UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, DC 20549
FORM 8-K
CURRENT REPORT PURSUANT TO
SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934
Date of Report: November 8, 2015
(Date of earliest event reported)
LOXO ONCOLOGY, INC.
(Exact Name of Registrant as Specified in Its Charter)
Delaware
(State or Other Jurisdiction of Incorporation)
001-36562 |
|
46-2996673 |
(Commission File Number) |
|
(IRS Employer Identification No.) |
One Landmark Square, Suite 1122 |
|
06901 |
(Address of Principal Executive Offices) |
|
(Zip Code) |
(203) 653-3880
(Registrants Telephone Number, Including Area Code)
Not Applicable
(Former name or former address, if changed since last report.)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Item 7.01 Regulation FD.
On November 8, 2015, Loxo Oncology, Inc. (Company) issued a press release announcing the results of the LOXO-101 Phase 1 trial as reported by study investigators. A copy of the press release is furnished as Exhibit 99.1 to this report and incorporated herein by reference. A copy of the slides presented by the study investigators are furnished as Exhibit 99.2 to this report and incorporated herein by reference.
The information furnished with this report, including Exhibit 99.1 and Exhibit 99.2, shall not 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 of that section, nor shall it be deemed incorporated by reference into any other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.
Item 9.01 Financial Statements and Exhibits
(d) Exhibits.
Exhibit |
|
Description of Exhibit |
|
|
|
99.1 |
|
Press release dated November 8, 2015. |
|
|
|
99.2 |
|
Slides presented by study investigators on November 8, 2015. |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|
Loxo Oncology, Inc. | |
|
| |
|
|
|
Date: November 9, 2015 |
By: |
/s/ Jennifer Burstein |
|
Name: |
Jennifer Burstein |
|
Title: |
Vice President of Finance and |
|
|
principal financial officer |
Exhibit 99.1
Loxo Oncology TRK Inhibitor LOXO-101 Demonstrates Promising Clinical Activity and Safety in Phase 1 Trial
Six Patients with TRK Fusion Cancers Enrolled; All Remain on Study
Three Patients with TRK Fusion Cancers Evaluable for Efficacy and All Show Objective Responses
Company to Host Investor Conference Call and Webcast to Review the Data on Monday, November 9, 2015 at 8:00 a.m. EST
STAMFORD, Conn., November 8, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, today announced new results from its Phase 1 open-label, dose-escalation trial of LOXO-101, a selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules, and the first preclinical data for its RET and FGFR programs. The data are being presented at the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.
Providing a LOXO-101 Phase 1 update, study investigators reported that, as of the October 20, 2015 data cutoff date, 30 patients with solid tumors refractory to standard therapy had been enrolled and treated, including six patients with cancers harboring TRK fusions. Three of the six patients with TRK fusion cancers had been on study sufficiently long for their first efficacy assessment, and all three had achieved an objective response at the first response assessment, as defined by standard RECIST criteria. All three of these patients remain in response and on study. The other three patients with TRK fusion cancers were recently enrolled and thus had not yet been evaluated for response as of the data cutoff date, though they all remain on study. In addition, LOXO-101 has been well tolerated, including the 100 mg twice-daily dose, which has been selected for Phase 2 study and has shown efficacy in TRK fusion patients. The majority of adverse events reported by investigators have been mild to moderate. A maximum tolerated dose (MTD) has not been defined, though near-term Phase 1 enrollment will focus on further characterizing the pharmacokinetics and safety of the 100 mg twice-daily dose dosing.
The efficacy we are seeing for LOXO-101, at a well-tolerated dose, is as compelling as any I have seen in Phase 1, said David Hong, M.D., deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston and presenter of the LOXO-101 oral presentation. As a community, we need to test for TRK fusions and make sure these patients find their way to a LOXO-101 study. I look forward to participating in the recently initiated Phase 2 trial.
We are very encouraged by the rapid and dramatic responses we are seeing in TRK fusion patients, which demonstrate LOXO-101s ability to effectively target these
genetically defined tumors, said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. As we look into 2016, we are focused on continuing to execute on our clinical development strategy for LOXO-101 and plan to release additional data from our Phase 1 study at a medical meeting next year. In addition, our preclinical posters show the progress we have made, with our partners at Array BioPharma, in developing other selective, purpose-built molecules with differentiated and best-in-class potential against highly actionable targets in oncology.
LOXO-101 Phase 1 Results
LOXO-101 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of October 20, 2015, 30 patients with advanced cancer had been treated at five dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID, and 200 mg QD. The median age of these patients is 55 (ranging from 28-76) and the median number of prior treatments was three (ranging from 0-11).
Safety Analysis
LOXO-101 has been well tolerated in the 30 patients treated as of October 20, 2015. Adverse events are reported regardless of attribution to study drug. Adverse events are generally consistent with those described after the last data cutoff of March 26, 2015, consisting of Grade 1 and 2 fatigue (33 percent), dizziness (30 percent), anemia (20 percent) and nausea (20 percent). Grade 3 adverse events reported included fatigue, anemia, abdominal pain, increased liver enzymes, delirium and syncope. No Grade 4 adverse events have been reported. The frequency of toxicities did not correlate with dose level. MTD has not yet been defined.
Efficacy Analysis
To date, six patients with cancers harboring TRK fusions have been enrolled, representing a broad range of tumor types: mammary analogue secretory cancer of the salivary glands (MASC) (n=2), soft tissue sarcoma, gastrointestinal stromal tumor, thyroid carcinoma, and non-small cell lung cancer. As of the October 20, 2015 data cutoff date, three patients had been evaluated for response, and all had achieved an objective response at first response assessment. A patient with soft tissue sarcoma harboring an LMNA-NTRK1 fusion remains on study for greater than eight months at a dose of 100 mg BID. This patient was the subject of a peer-reviewed research brief published in Cancer Discovery in July 2015. A patient with a gastrointestinal stromal tumor (GIST) harboring an ETV6-NTRK3 fusion remains on study for greater than four months at a dose of 150 mg BID. A patient with a MASC tumor harboring an ETV6-NTRK3 fusion remains on study for greater than three months at 100 mg BID. All three of these responding patients remain in response and on study as of October 20, 2015. The other three patients (thyroid carcinoma, non-small cell lung cancer, MASC) were recently enrolled and not yet evaluable for efficacy as of the data cutoff date.
On Monday, November 9, 2015, Loxo Oncology will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the LOXO-101 materials presented at the AACR-NCI-EORTC meeting. These materials will also be posted to the Loxo Oncology website.
Pipeline Program Updates
Loxo Oncology presented data from the companys novel Rearranged during Transfection (RET) and Fibroblast Growth Factor Receptor (FGFR) programs showing potential best-in-class selectivity and target coverage. Loxo Oncology expects to advance a RET inhibitor as its next Investigational New Drug (IND) application.
Upcoming Milestones for Loxo Oncology
Loxo Oncology continues to make significant progress across its pipeline. Milestones in 2016 are expected to include:
· Continued enrollment of the LOXO-101 Phase 2 global, multi-center, single-arm, open-label basket trial in adult patients with solid tumors that harbor a TRK fusion.
· Presentation of additional data from the ongoing Phase 1 study of LOXO-101 at a medical meeting in 2016.
· Initiate Phase 1 study of LOXO-101 in pediatric cancer patients, including an oral liquid formulation, in the first half of 2016.
· Initiate Phase 1 study of a selective RET inhibitor in late 2016 or early 2017.
Conference Call and Webcast Information
Loxo Oncology will host a conference call, live webcast with slides and Q&A on Monday, November 9, 2015 at 8:00 a.m. ET to discuss the LOXO-101 data and program updates. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 66690460. A live webcast of the presentation will be available at http://ir.loxooncology.com/. A replay of the webcast will be available shortly after the conclusion of the call and archived on the companys website for 30 days following the call.
About LOXO-101
LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions. For additional information about both the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.
About Loxo Oncology
Loxo Oncology is a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most
selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, thereby delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the companys website at www.loxooncology.com.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: anticipate, intend, plan, goal, seek, believe, project, estimate, expect, strategy, future, likely, may, should, will and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. Examples of forward-looking statements include, among others, statements we make regarding our partnerships, timing and success of our clinical trials, the potential therapeutic benefits and economic value of our lead product candidate, potential growth opportunities and potential market opportunities. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Quarterly Report on Form 10-Q, and other reports as filed from time to time with the Securities and Exchange Commission. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.
###
Contacts for Loxo Oncology, Inc.
Company:
Jacob S. Van Naarden
Vice President, Corporate Development and Strategy
jake@loxooncology.com
Investors:
Peter Rahmer
The Trout Group, LLC
646-378-2973
prahmer@troutgroup.com
Media:
Dan Budwick
Pure Communications, Inc.
973-271-6085
dan@purecommunicationsinc.com
Exhibit 99.2
Clinical safety and activity from a Phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions David S. Hong1, Marcia S. Brose2, Robert C. Doebele3, Alice T. Shaw4, Afshin Dowlati5, Todd M. Bauer6, Anna F. Farago4, Adriana Estrada-Bernal3, Anh T. Le3, Michael C. Cox7, Nisha Nanda7, Jennifer A. Low7, Howard A. Burris, III6 November 8, 2015 1 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 1MD Anderson Cancer Center, Houston, TX 2University of Pennsylvania, Philadelphia, PA 3University of Colorado, Aurora, CO 4Massachusetts General Hospital, Boston, MA 5University Hospitals Case Medical Center, Cleveland, OH 6Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN 7Loxo Oncology, South San Francisco, CA
Disclosures Author Disclosures David S. Hong Travel expenses supported by Loxo Oncology Marcia S. Brose None Robert C. Doebele Research grant from Loxo Oncology Alice T. Shaw None Afshin Dowlati None Todd M. Bauer None Anna F. Farago None Adriana Estrada-Bernal Research grant from Loxo Oncology Anh T. Le Research grant from Loxo Oncology Howard A. Burris, III None Michael C. Cox Nisha Nanda Jennifer A. Low Employees and shareholders of Loxo Oncology 2
TRK Fusions are Oncogenic and Signal Through Canonical Downstream Pathways Normal TRK Proteins Family of neurotrophin receptors TrkA (NTRK1) Pain, thermoregulation TrkB (NTRK2) Movement, memory, mood, appetite, body weight TrkC (NTRK3) Proprioception TRK Fusions Ligand binding domain replaced by 5 fusion partner; highly expressed by promoter of 5 fusion gene Ligand-independent activation 3 NTRK1/2/3 ERK AKT ERK AKT TrkA/B/C
TRK Fusions Found in Diverse Cancer Histologies 4 TRK Fusion Frequency <5% 525% >75% CNS Astrocytoma Brain low-grade glioma Glioblastoma GI Colorectal cancer Cholangiocarcinoma Pancreatic cancer Head and neck Squamous cell carcinoma Lung Adenocarcinoma Large cell neuroendocrine Other Acute myeloid leukemia Breast invasive carcinoma Melanoma Sarcoma Congenital mesoblastic nephroma Papillary thyroid cancer Pontine glioma Spitz nevi Mammary analogue secretory carcinoma (MASC) of the salivary glands Secretory breast carcinoma Infantile fibrosarcoma
LOXO-101: A Rationally Designed Selective TRK Inhibitor 5 Chartier M, Chénard T, Barker J, Najmanovich R. (2013) Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ 1:e126 TRK TRK LOXO-101 rationally designed High potency against TRKA, TRKB, TRKC and slow off-rate (T1/2 = 160 min) X-ray crystallography enables the knowledge of off-target homology High selectivity: limited inhibition of other kinases and >1,000x selective for other off targets
In Vivo: Tumor Regressions in TRK Fusion Xenografts LOXO-101 In Vitro and In Vivo Activity 6 In Vitro: Potency in TRK Fusion Cell Models; Spares Unselected Cell Models Courtesy of the Doebele lab. Doebele et al. Cancer Discov. 2015 Oct;5(10):1049-57 0 2 4 6 8 10 12 0 200 400 600 Time (Days) T u m o r V o l u m e C h a n g e ( % ) KM12 Line ( TPM3 - NTRK1 ; colon cancer) 0 2 4 6 8 10 12 -100 0 100 200 Time (Days) T u m o r V o l u m e C h a n g e ( % ) CUTO-3.29 Line ( MPRIP - NTRK1 ; lung cancer) 0.1 1 10 100 1000 10000 0 50 100 CUTO3.29 (MPRIP-NTRK1) KM12 (TPM3-NTRK1) MO91 (ETV6-NTRK3) LOXO-101 (nM) P e r c e n t o f C o n t r o l Fusion Lines 0.1 1 10 100 1000 10000 0 50 100 LOXO-101 (nM) P e r c e n t o f C o n t r o l H1650 H3122 HCC78 A549 H1299 SW837 HT29 HCT116 HCT15 Non-Fusion Lines 0 2 4 6 8 10 12 -100 -50 0 50 100 Time (Days) T u m o r V o l u m e C h a n g e ( % ) MO-91 Line ( ETV6 - NTRK3 ; AML) Vehicle Control 60 mg/kg/day 200 mg/kg/day
LOXO-101 Phase 1 Study Design Ongoing dose escalation study Advanced or metastatic solid tumors ECOG 0/1, normal organ function QD or BID oral continuous dosing, 28-day cycles Outcome measures Safety and tolerability Pharmacokinetics measured at cycle 1, days 1 and 8 Efficacy assessments conducted every other cycle starting C3D1 7 Dose Cohort Patients Enrolled 50mg QD 4 100mg QD 5 100mg BID 11 200mg QD 5 150mg BID 5 Data cutoff October 20, 2015
Baseline Characteristics characteristics Subjects (N= 30) Median age (range), years 55.0 (28 76) Sex Male / Female 18 (60%) / 12 (40%) Race White / Black / Other 20 (67%) / 6 (20%) / 4 (13%) Tumor Type Head and Neck 6 (20%) Lung 5 (17%) Pancreatic 3 (10%) Breast 2 (7%) Colorectal 2 (7%) Sarcoma 2 (7%) Thyroid 2 (7%) Other* 8 (27%) ECOG Status 0 / 1 12 (40%) / 18 (60%) Prior systemic anticancer therapy, n (%) 29 (97%) Median number of regimens (range) 3 (0-11) TRK-fusion positive Total 6 Mammary analogue secretory carcinoma (ETV6-NTRK3) 2 Soft tissue sarcoma (LMNA-NTRK1) 1 NSCLC (TPR-NTRK1) 1 Thyroid (ETV6-NTRK3) 1 GIST (ETV6-NTRK3) 1 8 *Includes n=1 each of anal, appendiceal peritoneal carcinomatosis, gallbladder, gastric, melanoma, retroperitoneal leiomyosarcoma, thymus, and cancer of unknown primary
RESULTS 9
Linear PK profile following oral administration shows high plasma exposure and no accumulation 100 mg BID: IC90 target coverage, favorable safety, and early efficacy LOXO-101 Exposure 10 The horizontal line representing TRKA IC90 refers to the total plasma concentration of LOXO-101 that is associated with an unbound concentration of LOXO-101 that is equal to its IC90 for inhibition of NGF-stimulated activity in a cellular assay. The IC90 values for TRKB and TRKC are not shown, but are similar to those of TRKA. Dotted lines in the right panel are inferred PK from the evening BID dose. LOXO-101 CMAX LOXO-101 EXPOSURE OVER TIME 0 6 12 18 24 1 10 100 1000 Time (h) C o n c e n t r a t i o n o f L O X O - 1 0 1 i n P l a s m a ( n g / m L ) TRKA IC 50 TRKA IC 90 50 mg QD (n=4) 100 mg QD (n=5) 100 mg BID (n=8) 150 mg BID (n= 4) 200 mg QD (n=2) 50 mg QD (n=4) 100 mg QD (n=5) 100 mg BID (n=8) 150 mg BID (n=5, 4) 200 mg QD (n=3, 2) 0 1000 2000 3000 4000 Dose C m a x o f L O X O - 1 0 1 i n P l a s m a ( n g / m L ) Day 1 Day 8 TRKA IC 90
LOXO-101 Phase 1 Interim Treatment-Emergent AEs, Regardless of Attribution to Study Drug Dose 100 mg BID (n=11) Total (n=30) Adverse Events (AEs)* Gr 3/4 All Gr Gr 3/4 All Gr n (%) n (%) n (%) n (%) Fatigue 0 2 (18%) 1 (3%) 10 (33%) Dizziness 0 5 (45%) 0 9 (30%) Anemia 0 2 (18%) 2 (7%) 6 (20%) Nausea 0 4 (36%) 0 6 (20%) Abdominal pain 0 2 (18%) 1 (3%) 5 (17%) Constipation 0 0 0 5 (17%) Cough 0 2 (18%) 0 5 (17%) Diarrhea 0 2 (18%) 0 5 (17%) Pyrexia 0 2 (18%) 0 5 (17%) Anxiety 0 1 (9%) 0 4 (13%) Increased ALP 0 2 (18%) 1 (3%) 4 (13%) Increased AST 1 (9%) 1 (9%) 3 (10%) 3 (10%) Delirium 1 (9%) 1 (9%) 2 (7%) 2 (7%) Syncope 0 0 2 (7%) 2 (7%) *Treatment-emergent adverse events (reported by > 10% of total subjects) or any Grade 3-4 events that occurred in at least 2 patients. 11
LOXO-101 Enrollment and Summary of Efficacy 6 patients with TRK fusions enrolled; all currently on study Soft tissue sarcoma (LMNA-NTRK1) GIST (ETV6-NTRK3) Mammary analogue secretory carcinoma (ETV6-NTRK3) Thyroid carcinoma (ETV6-NTRK3) Mammary analogue secretory carcinoma (ETV6-NTRK3) NSCLC (TPR-NTRK1) 24 unselected patients treated: 17 patients are off study due to disease progression, 2 patients are off study due to withdrawn consent, 1 patient is off study due to non-compliance, 1 patient is off study due to an adverse event, and 3 patients remain on study 3 objective responses to LOXO-101: 100% ORR of enrolled and evaluable TRK fusions All responses were seen at first restaging and all patients remain in response 12 3 patients evaluable for efficacy as of October 20, 2015 3 patients recently enrolled and not yet evaluable for efficacy
PATIENT CASES 13
Patient #1: LMNA-NTRK1 fusion soft tissue sarcoma 42 yo female with undifferentiated sarcoma progressed through epirubicin, ifosfamide, sorafenib, and doxorubicin 100mg BID Rapid resolution of dyspnea and hypoxemia Confirmed partial response Currently on study; 8+ months Study baseline Study cycle 9 day 1 14
Patient #2: ETV6-NTRK3 fusion GIST 55 yo male with GIST progressed through imatinib, sunitinib, sorafenib, nilotinib, and regorafenib 150mg BID Confirmed partial response Currently on study; 4+ months 15 CT PET Study baseline Study cycle 5 day 1 Study baseline Study cycle 3 day 1
Study baseline Study cycle 3 day 1 Patient #3: ETV6-NTRK3 fusion mammary analogue secretory carcinoma of the salivary gland (MASC) 33 yo male progressed through docetaxel, carboplatin and 5FU 100mg BID Partial response Currently on study; 3+ months 16
Conclusions LOXO-101 is a purpose-built, oral, selective and potent TRK inhibitor with tumor regression in TRK-fusion preclinical xenograft models PK analyses demonstrate very high Cmax (mean levels >IC90) and linear PK with no significant drug accumulation LOXO-101 is well tolerated, with most common adverse events including Grade 1/2 fatigue, dizziness, anemia, and nausea; MTD not yet defined 6 TRK fusions enrolled from March 2015 to October 2015 Rapid RECIST responses observed in first 3 of 3 patients harboring TRK gene fusions All TRK fusion patients are currently on study without progression, with the longest patient at 8+ months Loxo Oncology has begun accruing a Phase 2 basket trial in patients with advanced or metastatic solid tumors with a TRK gene fusion 17
LOXO-101 Phase 2 Adult Basket Trial First Patient Enrolled, October 2015 Adult solid tumors, including CNS tumors, with TRK fusion based on local or pre-existing testing Dose: 100mg BID Primary endpoint: Best overall response by RECIST or RANO Global study (20-30 sites) to enroll up to 18 patients per cohort NCT 02576431 18
Acknowledgements LOXO-101 patients and their families and caregivers Co-investigators and study support staffs This trial sponsored and supported by Loxo Oncology 19
X3KQU )P52+&($M-H$-?(?=/7?=S8C=[XC> 8CN(X ..CN18CN9XCNBX$@$! #L! end
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