8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8–K

CURRENT REPORT

Pursuant to Section 13 OR 15 (d)

of the Securities Exchange Act of 1934

Date of Report (Date of Earliest Event Reported): November 14, 2017

ZYNERBA PHARMACEUTICALS, INC.

(Exact Name of Issuer as Specified in Charter)

Delaware	001-37526	26-0389433
(State or Other Jurisdiction of Incorporation or Organization)	(Commission File Number)	(I.R.S. Employer Identification No.)

80 W. Lancaster Avenue, Suite 300
Devon, PA 19333

(Address of Principal Executive Offices)

(484) 581-7505

(Registrant’s Telephone Number, Including Area Code)

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:

oWritten communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

oSoliciting material pursuant to Rule 14a—12 under the Exchange Act (17 CFR 240.14a—12)

oPre—commencement communications pursuant to Rule 14d—2(b) under the Exchange Act (17 CFR 240.14d—2(b))

oPre—commencement communications pursuant to Rule 13e—4(c) under the Exchange Act (17 CFR 240.13e—4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company x

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. x

Item 2.02      Results of Operations and Financial Condition

On November 14, 2017, Zynerba Pharmaceuticals, Inc. (the “Company”) issued a press release announcing its financial results and operational highlights for the three and nine months ended September 30, 2017.  A copy of this press release is furnished as Exhibit 99.1 hereto.

The information furnished pursuant to this Item 2.02, including Exhibit 99.1, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, and shall not be deemed to be incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.

Item 8.01          Other Events

Attached as Exhibit 99.2 is a presentation that the Company will post on its website on November 14, 2017 and may use from time to time in presentations or discussions with investors, analysts and other parties.

Item 9.01Financial Statements and Exhibits.

(d) Exhibits

The following exhibits are being filed herewith:

Exhibit No.	Document
99.1	Press Release, dated November 14, 2017.
99.2	Zynerba Pharmaceuticals, Inc. Investor Presentation

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SIGNATURE

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.

Date: November 14, 2017

ZYNERBA PHARMACEUTICALS, INC.
By:	/s/ Suzanne Hanlon
	Name:  Suzanne Hanlon
	Title:  Secretary, General Counsel and Vice President, Human Resources

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EX-99.1

Exhibit 99.1

Zynerba Pharmaceuticals Reports Third Quarter 2017 Financial Results

and Operational Highlights

DEVON, Pa., November 14, 2017 — Zynerba Pharmaceuticals, Inc. (NASDAQ:ZYNE), a clinical-stage specialty pharmaceutical company dedicated to developing and commercializing innovative pharmaceutically-produced transdermal cannabinoid treatments, today reported financial results for the third quarter ended September 30, 2017 and provided an overview of recent operational highlights.

“We announced important data during the third quarter, including remarkable Phase 2 data from our FAB-C study of ZYN002 in children and adolescents with Fragile X syndrome,” said Armando Anido, Chairman and Chief Executive Officer. “We achieved the primary endpoint and numerous secondary endpoints with statistical significance compared to baseline, and anticipate moving into a pivotal program in Fragile X in the first half of 2018. Additionally, we look forward to outlining our path forward in Epilepsy, and meeting with the FDA to discuss our OA pivotal program in the first quarter of 2018.”

Third Quarter 2017 and Recent Highlights

ZYN002 in Fragile X Syndrome (FXS)

Announced Positive Results from FAB-C Open Label Exploratory Phase 2 Clinical Trial of ZYN002 Cannabidiol (CBD) Gel in Pediatric and Adolescent Fragile X Syndrome Patients; Company Expects to Initiate Pivotal Program in the First Half of 2018

A total of 20 patients were enrolled into the 12-week open label Phase 2 FAB-C trial to evaluate ZYN002 cannabidiol (CBD) gel in pediatric and adolescent patients with FXS.

·The study successfully met its primary endpoint, achieving a 46% improvement (p<0.0001) in the total score of Anxiety, Depression, and Mood Scale (ADAMS) at week twelve compared to baseline;

·The results of the secondary endpoints reinforce those demonstrated in the ADAMS. For example, ZYN002 also achieved clinically meaningful and statistically significant improvements compared to baseline in all measures of the Aberrant Behavior Checklist for Fragile X (ABC-FXS), which address the key symptoms of FXS including social avoidance, temper tantrums, repetitive movements, and hyperactivity;

·ZYN002 was shown to be extremely well tolerated, and the safety profile was consistent with previously released data from clinical trials;

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·Thirteen (13) of the 18 patients completing the study have enrolled into the 52-week open label extension and remain in the trial;

·The Company anticipates that it will meet with the U.S. Food and Drug Administration (FDA) in the first quarter of 2018 to discuss the results of the study and next steps, including a pivotal program expected to initiate in the first half of 2018; and

·The FDA has granted orphan-drug designation to Zynerba for the use of CBD for the treatment of FXS.

ZYN002 in Osteoarthritis

Announced Important Results from Phase 2 STOP Clinical Trial for ZYN002 CBD Gel in Adult Osteoarthritis Patients; Study Achieved Key Secondary Endpoints with Statistical Significance

Three hundred and twenty (320) patients were randomized into the double-blind, placebo-controlled Phase 2 STOP trial in osteoarthritis of the knee.

·Statistically significant results were achieved for a number of secondary endpoints, though the study did not achieve its primary endpoint of change from baseline in the weekly mean of the 24-hour average worst pain score at week 12;

·Importantly, the composite responder analysis (defined as a >30 percent reduction in worst average daily pain scores and a >20 percent improvement in the WOMAC physical function score) for 250 mg daily of ZYN002 4.2% CBD gel achieved statistical significance (p=0.016). This composite responder endpoint is consistent with the FDA guidelines requiring the use of both pain and function endpoints in pivotal osteoarthritis programs;

·ZYN002 was shown to be extremely well tolerated and the safety profile was consistent with previously released data from clinical trials; and

·Zynerba anticipates that it will meet with the FDA in the first quarter of 2018 to discuss the results of the study. The Company expects to initiate a pivotal Phase 2/3 program in 2018.

ZYN002 in Focal Seizures

Announced Results from Phase 2 STAR 1 Clinical Trial for ZYN002 CBD Gel in Adult Epilepsy Patients with Focal Seizures

A total of 188 patients were randomized in the Phase 2 STAR 1 double-blind, placebo-controlled clinical trial in adult patients with refractory epilepsy.

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·ZYN002 did not demonstrate a statistically significant reduction of focal seizures during the treatment period compared to the baseline period for either the high or low dose cohorts compared to placebo;

·The Company believes that the study failed to achieve its endpoints primarily due to a bimodal distribution of patient responses on placebo; approximately 24% of patients receiving placebo achieved >50% reductions in focal seizures, while the other approximately 76% of placebo patients showed no improvement or worsening of focal seizures; and

·ZYN002 was shown to be extremely well tolerated and the safety profile was consistent with previously released data from the Phase 1 trials.

Dosing Continues in the Phase 2 STAR 2 Open-Label Extension Trial for ZYN002 CBD Gel in Adult Epilepsy Patients; Clinically Meaningful Responses Achieved in Patients on ZYN002 for at least 6 Months

As of November 13, 2017, one hundred (100) patients remain in the STAR 2 open label trial, designed to evaluate long-term safety and tolerability of ZYN002 CBD gel across a range of doses. In the open-label extension study, patients are receiving ZYN002 for up to 52 weeks.

·Eighty-nine (89) patients have reached six months of drug exposure in STAR 2; and

·Clinically meaningful reductions in seizures (>50%) have been observed in patients on ZYN002 for at least six months.

Data from the ZYN002 epilepsy program have been accepted for poster presentation at the 2017 American Epilepsy Society (AES) Meeting.

Further analysis of data from STAR 1 and STAR 2 will clarify the study design and inclusion / exclusion criteria ahead of a new Phase 2 clinical study in epilepsy. The Company expects to outline its path forward in epilepsy in the first quarter of 2018.

ZYN001 Phase 1 Evaluation

Dosing Continues in the Phase 1 Program for ZYN001 Pro-drug of Tetrahydrocannabinol (THC) Delivered via Transdermal Patch

Dosing is underway in a Phase 1 program to assess ZYN001, a patent-protected, pro-drug of THC delivered via a patch. This first in man study is a randomized, double-blind, placebo-controlled Phase 1 trial. The safety, tolerability and pharmacokinetic profile of a single dose of ZYN001 versus placebo is initially being evaluated. Several formulations and patch wear times ranging from 24 hours to 7 days

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will be assessed in up to 48 healthy subjects. Based on results from the single dose portion of this trial, two formulations will be evaluated in multiple patch applications for 14 days in up to 32 healthy subjects who will be randomized 3:1 to ZYN001 or placebo. Results from this study are now expected in the first half of 2018. These data will inform the planned Phase 2 program for ZYN001, now expected to initiate in 2018.

Third Quarter 2017 Financial Results

As of September 30, 2017, cash and cash equivalents were $66.3 million, compared to $70.2 million as of June 30, 2017. Research and development expenses for the third quarter of 2017 were $5.8 million, including stock-based compensation of $0.6 million. General and administrative expenses for the third quarter of 2017 were $2.8 million, including stock-based compensation expense of $1.1 million. Net loss for the third quarter of 2017 was $8.3 million with basic and diluted net loss per share of $0.63.

Recent Equity Financing

On June 9, 2017, we entered into an Open Market Sales Agreement, or “at-the-market” (ATM) offering program, with Jefferies LLC, pursuant to which we may sell, from time to time, up to $50 million of our common stock. From September 28, 2017 through October 26, 2017, the Company has sold and issued 296,594 shares under its ATM program, at a weighted average selling price of $10.74 per share, for gross proceeds of $3.2 million. Net proceeds after deducting underwriting and commissions and offering expenses were $3.0 million. None of the proceeds were settled prior to September 30, 2017, and therefore the cash for the sale of these common shares will be recorded in the fourth quarter.

Financial Outlook

The Company believes that the cash and cash equivalent position of $66.3 million as of September 30, 2017 is sufficient to develop five Phase 3-ready programs and initiate at least one pivotal program and fund operations and capital requirements into 2019.

About Zynerba Pharmaceuticals, Inc.

Zynerba Pharmaceuticals (NASDAQ: ZYNE) is dedicated to improving the lives of people with severe health conditions where there is a high unmet medical need by developing and commercializing pharmaceutically-produced transdermal cannabinoid medicines designed to meet the rigorous efficacy and safety standards established by global regulatory agencies. Through the discovery and development of these life-changing medicines, Zynerba seeks to improve the lives of patients battling severe, chronic health conditions including Fragile X syndrome, epilepsy, osteoarthritis, fibromyalgia and peripheral neuropathic pain. Learn more at www.zynerba.com and follow the Company on Twitter at @ZynerbaPharma.

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Cautionary Note on Forward-Looking Statements

This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Company’s current expectations. For example, there can be no guarantee that the Company will obtain approval for ZYN002 or ZYN001 from the U.S. Food and Drug Administration (FDA) or foreign regulatory authorities; even if ZYN002 or ZYN001 are approved, the Company may not be able to obtain the label claims that it is seeking from the FDA. In addition, the Company’s cash and cash equivalents may not be sufficient to support its operating plan for as long as anticipated. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the success, cost and timing of the Company’s product development activities, studies and clinical trials; the success of competing products that are or become available; the Company’s ability to commercialize its product candidates; the size and growth potential of the markets for the Company’s product candidates, and the Company’s ability to service those markets; the Company’s ability to develop sales and marketing capabilities, whether alone or with potential future collaborators; the rate and degree of market acceptance of the Company’s product candidates; and the Company’s expectations regarding its ability to obtain and adequately maintain sufficient intellectual property protection for its product candidates. This list is not exhaustive and these and other risks are described in the Company’s periodic reports, including the annual report on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission and available at www.sec.gov. Any forward-looking statements that the Company makes in this press release speak only as of the date of this press release. The Company assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

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ZYNERBA PHARMACEUTICALS, INC.

CONSOLIDATED STATEMENTS OF OPERATIONS

(Unaudited)

	Three months ended						Nine months ended
	September 30, 2017			September 30, 2016			September 30, 2017			September 30, 2016
Revenue	$	—		$	—		$	—		$	7,250
Operating expenses:
Research and development	5,753,764			4,504,097			16,978,016			11,880,264
General and administrative	2,795,839			1,493,461			7,640,489			4,649,948
Total operating expenses	8,549,603			5,997,558			24,618,505			16,530,212
Loss from operations	(8,549,603		)	(5,997,558		)	(24,618,505		)	(16,522,962		)
Other income (expense):
Interest income	161,930			22,747			363,350			53,243
Foreign exchange gain (loss)	76,468			(6,270		)	361,450			(49,668		)
Total other income (expense)	238,398			16,477			724,800			3,575
Loss before income taxes	(8,311,205		)	(5,981,081		)	(23,893,705		)	(16,519,387		)
Income tax benefit	—			—			—			(27,543		)
Net loss	$	(8,311,205	)	$	(5,981,081	)	$	(23,893,705	)	$	(16,491,844	)
Net loss per share - basic and diluted	$	(0.63	)	$	(0.67	)	$	(1.87	)	$	(1.86	)
Basic and diluted weighted average shares outstanding	13,098,914			8,912,508			12,743,332			8,865,854
Non-cash stock-based compensation included above:
Research and development	$	591,898		$	292,385		$	1,722,456		$	916,036
General and administrative	1,130,745			513,019			2,544,260			1,465,906
Total	$	1,722,643		$	805,404		$	4,266,716		$	2,381,942

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ZYNERBA PHARMACEUTICALS, INC.

CONSOLIDATED BALANCE SHEETS

(Unaudited)

	September 30, 2017			December 31, 2016
Assets
Current assets:
Cash and cash equivalents	$	66,251,286		$	30,965,791
Incentive and tax receivables	3,617,956			3,613,943
Prepaid expenses and other current assets	3,010,144			1,830,958
Total current assets	72,879,386			36,410,692
Property and equipment, net	190,370			143,382
Other assets	200			200
Total assets	$	73,069,956		$	36,554,274
Liabilities and Stockholders’ Equity
Current liabilities:
Accounts payable	$	3,116,100		$	1,848,084
Accrued expenses	4,479,292			4,284,907
Deferred grant revenue	833,975			833,975
Total current liabilities	8,429,367			6,966,966
Stockholders’ equity:
Common stock	13,257			9,995
Additional paid-in capital	134,489,599			75,545,875
Accumulated deficit	(69,862,267		)	(45,968,562		)
Total stockholders’ equity	64,640,589			29,587,308
Total liabilities and stockholders’ equity	$	73,069,956		$	36,554,274

Investor Contacts

Jim Fickenscher, CFO and VP Corporate Development

Zynerba Pharmaceuticals

484.581.7483

fickenscherj@zynerba.com

Will Roberts, VP Investor Relations and Corporate Communications

Zynerba Pharmaceuticals

484.581.7489

robertsw@zynerba.com

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EX-99.2

Exhibit 99.2

November 2017 A clinical-stage specialty pharmaceutical company dedicated to the development and commercialization of innovative transdermal pharmaceutically-produced cannabinoid treatments for patients with high unmet medical needs

Disclaimer The statements in this presentation may include forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These statements, among other things relate to the future operations, opportunities or financial performance of Zynerba Pharmaceuticals, Inc. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Company’s current expectations. These and other risks are described in our filings with the Securities and Exchange Commission, available at www.sec.gov. Any forward-looking statements that the Company makes in this presentation speak only as of the date of this PRESENTATION. The Company assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this presentation. 2 © 2017 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba is a trademark of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners.

Company Highlights 3 Two pivotal study-ready ZYN002 programs (FXS and OA) Expected meetings with FDA in 1Q18 STAR 1 and STAR 2 epilepsy data accumulation/analyses ongoing Outline path forward in epilepsy: 1Q18 Global ownership of both proprietary product candidates with potential applicability to numerous disorders Experienced team with proven track record in CNS, pain, and transdermal delivery $66.3 million in cash and cash equivalents as of September 30, 2017 Runway into 2019 Additional $3.0 million in proceeds from ATM program from 9/28-10/26/17 to be recorded in fourth quarter

Compelling Pipeline with Multiple Anticipated Near-Term Milestones 4 ZYN002 patent protected through 2030 ZYN001 patent protected through 2031 Product Candidate Indication Preclinical Phase 1 Phase 2 Next Milestones ZYN001 – THC Pro-Drug Patch ZYN002 – CBD Gel Epilepsy in Adults with Focal Seizures Osteoarthritis Fragile X Syndrome (US FDA Orphan Drug Designation) Fibromyalgia Peripheral Neuropathic Pain Outline path forward in 1Q18 1Q18 FDA meeting; initiate pivotal Ph2/3 program in 2018 1Q18 FDA meeting; initiate pivotal Ph2/3 program in 1H18 Complete Phase 1 in 1H18 Phase 2 Initiation 2018

5 ZYN002 CBD Gel Clinical Program Developing pharmaceutically-produced CBD formulated as a patent-protected permeation-enhanced gel

ZYN002 – CBD Gel First and only patent-protected permeation-enhanced pharmaceutically-produced cannabidiol gel formulated for transdermal delivery The permeation enhancer in ZYN002 increases the delivery of CBD through the layers of the epidermis and into the circulatory system 6 CBD Delivery

7 ZYN002 CBD Gel Clinical Program Fragile X Syndrome

Fragile X Syndrome (FXS) Overview 8 Autism spectrum disorder with no approved treatment options ~71,000 US patients1; most common inherited intellectual disability X-linked dominant; affects both males and females2 Intellectual disability, attention problems, anxiety, social avoidance co-occur Autism, self injury, aggression and seizures common, particularly in males3 Early intervention gives children best chance of developing a full range of skills4 Significant financial burden / employment impact associated with disorder5 1 Data per The National Fragile X Foundation 2 The National Fragile X Foundation, Handbook of Fragile X-associated disorders, 3rd Addition 3 Centers for Disease Control and Prevention, Fragile X Syndrome: https://www.cdc.gov/ncbddd/fxs/data.html 4 NIH: https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/treatments.aspx 5 J Intellect Disabil Res. 2010 Oct;54(10):918-28. doi: 10.1111/j.1365-2788.2010.01320.x. Epub 2010 Aug 26

The Endocannabinoid (EC) System A Critical Pathway in Fragile X Syndrome ECs form a system of neurotransmitters that regulates emotional responses, behavioral reactivity to context, and social interaction Due to a mutation in FMR1, patients with FXS suffer from dysregulation of the EC system resulting in the significant social, behavioral, and cognitive deficits Modulation of the EC system with CBD may have therapeutic potential in ameliorating some of those symptoms Strong scientific rationale in FXS validated by Phase 2 clinical data 9 U.S. Orphan Drug designation for use of CBD as treatment of Fragile X syndrome May provide fastest pathway to approval

Fragile X Syndrome Open Label Phase 2 Clinical Trial 10 Maintenance Dosing initiated at CBD 50 mg Daily; may be titrated up to 250 mg* Daily Screening Titration Weeks 7 to 12 Day 1 to Week 6 Open label, doses of CBD 50 mg, 100 mg, or 250 mg* Daily 18 patients completed study *In 4.2% gel 20 patients enrolled Treatment of Fragile X Syndrome Anxiety and Behavioral Challenges with CBD (FAB-C) FAB-C Trial – Period 1 FAB-C Trial – Period 2 Up to 12 Months Extension Patients continue on maintenance dose Physician can titrate up or down 13 patients continued into extension

FAB-C Endpoints 11 Changes in Anxiety, Depression and Mood vs. Baseline as Measured by the ADAMS Scale Primary Endpoint (recommended by FDA) Secondary Endpoints Aberrant Behavior Checklist – FXS Specific (ABC-FXS) Clinical Global Impression – Improvement (CGI-I) Pediatric Anxiety Rating Scale (PARS-R) Visual Analog Scale (VAS): Anxiety, hyperactivity, and tantrum/mood lability Vineland Adaptive Behavior III (VABS-III): Communication, living skills, socialization Quality of Sleep: Sleep onset, total sleep, sleep onset latency, nighttime awakenings Pediatric Quality of Life (PedsQL™)

Positive FAB-C Open Label Phase 2 Efficacy Data Primary Endpoint: ADAMS Total Score ADAMS total score Improvement vs. baseline (N=20) Changes in Anxiety, Depression and Mood 46% (p<0.0001) ADAMS subscales Improvement vs. baseline (N=20) General Anxiety 54% (p<0.0001) Social Avoidance 53% (p<0.0002) Compulsive Behavior 50% (p=0.0262) Manic/Hyperactive Behavior 35% (p=0.0003) Depressed Mood 29% (p=0.1417) 12

ADAMS Subscales Week 12: Percent Improvement vs. 3rd party data* 13 Manic/hyperactive Behavior Depressed Mood Social Avoidance General Anxiety Compulsive Behavior Baseline: 9.4 Baseline: 8.1 8.7 Baseline: 2.8 Baseline: 3.0 3.1 Baseline: 10.2 Baseline: 6.9 7.5 Baseline: 10.0 Baseline: 7.9 8.3 Baseline: 2.8 Baseline: 3.0 3.4 * Ligsay, A., Van Dijck, A., Nguyen, D. V., Lozano, R., Chen, Y., Bickel, E. S., et al. (2017). A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile x syndrome. Journal of Neurodevelopmental Disorders, 9:26. 54.0% 15.7% 21.5% 52.9% 16.0% 15.9% 50.0% 17.7% 10.0% 35.1% 10.3% 8.6% 28.6% 16.1% -16.7% 0 10 20 30 40 ZYN002 -20 -10 0 10 20 30 Ganaxolone Placebo -20 -10 0 10 20 30 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002

Positive FAB-C Open Label Phase 2 Efficacy Data Key Secondary Endpoint: ABC-FXS 14 ABC-FXS subscale Improvement vs. baseline (N=20) Stereotypy: "Repetitive Movements" 59% (p=0.0006) Social Avoidance: "Seeks Isolation" 55% (p=0.0005) Socially Unresponsive/Lethargic: "Does Not Pay Attention" 53% (p=0.0034) Inappropriate Speech: "Repeats Words or Phrases" 43% (p=0.0018) Irritability: "Has Temper Tantrums" 42% (p=0.0096) Hyperactivity: "Disrupts Group Activities" 33% (p=0.0194)

ABC-FXS Subscales Week 12: Percent Improvement vs. 3rd party data* 15 Irritability Temper Tantrums Hyperactivity Disrupts Group Activities Socially Unresponsive / Lethargic Does Not Pay attention Social Avoidance Seeks Isolation Stereotypy Repetitive Movements Baseline: 18.2 Baseline: 18.9 19.6 Baseline: 14.5 Baseline: 13.9 13.9 Baseline: 8.7 Baseline: 6.6 6.9 Baseline: 5.1 Baseline: 3.5 3.1 Baseline: 7.9 Baseline: 7.4 7.1 Inappropriate Speech Repeats Words / Phrases Baseline: 6.1 Baseline: 6.0 6.3 * Ligsay, A., Van Dijck, A., Nguyen, D. V., Lozano, R., Chen, Y., Bickel, E. S., et al. (2017). A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile x syndrome. Journal of Neurodevelopmental Disorders, 9:26. 41.8% 17.9% 16.9% 33.1% 11.5% 18.7% 52.9% 17.4% 15.2% 54.9% 9.7% 31.4% 59.5% 9.9% 23.0% 42.6% 15.9% 15.0% 0 10 20 30 40 50 ZYN002 0 10 20 30 40 Ganaxolone Placebo 0 10 20 30 40 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002 0 10 20 30 40 50 60 Ganaxolone Placebo 0 10 20 30 40 50 60 ZYN002 0 10 20 30 40 50 Ganaxolone Placebo 0 10 20 30 40 50 ZYN002

16 Very well tolerated, consistent with previously reported clinical data Two sibling patients discontinued due to worsening of pre-existing eczema Four other patients experienced an AE; no SAEs No drug-related GI events No THC was detected in the plasma 13 patients continued into open label extension Positive FAB-C Open Label Phase 2 Safety Data

17 ZYN002 in Fragile X Syndrome: Next Steps Expect to meet with FDA in 1Q18 to discuss data and pivotal trial design Goal to begin pivotal Phase 2/3 program in pediatric and adolescent patients with FXS in 1H18 Assessing opportunity to present / publish full data set as soon as possible Evaluating opportunities for FDA fast-track, breakthrough status, and priority review

18 ZYN002 CBD Gel Clinical Program Osteoarthritis

Potential Path Forward for ZYN002 in Osteoarthritis 19 Phase 2 study data help clarify efficacy, safety, dose, inclusion and exclusion criteria, primary and secondary endpoints, placebo response in OA patients FDA guidelines require pain and function endpoints in pivotal OA programs ZYN002 achieved statistical significance in responder analysis of both pain and function for 250 mg of ZYN002 daily (p=0.016) Did not achieve primary endpoint of reduction from baseline in the weekly mean of the 24-hour average worst pain score at week 12 Excellent tolerability, consistent with previously released data FDA meeting anticipated in 1Q18 Initiation of pivotal Phase 2/3 program expected in 2018

20 ZYN002 CBD Gel Clinical Program Focal Seizures in Epilepsy

ZYN002 in Focal Seizures STAR 1 and STAR 2 21 Company believes that study failed to achieve endpoints due to bimodal distribution of patient responses on placebo: >50% reductions in focal seizures in ¼ of placebo patients No improvement or worsening of focal seizures in ¾ of placebo patients Excellent tolerability *As of November 13, 2017 STAR 1 STAR 2 100 patients remain in study* 89 patients have reached 6 months of drug exposure* Clinically meaningful reductions of seizures (>50%) observed in patients on ZYN002 for >6 months Excellent tolerability Data to be presented at the 2017 meeting of the American Epilepsy Society (AES) Further analysis of data from STAR 1 and STAR 2 will clarify the study design and inclusion / exclusion criteria ahead of a new Phase 2 clinical study in epilepsy Path forward in epilepsy will be outlined in 1Q18

22 ZYN001 THC Pro-Drug Patch Clinical Program Studying a pharmaceutically-produced pro-drug of THC in a state-of-the-art drug-adhesive matrix transdermal patch

ZYN001 – THC Pro-Drug Patch 23 Patent-protected pharmaceutically-produced D-glyceric acid ester-Δ9-tetrahydrocannabinol in a transdermal patch ZYN001 is a pro-drug A drug administered in an inactive or less active form, designed to enable more effective delivery, and then converted into a different form through a normal metabolic process Unlike THC, ZYN001 is able to be efficiently absorbed into the skin through transdermal delivery After crossing the stratum corneum, ZYN001 is hydrolyzed to THC and glyceric acid under physiological conditions Structure & Conversion Delivery ZYN001

Note: Based upon FDA approved patch products. These results are not indicative of any preclinical or clinical data for ZYN001. Potential Benefits of Patch Technology 24 Requirement Purpose Non-oral Avoids first-pass metabolism with increased bioavailability and more consistent plasma levels Controlled More consistent, controlled and sustained delivery No “peaks and valleys” as seen with oral Safe Improved safety profile with lower peak plasma levels Non-invasive Blood Level Time Max. Effective Level Min. Effective Level Oral Dosage Form Transdermal System Illustrative Controlled Delivery

ZYN001 Phase 1 Clinical Trial Underway 25 24 hours 3.5 days 7 days Part 2: Multiple Dose Part 1: Single Dose 3:1 randomization, placebo controlled Multiple doses over 14 days Two formulations selected from Part 1 Multiple formulations of ZYN001 tested in each group 3:1 randomization, placebo controlled 3:1 randomization, placebo controlled Note: Subject to change due to further regulatory, clinical and other considerations.

Has an analgesic effect in chronic pain models Acts at many sites along pain transmission pathways Third-party clinical data on Nabilone (THC analogue) in patients with fibromyalgia supportive of rationale Approximately 6 million US patients* Potential for THC in Large Indications Role as a CB1 Agonist Modulates Activity 26 Modulates nociceptive thresholds by regulating neuronal activity Third-party clinical data of THC and vaporized/smoked/inhaled cannabis in neuropathic pain supportive of rationale Approximately 15 million US patients* Fibromyalgia Peripheral Neuropathic Pain *Data per Decision Resources

Zynerba Remains Well Positioned in the High-Growth Cannabinoid Space 27 Two pivotal study-ready ZYN002 programs (FXS and OA) Expected meetings with FDA in 1Q18 STAR 1 and STAR 2 epilepsy data accumulation/analyses ongoing Path forward in epilepsy: 1Q18 Global ownership of both proprietary product candidates with potential applicability to numerous disorders Experienced team with proven track record in CNS, pain, and transdermal delivery $66.3 million in cash and cash equivalents as of September 30, 2017 Runway into 2019 Additional $3.0 million in proceeds from ATM program from 9/28-10/26/17 to be recorded in fourth quarter

Randi J. Hagerman, MD Medical Director, UC Davis MIND Institute, Distinguished Professor, Endowed Chair in Fragile X Research, Department of Pediatrics, UC Davis School of Medicine Steven J. Siegel, MD, PhD Chair, Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California Nicole Tartaglia, MD Associate Professor, Pediatrics-Developmental Pediatrics, University of Colorado Denver School of Medicine / Children’s Hospital of Colorado Daniel Clauw, MD Professor of Anesthesiology, Medicine (Rheumatology) & Psychiatry, University of Michigan Philip Mease, MD Clinical Professor, University of Washington, Seattle; Director of Rheumatology Research, Swedish Medical Center Lesley Arnold, MD Professor of Psychiatry and Behavioral Neuroscience, University of Cincinnati Jacqueline French, MD Professor of Neurology, NYU Langone Medical Center Daniel Friedman, MD Clinical Assistant Professor, Department of Psychiatry, NYU Langone Medical Center John Messenheimer, MD Consultant, Neurologist/Epileptologist, John Messenheimer PLLC Michael Rogawski, MD, PhD Professor of Neurology, UC Davis Center for Neuroscience Rodney Radtke, MD Professor of Neurology, Duke University Medical Center Steven P. Cohen, MD Professor Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine Mark Wallace, MD Chair, Division of Pain Medicine, University of California San Diego Donald Abrams, MD Professor, University of California San Francisco School of Medicine, Chief of Hematology-Oncology at SF General Hospital Scientific Advisory Board 28 Epilepsy Fragile X Syndrome Osteoarthritis and Fibromyalgia Pain

Investor Relations 29 484.581.7505 investorrelations@zynerba.com www.zynerba.com @ZynerbaPharma Zynerba Zynerba Investor Contact Will Roberts, VP, Investor Relations and Corporate Communications 484.581.7489 NASDAQ: ZYNE Analyst Coverage* Piper Jaffray: Charles C. Duncan, PhD Roth: Michael Higgins Cantor Fitzgerald: Elemer Piros, PhD Canaccord Genuity: Arlinda Lee, PhD Oppenheimer: Derek Archila Jefferies: Biren Amin, PhD H.C. Wainwright: Oren Livnat Maxim: Gabrielle Zhou * Note: Any opinions, estimates or forecasts regarding Zynerba Pharmaceuticals, Inc.’s performance made by these analysts are theirs alone and do not represent opinions, forecasts or predictions of Zynerba Pharmaceuticals, Inc. or its management. Zynerba Pharmaceuticals, Inc. does not by its reference above imply its endorsement of or concurrence with such information, conclusions or recommendations.

November 2017 A clinical-stage specialty pharmaceutical company dedicated to the development and commercialization of innovative transdermal pharmaceutically-produced cannabinoid treatments for patients with high unmet medical needs