstances. In many instances, we could have reasonably used different accounting estimates, and in other instances changes in the accounting estimates are reasonably likely to occur from period to period. Accordingly, actual results could differ significantly from management’s estimates. To the extent that there are material differences between these estimates and actual results, our future consolidated financial statement presentation, financial condition, results of operations and cash flows will be affected.
While our significant accounting policies are described in the notes to our consolidated financial statements, we believe that the following critical accounting policies are most important to understanding and evaluating our reported consolidated financial results, as these policies relate to the more significant areas involving management’s judgments and estimates.
93
We generate revenue from collaboration and license agreements related to the development and commercialization of our product candidates. We recognize revenue when persuasive evidence of an arrangement exists, services have been performed or products have been delivered, the fee is fixed and determinable and collection is reasonably assured. Collaboration and license agreements may include non-refundable upfront payments or reimbursement of research and development costs, contingent consideration payments based on achievement of defined milestones, and royalties on sales of commercialized products. Our responsibilities under collaboration and license agreements may include the transfer of intellectual property rights, such as licenses, obligations to provide research and development services, product supply and regulatory approval services, and participation on certain development and commercialization committees. For upfront payments that are recorded as deferred revenue and being recognized over the estimated period of performance, we regularly review the estimated periods of performance based on the progress made under each arrangement. The estimated performance period may change over the course of an arrangement’s term. Such a change could have a material impact on the amount of revenue recorded in future periods.
Multiple Element Arrangements
To determine the appropriate revenue recognition for payments to us under our collaboration and license agreements with multiple element arrangements, we evaluate whether the non-contingent deliverables of an arrangement represent separate units of accounting or a single unit of accounting. For non-contingent deliverables of an arrangement to represent separate units of accounting, the delivered elements each must have standalone value to the customer. Factors to determine standalone value include whether the deliverable is proprietary to us, whether the customer can use the license or other deliverables for their intended purpose without the receipt of the remaining elements and whether there are other vendors that can provide the undelivered items. Deliverables that meet these criteria are considered separate units of accounting. Deliverables that do not meet these criteria are combined and accounted for as a single unit of accounting.
Acquired In-Process Research and Development Expenses
We expense in-process research and development projects acquired as part of asset acquisitions that have no alternative future use. The fair value assigned to incomplete research projects that have not reached technological feasibility and are acquired in business combinations are capitalized and accounted for as indefinite-lived intangible assets, subject to impairment testing until completion or abandonment of the applicable project. We determined that the acquired in-process research and development related to the Roche Agreement had no alternative future use and recorded an expense of $128.6 million during the year ended December 31, 2017 in the consolidated statements of operations as acquired in-process research and development expense. This expense was comprised of the initial payment of $80.0 million, which was made in October 2017, and the payments due in 2018 totaling $55.0 million that were measured with a discount rate used to value the payments at present value as of the effective date of the Roche Agreement.
Accrued Research and Development Expenses
We record accruals for estimated costs of research, preclinical, non-clinical and clinical studies and manufacturing activities, which are a significant component of research and development expenses. A substantial portion of our ongoing research and development activities is conducted by third-party service providers, including contract research organizations (“CROs”). Our contracts with CROs generally include pass-through fees such as regulatory expenses, investigator fees, travel costs and other miscellaneous costs, including shipping and printing fees. The financial terms of these contracts are subject to negotiations, which vary from contract to contract and may result in payment flows that do not match the periods over which materials or services are provided to us. We accrue the costs incurred under agreements with these third parties based on our estimate of actual work completed in accordance with the respective agreements. In the event we make advance payments, the payments are recorded as a prepaid expense and recognized as the services are performed. We determine the estimated costs through discussions with internal personnel and external service providers as to the progress or stage of completion of the services and the agreed-upon fees to be paid for such services. We accrue for costs associated with unused drug supplies that are both probable and estimable.
94
We make significant judgments and estimates in determining the accrual balance in each reporting period. As actual costs become known, we adjust our accruals. Although we do not expect our estimates to be materially different from amounts actually incurred, such estimates for the status and timing of services performed relative to the actual status and timing of services performed may vary and could result in us reporting amounts that are too high or too low in any particular period. Our accrual is dependent, in part, upon the receipt of timely and accurate reporting from CROs and other third-party vendors. Variations in the assumptions used to estimate accruals including, but not limited to, the number of patients enrolled, the rate of patient enrollment and the actual services performed, may vary from our estimates, resulting in adjustments to clinical trial expenses in future periods. Changes in these estimates that result in material changes to our accruals could materially affect our consolidated financial condition and results of operations.
Deferred Tax Assets and Liabilities and Uncertain Tax Positions
We use the liability method to account for income taxes. Under this method, deferred tax assets and liabilities are determined based on differences between the financial statement carrying amounts of existing assets and liabilities and their tax bases. Deferred tax assets and liabilities are measured using enacted tax rates applied to taxable income in the years in which those temporary differences are expected to be recovered or settled. We establish a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to be realizable. Financial statement effects of uncertain tax positions are recognized when it is more likely than not, based on the technical merits of the position, that they will be sustained upon examination. If the tax positions are not more likely than not to be sustained upon examination, we record reserves against those positions. Interest and penalties related to unrecognized tax benefits are included within our provision for income tax.
As of December 31, 2017, we had net operating loss (“NOL”) carryforwards available to reduce future taxable income, if any, for federal, California and Canadian income tax purposes of $452.2 million, $44.2 million and $3.2 million, respectively. The federal and California NOL carryforwards will begin expiring during the year ended December 31, 2030 and the Canadian NOL carryforwards will begin expiring during the year ended December 31, 2028.
As of December 31, 2017, we also had research and development credit carryforwards of $7.2 million, $4.4 million and $0.5 million available to reduce future taxable income, if any, for federal, California and Canadian income tax purposes, respectively. The federal and Canadian credit carryforwards will begin expiring in 2031 and the California state credit carryforwards have no expiration dates.
We have experienced at least one ownership change since inception and utilization of NOL carryforwards will therefore be subject to annual limitation, pursuant to Internal Revenue Code Section 382. Our ability to use our remaining NOL carryforwards may be further limited if we experience a Section 382 ownership change in connection with future changes in our stock ownership.
95
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||
|
|
|
Year Ended December 31, |
|
|
Change from 2016 to 2017 |
|
|
Change from 2015 to 2016 |
|
|||||||||||||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|
$ |
|
|
% |
|
|
$ |
|
|
% |
|
|||||||
|
|
(in thousands, except percentages) |
|
||||||||||||||||||||||||||
|
Revenue: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Collaboration and license revenue |
|
$ |
4,541 |
|
|
$ |
22,585 |
|
|
$ |
7,300 |
|
|
$ |
(18,044 |
) |
|
(80)% |
|
|
$ |
15,285 |
|
|
209% |
|
||
|
Operating expenses: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Research and development |
|
|
104,409 |
|
|
|
83,166 |
|
|
|
66,831 |
|
|
|
21,243 |
|
|
|
26 |
|
|
|
16,335 |
|
|
|
24 |
|
|
Acquired in-process research and development |
|
|
128,555 |
|
|
|
— |
|
|
|
— |
|
|
|
128,555 |
|
|
* |
|
|
|
— |
|
|
* |
|
||
|
General and administrative |
|
|
71,903 |
|
|
|
30,043 |
|
|
|
17,721 |
|
|
|
41,860 |
|
|
|
139 |
|
|
|
12,322 |
|
|
|
70 |
|
|
Impairment of intangible assets |
|
|
— |
|
|
|
— |
|
|
|
2,394 |
|
|
|
— |
|
|
* |
|
|
|
(2,394 |
) |
|
* |
|
||
|
Total operating expenses |
|
|
304,867 |
|
|
|
113,209 |
|
|
|
86,946 |
|
|
|
191,658 |
|
|
|
169 |
|
|
|
26,263 |
|
|
|
30 |
|
|
Loss from operations |
|
|
(300,326 |
) |
|
|
(90,624 |
) |
|
|
(79,646 |
) |
|
|
(209,702 |
) |
|
|
231 |
|
|
|
(10,978 |
) |
|
|
14 |
|
|
Interest and other income, net |
|
|
5,205 |
|
|
|
1,540 |
|
|
|
896 |
|
|
|
3,665 |
|
|
|
238 |
|
|
|
644 |
|
|
|
72 |
|
|
Interest expense |
|
|
(8,140 |
) |
|
|
— |
|
|
|
(147 |
) |
|
|
(8,140 |
) |
|
* |
|
|
|
147 |
|
|
* |
|
||
|
Loss on extinguishment of debt |
|
|
— |
|
|
|
— |
|
|
|
(124 |
) |
|
|
— |
|
|
* |
|
|
|
124 |
|
|
* |
|
||
|
Loss before taxes |
|
|
(303,261 |
) |
|
|
(89,084 |
) |
|
|
(79,021 |
) |
|
|
(214,177 |
) |
|
|
240 |
|
|
|
(10,063 |
) |
|
|
13 |
|
|
Benefit for income taxes |
|
|
— |
|
|
|
— |
|
|
|
(622 |
) |
|
|
— |
|
|
* |
|
|
|
622 |
|
|
* |
|
||
|
Net loss |
|
$ |
(303,261 |
) |
|
$ |
(89,084 |
) |
|
$ |
(78,399 |
) |
|
$ |
(214,177 |
) |
|
240% |
|
|
$ |
(10,685 |
) |
|
14% |
|
||
|
* |
Percentage not meaningful |
Revenue. Our revenue has been primarily comprised of upfront and milestone payments in connection with the UCB Agreement and our exclusive license agreement with Maruho, which grants Maruho an exclusive license to develop and commercialize glycopyrronium tosylate for the treatment of hyperhidrosis in Japan (“Maruho G.T. Agreement”).
For the year ended December 31, 2017, we recognized collaboration and license revenue of $4.3 million related to the $25.0 million upfront payment pursuant to the Maruho G.T. Agreement and $0.3 million pursuant to the Transition Agreement. For the year ended December 31, 2016, we recognized $21.4 million in collaboration revenue related to two $10.7 million development milestones achieved pursuant to the UCB Agreement for the completion of a clinical study report for a Phase 3 clinical trial for Cimzia in December 2016, and $1.2 million in collaboration and license revenue related to the $25.0 million upfront payment pursuant to the Maruho G.T. Agreement. We recognized $7.3 million in collaboration revenue in the year ended December 31, 2015 related to a milestone achieved pursuant to the UCB Agreement for the completion of patient enrollment in the first Phase 3 clinical trial for Cimzia in September 2015.
Research and Development. Research and development expenses include external costs incurred for the development of our product candidates, including third-party expenses necessary for conducting clinical studies and developing and manufacturing clinical trial supplies, and internal expenses consisting primarily of salaries and related costs, including stock-based compensation expense, for personnel in our research and development functions. We track external research and development costs incurred for each of our product candidates. We do not track our internal research and development costs by product candidate, as these costs are typically spread across multiple product candidates. We expense research and development costs as they are incurred.
96
The following table summarizes our research and development expenses incurred during the respective periods:
|
|
|
Phase of |
|
|
|
|
|
|
|
|
|
|
|
|
|
$ Change |
|
|
$ Change |
|
||
|
|
|
Development as of |
|
|
|
|
from |
|
|
from |
|
|||||||||||
|
|
|
December 31, |
|
Year Ended December 31, |
|
|
2016 to |
|
|
2015 to |
|
|||||||||||
|
|
|
2017 |
|
2017 |
|
|
2016 |
|
|
2015 |
|
|
2017 |
|
|
2016 |
|
|||||
|
|
|
(in thousands) |
|
|||||||||||||||||||
|
External costs incurred by product candidate: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Glycopyrronium tosylate1 |
|
Phase 3 Complete |
|
$ |
13,637 |
|
|
$ |
18,016 |
|
|
$ |
16,444 |
|
|
$ |
(4,379 |
) |
|
$ |
1,572 |
|
|
Olumacostat glasaretil2 |
|
Phase 3 |
|
|
34,179 |
|
|
|
9,788 |
|
|
|
9,499 |
|
|
|
24,391 |
|
|
|
289 |
|
|
Lebrikizumab3 |
|
Phase 2 |
|
|
1,217 |
|
|
|
— |
|
|
|
— |
|
|
|
1,217 |
|
|
|
— |
|
|
Cimzia4 |
|
Phase 3 |
|
|
19,617 |
|
|
|
30,371 |
|
|
|
25,827 |
|
|
|
(10,754 |
) |
|
|
4,544 |
|
|
Other research and development expenses |
|
|
|
|
2,012 |
|
|
|
1,551 |
|
|
|
259 |
|
|
|
461 |
|
|
|
1,292 |
|
|
Internal costs |
|
|
|
|
33,747 |
|
|
|
23,440 |
|
|
|
14,802 |
|
|
|
10,307 |
|
|
|
8,638 |
|
|
Total research and development expenses |
|
|
|
$ |
104,409 |
|
|
$ |
83,166 |
|
|
$ |
66,831 |
|
|
$ |
21,243 |
|
|
$ |
16,335 |
|
|
1. |
In June 2016, we announced topline results from the pivotal trials of the glycopyrronium tosylate Phase 3 program. In December 2016, the treatment period for ARIDO, an open-label Phase 3 trial assessing the long-term safety of glycopyrronium tosylate, was completed. We submitted an NDA to the FDA and, in November 2017, we announced that the FDA had accepted our NDA for substantive review with a PDUFA date for the completion of the FDA’s review of the NDA by June 30, 2018. |
|
2. |
In May 2016, we announced topline results from the olumacostat glasaretil Phase 2b study. Based on these results, we initiated a Phase 3 program in December 2016, announced completion of enrollment in the two pivotal clinical trials, CLAREOS-1 and CLAREOS-2, in October 2017 and expect to announce topline results from these trials in the first quarter of 2018. |
|
3. |
In connection with the Roche Agreement, which became effective in September 2017, we acquired the exclusive, worldwide rights to develop and commercialize lebrikizumab for atopic dermatitis and all other indications except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab in the Retained Field, and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. We initiated a Phase 2b dose-ranging study assessing lebrikizumab in adult patients with moderate-to-severe atopic dermatitis in January 2018. The acquired in-process research and development expenses of $128.6 million related to the Roche Agreement are not included in this table. |
|
4. |
In December 2014, we commenced a Phase 3 clinical program for Cimzia. We announced topline results for the three clinical trials in this Phase 3 program, CIMPASI-2, CIMPASI-1 and CIMPACT, in October 2016, December 2016 and January 2017, respectively. UCB submitted a supplemental Biologics License Application to the FDA and a Type II Variation to the European Medicines Agency in July 2017 to support potential approvals for Cimzia as a treatment option for patients with moderate-to-severe chronic plaque psoriasis. In November 2017, we entered into the Transition Agreement with UCB, which provided for an orderly transition of the development and commercialization activities under the UCB Agreement from us to UCB and terminated the collaboration on February 15, 2018. |
Research and development expenses increased $21.2 million, or 26%, for the year ended December 31, 2017 compared to the year ended 2016. This increase was primarily due to a $25.6 million increase in external costs primarily to advance our olumacostat glasaretil product candidate and a $10.3 million increase in internal costs related to headcount growth and associated expenses. These increases in research and development expenses were partially offset by a $15.1 million decrease in external costs associated with our Cimzia and glycopyrronium tosylate product candidates.
97
Research and development expenses increased $16.3 million, or 24%, for the year ended December 31, 2016 compared to the year ended December 31, 2015. This increase was primarily due to an $8.6 million increase in internal costs related to headcount growth and associated expenses, a $6.4 million increase in external costs primarily to advance our Cimzia and glycopyrronium tosylate product candidates and a $1.3 million increase in other research and development costs primarily related to the payment of $1.5 million upfront consideration in the form of shares of common stock under an agreement with Takeda Pharmaceutical Company Limited (“Takeda”), pursuant to which we acquired the right to evaluate and conduct research on Takeda compounds directed to each of three biological targets and an option to license exclusive worldwide rights to selected compounds from each of these three programs.
We expect our research and development expenses to increase as we continue clinical trials, prepare for regulatory submissions, expand our manufacturing activities, develop new product candidates resulting from our early-stage research programs or business development activities and expand our development organization and capabilities. The timing and amount of expenses incurred will depend largely upon the outcomes of current or future clinical studies for our product candidates, related regulatory requirements and manufacturing costs and the timing and cost of potential additions to our portfolio of product candidates.
Acquired in-process research and development. Acquired in-process research and development expenses consist of in-process research and development projects acquired as part of asset acquisitions that have no future alternative use. Ongoing costs incurred for the development of our product candidates acquired in an asset acquisition are classified as research and development expenses.
Acquired in-process research and development expense was $128.6 million for the year ended December 31, 2017 related to the initial $80.0 million payment made to Roche in October 2017 and the present value of the two additional payments totaling $55.0 million due to Roche in 2018 pursuant to the terms of the Roche Agreement.
No acquired in-process research and development expense was recorded for the years ended December 31, 2016 or 2015.
General and Administrative. General and administrative expenses consist primarily of salaries and related costs, including stock-based compensation, for personnel in our general and administrative functions, including our sales and marketing functions. Other general and administrative expenses include professional fees for audit, tax, legal, market research and commercial planning services.
General and administrative expenses increased 139% to $71.9 million for the year ended December 31, 2017 compared to the year ended December 31, 2016. This increase was primarily due to a $22.6 million increase in external costs to build out our infrastructure and prepare for our first product launch and a $19.2 million increase in internal costs related to headcount growth and associated expenses.
General and administrative expenses increased $12.3 million, or 70%, for the year ended December 31, 2016 compared to the year ended December 31, 2015. This increase was due to headcount growth and associated expenses, higher market research and planning related expenses and a transaction advisory fee paid in connection with the Maruho G.T. Agreement.
We expect our general and administrative expenses to increase substantially in the future as we expand our operating activities, increase our headcount, build out our infrastructure and, if glycopyrronium tosylate is approved, execute and prepare for our first product launch.
Impairment of Intangible Assets. In 2015, we recorded an impairment charge of $2.4 million against certain intangible assets based on our decision to discontinue further development efforts on our DRM05 and DRM02 early-stage programs.
No impairment charge was recorded during the years ended December 31, 2017 and 2016.
98
Interest and Other Income, Net. Interest and other income, net increased 238% to $5.2 million for the year ended December 31, 2017 compared to the year ended December 31, 2016, primarily due to an increase in interest income earned from our cash equivalents and investments.
Interest and other income, net increased $0.6 million for the year ended December 31, 2016 compared to the year ended December 31, 2015, primarily due to an increase in interest income earned from our cash equivalents and investments.
Interest Expense. Interest expense was $8.1 million for the year ended December 31, 2017, resulting from interest incurred on the Notes and the amortization of discount related to the Notes and the two payments totaling $55.0 million due to Roche in 2018.
Interest expense decreased $0.1 million to zero for the year ended December 31, 2016 compared to the year ended December 31, 2015, as we had no outstanding debt during the year ended December 31, 2016.
(Benefit) Provision for Income Taxes. No provision for income tax was recorded for the years ended December 31, 2017 and December 31, 2016. The $0.6 million benefit for income tax in 2015 relates to the decrease in deferred tax liability resulting from the impairment charge recorded during the year pertaining to certain acquired intangible assets. The deferred tax liability was originally established for the book‑tax differences related to the indefinitely lived intangible assets at the time of the Valocor acquisition in 2011.
Liquidity and Capital Resources
Since our inception, we have financed our operations primarily through the issuance and sale of equity securities.
On November 2, 2015, we filed a shelf registration on Form S-3 with the U.S. Securities and Exchange Commission (“SEC”) for the issuance and sale of up to an aggregate offering of $300.0 million of shares of our common stock, preferred stock, debt securities, warrants to purchase our common stock, preferred stock or debt securities, subscription rights to purchase our common stock, preferred stock or debt securities and/or units consisting of some or all of these securities.
On June 13, 2016, we sold 5,175,000 shares of our common stock in our shelf offering pursuant to a registration statement on Form S-3 (“Shelf Offering”) and received gross proceeds of $144.9 million and net proceeds of approximately $135.6 million, after deducting underwriting discounts and commissions of $8.7 million and offering expenses of approximately $0.6 million. The shelf registration also provides that we may issue and sell up to an aggregate offering of $75.0 million of our common stock through an at-the-market sales agreement with Cowen and Company, LLC. As of December 31, 2017, no sales had been made under this at-the-market sales agreement and $75.0 million of common stock remained available to be sold, subject to certain conditions as specified in the sales agreement.
Additionally, in February 2017, we filed an automatic shelf registration statement on Form S-3 for the potential offering, issuance and sale by us of shares of our common stock. In March 2017, we sold 5,750,000 shares of our common stock pursuant to our 2017 Public Offering and received gross proceeds of $193.8 million and net proceeds of $181.5 million, after deducting underwriting discounts and commissions of $11.6 million and offering expenses of $0.7 million.
In May 2017, we sold $287.5 million aggregate principal amount of Notes in a private placement to qualified institutional buyers and received net proceeds of $278.3 million, after deducting the initial purchasers’ discounts of $8.6 million and issuance costs of $0.6 million.
99
As of December 31, 2017, we had $551.0 million of cash and cash equivalents and investments. Our cash and cash equivalents and investments are held in a variety of interest-bearing instruments, including money market funds, U.S. Treasury securities, corporate debt, repurchase agreements, U.S. Government agency securities and commercial paper. Cash in excess of immediate requirements is invested with a view toward liquidity and capital preservation, and we seek to minimize the potential effects of concentration and degrees of risk.
Our primary use of cash is to fund our operating expenses, including costs to acquire in-process research and development projects. As of December 31, 2017, we had an accumulated deficit of $553.4 million. We expect to incur additional losses and expend substantial cash resources for the foreseeable future for the clinical development and potential commercialization of our product candidates and development of any other indications and product candidates we may choose to pursue, and to support the administrative and reporting requirements of a public company.
Cash Flows
The following table shows a summary of our cash flows for each of the years ended December 31, 2017, 2016 and 2015 (in thousands):
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Net cash (used in) provided by: |
|
|
|
|
|
|
|
|
|
|
|
|
|
Operating activities |
|
$ |
(103,963 |
) |
|
$ |
(74,111 |
) |
|
$ |
(48,442 |
) |
|
Investing activities |
|
|
(104,430 |
) |
|
|
(130,288 |
) |
|
|
(2,603 |
) |
|
Financing activities |
|
|
462,523 |
|
|
|
138,950 |
|
|
|
102,929 |
|
|
Net increase (decrease) in cash and cash equivalents |
|
$ |
254,130 |
|
|
$ |
(65,449 |
) |
|
$ |
51,884 |
|
Operating Activities. Net cash used in operating activities was $104.0 million for the year ended December 31, 2017 and consisted primarily of a net loss of $303.3 million, partially offset by $155.2 million in non-cash charges and a $44.1 million decrease in net operating assets. Non‑cash charges included $128.6 million in acquired in-process research and development expense related to the Roche Agreement, $20.7 million of stock‑based compensation expense and $2.4 million of net amortization of premiums on available‑for‑sale securities. The decrease in net operating assets consisted primarily of a $21.3 million decrease in collaboration receivables attributable to the receipt of payments from UCB in 2017 in relation to the third and fourth milestones, which were recognized in the fourth quarter of 2016, a $10.0 million increase in refund liability related to the Transition Agreement, a $7.6 million increase in accrued liabilities, a $6.2 million decrease in prepaid expenses and other current assets and a $1.5 million increase in accounts payable, partially offset by a $3.5 million decrease in deferred revenue.
Net cash used in operating activities was $74.1 million for the year ended December 31, 2016 and consisted primarily of a net loss of $89.1 million, partially offset by $14.5 million in non-cash charges and a $0.5 million decrease in net operating assets. Non‑cash charges included $11.0 million of stock‑based compensation expense, $1.9 million of amortization of premiums on available‑for‑sale securities and $1.5 million of common stock issued in connection with the Takeda Agreement. The decrease in net operating assets consisted primarily of a $23.8 million increase in deferred revenue and a $4.3 million increase in accounts payable, partially offset by a $21.4 million increase in collaboration receivables and a $6.8 million increase in prepaid expenses and other current assets.
Net cash used in operating activities was $48.4 million for the year ended December 31, 2015 and consisted primarily of our net loss of $78.4 million, partially offset by $9.7 million in non‑cash charges and a $20.2 million decrease in net operating assets. Non‑cash charges included $5.1 million of stock‑based compensation expense, $2.4 million of impairment charges against certain intangible assets and $2.0 million of amortization of premiums on available‑for‑sale securities. The decrease in net operating assets was driven primarily by a $10.4 million increase in accrued liabilities, a $7.3 million decrease in collaboration receivables and a $3.6 million increase in accounts payable, partially offset by a $1.2 million increase in prepaid expenses and other current assets.
100
Investing Activities. Net cash used in investing activities for the year ended December 31, 2017 was $104.4 million, which resulted primarily from purchases of investments of $302.4 million and from the payment made for the acquisition of in-process research and development pursuant to the Roche Agreement of $80.0 million, partially offset by proceeds from maturities of investments of $278.6 million.
Net cash used in investing activities for the year ended December 31, 2016 was $130.3 million, which resulted primarily from purchases of investments of $252.2 million, partially offset by proceeds from maturities of investments of $122.6 million.
Net cash used in investing activities for the year ended December 31, 2015 was $2.6 million, which resulted primarily from purchases of investments of $60.3 million, partially offset by proceeds from maturities of investments of $57.9 million.
Financing Activities. Net cash provided by financing activities for the year ended December 31, 2017 was $462.5 million, which resulted primarily from net proceeds of $181.5 million from our 2017 Public Offering and net proceeds of $278.3 million from the sale of the Notes.
Net cash provided by financing activities for the year ended December 31, 2016 was $139.0 million, which resulted primarily from net proceeds from our Shelf Offering of $135.6 million.
Net cash provided by financing activities for the year ended December 31, 2015 was $102.9 million, which consisted primarily of $104.0 million of net proceeds from the sale of our common stock in an underwritten follow-on public offering in August 2015, partially offset by $2.1 million from the repayment of our bank term loan.
Operating and Capital Expenditure Requirements
We have incurred losses since inception and anticipate that we will continue to generate losses for the foreseeable future. We expect the losses to increase as we continue the development of, and seek regulatory approvals for, our product candidates and prepare for potential commercialization and commercialize any approved products. We believe that our existing cash and cash equivalents and investments as of December 31, 2017 are sufficient to meet our anticipated cash requirements into the second half of 2019 and to: complete and generate topline results from our ongoing Phase 3 pivotal clinical trials for olumacostat glasaretil and Phase 2b dose-ranging study for lebrikizumab; commercialize our glycopyrronium tosylate product candidate, assuming that we receive the necessary regulatory approvals; complete registration-enabling activities and submit an NDA to the FDA for potential approval related to olumacostat glasaretil assuming the data from our Phase 3 clinical trials are positive; and continue potential lifecycle management activities related to our product candidates. However, we expect we will need to raise substantial additional financing in the future to fund our operations. In order to meet these additional cash requirements, we may seek to sell additional equity or convertible debt securities that may result in dilution to our stockholders. If we raise additional funds through the issuance of convertible debt securities, these securities could have rights senior to those of our common stock and could contain covenants that restrict our operations. We cannot ensure that additional financing will be available to us in the amounts we need or that such financing will be available on terms acceptable to us, if at all. If we are unable to raise additional capital when required or on acceptable terms, we may be required to significantly delay, scale back or discontinue one or more of our product development programs or other aspects of our business plan or relinquish, license or otherwise dispose of rights to products or product candidates that we would otherwise seek to commercialize or develop ourselves on terms that are less favorable than might otherwise be available, any of which could have a material adverse effect on our business, results of operations and financial condition. Please see “Part I, Item 1A, Risk Factors” for additional risks associated with our substantial capital requirements.
101
Contractual Obligations and Other Commitments
The following table summarizes our contractual obligations as of December 31, 2017:
|
|
|
Payment Due by Period |
|
|||||||||||||||||
|
|
|
Total |
|
|
Less than One Year |
|
|
1 – 3 Years |
|
|
3 – 5 Years |
|
|
More than 5 Years |
|
|||||
|
|
|
(in thousands) |
|
|||||||||||||||||
|
Refund liability |
|
$ |
10,000 |
|
|
$ |
10,000 |
|
|
$ |
— |
|
|
$ |
— |
|
|
$ |
— |
|
|
Operating lease obligations |
|
|
23,580 |
|
|
|
4,348 |
|
|
|
9,695 |
|
|
|
6,935 |
|
|
|
2,602 |
|
|
Convertible notes |
|
|
326,336 |
|
|
|
8,625 |
|
|
|
17,250 |
|
|
|
300,461 |
|
|
|
— |
|
|
Roche license payments |
|
|
55,000 |
|
|
|
55,000 |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
Total contractual obligations |
|
$ |
414,916 |
|
|
$ |
77,973 |
|
|
$ |
26,945 |
|
|
$ |
307,396 |
|
|
$ |
2,602 |
|
Pursuant to the Transition Agreement, we are obligated to reimburse UCB for up to $10.0 million of development costs incurred by UCB in connection with the development of Cimzia during the first half of 2018. If the aggregate development costs to be reimbursed are less than $10.0 million, we will pay UCB the difference between such aggregate costs and $10.0 million.
Pursuant to the Roche Agreement, we made an initial payment of $80.0 million in October 2017. Additionally, payments of $25.0 million and $30.0 million are due in September 2018 and December 2018, respectively, or upon the earlier achievement of certain development milestones.
Also related to the Roche Agreement, we will be obligated to make additional payments upon the achievement of certain milestones, comprising $40.0 million upon the initiation of the first Phase 3 clinical study, up to $210.0 million upon the achievement of regulatory and first commercial sale milestones in certain territories and up to $1.0 billion based on the achievement of certain thresholds for net sales of lebrikizumab for indications other than interstitial lung diseases. Upon regulatory approval, if obtained, we will make royalty payments representing percentages of net sales that range from the high single-digits to the high teens. These amounts are not included in the table above.
In addition, we have certain obligations under licensing agreements with third parties contingent upon achieving various development, regulatory and commercial milestones. Pursuant to our license agreement with Rose U LLC (“Rose U”) and related agreement with Stiefel Laboratories, Inc., a GSK company, with respect to our glycopyrronium tosylate product candidate, we are required to pay additional amounts totaling up to $4.1 million upon the achievement of specified regulatory, commercialization and other milestones. In addition, we are obligated to pay Rose U low‑to‑mid single‑digit royalties on net product sales and low double‑digit royalties on sublicense fees and certain milestone, royalty and other contingent payments received from sublicensees, to the extent such amounts are in excess of the milestone and royalty payments we are obligated to pay Rose U directly upon the events or sales triggering such payments. These amounts are not included in the table above.
102
In May 2017, we sold $287.5 million aggregate principal amount of Notes in a private placement. We received net proceeds of $278.3 million, after deducting the initial purchasers’ discounts of $8.6 million and issuance costs of $0.6 million. The Notes were issued pursuant to an Indenture, dated as of May 16, 2017 (the “Indenture”), between us and U.S. Bank National Association, as trustee. The Notes are senior, unsecured obligations and bear interest at a rate of 3.00% per year, payable in cash semi-annually in arrears on May 15 and November 15 of each year, beginning on November 15, 2017. The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms.
The Notes are convertible into shares of our common stock, par value $0.001 per share, at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock. The conversion rate and the corresponding conversion price are subject to adjustment upon the occurrence of certain events, but will not be adjusted for any accrued and unpaid interest. Holders of the Notes who convert their Notes in connection with a make-whole fundamental change (as defined in the Indenture) are, under certain circumstances, entitled to an increase in the conversion rate. Additionally, in the event of a fundamental change, holders of the Notes may require us to repurchase all or a portion of their Notes at a price equal to 100% of the principal amount of Notes, plus any accrued and unpaid interest, including any additional interest to, but excluding, the repurchase date. Holders of the Notes may convert all or a portion of their Notes at their option at any time prior to the close of business on the business day immediately prior to May 15, 2022, in multiples of $1,000 principal amount.
Segment Information
We have one primary business activity and operate in one reportable segment.
Off‑Balance Sheet Arrangements
We have not entered into any off-balance sheet arrangements, as defined in Item 303(a)(4) of Regulation S-K promulgated under the Exchange Act, and do not have any holdings in variable interest entities.
Recent Accounting Pronouncements
The information required by this item is included in Item 8, Note 2, Summary of Significant Accounting Policies in our Consolidated Financial Statements included in this Annual Report on Form 10‑K.
We are exposed to market risks in the ordinary course of our business. These risks primarily include risk related to interest rate sensitivities.
Interest Rate Risk
As of December 31, 2017 and December 31, 2016, we had cash and cash equivalents and investments of $551.0 million and $276.5 million, respectively, which consisted of money market funds, U.S. Treasury securities, corporate debt, repurchase agreements, U.S. Government agency securities, commercial paper and certificates of deposit. These interest‑earning instruments carry a degree of interest rate risk; however, historical fluctuations in interest income have not been significant. To reduce the volatility relating to these exposures, we have put investment and risk management policies and procedures in place. We do not enter into investments for trading or speculative purposes and have not used any derivative financial instruments to manage our interest rate risk exposure. We performed a sensitivity analysis to determine the impact a change in interest rates would have on the value of our investment portfolio. We have estimated that a hypothetical 100 basis point increase in interest rates would have resulted in a decrease in the fair market value of our investment portfolio of approximately $1.0 million and $1.2 million as of December 31, 2017 and 2016, respectively. We have not been exposed nor do we anticipate being exposed to material risks due to changes in interest rates.
103
We are subject to interest rate sensitivity on our outstanding 3.00% Convertible Senior Notes due 2022 (“Notes”) that were sold in a private placement to qualified institutional buyers. Increases in interest rates would result in a decrease in the fair value of our outstanding debt and decreases in interest rates would result in an increase in the fair value of our outstanding debt. The Notes are senior, unsecured obligations and bear interest at a rate of 3.00% per year, payable in cash semi-annually in arrears on May 15 and November 15 of each year, beginning on November 15, 2017. The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms. The Notes are convertible into shares of our common stock, par value $0.001 per share, at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock.
104
INDEX TO CONSOLIDATED FINANCIAL STATEMENTS
|
106 |
|
|
Consolidated Financial Statements |
|
|
107 |
|
|
108 |
|
|
109 |
|
|
110 |
|
|
111 |
|
|
112 |
105
REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM
The Board of Directors and Stockholders
Dermira, Inc.
Opinion on the Financial Statements
We have audited the accompanying consolidated balance sheets of Dermira, Inc. (the “Company”) as of December 31, 2017 and 2016, the related consolidated statements of operations, comprehensive loss, stockholders’ equity, and cash flows, for each of the three years in the period ended December 31, 2017, and the related notes (collectively referred to as the “financial statements”). In our opinion, the financial statements present fairly, in all material respects, the financial position of the Company as of December 31, 2017 and 2016, and the results of its operations and its cash flows for each of the three years in the period ended December 31, 2017, in conformity with US generally accepted accounting principles.
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the Company’s internal control over financial reporting as of December 31, 2017, based on criteria established in Internal Control-Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 Framework) and our report dated February 22, 2018 expressed an unqualified opinion thereon.
Basis for Opinion
These financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures include examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.
/s/ Ernst & Young LLP
We have served as the Company’s auditor since 2010.
San Jose, California
February 22, 2018
106
(in thousands, except per share amounts)
|
|
|
December 31, |
|
|||||
|
|
|
2017 |
|
|
2016 |
|
||
|
Assets |
|
|
|
|
|
|
|
|
|
Current assets: |
|
|
|
|
|
|
|
|
|
Cash and cash equivalents |
|
$ |
295,923 |
|
|
$ |
41,793 |
|
|
Short-term investments |
|
|
255,070 |
|
|
|
210,149 |
|
|
Collaboration receivables |
|
|
52 |
|
|
|
21,400 |
|
|
Prepaid expenses and other current assets |
|
|
5,569 |
|
|
|
10,649 |
|
|
Total current assets |
|
|
556,614 |
|
|
|
283,991 |
|
|
Property and equipment, net |
|
|
1,433 |
|
|
|
1,127 |
|
|
Long-term investments |
|
|
— |
|
|
|
24,551 |
|
|
Intangible assets |
|
|
1,126 |
|
|
|
1,126 |
|
|
Goodwill |
|
|
771 |
|
|
|
771 |
|
|
Other assets |
|
|
850 |
|
|
|
1,035 |
|
|
Total assets |
|
$ |
560,794 |
|
|
$ |
312,601 |
|
|
Liabilities and stockholders’ equity |
|
|
|
|
|
|
|
|
|
Current liabilities: |
|
|
|
|
|
|
|
|
|
Accounts payable |
|
$ |
15,094 |
|
|
$ |
13,500 |
|
|
Accrued liabilities |
|
|
25,115 |
|
|
|
17,227 |
|
|
Refund liability |
|
|
10,000 |
|
|
|
— |
|
|
Accrued payments related to acquired in-process research and development |
|
|
50,161 |
|
|
|
— |
|
|
Deferred revenue, current |
|
|
4,988 |
|
|
|
4,265 |
|
|
Total current liabilities |
|
|
105,358 |
|
|
|
34,992 |
|
|
Long-term liabilities: |
|
|
|
|
|
|
|
|
|
Deferred revenue, non-current |
|
|
25,286 |
|
|
|
29,550 |
|
|
Convertible notes, net |
|
|
279,389 |
|
|
|
— |
|
|
Deferred tax liability |
|
|
194 |
|
|
|
194 |
|
|
Other long-term liabilities |
|
|
918 |
|
|
|
495 |
|
|
Total liabilities |
|
|
411,145 |
|
|
|
65,231 |
|
|
Commitments and contingencies (Note 8) |
|
|
|
|
|
|
|
|
|
Stockholders’ equity: |
|
|
|
|
|
|
|
|
|
Preferred stock, $0.001 par value per share; 10,000 shares authorized as of December 31, 2017; no shares issued and outstanding as of December 31, 2017 or 2016 |
|
|
— |
|
|
|
— |
|
|
Common stock, $0.001 par value per share; 500,000 shares authorized as of December 31, 2017; 41,798 and 35,652 shares issued and outstanding as of December 31, 2017 and 2016, respectively |
|
|
42 |
|
|
|
36 |
|
|
Additional paid-in capital |
|
|
703,215 |
|
|
|
497,718 |
|
|
Accumulated other comprehensive loss |
|
|
(215 |
) |
|
|
(252 |
) |
|
Accumulated deficit |
|
|
(553,393 |
) |
|
|
(250,132 |
) |
|
Total stockholders’ equity |
|
|
149,649 |
|
|
|
247,370 |
|
|
Total liabilities and stockholders’ equity |
|
$ |
560,794 |
|
|
$ |
312,601 |
|
The accompanying notes are an integral part of these consolidated financial statements.
107
CONSOLIDATED STATEMENTS OF OPERATIONS
(in thousands, except per share amounts)
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Revenue: |
|
|
|
|
|
|
|
|
|
|
|
|
|
Collaboration and license revenue |
|
$ |
4,541 |
|
|
$ |
22,585 |
|
|
$ |
7,300 |
|
|
Operating expenses: |
|
|
|
|
|
|
|
|
|
|
|
|
|
Research and development |
|
|
104,409 |
|
|
|
83,166 |
|
|
|
66,831 |
|
|
Acquired in-process research and development |
|
|
128,555 |
|
|
|
— |
|
|
|
— |
|
|
General and administrative |
|
|
71,903 |
|
|
|
30,043 |
|
|
|
17,721 |
|
|
Impairment of intangible assets |
|
|
— |
|
|
|
— |
|
|
|
2,394 |
|
|
Total operating expenses |
|
|
304,867 |
|
|
|
113,209 |
|
|
|
86,946 |
|
|
Loss from operations |
|
|
(300,326 |
) |
|
|
(90,624 |
) |
|
|
(79,646 |
) |
|
Interest and other income, net |
|
|
5,205 |
|
|
|
1,540 |
|
|
|
896 |
|
|
Interest expense |
|
|
(8,140 |
) |
|
|
— |
|
|
|
(147 |
) |
|
Loss on extinguishment of debt |
|
|
— |
|
|
|
— |
|
|
|
(124 |
) |
|
Loss before taxes |
|
|
(303,261 |
) |
|
|
(89,084 |
) |
|
|
(79,021 |
) |
|
Benefit for income taxes |
|
|
— |
|
|
|
— |
|
|
|
(622 |
) |
|
Net loss |
|
$ |
(303,261 |
) |
|
$ |
(89,084 |
) |
|
$ |
(78,399 |
) |
|
Net loss per share, basic and diluted |
|
$ |
(7.48 |
) |
|
$ |
(2.70 |
) |
|
$ |
(2.93 |
) |
|
Weighted-average common shares used to compute net loss per share, basic and diluted |
|
|
40,562 |
|
|
|
33,045 |
|
|
|
26,727 |
|
The accompanying notes are an integral part of these consolidated financial statements.
108
CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS
(In thousands)
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Net loss |
|
$ |
(303,261 |
) |
|
$ |
(89,084 |
) |
|
$ |
(78,399 |
) |
|
Other comprehensive income (loss): |
|
|
|
|
|
|
|
|
|
|
|
|
|
Unrealized gain (loss) on available-for-sale securities |
|
|
37 |
|
|
|
(155 |
) |
|
|
114 |
|
|
Total comprehensive loss |
|
$ |
(303,224 |
) |
|
$ |
(89,239 |
) |
|
$ |
(78,285 |
) |
The accompanying notes are an integral part of these consolidated financial statements.
109
CONSOLIDATED STATEMENTS OF STOCKHOLDERS’ EQUITY
(In thousands)
|
|
|
Common Stock |
|
|
Additional Paid-In |
|
|
Accumulated Other Comprehensive |
|
|
Accumulated |
|
|
Total Stockholders’ |
|
|||||||||
|
|
|
Shares |
|
|
Amount |
|
|
Capital |
|
|
Loss |
|
|
Deficit |
|
|
Equity |
|
||||||
|
Balance at December 31, 2014 |
|
|
24,629 |
|
|
$ |
25 |
|
|
$ |
236,414 |
|
|
$ |
(211 |
) |
|
$ |
(82,649 |
) |
|
$ |
153,579 |
|
|
Issuance of common stock in connection with follow-on offering, net of underwriting discounts, commissions and issuance costs of $7,216 |
|
|
5,175 |
|
|
|
5 |
|
|
|
104,042 |
|
|
|
— |
|
|
|
— |
|
|
|
104,047 |
|
|
Exercise of stock options |
|
|
112 |
|
|
|
— |
|
|
|
279 |
|
|
|
— |
|
|
|
— |
|
|
|
279 |
|
|
Purchases under employee stock purchase plan |
|
|
57 |
|
|
|
— |
|
|
|
723 |
|
|
|
— |
|
|
|
— |
|
|
|
723 |
|
|
Stock-based compensation |
|
|
— |
|
|
|
— |
|
|
|
5,132 |
|
|
|
— |
|
|
|
— |
|
|
|
5,132 |
|
|
Unrealized gain on investments |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
114 |
|
|
|
— |
|
|
|
114 |
|
|
Net loss |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
(78,399 |
) |
|
|
(78,399 |
) |
|
Balance at December 31, 2015 |
|
|
29,973 |
|
|
|
30 |
|
|
|
346,590 |
|
|
|
(97 |
) |
|
|
(161,048 |
) |
|
|
185,475 |
|
|
Issuance of common stock in connection with shelf offering, net of underwriting discounts, commissions and issuance costs of $9,264 |
|
|
5,175 |
|
|
|
5 |
|
|
|
135,630 |
|
|
|
— |
|
|
|
— |
|
|
|
135,635 |
|
|
Issuance of common stock in connection with license agreement |
|
|
46 |
|
|
|
— |
|
|
|
1,453 |
|
|
|
— |
|
|
|
— |
|
|
|
1,453 |
|
|
Issuance of common stock upon restricted stock unit settlement, net of shares withheld for taxes |
|
|
11 |
|
|
|
— |
|
|
|
(76 |
) |
|
|
— |
|
|
|
— |
|
|
|
(76 |
) |
|
Exercise of stock options |
|
|
383 |
|
|
|
1 |
|
|
|
2,142 |
|
|
|
— |
|
|
|
— |
|
|
|
2,143 |
|
|
Purchases under employee stock purchase plan |
|
|
64 |
|
|
|
— |
|
|
|
976 |
|
|
|
— |
|
|
|
— |
|
|
|
976 |
|
|
Stock-based compensation |
|
|
— |
|
|
|
— |
|
|
|
11,003 |
|
|
|
— |
|
|
|
— |
|
|
|
11,003 |
|
|
Unrealized loss on investments |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
(155 |
) |
|
|
— |
|
|
|
(155 |
) |
|
Net loss |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
(89,084 |
) |
|
|
(89,084 |
) |
|
Balance at December 31, 2016 |
|
|
35,652 |
|
|
|
36 |
|
|
|
497,718 |
|
|
|
(252 |
) |
|
|
(250,132 |
) |
|
|
247,370 |
|
|
Issuance of common stock in connection with public offering, net of underwriting discounts, commissions and issuance costs of $12,237 |
|
|
5,750 |
|
|
|
6 |
|
|
|
181,532 |
|
|
|
— |
|
|
|
— |
|
|
|
181,538 |
|
|
Issuance of common stock in connection with license agreement |
|
|
20 |
|
|
|
— |
|
|
|
523 |
|
|
|
— |
|
|
|
— |
|
|
|
523 |
|
|
Issuance of common stock upon restricted stock unit settlement, net of shares withheld for taxes |
|
|
53 |
|
|
|
— |
|
|
|
(267 |
) |
|
|
— |
|
|
|
— |
|
|
|
(267 |
) |
|
Exercise of stock options |
|
|
243 |
|
|
|
— |
|
|
|
1,589 |
|
|
|
— |
|
|
|
— |
|
|
|
1,589 |
|
|
Purchases under employee stock purchase plan |
|
|
80 |
|
|
|
— |
|
|
|
1,417 |
|
|
|
— |
|
|
|
— |
|
|
|
1,417 |
|
|
Stock-based compensation |
|
|
— |
|
|
|
— |
|
|
|
20,703 |
|
|
|
— |
|
|
|
— |
|
|
|
20,703 |
|
|
Unrealized gain on investments |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
37 |
|
|
|
— |
|
|
|
37 |
|
|
Net loss |
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
— |
|
|
|
(303,261 |
) |
|
|
(303,261 |
) |
|
Balance at December 31, 2017 |
|
|
41,798 |
|
|
$ |
42 |
|
|
$ |
703,215 |
|
|
$ |
(215 |
) |
|
$ |
(553,393 |
) |
|
$ |
149,649 |
|
The accompanying notes are an integral part of these consolidated financial statements.
110
CONSOLIDATED STATEMENTS OF CASH FLOWS
(in thousands)
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Cash flows from operating activities |
|
|
|
|
|
|
|
|
|
|
|
|
|
Net loss |
|
$ |
(303,261 |
) |
|
$ |
(89,084 |
) |
|
$ |
(78,399 |
) |
|
Adjustments to reconcile net loss to net cash used in operating activities: |
|
|
|
|
|
|
|
|
|
|
|
|
|
Depreciation and amortization |
|
|
339 |
|
|
|
123 |
|
|
|
72 |
|
|
Stock-based compensation |
|
|
20,703 |
|
|
|
11,003 |
|
|
|
5,132 |
|
|
Acquired in-process research and development |
|
|
128,555 |
|
|
|
— |
|
|
|
— |
|
|
Amortization of discount for payments related to acquired in-process research and development |
|
|
1,606 |
|
|
|
— |
|
|
|
— |
|
|
Net amortization of premiums on available-for-sale securities |
|
|
2,366 |
|
|
|
1,879 |
|
|
|
2,012 |
|
|
Amortization of convertible note discount and issuance costs |
|
|
1,143 |
|
|
|
— |
|
|
|
— |
|
|
Common stock issued in connection with license agreement |
|
|
523 |
|
|
|
1,453 |
|
|
|
— |
|
|
Impairment of intangible assets |
|
|
— |
|
|
|
— |
|
|
|
2,394 |
|
|
Loss on extinguishment of debt |
|
|
— |
|
|
|
— |
|
|
|
124 |
|
|
Changes in assets and liabilities: |
|
|
|
|
|
|
|
|
|
|
|
|
|
Collaboration receivables |
|
|
21,348 |
|
|
|
(21,400 |
) |
|
|
7,300 |
|
|
Prepaid expenses and other current assets |
|
|
6,233 |
|
|
|
(6,838 |
) |
|
|
(1,219 |
) |
|
Other assets |
|
|
485 |
|
|
|
90 |
|
|
|
395 |
|
|
Accounts payable |
|
|
1,542 |
|
|
|
4,266 |
|
|
|
3,607 |
|
|
Accrued liabilities |
|
|
7,573 |
|
|
|
454 |
|
|
|
10,395 |
|
|
Refund liability |
|
|
10,000 |
|
|
|
— |
|
|
|
— |
|
|
Other long-term liabilities |
|
|
423 |
|
|
|
128 |
|
|
|
367 |
|
|
Deferred revenue |
|
|
(3,541 |
) |
|
|
23,815 |
|
|
|
— |
|
|
Deferred taxes |
|
|
— |
|
|
|
— |
|
|
|
(622 |
) |
|
Net cash used in operating activities |
|
|
(103,963 |
) |
|
|
(74,111 |
) |
|
|
(48,442 |
) |
|
Cash flows from investing activities |
|
|
|
|
|
|
|
|
|
|
|
|
|
Purchases of available-for-sale securities |
|
|
(302,432 |
) |
|
|
(252,175 |
) |
|
|
(60,276 |
) |
|
Maturities of available-for-sale securities |
|
|
278,580 |
|
|
|
122,640 |
|
|
|
57,875 |
|
|
Acquisition of in-process research and development |
|
|
(80,000 |
) |
|
|
— |
|
|
|
— |
|
|
Increase in restricted cash |
|
|
(300 |
) |
|
|
— |
|
|
|
— |
|
|
Purchase of property and equipment |
|
|
(278 |
) |
|
|
(753 |
) |
|
|
(202 |
) |
|
Net cash used in investing activities |
|
|
(104,430 |
) |
|
|
(130,288 |
) |
|
|
(2,603 |
) |
|
Cash flows from financing activities |
|
|
|
|
|
|
|
|
|
|
|
|
|
Net proceeds from issuance of common stock in connection with equity financings |
|
|
181,538 |
|
|
|
135,907 |
|
|
|
104,047 |
|
|
Net proceeds from issuance of convertible notes |
|
|
278,246 |
|
|
|
— |
|
|
|
— |
|
|
Net proceeds from issuance of common stock in connection with equity awards |
|
|
2,739 |
|
|
|
3,043 |
|
|
|
1,002 |
|
|
Payment to extinguish term loan |
|
|
— |
|
|
|
— |
|
|
|
(2,120 |
) |
|
Net cash provided by financing activities |
|
|
462,523 |
|
|
|
138,950 |
|
|
|
102,929 |
|
|
Net increase (decrease) in cash and cash equivalents |
|
|
254,130 |
|
|
|
(65,449 |
) |
|
|
51,884 |
|
|
Cash and cash equivalents at beginning of year |
|
|
41,793 |
|
|
|
107,242 |
|
|
|
55,358 |
|
|
Cash and cash equivalents at end of year |
|
$ |
295,923 |
|
|
$ |
41,793 |
|
|
$ |
107,242 |
|
|
Supplemental disclosure of cash flow information |
|
|
|
|
|
|
|
|
|
|
|
|
|
Interest paid |
|
$ |
4,289 |
|
|
$ |
— |
|
|
$ |
123 |
|
|
Supplemental disclosure of noncash investing activities |
|
|
|
|
|
|
|
|
|
|
|
|
|
Acquisition of in-process research and development |
|
$ |
48,555 |
|
|
$ |
— |
|
|
$ |
— |
|
|
Acquisition of property and equipment under accounts payable and accrued liabilities |
|
$ |
367 |
|
|
$ |
111 |
|
|
$ |
50 |
|
The accompanying notes are an integral part of these consolidated financial statements.
111
NOTES TO CONSOLIDATED FINANCIAL STATEMENTS
1. Organization
We were incorporated in the State of Delaware in August 2010 under the name Skintelligence, Inc. We changed our name to Dermira, Inc. in September 2011. In August 2011, we acquired Valocor Therapeutics, Inc., which was subsequently renamed Dermira (Canada), Inc. (“Dermira Canada”) and is our wholly owned subsidiary. We are a biopharmaceutical company dedicated to bringing biotech ingenuity to medical dermatology by delivering differentiated, new therapies to the millions of patients living with chronic skin conditions. We are committed to understanding the needs of both patients and physicians and using our insight to identify and develop leading-edge medical dermatology programs. Our pipeline includes three late-stage product candidates that could have a profound impact on the lives of patients: glycopyrronium tosylate (formerly DRM04), for which a New Drug Application is under review by the U.S. Food and Drug Administration (“FDA”) for the treatment of primary axillary hyperhidrosis (underarm sweating beyond what is needed for normal body temperature regulation); olumacostat glasaretil (formerly DRM01), in Phase 3 development for the treatment of acne vulgaris; and lebrikizumab, in Phase 2b development for the treatment of moderate-to-severe atopic dermatitis. We are headquartered in Menlo Park, California.
2. Summary of Significant Accounting Policies
Significant accounting policies followed in the preparation of these consolidated financial statements are as follows:
Basis of Presentation
Our consolidated financial statements have been prepared in conformity with U.S. generally accepted accounting principles (“U.S. GAAP”). The accompanying consolidated financial statements include the accounts of our wholly owned subsidiary, Dermira Canada. All intercompany accounts and transactions have been eliminated in consolidation.
Use of Estimates
The preparation of consolidated financial statements in conformity with U.S. GAAP requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and disclosures of contingent assets and liabilities at the date of the consolidated financial statements and reported amounts of revenues and expenses during the reporting periods. On an ongoing basis, we evaluate our estimates, including those related to revenue recognition, acquired in-process research and development, investments, accrued research and development expenses, goodwill, intangible assets, other long-lived assets, stock-based compensation and the valuation of deferred tax assets. We base our estimates on our historical experience and also on assumptions that we believe are reasonable; however, actual results could significantly differ from those estimates.
Risks and Uncertainties
Our product candidates require approvals from the FDA and foreign regulatory agencies prior to commercial sales in the United States or foreign jurisdictions, respectively. There can be no assurance that our current or future product candidates will receive the necessary approvals. If approval is denied or delayed, it may have a material adverse impact on our business and our financial condition.
112
We are subject to risks common to early-stage companies in the pharmaceutical industry, including dependence on the clinical and commercial success of our product candidates, ability to obtain regulatory approval of our product candidates, compliance with regulatory requirements, the need for substantial additional financing to achieve our goals, uncertainty of broad adoption of our approved products, if any, by physicians and patients, significant competition and ability to manage third-party manufacturers, suppliers and contract research organizations (“CROs”).
Cash and Cash Equivalents
We consider all highly liquid investments with original maturities at the date of purchase of three months or less to be cash equivalents. Cash and cash equivalents include money market funds, U.S. Treasury securities, corporate debt, repurchase agreements, commercial paper and certificates of deposit.
Investments
We classify our investments in money market funds and fixed income securities as available-for-sale securities. Fixed income securities consist of U.S. Treasury securities, corporate debt, repurchase agreements, U.S. Government agency securities and commercial paper. The specific identification method is used to determine the cost basis of fixed income securities sold. These securities are recorded on the consolidated balance sheets at fair value. Unrealized gains and losses on these securities are included as a separate component of accumulated other comprehensive income (loss). The cost of investment securities is adjusted for amortization of premiums and accretion of discounts to maturity. Such amortization and accretion are included in interest and other income, net. Realized gains and losses and declines in fair value judged to be other than temporary, if any, are also included in interest and other income, net. We classify our available‑for‑sale securities as current or long term primarily based on the remaining contractual maturity of the securities.
Concentration of Credit Risk
Financial instruments that potentially subject us to a concentration of credit risk consist primarily of cash and cash equivalents, investments and receivables under our collaboration and license agreements. We invest in money market funds, U.S. Treasury securities, corporate debt, repurchase agreements, U.S. Government agency securities, commercial paper and certificates of deposits. Bank deposits are held primarily by a single financial institution and these deposits may exceed insured limits. We are exposed to credit risk in the event of a default by the financial institutions holding our cash and cash equivalents and issuers of investments to the extent recorded on the consolidated balance sheets. Our investment policy limits investments to money market funds, certain types of debt securities issued by the U.S. Government and its agencies, corporate debt, repurchase agreements, commercial paper, certificates of deposit and municipal bonds and places restrictions on the credit ratings, maturities and concentration by type and issuer.
Collaboration receivables are typically unsecured. Accordingly, we may be exposed to credit risk generally associated with our collaboration and license agreements. To date, we have not experienced any losses related to these receivables.
Fair Value Measurement
Fair value is defined as the price that would be received to sell an asset or paid to transfer a liability in an orderly transaction between market participants at the measurement date. We primarily apply the market approach for recurring fair value measurements.
We measure certain financial assets and liabilities at fair value based on the exchange price that would be received for an asset or paid to transfer a liability (an exit price) in the principal or most advantageous market for the asset or liability in an orderly transaction between market participants. The carrying amount of our cash and cash equivalents, investments, collaboration receivables, prepaid expenses, accounts payable and accrued liabilities approximate fair value due to their short maturities.
113
Our non‑financial assets, such as intangible assets and property and equipment, are only recorded at fair value if an impairment charge is recognized.
Property and Equipment
Property and equipment are stated at cost, subject to adjustments for impairments, less accumulated depreciation and amortization. Property and equipment consist primarily of computer equipment, internal use software, leasehold improvements and furniture. Depreciation and amortization is calculated using the straight‑line method over the estimated useful lives of the related assets, ranging from three to five years. Leasehold improvements are amortized over the shorter of the lease term or the estimated useful lives of the respective assets. Maintenance and repairs that do not extend the life of or improve an asset are expensed in the period incurred.
Internal use software costs incurred in connection with obtaining or developing internal use software are capitalized. This includes external direct costs of material and services. Capitalized internal use software costs are included in property and equipment and are amortized using the straight‑line method over five years. Costs incurred during the preliminary project stage and post‑implementation stage, as well as maintenance and training costs, are expensed as incurred.
Revenue Recognition
We generate revenue from collaboration and license agreements related to the development and commercialization of our product candidates. We recognize revenue when persuasive evidence of an arrangement exists, services have been performed or products have been delivered, the fee is fixed and determinable and collection is reasonably assured. Collaboration and license agreements may include non-refundable upfront payments or reimbursement of research and development costs, contingent consideration payments based on achievement of defined milestones, and royalties on sales of commercialized products. Our responsibilities under collaboration and license agreements may include the transfer of intellectual property rights, such as licenses, obligations to provide research and development services, product supply and regulatory approval services, and participation on certain development and commercialization committees. For upfront payments that are recorded as deferred revenue and being recognized over the estimated period of performance, we regularly review the estimated periods of performance based on the progress made under each arrangement. The estimated performance period may change over the course of an arrangement’s term. Such a change could have a material impact on the amount of revenue recorded in future periods.
Multiple Element Arrangements
To determine the appropriate revenue recognition for payments to us under our collaboration and license agreements with multiple element arrangements, we evaluate whether the non-contingent deliverables of an arrangement represent separate units of accounting or a single unit of accounting. For non-contingent deliverables of an arrangement to represent separate units of accounting, the delivered elements each must have standalone value to the customer. Factors to determine standalone value include whether the deliverable is proprietary to us, whether the customer can use the license or other deliverables for their intended purpose without the receipt of the remaining elements and whether there are other vendors that can provide the undelivered items. Deliverables that meet these criteria are considered separate units of accounting. Deliverables that do not meet these criteria are combined and accounted for as a single unit of accounting.
114
Milestones and Other Contingent Payments
We have adopted the milestone method as described in Accounting Standards Codification 605-28, Milestone Method of Revenue Recognition. Under the milestone method, contingent consideration received from the achievement of a substantive milestone is recognized in its entirety in the period in which the milestone is achieved. A milestone is defined as an event having all of the following characteristics: (1) there is substantive uncertainty at the date the arrangement is entered into that the event will be achieved; (2) the event can only be achieved based in whole or in part on either our performance or a specific outcome resulting from our performance; and (3) if achieved, the event would result in additional payments being due to us. Contingent payments that do not meet the definition of a milestone are recognized in the same manner as the consideration for the combined unit of accounting. If we have no remaining performance obligations under the combined unit of accounting, any contingent payments would be recognized as revenue upon the achievement of the triggering event.
We evaluate whether milestones meet all of the following conditions to be considered substantive: (1) the consideration is commensurate with either of (a) our performance to achieve the milestone or (b) the enhancement of the value of the delivered item or items as a result of a specific outcome resulting from our performance to achieve the milestone; (2) the consideration relates solely to past performance; and (3) the consideration is reasonable relative to all the deliverables and payment terms within the arrangement. Substantive milestones are recognized as revenue upon achievement of the milestone and when collectability is reasonably assured.
Acquired In-Process Research and Development Expenses
We expense in-process research and development projects (“IPR&D”) acquired as part of asset acquisitions that have no alternative future use. The fair value assigned to incomplete research projects that have not reached technological feasibility and are acquired in business combinations are capitalized and accounted for as indefinite-lived intangible assets.
Impairment of Long‑Lived Assets
We assess changes in the performance of our product candidates in relation to our expectations, and industry, economic and regulatory conditions and make assumptions regarding estimated future cash flows in evaluating the value of our property and equipment, goodwill and IPR&D.
We periodically evaluate whether current facts or circumstances indicate that the carrying values of our long‑lived assets may not be recoverable. If such facts or circumstances are determined to exist, an estimate of the undiscounted future cash flows of these assets is compared to the carrying value to determine whether impairment exists. If the asset is determined to be impaired, the loss is measured based on the difference between the asset’s fair value and its carrying value. If quoted market prices are not available, we will estimate fair value using a discounted value of estimated future cash flows approach.
Goodwill represents the excess of the consideration transferred over the fair value of the net assets acquired in connection with the acquisition of Valocor. We test goodwill for impairment on an annual basis as of October of each year, or more frequently if impairment indicators exist, by first assessing qualitative factors to determine whether it is more likely than not that the fair value of the goodwill is less than its carrying amount. Some of the factors considered by us in our assessment include general macro‑economic conditions, conditions specific to the industry and market, and the successful development of our product candidates. If we conclude it is more likely than not that the fair value of the goodwill is less than its carrying amount, a quantitative fair value test is performed.
115
IPR&D represents the fair value assigned to incomplete research projects that we acquired through the acquisition of Valocor which, at the time of acquisition, had not reached technological feasibility. The amount was capitalized and accounted for as indefinite‑lived intangible assets, subject to impairment testing until completion or abandonment of the applicable project. We test IPR&D for impairment annually as of October of each year, or more frequently if impairment indicators exist, by first assessing qualitative factors to determine whether it is more likely than not that the fair value of the IPR&D intangible asset is less than its carrying amount. If we conclude it is more likely than not that the fair value is less than the carrying amount, a quantitative test that compares the fair value of the IPR&D intangible asset with its carrying value is performed. If we discontinue or abandon a program related to IPR&D and determine that there are no other indicators of value, we will impair the entire amount of the related intangible asset.
Research and Development Expenses
We expense research and development costs as they are incurred. Our research and development expenses consist primarily of costs incurred for the development of our product candidates and include: (1) expenses incurred under agreements with CROs, investigative sites and consultants to conduct clinical trials and preclinical and non-clinical studies; (2) costs to acquire, develop and manufacture supplies for clinical trials and other studies, including fees paid to contract manufacturing organizations; (3) salaries and related costs, including stock-based compensation and travel expenses, for personnel in research and development functions; (4) costs related to compliance with drug development regulatory requirements; (5) depreciation and other allocated facility-related and overhead expenses; and (6) licensing fees and milestone payments incurred under product or data license agreements.
Accrued Research and Development Expenses
We record accruals for estimated costs of research, preclinical, non-clinical and clinical studies and manufacturing activities, which are a significant component of research and development expenses. A substantial portion of our ongoing research and development activities is conducted by third-party service providers, including CROs. Our contracts with CROs generally include pass-through fees such as regulatory expenses, investigator fees, travel costs and other miscellaneous costs, including shipping and printing fees. The financial terms of these contracts are subject to negotiations, which vary from contract to contract and may result in payment flows that do not match the periods over which materials or services are provided to us. We accrue the costs incurred under agreements with these third parties based on our estimate of actual work completed in accordance with the respective agreements. In the event we make advance payments, the payments are recorded as a prepaid expense and recognized as the services are performed. We determine the estimated costs through discussions with internal personnel and external service providers as to the progress or stage of completion of the services and the agreed-upon fees to be paid for such services. We accrue for costs associated with unused drug supplies that are both probable and estimable.
Amortization of Debt Discount and Issuance Costs
Debt discount and issuance costs, consisting of legal and other fees directly related to the debt, are offset against gross proceeds from the issuance of the convertible notes and are amortized to interest expense over the estimated life of the convertible notes based on the effective interest method.
Income Taxes
We use the liability method to account for income taxes. Under this method, deferred tax assets and liabilities are determined based on differences between the financial statement carrying amounts of existing assets and liabilities and their tax bases. Deferred tax assets and liabilities are measured using enacted tax rates applied to taxable income in the years in which those temporary differences are expected to be recovered or settled. A valuation allowance is established when necessary to reduce deferred tax assets to the amount expected to be realized. Financial statement effects of uncertain tax positions are recognized when it is more likely than not, based on the technical merits of the position, that it will be sustained upon examination. Interest and penalties related to unrecognized tax benefits are included within the provision for income tax.
116
We maintain equity incentive plans under which incentive stock options may be granted to employees and nonqualified stock options, restricted stock awards, restricted stock units and stock appreciation rights may be granted to employees, directors, consultants and advisors. In addition, we maintain an employee stock purchase plan (“ESPP”) under which employees may purchase shares of our common stock through payroll deductions.
Stock-based compensation expense related to stock options granted to employees and directors is recognized based on the grant‑date estimated fair values, net of an estimated forfeiture rate, using the Black‑Scholes option pricing model. The value of the portion of the award that is ultimately expected to vest is recognized as expense ratably over the requisite service period. We estimate our forfeiture rate based on an analysis of our actual forfeitures and the experience of other companies in the same industry, and will continue to evaluate the adequacy of the forfeiture rate assumption based on actual forfeitures, analysis of employee turnover and other related factors.
Stock‑based compensation expense related to stock options granted to non‑employees is recognized based on the fair value of the stock options, determined using the Black‑Scholes option pricing model, as they are earned. The awards vest over the time period during which the non‑employee provides services to us. The fair value of the non-employee options is remeasured at each reporting period.
Stock-based compensation expense related to restricted stock units granted to employees is recognized based on the grant-date fair value of each award and recorded as expense over the vesting period using the straight-line method, net of estimated forfeitures.
Stock-based compensation expense related to the ESPP is recognized based on the fair value of each award estimated on the first day of the offering period using the Black‑Scholes option pricing model and recorded as expense over the service period using the straight‑line method.
Deferred Rent
Rent expense is recognized on a straight‑line basis over the non‑cancelable term of our operating lease and, accordingly, we record the difference between cash rent payments and the recognition of rent expense as a deferred rent liability.
Net Loss Per Share
Basic net loss per share is calculated by dividing the net loss by the weighted‑average number of shares of common stock outstanding during the period, without consideration for dilutive potential shares of common stock. Diluted net loss per share is the same as basic net loss per share, since the effects of potentially dilutive securities are antidilutive for all periods presented.
The following common stock equivalent shares were not included in the computations of diluted net loss per share for the periods presented because their effect was antidilutive (in thousands):
|
|
|
Outstanding as of December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Stock options to purchase common stock |
|
|
6,022 |
|
|
|
4,526 |
|
|
|
3,814 |
|
|
Shares subject to outstanding restricted stock units |
|
|
296 |
|
|
|
148 |
|
|
|
— |
|
|
Estimated shares issuable under the ESPP |
|
|
208 |
|
|
|
63 |
|
|
|
105 |
|
|
Shares issuable upon conversion of convertible notes |
|
|
8,110 |
|
|
|
— |
|
|
|
— |
|
|
|
|
|
14,636 |
|
|
|
4,737 |
|
|
|
3,919 |
|
117
Recent Accounting Pronouncements
In January 2017, the Financial Accounting Standards Board (“FASB’) issued Accounting Standards Update (“ASU”) 2017-04, Intangibles-Goodwill and Other: Simplifying the Test for Goodwill Impairment (“ASU 2017-04”), to simplify the current requirements for testing goodwill for impairment by eliminating the second step of the two-step impairment test to measure the amount of an impairment loss. ASU 2017-04 is effective for fiscal years beginning after December 15, 2019 or on any interim periods within those fiscal years. Early adoption is permitted for interim or annual goodwill impairment tests performed on testing dates after January 1, 2017. We early adopted ASU 2014-12 in the fourth quarter of 2017. The adoption of this standard did not have a material impact on our consolidated financial statements.
In March 2016, the FASB issued ASU 2016-09, Improvements to Employee Share-Based Payment Accounting (“ASU 2016-09”), which amends Accounting Standards Codification Topic 718, Compensation — Stock Compensation. ASU 2016-09 simplifies several aspects of the accounting for share-based payment transactions, including the income tax consequences, classification of awards as either equity or liabilities and classification on the statement of cash flows. ASU 2016-09 is effective for fiscal years beginning after December 15, 2016 and interim periods within those fiscal years. We adopted this standard in the first quarter of 2017. The adoption of this standard did not have a material impact on our consolidated financial statements.
In February 2016, the FASB issued ASU 2016-02, Leases (Topic 842) (“ASU 2016-02” or “Topic 842”). ASU 2016-02 is aimed at making leasing activities more transparent and comparable, and requires lessees to recognize substantially all leases on their balance sheet as a right-of-use asset and a corresponding lease liability, including leases currently accounted for as operating leases. ASU 2016-02 is effective for fiscal years beginning after December 15, 2018 and interim periods within those fiscal years. Early adoption is permitted. We are currently evaluating the impact that the adoption of ASU 2016-02 will have on our consolidated financial statements and related disclosures. We expect the implementation of Topic 842 to have an impact on our consolidated financial statements and related disclosures as we had aggregate future minimum lease payments of approximately $23.6 million as of December 31, 2017. We anticipate recognition of additional assets and corresponding liabilities related to these leases on our consolidated balance sheet.
Effective January 1, 2018, we adopted ASU 2014-09, Revenue from Contracts with Customers (Topic 606) (“ASU 2014-09” or “Topic 606”). ASU 2014-09’s core principle is that a company will recognize revenue when it transfers promised goods or services to customers in an amount that reflects the consideration to which the company expects to be entitled in exchange for those goods or services. ASU 2014-09 defines a five-step process to achieve this core principle and, in doing so, companies may need to use more judgment and make more estimates than under the currently effective guidance. These may include identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price, and allocating the transaction price to each separate performance obligation. Since ASU 2014-09 was issued, several additional ASUs have been issued and incorporated within Topic 606 to clarify various elements of the guidance.
Our revenues are derived from collaboration and license arrangements. The consideration we are eligible to receive under our collaboration and license arrangements includes upfront payments, milestone payments, and royalties. As part of our adoption efforts, we have completed the assessment of our collaboration and license agreements under Topic 606. We adopted Topic 606 in the first quarter of 2018 using the modified retrospective method which consists of applying and recognizing the cumulative effect of Topic 606 at the date of initial application and providing certain additional disclosures as defined per Topic 606. We currently anticipate that we will record a cumulative adjustment to decrease deferred revenue and accumulated deficit by approximately $29.9 million, as of January 1, 2018, to reflect the impact of the adoption of Topic 606. The cumulative adjustment relates primarily to our agreements with Maruho Co., Ltd. (“Maruho”) which are described further in Note 9 Collaboration and License Agreements. Under the Right of First Negotiation Agreement we entered into with Maruho in March 2013 (“Maruho Right of First Negotiation Agreement”), we concluded that there are no remaining performance obligations under Topic 606 as of the date of the adoption. As a result, a cumulative adjustment to reduce deferred revenue of $10 million will be recorded. Under the Exclusive License Agreement we entered into with Maruho in September 2016 (“Maruho G.T. Agreement”), we concluded that the license for the intellectual property was distinct from our ongoing manufacturing obligations. As a result, a cumulative adjustment to reduce deferred revenue of $19.6 million will be recorded.
118
Fair value is defined as the exchange price that would be received for an asset or paid to transfer a liability (an exit price) in the principal or most advantageous market for the asset or liability in an orderly transaction between market participants on the measurement date. Valuation techniques used to measure fair value should maximize the use of observable inputs and minimize the use of unobservable inputs. The accounting guidance for fair value establishes a three-level hierarchy for disclosure of fair value measurements, as follows:
Level 1—Inputs are unadjusted, quoted prices in active markets for identical assets or liabilities at the measurement date.
Level 2—Inputs (other than quoted market prices included in Level 1) that are either directly or indirectly observable, such as quoted prices for similar assets or liabilities, quoted prices in markets that are not active or other inputs that are observable or can be corroborated by observable market data for substantially the full term of the instrument’s anticipated life.
Level 3—Unobservable inputs that are supported by little or no market activity and reflect our best estimate of what market participants would use in pricing the asset or liability at the measurement date. Consideration is given to the risk inherent in the valuation technique and the risk inherent in the inputs to the model.
A financial instrument’s categorization within the valuation hierarchy is based upon the lowest level of input that is significant to the fair value measurement.
Where quoted prices are available in an active market, securities are classified as Level 1. When quoted market prices are not available for the specific security, then we estimate fair value by using quoted prices for identical or similar instruments in markets that are not active and model‑based valuation techniques for which all significant inputs are observable in the market or can be corroborated by observable market data for substantially the full term of the assets. Where applicable, these models project future cash flows and discount the future amounts to a present value using market‑based observable inputs obtained from various third‑party data providers, including but not limited to benchmark yields, reported trades and broker/dealer quotes. There were no transfers between Level 1 and Level 2 during the periods presented.
The following tables set forth the fair value of our financial assets, which consists of investments classified as available-for-sale securities, that were measured on a recurring basis (in thousands):
|
|
|
|
|
As of December 31, 2017 |
|
|||||||||||||
|
|
|
Fair Value Hierarchy Level |
|
Amortized Cost |
|
|
Gross Unrealized Gains |
|
|
Gross Unrealized Losses |
|
|
Fair Value |
|
||||
|
Financial assets: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Money market funds |
|
Level 1 |
|
$ |
187,649 |
|
|
$ |
— |
|
|
$ |
— |
|
|
$ |
187,649 |
|
|
U.S. Treasury securities |
|
Level 1 |
|
|
13,968 |
|
|
— |
|
|
|
(5 |
) |
|
|
13,963 |
|
|
|
Corporate debt |
|
Level 2 |
|
|
189,287 |
|
|
|
2 |
|
|
|
(194 |
) |
|
|
189,095 |
|
|
Repurchase agreements |
|
Level 2 |
|
|
60,500 |
|
|
— |
|
|
— |
|
|
|
60,500 |
|
||
|
U.S. Government agency securities |
|
Level 2 |
|
|
25,466 |
|
|
— |
|
|
|
(18 |
) |
|
|
25,448 |
|
|
|
Commercial paper |
|
Level 2 |
|
|
71,864 |
|
|
— |
|
|
— |
|
|
|
71,864 |
|
||
|
Total investments |
|
|
|
$ |
548,734 |
|
|
$ |
2 |
|
|
$ |
(217 |
) |
|
$ |
548,519 |
|
119
|
|
|
|
|
As of December 31, 2016 |
|
|||||||||||||
|
|
|
Fair Value Hierarchy Level |
|
Amortized Cost |
|
|
Gross Unrealized Gains |
|
|
Gross Unrealized Losses |
|
|
Fair Value |
|
||||
|
Financial assets: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Money market funds |
|
Level 1 |
|
$ |
5,115 |
|
|
$ |
— |
|
|
$ |
— |
|
|
$ |
5,115 |
|
|
U.S. Treasury securities |
|
Level 1 |
|
|
6,112 |
|
|
|
1 |
|
|
|
(1 |
) |
|
|
6,112 |
|
|
Corporate debt |
|
Level 2 |
|
|
169,112 |
|
|
|
6 |
|
|
|
(240 |
) |
|
|
168,878 |
|
|
Repurchase agreements |
|
Level 2 |
|
|
22,550 |
|
|
|
— |
|
|
|
— |
|
|
|
22,550 |
|
|
U.S. Government agency securities |
|
Level 2 |
|
|
41,384 |
|
|
|
— |
|
|
|
(18 |
) |
|
|
41,366 |
|
|
Commercial paper |
|
Level 2 |
|
|
30,836 |
|
|
|
— |
|
|
|
— |
|
|
|
30,836 |
|
|
Certificates of deposit |
|
Level 2 |
|
|
901 |
|
|
|
— |
|
|
|
— |
|
|
|
901 |
|
|
Total investments |
|
|
|
$ |
276,010 |
|
|
$ |
7 |
|
|
$ |
(259 |
) |
|
$ |
275,758 |
|
As of December 31, 2017, we did not hold any investments with a maturity exceeding one year. Unrealized losses related to investments in a continuous loss position for 12 months or more were insignificant. The unrealized losses on the available‑for‑sale investments are related to U.S. Treasury securities, corporate debt and U.S. Government agency securities. We have determined that the gross unrealized losses on our securities as of December 31, 2017 were temporary in nature. Factors considered in determining whether a loss is temporary include the length of time and extent to which the investment’s fair value has been less than the cost basis; the financial condition and near‑term prospects of the investee; the extent of the loss related to the credit of the issuer; the expected cash flows from the security; and our intent to sell the security and whether or not we will be required to sell the security before the recovery of its amortized cost. We do not intend to sell the securities that are in an unrealized loss position and it is not more likely than not that we will be required to sell the investments before recovery of the amortized cost bases. The realized gains or losses on the available‑for‑sale investments were insignificant during the year ended December 31, 2017.
The estimated fair value of our convertible notes was $311.1 million as of December 31, 2017 and was based upon observable, Level 2 inputs, including pricing information from recent trades of the convertible notes as of December 31, 2017.
See Note 9 for information relating to payments which were measured using unobservable, Level 3 inputs, including a discount rate.
4. Property and Equipment
Property and equipment consisted of the following (in thousands):
|
|
|
December 31, |
|
|||||
|
|
|
2017 |
|
|
2016 |
|
||
|
Computer and other equipment |
|
$ |
289 |
|
|
$ |
246 |
|
|
Internal use software |
|
|
477 |
|
|
|
368 |
|
|
Leasehold improvements |
|
|
809 |
|
|
|
429 |
|
|
Office furniture |
|
|
369 |
|
|
|
282 |
|
|
Total property and equipment |
|
|
1,944 |
|
|
|
1,325 |
|
|
Less accumulated depreciation and amortization |
|
|
(511 |
) |
|
|
(198 |
) |
|
Property and equipment, net |
|
$ |
1,433 |
|
|
$ |
1,127 |
|
Property and equipment depreciation and amortization expense for the years ended December 31, 2017, 2016 and 2015 was $0.3 million, $0.1 million and $0.1 million, respectively.
120
Accrued liabilities consisted of the following (in thousands):
|
|
|
December 31, |
|
|||||
|
|
|
2017 |
|
|
2016 |
|
||
|
Accrued outside research and development services |
|
$ |
9,065 |
|
|
$ |
10,046 |
|
|
Accrued compensation |
|
|
9,427 |
|
|
|
5,839 |
|
|
Accrued professional and consulting services |
|
|
4,411 |
|
|
|
1,042 |
|
|
Accrued interest |
|
|
1,102 |
|
|
|
— |
|
|
Other |
|
|
1,110 |
|
|
|
300 |
|
|
Total accrued liabilities |
|
$ |
25,115 |
|
|
$ |
17,227 |
|
6. Intangible Assets
In‑Process Research and Development
In connection with the acquisition of Valocor in 2011, we acquired intangible assets that were associated with IPR&D projects relating to preclinical product candidates. The acquisition‑date fair value of these intangible assets was $3.5 million. These assets are considered to be indefinite‑lived and are not amortized, but are tested for impairment on an annual basis, as well as between annual tests if there are changes in circumstances that would indicate a reduction in the fair value of the IPR&D projects below their respective carrying amounts. If and when development is complete, the associated assets would be deemed finite‑lived and would then be amortized based on their respective estimated useful lives.
There was no impairment charge against intangible assets in the years ended December 31, 2017 or 2016. During the year ended December 31, 2015, we recorded an impairment charge of $2.4 million to IPR&D in the consolidated statements of operations. In December 2015 and February 2016, we received the results from certain research and development experiments related to our DRM05 and DRM02 early‑stage product candidates, respectively. Based on the results of these experiments, we made the decision to discontinue further efforts on these programs. The intangible assets related to these product candidates were written off in full. DRM02 is a PDE4 inhibitor that was under preclinical development for the treatment of inflammatory skin diseases, and DRM05 is a photodynamic therapy that was under preclinical development for the treatment of acne vulgaris. Both of these compounds were acquired in the Valocor acquisition in 2011.
Goodwill
We recorded the goodwill resulting from the Valocor acquisition separately on our consolidated balance sheets as of the acquisition date. Goodwill is tested for impairment on an annual basis, as well as between annual tests if there are changes in circumstances that would indicate a reduction in the fair value of the goodwill below its carrying amount. There was no impairment charge against goodwill in the years ended December 31, 2017, 2016 or 2015.
121
In May 2017, we sold $287.5 million aggregate principal amount of 3.00% Convertible Senior Notes due 2022 (“Notes”) in a private placement. We received net proceeds of $278.3 million, after deducting the initial purchasers’ discounts of $8.6 million and issuance costs of $0.6 million. The Notes were issued pursuant to an Indenture, dated as of May 16, 2017 (the “Indenture”), between us and U.S. Bank National Association, as trustee. The Notes are senior, unsecured obligations and bear interest at a rate of 3.00% per year, payable in cash semi-annually in arrears on May 15 and November 15 of each year, beginning on November 15, 2017. The Notes mature on May 15, 2022, unless earlier converted or repurchased in accordance with their terms.
The Notes are convertible into shares of our common stock, par value $0.001 per share, at an initial conversion rate of 28.2079 shares of common stock per $1,000 principal amount of the Notes, which is equivalent to an initial conversion price of approximately $35.45 per share of common stock. The conversion rate and the corresponding conversion price are subject to adjustment upon the occurrence of certain events, but will not be adjusted for any accrued and unpaid interest. Holders of the Notes who convert their Notes in connection with a make-whole fundamental change (as defined in the Indenture) are, under certain circumstances, entitled to an increase in the conversion rate. Additionally, in the event of a fundamental change, holders of the Notes may require us to repurchase all or a portion of their Notes at a price equal to 100% of the principal amount of Notes, plus any accrued and unpaid interest, including any additional interest to, but excluding, the repurchase date. Holders of the Notes may convert all or a portion of their Notes at their option at any time prior to the close of business on the business day immediately prior to May 15, 2022, in multiples of $1,000 principal amount.
As of December 31, 2017, there were unamortized issuance costs and debt discounts of $8.1 million, which were recorded as a direct deduction from the Notes on the consolidated balance sheets.
During the year ended December 31, 2015, we repaid a term loan prior to the maturity date and recorded a loss on extinguishment of debt of $0.1 million, which consisted of the write-off of the debt discount and accrued final repayment fee. The loss was included in the consolidated statements of operations as a loss on debt extinguishment.
8. Commitments and Contingencies
Facility Lease
We lease our corporate headquarters in Menlo Park, California under a non-cancelable operating lease agreement initially entered into in July 2014 and amended in September 2014 (“Initial Lease”). Pursuant to the Initial Lease, we leased 18,651 square feet of space in a multi-suite building (the “Building”). Rent payments under the Initial Lease included base rent of $97,918 per month during the first year of the Initial Lease with an annual increase of three percent, and additional monthly fees to cover our share of certain facility expenses, including utilities, property taxes, insurance and maintenance.
The Initial Lease was amended in December 2015 to provide for our lease of an additional 26,541 square feet of space in the building, commencing December 2016 (“Amended Lease”). Rent payments for the additional space included base rent of $135,426 per month during the first year of the Amended Lease period with an annual increase of three percent, and additional monthly fees to cover our share of certain facility expenses, including utilities, property taxes, insurance and maintenance.
The Amended Lease was further amended in April 2016 to accelerate our lease commencement date for the additional space, subject to certain conditions, from December 2016 to (1) May 2016 with respect to 2,882 square feet of the additional space, and (2) October 2016 with respect to 23,659 square feet of the additional space (as further amended, “Lease”). The Lease will expire on December 31, 2021, subject to our option to renew the Lease for an additional five-year term.
122
Pursuant to the terms of the Lease, we provided the lessor with a $500,000 letter of credit in August 2014, which is collateralized by a money market account. The letter of credit may be used by or drawn upon by the lessor in the event of our default of certain terms of the Lease. If no such event of default has occurred or then exists, the letter of credit may be reduced to $350,000 after June 1, 2019. The collateralized money market account is restricted cash and recorded in our consolidated balance sheets in other assets.
In September 2017, we entered into a sublease agreement (“Sublease”) pursuant to which we expanded our office space by subleasing an additional 23,798 square feet of space in the Building. Rent payments for the Sublease include base rent of $139,218 per month during the first year of the Sublease with an annual increase of three percent, and additional monthly fees to cover our share of certain facility expenses, including utilities, property taxes, insurance and maintenance. The Sublease term commenced on December 20, 2017, and will end on April 30, 2024, unless terminated early pursuant to the terms of the Sublease.
Pursuant to the terms of the Sublease, in October 2017, we provided the sublessor with a $300,000 irrevocable commercial letter of credit, which is collateralized by a money market account. The letter of credit may be used by or drawn upon by the sublessor in the event of our default of certain terms of the Sublease. The collateralized money market account is restricted cash and recorded in our consolidated balance sheets in other assets.
Rent expense for the years ended December 31, 2017, 2016 and 2015 was $4.4 million, $2.3 million and $1.5 million, respectively. The terms of the Lease and the Sublease provide for rental payments on a monthly basis on a graduated scale. We recognize rent expense on a straight‑line basis over the lease period and have accrued for rent expense incurred but not paid.
As of December 31, 2017, the aggregate total future minimum lease payments under the Lease and Sublease were as follows (in thousands):
|
Year Ending December 31, |
|
|
|
|
2018 |
$ |
4,348 |
|
|
2019 |
|
4,777 |
|
|
2020 |
|
4,918 |
|
|
2021 |
|
5,056 |
|
|
2022 |
|
1,879 |
|
|
Thereafter |
|
2,602 |
|
|
Total payments |
$ |
23,580 |
|
The table above excludes approximately $10.1 million of additional rent due over the period of the Lease and Sublease to cover our share of facility expenses, including utilities, property taxes, insurance and maintenance.
9. Collaboration and License Agreements
We recognized revenue related to the collaboration and license agreements for the period presented as follows (in thousands):
|
|
Year Ended December 31, |
|
|||||||
|
|
2017 |
|
2016 |
|
2015 |
|
|||
|
Maruho |
$ |
4,265 |
|
$ |
1,185 |
|
$ |
— |
|
|
UCB |
|
276 |
|
|
21,400 |
|
|
7,300 |
|
|
|
$ |
4,541 |
|
$ |
22,585 |
|
$ |
7,300 |
|
123
In March 2013, we entered into the Maruho Right of First Negotiation Agreement with Maruho, pursuant to which we provided Maruho with certain information and the right to negotiate an exclusive license to develop and commercialize certain of our products in specified territories. In connection with the entry into this agreement, Maruho paid us $10.0 million (“Maruho Payment”), which will be credited against certain payments payable by Maruho to us if we and Maruho enter into a license agreement for any of our products with Maruho. Maruho’s right of first negotiation expired in December 2016, but the right to credit the Maruho Payment against certain payments under any future license agreement for our products remains. As of December 31, 2017 and December 31, 2016, we recorded the $10.0 million payment related to the Maruho Right of First Negotiation Agreement as deferred revenue, non-current in our consolidated balance sheets.
In connection with the execution of the Right of First Negotiation Agreement, Maruho purchased 1,187,014 shares of our Series B convertible preferred stock for an aggregate purchase price of $10.0 million.
In September 2016, we entered into the Maruho G.T. Agreement with Maruho, which grants Maruho an exclusive license to develop and commercialize glycopyrronium tosylate for the treatment of hyperhidrosis in Japan. Pursuant to the terms of the Maruho G.T. Agreement, we received an upfront payment of $25.0 million from Maruho in October 2016 and are eligible to receive additional payments totaling up to $70.0 million, contingent upon the achievement of certain milestones associated with submission and approval of a marketing application in Japan and certain sales thresholds, as well as royalty payments based on a percentage of net product sales in Japan. The Maruho G.T. Agreement further provides that Maruho will be responsible for funding all development and commercial costs for the program in Japan and, until such time, if any, as Maruho elects to establish its own source of supply of drug product, Maruho will purchase product supply from us for development and, if applicable, commercial purposes at cost. The Maruho G.T. Agreement is unrelated to, and the exclusive license of glycopyrronium tosylate in Japan to Maruho was not subject to the terms of, the existing Maruho Right of First Negotiation Agreement.
We identified the following non-contingent deliverables under the Maruho G.T. Agreement: (1) the transfer of intellectual property rights (the “license”) and (2) the supply of drug materials for clinical development purposes. We concluded that the license is not a separate unit of accounting because Maruho cannot obtain benefit from the use of the license rights for their intended purpose without the product supplied by us. Even if Maruho elects to establish its own supply of drug product, it must rely upon us to supply the drug substance necessary for Maruho’s development because Maruho does not have the right to manufacture the drug substance. We determined that neither of the deliverables has standalone value and, therefore, the deliverables are accounted for as one combined unit of accounting, with the upfront payment recognized as revenue on a straight-line basis over the estimated period of performance. We regularly evaluate the reasonableness of the estimated period of performance and revise the amortization of deferred revenue as deemed appropriate on a prospective basis.
Milestone payments under the Maruho G.T. Agreement could total up to $70.0 million. If regulatory approval for glycopyrronium tosylate is achieved and the product is commercialized in Japan, we would recognize any royalty revenue received from Maruho based on Maruho’s net sales of the drug product in Japan.
Unless earlier terminated, the Maruho G.T. Agreement will remain in effect until the later of: (1) expiration or abandonment of the last valid claim of the applicable patent rights in Japan; (2) expiration of any market exclusivity in Japan granted by the applicable regulatory authority; and (3) 15 years following the date of the first commercial sale of the drug product in Japan.
For the year ended December 31, 2017, we recognized collaboration and license revenue related to the Maruho G.T. Agreement of $4.3 million in connection with the $25.0 million upfront payment. In addition, as of December 31, 2017, we have a deferred revenue balance related to the Maruho G.T. Agreement of $19.6 million, of which $4.3 million is recorded in deferred revenue, current on the consolidated balance sheets.
124
In March 2014, we and UCB Pharma S.A. (“UCB”), entered into a Development and Commercialisation Agreement, dated March 21, 2014 (“UCB Agreement”), which provided that we would (a) develop Cimzia (certolizumab pegol) for the treatment of psoriasis in order for UCB to seek regulatory approval from the FDA, the European Medicines Agency and the Canadian federal department for health, and (b) upon the grant of regulatory approval in the United States and Canada, promote sales of Cimzia to dermatologists and conduct related medical affairs activities in the United States and Canada. The UCB Agreement also provided either party with the right to terminate the agreement under certain terms. We expressed our intent to terminate the UCB Agreement in accordance with its terms.
As a result, we and UCB entered into an agreement on November 6, 2017 to effect the termination of the UCB Agreement and an orderly transition of the development and commercialization activities under the UCB Agreement from us to UCB (“Transition Agreement”). The Transition Agreement, among other things, (a) terminated the UCB Agreement on February 15, 2018, (b) provided for the repurchase by UCB of all product rights, licenses and intellectual property relating to Cimzia, (c) specified the responsibilities and obligations of us and UCB in connection with the transition of certain activities under the UCB Agreement from us to UCB as a result of the termination of the UCB Agreement, (d) terminated UCB’s right to designate a director nominee to our board of directors and (e) provided for the resignation of UCB’s designee from our board of directors.
Pursuant to the UCB Agreement, there were no termination or penalty payments required by either party. In consideration for the repurchase of all product rights, licenses and intellectual property relating to Cimzia, UCB paid us $11.0 million in November 2017 and, upon approval of Cimzia in psoriasis in the United States, will pay us an additional $39.0 million within 30 days of such approval. We are obligated to reimburse UCB for up to $10.0 million of development costs incurred by UCB in connection with the development of Cimzia between January 1, 2018 and June 30, 2018. If the aggregate development costs reimbursed by us to UCB during this six-month period are less than $10.0 million, we will pay UCB the difference between such aggregate costs and $10.0 million. These terms replace the provisions of the UCB Agreement pursuant to which we would have been eligible to recoup our external development costs incurred related to the Cimzia program, net of milestones received, through a royalty on future net sales of Cimzia. The $10.0 million payable to UCB is recorded on our consolidated balance sheets as refund liability. The $1.0 million net consideration from the $11.0 million payment received from UCB and the $10.0 million refund liability due to UCB will be recognized as revenue over the period in which we are obligated to perform transition services pursuant to the Transition Agreement.
Roche Agreement
In August 2017, we entered into a licensing agreement (“Roche Agreement”) with F. Hoffmann-La Roche Ltd and Genentech, Inc. (together, “Roche”), pursuant to which we obtained exclusive, worldwide rights to develop and commercialize lebrikizumab, an injectable, humanized antibody targeting interleukin 13, for atopic dermatitis and all other indications, except Roche retains certain rights, including exclusive rights to develop and promote lebrikizumab for interstitial lung diseases, such as idiopathic pulmonary fibrosis (“Retained Field”), and rights to use lebrikizumab for internal research purposes and for in vitro diagnostic purposes. The Roche Agreement became effective in September 2017 upon the early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended. Unless earlier terminated, the Roche Agreement will remain in effect until no royalty or other payment obligations are or may become due.
125
Under the terms of the Roche Agreement, we made an initial payment of $80.0 million to Roche in October 2017 and will make additional payments to Roche in 2018 totaling $55.0 million. We will also be obligated to make payments upon the achievement of certain milestones, comprising $40.0 million upon the initiation of the first Phase 3 clinical study, up to $210.0 million upon the achievement of regulatory and first commercial sale milestones in certain territories and up to $1.0 billion based on the achievement of certain thresholds for net sales of lebrikizumab for indications other than interstitial lung diseases. Upon regulatory approval, if obtained, we will make royalty payments representing percentages of net sales that range from the high single-digits to the high teens. Royalty payments will be made from the first commercial sale date in a country (other than for the Retained Field) in such country and end on the later of the date that is (a) ten years after the date of the first commercial sale of lebrikizumab (other than for the Retained Field) in such country, (b) the expiration of the last to expire valid claim of the applicable licensed compound patent rights, Dermira patent rights or joint patent rights in such country covering the use, manufacturing, import, offering for sale, or sale of lebrikizumab (other than for the Retained Field) in such country, (c) the expiration of the last to expire valid claim of the applicable licensed non-compound patent rights in such country covering the use, import, offering for sale, or sale of the product in such country, or (d) the expiration of the last to expire regulatory exclusivity conferred by the applicable regulatory authority in such country for lebrikizumab (other than for the Retained Field).
We determined that the acquired IPR&D related to the Roche Agreement had no alternative future use and recorded an expense of $128.6 million during the year ended December 31, 2017 in the consolidated statements of operations as acquired in-process research and development expense. This expense was comprised of the initial payment of $80.0 million, which was made in October 2017, and the payments due in 2018 totaling $55.0 million. The payments due in 2018 were measured on a non-recurring basis using unobservable, Level 3 inputs, including a discount rate used to value the payments at present value as of the effective date of the Roche Agreement. As of December 31, 2017, on the consolidated balance sheets, we recorded $50.2 million to accrued payments related to acquired in-process research and development, current, for the $25.0 million and $30.0 million payments due by September 2018 and December 2018, respectively. The remaining milestone payments will be recognized when the contingency related to the milestone is resolved and the consideration is paid or becomes payable.
Rose U Agreement
In April 2013, we entered into an exclusive license agreement with Rose U LLC (“Rose U”) to license certain patents, patent applications and know-how related to our hyperhidrosis program. This agreement includes a sublicense and assignment of certain know-how licensed and assigned to Rose U by Stiefel Laboratories, Inc., a GSK company (“Stiefel”), the prior licensee of such patents. In connection with this agreement, we also entered into a letter agreement with Stiefel. As of December 31, 2017, we have paid license and other fees of $0.8 million to Rose U and are required to pay additional amounts totaling up to $4.1 million upon the achievement of specified regulatory, commercialization and other milestones under these agreements to Rose U and Stiefel. In addition, we are also obligated to pay Rose U low-to-mid single-digit royalties on net product sales and low double-digit royalties on sublicense fees and certain milestone, royalty and other contingent payments received from sublicensees, to the extent such amounts are in excess of the milestone and royalty payments we are obligated to pay Rose U directly upon the events or sales triggering such payments.
10. Stock‑Based Compensation
Equity Incentive Plan
In 2010, we adopted the 2010 Equity Incentive Plan (the “2010 Plan”) which provided for the granting of stock options to our employees, directors and consultants. In September 2014, our board of directors approved the 2014 Equity Incentive Plan (the “2014 EIP”), which became effective on October 1, 2014, the day prior to the effective date of our registration statement on Form S‑1. As of the effective date of the 2014 EIP, the 2010 Plan was terminated and no further stock awards will be granted pursuant to the 2010 Plan. Outstanding stock options granted under the 2010 Plan will continue to be governed by the provisions of the 2010 Plan until the earlier of the stock option’s expiration or exercise.
126
The 2014 EIP authorizes the reservation of 1,896,551 shares of our common stock, plus any shares reserved or remaining for issuance, or that become available upon forfeiture of outstanding stock options or our repurchase of shares granted pursuant to an equity award, in each case, under the 2010 Plan. On January 1 of each of the first 10 years commencing after the effective date of our initial public offering (“IPO”), the number of shares of our common stock reserved for issuance under the 2014 EIP will increase automatically by an amount equal to 4% of the number of shares of our common stock outstanding on the preceding December 31, unless our board of directors elects to authorize a lesser number of shares. As of December 31, 2017, we had reserved 5,486,079 shares of common stock for issuance under the 2014 EIP. Effective January 1, 2018, an additional 1,671,902 shares of common stock were reserved for issuance.
The 2014 EIP provides for the granting of stock options and restricted stock units to our employees, officers, directors, consultants and advisors. Stock options granted under the 2014 EIP may be either incentive stock options or nonqualified stock options. Incentive stock options (“ISOs”) may be granted only to our employees, including officers and directors who are also employees. Nonqualified stock options (“NSOs”) may be granted to our employees, officers, directors, consultants and advisors. The exercise price of stock options granted under the 2014 EIP must be at least equal to the fair market value of the common stock on the date of grant, except that an ISO granted to an employee who owns more than 10% of the shares of our common stock shall have an exercise price of no less than 110% of the fair value per share on the grant date and expire five years from the date of grant. The maximum term of stock options granted under the 2014 EIP is 10 years, unless subject to the provisions regarding 10% stockholders. Our stock options granted to new employees generally vest over four years at a rate of 25% upon the first anniversary of the vesting commencement date and monthly thereafter. All of our other stock options granted to employees generally vest monthly over four years from the vesting commencement date. Restricted stock units granted under the 2014 EIP generally vest within four years.
Stock Options
The following table reflects a summary of stock option activity for the specified period (in thousands, except per share amounts):
|
|
|
Shares Subject to Outstanding Stock Options |
|
|
Weighted- Average Exercise Price Per Share |
|
|
Weighted- Average Remaining Contractual Term (in years) |
|
|
Aggregate Intrinsic Value |
|
||||
|
Stock options outstanding at December 31, 2014 |
|
|
3,401 |
|
|
$ |
6.88 |
|
|
|
8.6 |
|
|
$ |
80,757 |
|
|
Stock options granted |
|
|
560 |
|
|
|
22.05 |
|
|
|
|
|
|
|
|
|
|
Stock options exercised |
|
|
(112 |
) |
|
|
4.49 |
|
|
|
|
|
|
|
|
|
|
Stock options forfeited |
|
|
(35 |
) |
|
|
12.15 |
|
|
|
|
|
|
|
|
|
|
Stock options outstanding at December 31, 2015 |
|
|
3,814 |
|
|
$ |
9.19 |
|
|
|
7.9 |
|
|
$ |
96,954 |
|
|
Stock options granted |
|
|
1,148 |
|
|
|
27.21 |
|
|
|
|
|
|
|
|
|
|
Stock options exercised |
|
|
(382 |
) |
|
|
5.60 |
|
|
|
|
|
|
|
|
|
|
Stock options forfeited |
|
|
(54 |
) |
|
|
21.60 |
|
|
|
|
|
|
|
|
|
|
Stock options outstanding at December 31, 2016 |
|
|
4,526 |
|
|
$ |
13.92 |
|
|
|
7.5 |
|
|
$ |
74,765 |
|
|
Stock options granted |
|
|
1,874 |
|
|
|
30.96 |
|
|
|
|
|
|
|
|
|
|
Stock options exercised |
|
|
(243 |
) |
|
|
6.53 |
|
|
|
|
|
|
|
|
|
|
Stock options forfeited |
|
|
(135 |
) |
|
|
30.35 |
|
|
|
|
|
|
|
|
|
|
Stock options outstanding at December 31, 2017 |
|
|
6,022 |
|
|
$ |
19.15 |
|
|
|
7.4 |
|
|
$ |
59,461 |
|
|
Vested and expected to vest as of December 31, 2017 |
|
|
5,888 |
|
|
$ |
18.93 |
|
|
|
7.3 |
|
|
$ |
59,275 |
|
|
Exercisable as of December 31, 2017 |
|
|
3,443 |
|
|
$ |
12.76 |
|
|
|
6.3 |
|
|
$ |
53,425 |
|
The total estimated grant date fair value of stock options vested during the years ended December 31, 2017, 2016 and 2015 was $15.6 million, $8.3 million and $4.7 million, respectively. The total intrinsic value of stock options exercised during the years ended December 31, 2017, 2016 and 2015 was $5.9 million, $9.5 million and $3.6 million, respectively.
127
During the years ended December 31, 2017, 2016 and 2015, we granted stock options to employees and directors to purchase shares of common stock with a weighted‑average grant date fair value of $19.66, $16.72 and $12.49 per share, respectively. As of December 31, 2017, the total unrecognized compensation expense was $38.6 million, which we expect to recognize over a period of approximately 2.7 years.
We estimated the fair value of stock options using the Black‑Scholes option pricing model. The fair value of employee stock options is being amortized on a straight‑line basis over the requisite service period of the awards. The fair value of the employee stock options was estimated using the following weighted‑average assumptions:
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Expected term (in years) |
|
|
6.0 |
|
|
|
6.0 |
|
|
|
6.1 |
|
|
Expected volatility |
|
|
70.4 |
% |
|
|
68.4 |
% |
|
|
64.1 |
% |
|
Risk–free interest rate |
|
|
2.0 |
% |
|
|
1.4 |
% |
|
|
1.9 |
% |
|
Expected dividend rate |
|
|
0.0 |
% |
|
|
0.0 |
% |
|
|
0.0 |
% |
Expected Term: We determine the expected term using the simplified method (based on the midpoint between the vesting date and the end of the contractual term).
Expected Volatility: As we do not have sufficient historical stock price information to meet the expected life of the stock-based awards, our approach to estimating expected volatility is to phase in our own common stock trading history and supplement the remaining historical information with a blended volatility from the trading history from the common stock of the set of comparable publicly traded biopharmaceutical companies. We will continue to apply this process until a sufficient amount of historical information regarding the volatility of our own stock price becomes available.
Risk‑Free Interest Rate: We determine the risk-free interest rate based on the U.S. Treasury yield in effect at the time of the grant for zero coupon U.S. Treasury notes with remaining terms similar to the expected term of the stock options.
Expected Dividend Rate: We have never paid any dividends and do not anticipate paying any dividends in the foreseeable future, and therefore used an expected dividend rate of zero in the valuation model.
During the year ended December 31, 2017, we did not grant stock options to non-employees and the compensation expense related to options granted to non-employees in prior years was immaterial.
128
The fair value of restricted stock units (“RSUs”) is determined based on the value of the underlying common stock on the date of grant. The expenses relating to these RSUs are recognized over their respective vesting periods. The following table reflects a summary of RSU activity for the specified period (in thousands, except per share amounts):
|
|
|
Shares Subject to Outstanding RSUs |
|
|
Weighted- Average Grant Date Fair Value Per Share |
|
||
|
RSUs outstanding at December 31, 2015 |
|
|
— |
|
|
$ |
— |
|
|
RSUs granted |
|
|
162 |
|
|
|
27.14 |
|
|
RSUs vested and settled |
|
|
(13 |
) |
|
|
26.37 |
|
|
RSUs forfeited |
|
|
(1 |
) |
|
|
26.37 |
|
|
RSUs outstanding at December 31, 2016 |
|
|
148 |
|
|
$ |
27.21 |
|
|
RSUs granted |
|
|
222 |
|
|
|
32.68 |
|
|
RSUs vested and settled |
|
|
(65 |
) |
|
|
28.88 |
|
|
RSUs forfeited |
|
|
(9 |
) |
|
|
31.86 |
|
|
RSUs outstanding at December 31, 2017 |
|
|
296 |
|
|
$ |
30.81 |
|
The total grant date fair value of RSUs vested during the years ended December 31, 2017 and 2016 was $1.9 million and $0.4 million, respectively. The total vesting date fair value of RSUs vested during the years ended December 31, 2017 and 2016 was $1.5 million and $0.4 million, respectively. No RSUs were granted or outstanding during the year ended December 31, 2015.
As of December 31, 2017, the total unrecognized compensation expense was $7.0 million, which we expect to recognize over a period of approximately 2.4 years.
Employee Stock Purchase Plan
On September 9, 2014, our board of directors adopted and approved the 2014 Employee Stock Purchase Plan (“2014 ESPP”), which became effective on October 2, 2014, the day that our registration statement on Form S‑1 was declared effective. On January 1 of each of the first 10 years commencing after the effective date of the IPO, the number of shares of our common stock reserved for issuance under the 2014 ESPP will increase automatically by an amount equal to 1% of the number of shares of our common stock outstanding on the preceding December 31, unless our board of directors or compensation committee elects to authorize a lesser number of shares. As of December 31, 2017, we had reserved 1,204,258 shares of common stock for issuance under the 2014 ESPP. Effective January 1, 2018, an additional 417,975 shares of common stock were reserved for issuance.
Subject to certain limitations, our employees may elect to have 1% to 15% of their compensation withheld through payroll deductions to purchase shares of common stock under the 2014 ESPP. Employees purchase shares of common stock at a price per share equal to 85% of the lower of the fair market value at the start or end of the two‑year offering period. Compensation expense related to the 2014 ESPP for the years ended December 31, 2017, 2016 and 2015 was approximately $0.9 million, $0.6 million and $0.4 million, respectively.
129
The fair value of each employee stock purchase right grant is estimated using the Black‑Scholes option pricing model and is recognized as expense using the straight‑line method. The weighted‑average estimated fair value of employee stock purchase rights granted pursuant to the 2014 ESPP during the years ended December 31, 2017, 2016 and 2015 was $11.06, $14.53 and $8.03 per share, respectively, and was based on the following assumptions:
|
|
|
Year ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Expected term (in years) |
|
|
1.3 |
|
|
|
1.3 |
|
|
|
1.3 |
|
|
Expected volatility |
|
|
71.6 |
% |
|
|
75.8 |
% |
|
|
56.0 |
% |
|
Risk–free interest rate |
|
|
1.6 |
% |
|
|
0.7 |
% |
|
|
0.4 |
% |
|
Expected dividend rate |
|
|
0.0 |
% |
|
|
0.0 |
% |
|
|
0.0 |
% |
Equity Inducement Plan
In January 2018, we adopted the 2018 Equity Inducement Plan (“2018 Inducement Plan”), which provided for the granting of nonstatutory stock options and restricted stock units to newly hired employees as a material inducement to their acceptance of employment with us in accordance with Nasdaq Listing Rule 5635(c)(4). The 2018 Inducement Plan authorized the reservation of 1,200,000 shares of our common stock for future issuance.
Total Stock‑Based Compensation
Total stock‑based compensation expense related to the 2010 Plan, the 2014 EIP and the 2014 ESPP was allocated as follows (in thousands):
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Year ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Research and development |
|
$ |
8,006 |
|
|
$ |
4,039 |
|
|
$ |
1,984 |
|
|
General and administrative |
|
|
12,697 |
|
|
|
6,964 |
|
|
|
3,148 |
|
|
Total stock-based compensation expense |
|
$ |
20,703 |
|
|
$ |
11,003 |
|
|
$ |
5,132 |
|
11. Employee Benefit Plan
We sponsor a 401(k) defined contribution plan for our employees. This plan provides for tax‑deferred salary deductions for all employees. Employee contributions are voluntary. Employees may contribute up to 100% of their annual compensation to this plan, as limited by an annual maximum amount as determined by the Internal Revenue Service. We may match employee contributions in amounts to be determined at our sole discretion. We made no contributions to the plan for the years ended December 31, 2017, 2016 or 2015.
12. Income Taxes
We recorded no provision or benefit for income taxes during the years ended December 31, 2017 and 2016. We had a benefit for income taxes of $0.6 million for the year ended December 31, 2015. The benefit for income tax related to the reduction in the deferred tax liability resulting from the impairment charge to IPR&D, which was not recognized for tax purposes.
130
Significant components of our deferred tax assets and liabilities as of December 31, 2017 and 2016 consisted of the following (in thousands):
|
|
|
As of December 31, |
|
|||||
|
|
|
2017 |
|
|
2016 |
|
||
|
Deferred tax assets: |
|
|
|
|
|
|
|
|
|
Net operating loss carryforwards |
|
$ |
99,710 |
|
|
$ |
74,586 |
|
|
Depreciation and amortization |
|
|
423 |
|
|
|
463 |
|
|
Research and development credits |
|
|
7,415 |
|
|
|
4,552 |
|
|
Deferred revenue |
|
|
6,207 |
|
|
|
3,400 |
|
|
Accruals and stock-based compensation expense |
|
|
10,968 |
|
|
|
5,457 |
|
|
Total deferred tax assets |
|
|
124,723 |
|
|
|
88,458 |
|
|
Valuation allowance |
|
|
(124,723 |
) |
|
|
(88,458 |
) |
|
Net deferred tax assets |
|
|
— |
|
|
|
— |
|
|
Deferred tax liabilities: |
|
|
|
|
|
|
|
|
|
Acquired IPR&D |
|
|
(194 |
) |
|
|
(194 |
) |
|
Total deferred tax liabilities |
|
|
(194 |
) |
|
|
(194 |
) |
|
Net deferred tax liabilities |
|
$ |
(194 |
) |
|
$ |
(194 |
) |
Reconciliations of the statutory federal income tax benefit rate to our effective tax for the years ended December 31, 2017, 2016 and 2015 are as follows:
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Tax (benefit) at statutory federal rate |
|
|
34.0 |
% |
|
|
34.0 |
% |
|
|
34.0 |
% |
|
Foreign tax, net of federal benefit |
|
|
— |
|
|
|
— |
|
|
|
(1.1 |
) |
|
Permanent differences |
|
|
(1.1 |
) |
|
|
(1.2 |
) |
|
|
(0.8 |
) |
|
Research and development credits |
|
|
0.8 |
|
|
|
2.0 |
|
|
|
0.7 |
|
|
Federal deferred remeasurement |
|
|
(22.9 |
) |
|
|
— |
|
|
|
— |
|
|
Change in valuation allowance |
|
|
(10.8 |
) |
|
|
(34.8 |
) |
|
|
(32.0 |
) |
|
Effective tax rate |
|
|
0.0 |
% |
|
|
0.0 |
% |
|
|
0.8 |
% |
A valuation allowance is provided when it is more likely than not that the deferred tax assets will not be realized. We have established a valuation allowance to offset deferred tax assets as of December 31, 2017 and 2016 due to the uncertainty of realizing future tax benefits from our net operating loss carryforwards and other deferred tax assets. Our valuation allowance increased by approximately $36.3 million and $31.7 million for the years ended December 31, 2017 and 2016, respectively.
On December 22, 2017, the Tax Cuts and Jobs Acts (“Tax Act”) was signed into law. The Tax Act, among other changes, lowers our federal tax rate from 34% to 21%. Based on provisions of the Tax Act, we remeasured our deferred tax assets and liabilities to reflect the lower statutory tax rate. However, since we established a valuation allowance to offset our deferred tax assets, there is no impact to our effective tax rate, as any changes to deferred taxes would be offset by the valuation allowance. Our deferred tax remeasurement is provisional and is subject to revision as we complete our analysis of the Tax Act, collect and prepare necessary data and interpret any additional guidance issued by standard-setting bodies. We currently anticipate finalizing and recording any resulting adjustments related to the tax effects of the Tax Act in 2018.
As of December 31, 2017, we had net operating loss (“NOL”) carryforwards available to reduce future taxable income, if any, for federal, California and Canadian income tax purposes of $452.2 million, $44.2 million and $3.2 million, respectively. The federal and California NOL carryforwards will begin expiring during the year ended December 31, 2030 and the Canadian NOL carryforwards will begin expiring during the year ended December 31, 2028.
131
As of December 31, 2017, we also had research and development credit carryforwards of $7.2 million, $4.4 million and $0.5 million available to reduce future taxable income, if any, for federal, California and Canadian income tax purposes, respectively. The federal and Canadian credit carryforwards will begin expiring in 2031 and the California state credit carryforwards has no expiration date.
In general, if we experience a greater than 50 percentage point aggregate change in ownership over a three‑year period (a Section 382 ownership change), utilization of our pre‑change NOL carryforwards is subject to an annual limitation under Section 382 of the Internal Revenue Code (California has similar laws). The annual limitation generally is determined by multiplying the value of our stock at the time of such ownership change (subject to certain adjustments) by the applicable long‑ term tax‑exempt rate. Such limitations may result in expiration of a portion of the NOL carryforwards before utilization. We have experienced at least one ownership change since inception and utilization of NOL carryforwards will therefore be subject to annual limitation. In addition, our ability to use our remaining NOL carryforwards may be further limited if we experience a Section 382 ownership change in connection with future changes in our stock ownership.
We recognize uncertain tax positions when it is more likely than not, based on the technical merits, that the position will not be sustained upon examination. The guidance also clarifies the financial statement classification of tax‑related penalties and interest and sets forth new disclosure regarding unrecognized tax benefits. Our policy is to include interest and penalties, if any, related to unrecognized tax benefits within our provision for income taxes.
As we have a full valuation allowance against our deferred tax assets, the unrecognized tax benefits will reduce the deferred tax assets and the valuation allowance in the same amount. We do not expect the amount of unrecognized tax benefits to change significantly in the next 12 months. A summary of the activity of the unrecognized tax benefits is as follows (in thousands):
|
|
|
Year Ended December 31, |
|
|||||||||
|
|
|
2017 |
|
|
2016 |
|
|
2015 |
|
|||
|
Unrecognized benefit - beginning of year |
|
$ |
3,022 |
|
|
$ |
1,072 |
|
|
$ |
635 |
|
|
Gross increases - current year tax provisions |
|
|
1,603 |
|
|
|
1,327 |
|
|
|
437 |
|
|
Gross increases - prior year tax positions |
|
|
— |
|
|
|
623 |
|
|
|
— |
|
|
Unrecognized benefit - end of year |
|
$ |
4,625 |
|
|
$ |
3,022 |
|
|
$ |
1,072 |
|
We file income tax returns in the United States, California and other state tax jurisdictions and Canada. We are not currently under examination by income tax authorities in federal, state, Canadian or other jurisdictions. All tax returns for 2012 and later will remain open for examination by the federal, state and Canadian authorities for three, four and four years, respectively. The U.S. federal and U.S. state taxing authorities may choose to audit tax returns for tax years beyond the statute of limitation period due to significant tax attribute carryforwards from prior years, making adjustments only to carryforward attributes.
132
13. Quarterly Results of Operations (Unaudited)
The following table contains quarterly financial information for 2017 and 2016.
We believe that the following information reflects all normal recurring adjustments necessary for a fair statement of the information for the periods presented. The operating results for any quarter are not necessarily indicative of results for any future period.
|
|
|
2017 |
|
|||||||||||||
|
(Amounts in thousands, except per share amounts) |
|
First Quarter |
|
|
Second Quarter |
|
|
Third Quarter |
|
|
Fourth Quarter |
|
||||
|
Revenue |
|
$ |
1,066 |
|
|
$ |
1,066 |
|
|
$ |
1,066 |
|
|
$ |
1,343 |
|
|
Operating expenses* |
|
|
31,186 |
|
|
|
39,565 |
|
|
|
179,097 |
|
|
|
55,019 |
|
|
Net loss |
|
|
(29,509 |
) |
|
|
(38,566 |
) |
|
|
(179,174 |
) |
|
|
(56,012 |
) |
|
Net loss per share, basic and diluted |
|
$ |
(0.79 |
) |
|
$ |
(0.93 |
) |
|
$ |
(4.30 |
) |
|
$ |
(1.34 |
) |
|
* |
During the third quarter of 2017, we recognized acquired in-process research and development expenses of $128.6 million related to the Roche Agreement, which is included in operating expenses in this table. |
|
|
|
2016 |
|
|||||||||||||
|
(Amounts in thousands, except per share amounts) |
|
First Quarter |
|
|
Second Quarter |
|
|
Third Quarter |
|
|
Fourth Quarter |
|
||||
|
Revenue |
|
$ |
— |
|
|
$ |
— |
|
|
$ |
119 |
|
|
$ |
22,466 |
|
|
Operating expenses |
|
|
28,755 |
|
|
|
28,041 |
|
|
|
26,060 |
|
|
|
30,353 |
|
|
Net loss |
|
|
(28,436 |
) |
|
|
(27,755 |
) |
|
|
(25,510 |
) |
|
|
(7,383 |
) |
|
Net loss per share, basic and diluted |
|
$ |
(0.95 |
) |
|
$ |
(0.89 |
) |
|
$ |
(0.72 |
) |
|
$ |
(0.21 |
) |
133
None.
Evaluation of Disclosure Controls and Procedures
We maintain disclosure controls and procedures that are designed to ensure that information required to be disclosed in our reports under the Securities Exchange Act of 1934, as amended, or the Exchange Act, and the rules and regulations thereunder, is recorded, processed, summarized and reported within the time periods specified in the SEC’s rules and forms and that such information is accumulated and communicated to our management, including our principal executive officer and principal financial officer, or persons performing similar functions, as appropriate, to allow for timely decisions regarding required or necessary disclosure. In designing and evaluating the disclosure controls and procedures, management recognizes that any controls and procedures, no matter how well designed and operated, can provide only reasonable, not absolute, assurance of achieving the desired control objectives, and we are required to apply judgment in evaluating the cost‑benefit relationship of possible controls and procedures.
As required by Rule 13a‑15(b) under the Exchange Act, our management, under the supervision and with the participation of our principal executive officer and principal financial officer, has evaluated the effectiveness of the design and operation of our disclosure controls and procedures (as such term is defined in Rules 13a‑15(e) and 15d‑15(e) under the Exchange Act) as of December 31, 2017. Based on such evaluation, our principal executive officer and principal financial officer have concluded that, as of December 31, 2017, our disclosure controls and procedures were effective at the reasonable assurance level.
Management’s Annual Report on Internal Control over Financial Reporting
Management is responsible for establishing and maintaining adequate internal control over financial reporting, as such term is defined in Exchange Act Rules 13a‑15(f) and 15(d)‑15(f). Our internal control over financial reporting includes those policies and procedures that (i) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of our assets; (ii) provide reasonable assurance that transactions are recorded as necessary to permit preparation of the financial statements in accordance with generally accepted accounting principles, and that our receipts and expenditures are being made only in accordance with authorizations of our management and directors; and (iii) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use or disposition of our assets that could have a material effect on the financial statements.
Internal control over financial reporting is designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements prepared for external purposes in accordance with generally accepted accounting principles. Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
Our management, with the participation of our principal executive officer and principal financial officer, conducted an evaluation of the effectiveness of our internal control over financial reporting based on the framework in Internal Control—Integrated Framework (2013) issued by the Committee of Sponsoring Organizations of the Treadway Commission. Based on our evaluation under the framework in Internal Control—Integrated Framework, management concluded that our internal control over financial reporting was effective as of December 31, 2017.
Our independent registered public accounting firm has issued an attestation report on our internal control over financial reporting as included below.
134
Changes in Internal Control over Financial Reporting
There were no changes in our internal controls over financial reporting identified in connection with the evaluation required by Rules 13a‑15(d) and 15d‑15(d) of the Exchange Act that occurred during the fiscal quarter ended December 31, 2017 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.
Report of Independent Registered Public Accounting Firm
The Board of Directors and Stockholders of Dermira, Inc.
Opinion on Internal Control over Financial Reporting
We have audited Dermira, Inc.’s internal control over financial reporting as of December 31, 2017, based on criteria established in Internal Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission 2013 framework (the COSO criteria). In our opinion, Dermira, Inc. (the Company) maintained, in all material respects, effective internal control over financial reporting as of December 31, 2017, based on the COSO criteria.
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the consolidated balance sheets of the Company as of December 31, 2017 and 2016, the related consolidated statements of operations, comprehensive loss, stockholders’ equity, and cash flows, for each of the three years in the period ended December 31, 2017 and related notes and our report dated February 22, 2018 expressed an unqualified opinion thereon.
Basis for Opinion
The Company’s management is responsible for maintaining effective internal control over financial reporting and for its assessment of the effectiveness of internal control over financial reporting included in the accompanying Management’s Report on Internal Control over Financial Reporting. Our responsibility is to express an opinion on the Company’s internal control over financial reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects. Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our opinion.
Definition and Limitations of Internal Control Over Financial Reporting
A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control over financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial statements.
135
Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
/s/ Ernst & Young LLP
San Jose, California
February 22, 2018
None.
136
Certain information required by Part III is omitted from this annual report on Form 10‑K and is incorporated herein by reference to our definitive Proxy Statement for our 2018 Annual Meeting of Stockholders (“Proxy Statement”), which we intend to file pursuant to Regulation 14A of the Securities Exchange Act of 1934, as amended, within 120 days after December 31, 2017.
Pursuant to General Instruction G(3) of Form 10‑K, the information required by this Item 10 relating to our executive officers is included under the caption “Executive Officers” in Part I of this Form 10‑K. The other information required by this item is incorporated herein by reference to information contained in the Proxy Statement for our 2018 Annual Meeting of Stockholders.
The information required by this item is incorporated herein by reference to information contained in the Proxy Statement for our 2018 Annual Meeting of Stockholders.
|
ITEM 12. |
SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER MATTERS |
The information required by this item is incorporated herein by reference to information contained in the Proxy Statement for our 2018 Annual Meeting of Stockholders.
The information required by this item is incorporated herein by reference to information contained in the Proxy Statement for our 2018 Annual Meeting of Stockholders.
The information required by this item is incorporated herein by reference to information contained in the Proxy Statement for our 2018 Annual Meeting of Stockholders.
137
|
(a) |
The following documents are filed as part of this report: |
|
|
(1) |
Financial Statements |
Our Consolidated Financial Statements are listed in the “Index to Consolidated Financial Statements” under Part II. Item 8 of this Annual Report on Form 10‑K.
|
|
(2) |
Financial Statement Schedules |
Financial statement schedules have been omitted in this report because they are not applicable, not required under the instructions, or the information requested is set forth in the consolidated financial statements or related notes thereto.
|
(b) |
Exhibits. The list of exhibits filed with this report is set forth in the Exhibit Index preceding the signature pages and is incorporated herein by reference. |
None.
138
|
Exhibit |
|
|
|
Incorporated by Reference |
|
Filed |
||||||
|
Number |
|
Description of Document |
|
Form |
|
File No. |
|
Exhibit |
|
Filing Date |
|
Herewith |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
10‑Q |
|
001‑36668 |
|
3.1 |
|
11/12/2014 |
|
|
||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
10‑Q |
|
001‑36668 |
|
3.2 |
|
11/12/2014 |
|
|
||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
S‑1 |
|
333‑198410 |
|
4.1 |
|
08/27/2014 |
|
|
||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
S‑1 |
|
333‑198410 |
|
4.2 |
|
08/27/2014 |
|
|
||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
S‑1 |
|
333‑198410 |
|
10.1 |
|
09/19/2014 |
|
|
||
|
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S‑1 |
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333‑198410 |
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10.2 |
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08/27/2014 |
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10‑Q |
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001‑36668 |
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10.3 |
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11/12/2014 |
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2014 Employee Stock Purchase Plan and form of subscription agreement. |
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10‑Q |
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001‑36668 |
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10.4 |
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11/12/2014 |
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S‑1 |
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333‑198410 |
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10.5 |
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08/27/2014 |
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10‑K |
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001‑36668 |
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10.6 |
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03/25/2015 |
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S‑1 |
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333‑198410 |
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10.6 |
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08/27/2014 |
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10‑K |
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001‑36668 |
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10.8 |
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02/28/2017 |
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10‑K |
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001‑36668 |
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10.9 |
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02/28/2017 |
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S‑1 |
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333‑198410 |
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10.9 |
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09/29/2014 |
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Exclusive License Agreement, dated April 26, 2013, by and between the Registrant and Rose U LLC. |
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S‑1 |
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333‑198410 |
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10.10 |
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09/29/2014 |
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10‑K |
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001‑36668 |
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10.10 |
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03/25/2015 |
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S‑1 |
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333‑198410 |
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10.12 |
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09/29/2014 |
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139
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Incorporated by Reference |
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Filed |
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Number |
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Description of Document |
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Form |
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File No. |
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Exhibit |
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Filing Date |
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Herewith |
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S‑1 |
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333‑198410 |
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10.13 |
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09/12/2014 |
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10-K |
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001‑36668 |
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10.13 |
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03/04/2016 |
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Third Amendment to Lease, dated April 29, 2016, by and between the Registrant and Middlefield Park. |
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10-Q |
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001‑36668 |
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10.1 |
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08/08/2016 |
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S‑1 |
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333‑198410 |
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10.14 |
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09/12/2014 |
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10-Q |
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001‑36668 |
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10.1 |
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11/07/2016 |
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S-8 |
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333-222865 |
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99.3 |
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02/05/2018 |
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Transition Agreement, dated November 6, 2017, by and between the Registrant and UCB Pharma S.A. |
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X |
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101.INS |
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XBRL Instance Document. |
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X |
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101.SCH |
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XBRL Taxonomy Extension Schema Document. |
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X |
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101.CAL |
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XBRL Taxonomy Extension Calculation Linkbase Document. |
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X |
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101.DEF |
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XBRL Taxonomy Extension Definition Linkbase Document. |
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X |
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101.LAB |
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XBRL Taxonomy Extension Label Linkbase Document. |
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X |
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101.PRE |
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XBRL Taxonomy Extension Presentation Linkbase Document. |
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X |
140
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† |
Portions of this exhibit, which have been granted confidential treatment by the Securities and Exchange Commission pursuant to a request for confidential treatment under Rule 406 promulgated under the Securities Act, have been omitted. |
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# |
Represents a management contract or compensatory plan. |
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* |
As contemplated by SEC Release No. 33‑8212, these exhibits are furnished with this Annual Report on Form 10‑K and are not deemed filed with the Securities and Exchange Commission and are not incorporated by reference in any filing of Dermira, Inc. under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended, whether made before or after the date hereof and irrespective of any general incorporation language contained in such filings. |
141
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this Annual Report on Form 10‑K to be signed on its behalf by the undersigned, thereunto duly authorized, in Menlo Park, California, on the 22nd day of February 2018.
|
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DERMIRA, INC. |
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By: |
/s/ Thomas G. Wiggans |
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Thomas G. Wiggans Chief Executive Officer and Chairman of the Board (Principal Executive Officer) |
KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Thomas G. Wiggans and Andrew L. Guggenhime, jointly and severally, as his or her true and lawful attorneys‑in‑fact, proxies and agents, with full power of substitution and resubstitution, for him or her, and in his or her name, place and stead, in any and all capacities, to sign any and all amendments to this report, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the Securities and Exchange Commission, granting unto said attorneys‑in‑fact, proxies and agents full power and authority to do and perform each and every act and thing requisite or necessary to be done in and about the premises hereby ratifying and confirming all that said attorneys‑in‑fact, proxies and agents, or his substitute or substitutes, may lawfully do or cause to be done by virtue hereof.
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, this report has been signed below by the following persons on behalf of the Registrant and in the capacities and on the dates indicated.
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Signature |
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Title |
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Date |
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/s/ Thomas G. Wiggans |
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Chief Executive Officer and Chairman of the |
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February 22, 2018 |
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Thomas G. Wiggans |
Board (Principal Executive Officer) |
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/s/ Andrew L. Guggenhime |
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Chief Operating Officer and Chief Financial Officer |
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February 22, 2018 |
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Andrew L. Guggenhime |
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(Principal Financial and Accounting Officer) |
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/s/ Eugene A. Bauer M.D. |
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Chief Medical Officer and Director |
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February 22, 2018 |
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Eugene A. Bauer |
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/s/ David E. Cohen, M.D., M.P.H. |
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Director |
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February 22, 2018 |
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David E. Cohen, M.D., M.P.H. |
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/s/ Fred B. Craves |
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Lead Independent Director |
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February 22, 2018 |
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Fred B. Craves |
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/s/ Matthew K. Fust |
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Director |
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February 22, 2018 |
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Matthew K. Fust |
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/s/ Mark D. Mcdade |
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Director |
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February 22, 2018 |
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Mark D. McDade |
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/s/ Jake R. Nunn |
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Director |
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February 22, 2018 |
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Jake R. Nunn |
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/s/ William R. Ringo |
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Director |
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February 22, 2018 |
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William R. Ringo |
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/s/ Kathleen Sebelius |
|
Director |
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February 22, 2018 |
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Kathleen Sebelius |
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142