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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): June 21, 2022

 

 

 

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:

 

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

 

¨ Soliciting material pursuant to Rule 14a–12 under the Exchange Act (17 CFR 240.14a–12)

 

¨ Pre–commencement communications pursuant to Rule 14d–2(b) under the Exchange Act (17 CFR 240.14d–2(b))

 

¨ Pre–commencement communications pursuant to Rule 13e–4(c) under the Exchange Act (17 CFR 240.13e–4(c))

 

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class   Trading Symbol(s)   Name of each exchange on which registered
Common Stock, $0.001 par value per share   ZYNE   The Nasdaq Global Market

 

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 ¨

 

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. ¨

 

 

 

 

 

 

Item 8.01 Other Events

 

On June 21, 2022, Zynerba Pharmaceuticals, Inc. (the “Company”) issued a press release announcing positive top line results from the open-label Phase 2 INSPIRE trial of Zygel in 22q11.2 Deletion Syndrome. A copy of the press release is attached hereto as Exhibit 99.1 and incorporated herein by reference.

 

Attached as Exhibit 99.2 is a slide presentation that the Company posted on its website on June 21, 2022 and may use from time to time in presentations or discussions with investors, analysts and other parties.

 

Item 9.01 Financial Statements and Exhibits

 

The following exhibit is being filed herewith:

(d) Exhibits

 

Exhibit
No.		   Document
     
99.1   Press Release, dated June 21, 2022
99.2   Zynerba Pharmaceuticals, Inc. Investor Presentation
104   The cover page from this Current Report on Form 8-K, formatted in Inline XBRL

 

 

 

 

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: June 22, 2022

 

  ZYNERBA PHARMACEUTICALS, INC.
   
  By: /s/ Albert P. Parker                   
    Name: Albert P. Parker
    Title: Chief Legal Officer

 

 

 

 

Exhibit 99.1

 

 

 

Zynerba Pharmaceuticals Announces Positive Top Line Results from Open-Label Phase 2 INSPIRE Trial of Zygel™ in 22q11.2 Deletion Syndrome

 

– The INSPIRE trial achieved statistically significant and clinically meaningful improvements from baseline in multiple efficacy assessments –

 

– Safety data reinforce excellent tolerability profile of Zygel –

 

– Company will focus resources on FXS and 22q development –

 

– Cash runway extended through the end of 2023 / early 2024 –

 

– Zynerba to host conference call and webcast tomorrow, June 22, 2022 at 9:00 a.m. ET –

 

DEVON, Pa., June 21, 2022 – Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced positive top line results from the exploratory, open label Phase 2 INSPIRE (Assessing the Impact of Zygel [Transdermal CBD Gel] on Pediatric Behavioral and Emotional Symptoms of 22q11.2 Deletion Syndrome) trial. Based on the positive Phase 2 data, the Company will request a meeting with the U.S. Food and Drug Administration (FDA) to discuss the data and the regulatory path forward.

 

The Phase 2 trial was designed for signal detection by assessing the safety, tolerability and efficacy of Zygel (also known as ZYN002) for the treatment of behavioral symptoms of chromosome 22q11.2 deletion syndrome (22q) in children and adolescents. Zygel was administered to patients with 22q as add-on therapy to their standard of care and utilized a variety of efficacy assessments. Key findings from the trial disclosed today include:

 

§The total score and all five subscales of the Anxiety, Depression and Mood Scale (ADAMS) showed statistically significant improvements at 14 weeks of treatment compared to baseline;

 

§All five subscales of the Aberrant Behavior Checklist – Community (ABC-C) showed statistically significant improvements at 14 weeks of treatment compared to baseline;

 

§The Pediatric Anxiety Rating Scale (PARS – R) showed statistically significant improvements at 14 weeks of treatment compared to baseline;

 

§The majority of patients showed clinically meaningful improvements at week 14 as demonstrated by the Clinical Global Impression – Improvement (CGI-I). Seventy-five percent of patients were rated by the clinicians as “improved”, “much improved” or “very much improved” with nearly two-thirds (62.5%) of the patients being “much improved” or “very much improved”;

 

§Zygel was shown to be well tolerated, and the safety profile was consistent with previously released data from other Zygel clinical trials.

 

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“I am encouraged with the results from the INSPIRE trial, particularly with the potential for real reductions in general anxiety, social withdrawal, and social avoidance in children and adolescents with chromosome 22q11.2 deletion syndrome,” said Tony J. Simon, Ph.D. Professor Emeritus at the University of California, Davis School of Medicine and the UC Davis MIND Institute. “I’m especially encouraged that ZYN002 is a unique, cannabidiol gel free of THC and manufactured to pharmaceutical specifications. Children and adolescents with 22q should avoid THC which may increase the likelihood of developing psychosis. I look forward to the further development of ZYN002 for this underserved population.”

 

“We believe the data from this Phase 2 trial are very encouraging and reinforce the potential of Zygel for the treatment of behavioral symptoms in children and adolescents with 22q, and we look forward to discussing the regulatory path forward with the FDA with these data in hand,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “In the near term, we will focus our resources on completing the RECONNECT trial for children and adolescents with Fragile X syndrome and progressing 22q.”

 

INSPIRE Trial Design

 

The 14-week INSPIRE trial was an open-label, Phase 2 clinical trial designed to evaluate the safety, tolerability and efficacy of Zygel in children and adolescents (ages four through 15) with genetically-confirmed 22q11.2 deletion syndrome. Enrolled patients received weight-based doses of 250 mg or 500 mg daily of Zygel. Patients were allowed to increase the daily dose after six weeks of treatment to 500 mg and 750 mg if the investigator felt such increase was appropriate. One patient’s dose was increased from 250 mg to 500 mg, and no patients increased to 750 mg in the treatment period. At the completion of the trial, thirteen (13) patients entered into an extension study for up to six months.

 

Patient Disposition and Baseline Demographics

 

Twenty (20) patients were enrolled in the trial, which was conducted at two clinical sites in Australia and one clinical site in the U.S. All 20 patients are included in the safety analysis. Seventeen (17) patients completed the 14-week trial and three patients discontinued. One patient was lost to follow-up, one patient withdrew due to adverse events not related to Zygel, and one patient withdrew consent. Efficacy analyses included 16 patients as one patient did not have valid assessments at week 14.

 

The mean age of patients enrolled in the trial was 9.9 years, and twelve (60%) of the patients were male. Patients weighed between 13.7 and 79.8 kilograms (mean=37.4; median=33.5).

 

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Top-line Efficacy Results

 

As a signal-seeking Phase 2 trial, multiple efficacy assessments were administered, including the Anxiety, Depression and Mood Scale (ADAMS), the Aberrant Behavior Checklist – Community (ABC-C), the Pediatric Anxiety Ratings Scale (PARS – R) and Clinical Global Impression – Severity and Improvement.

 

Results of the ADAMS:

 

           Change from   Mean %       Median % 
Subscale  Baseline   Week 14   Baseline   Improvement   p Value   Improvement 
Total Score  36.1   17.7   -18.4   45.3%  0.0005   43.0%
General Anxiety  10.4   5.1   -5.4   43.6%  0.0005   48.8%
Depressed Mood  7.6   3.4   -4.3   50.3%  0.0033   52.8%
Social Avoidance  8.7   4.3   -4.4   41.3%  0.0084   50.0%
Obsessive/Compulsive Behavior  3.0   1.1   -1.9   64.0%  0.0037   66.7%
Manic / Hyperactive Behavior  7.6   4.4   -3.1   38.2%  0.0032   27.4%

 

Results of the ABC-C:

 

           Change from   Mean %       Median % 
Subscale  Baseline   Week 14   Baseline   Improvement   p Value   Improvement 
Social Withdrawal  14.4   7.9   -6.4   27.6%  0.0110   46.4%
Inappropriate Speech  4.2   2.4   -1.8   18.3%  0.0166   50.0%
Stereotypic Behavior  3.9   1.6   -2.3   52.1%  0.0155   58.3%
Irritability  18.4   10.0   -8.4   36.3%  0.0055   39.6%
Hyperactivity  18.1   10.4   -7.6   16.5%  0.0091   38.1%

 

Results of the PARS – R:

 

           Change from   Mean %       Median % 
   Baseline   Week 14   Baseline   Improvement   p Value   Improvement 
Total Score  14.7   8.5   -6.2   40.6%  0.0005   40.0%

 

Results of the CGI-I:

 

The investigators rated 12 of 16 patients (75%) as improved, “much improved” or “very much improved” at week 14, with 62.5% being “much improved” or “very much improved”.

 

Safety Data

 

Zygel was shown to be well tolerated, and the safety profile was consistent with previously released data from other Zygel clinical trials. Three patients reported treatment related adverse events which were all mild application site adverse events.  One patient discontinued treatment due to adverse events not related to Zygel.

 

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Prioritizing Orphan Development Programs; Cash Runway Extended to Late 2023 / Early 2024

 

In the near term the Company has decided to prioritize its resources on Fragile X syndrome (FXS) and 22q, both of which have been granted orphan drug designation by the FDA and both of which have no approved products. While the data from the Company’s autism spectrum disorder (ASD) clinical development program to date are compelling, given the difficult financing market, the Company will defer the start of the Phase 3 development program in ASD previously planned for the second half of 2022. As a result, the Company now believes its $69.7 million of cash and cash equivalents as of March 31, 2022 are sufficient to fund planned operations and capital requirements through the end of 2023 or early 2024, after the expected availability of top line results from its confirmatory pivotal Phase 3 RECONNECT trial of Zygel in patients with FXS.

 

Conference call information

 

Zynerba management will host a live conference call and webcast tomorrow, June 22, 2022, at 9:00 a.m. Eastern Time to discuss results of the INSPIRE trial and updates to its clinical development plans. The call can be accessed by dialing (866) 573-0180 (U.S. and Canada) or (430) 775-1345 (international) and referencing conference ID 4453857. To access the live webcast or the replay, visit the investor page of the Company’s website at http://ir.zynerba.com/. The webcast will be recorded and available on the Company’s website for 30 days.

 

About 22q11.2 Deletion Syndrome (22q)

 

As the second most common chromosomal disorder after Down syndrome, 22q is caused by a small missing piece of the 22nd chromosome. The deletion occurs near the middle of the chromosome at a location designated q11.2. It is considered a mid-line condition, with physical symptoms including characteristic palate abnormalities, heart defects, immune dysfunction, and esophageal / GI issues, as well as debilitating neuropsychiatric and behavioral challenges. Anxiety is among the most common neuropsychiatric symptoms of 22q and researchers have found that for children with 22q, anxiety is linked to poorer adaptive behaviors such as self-care and communication skills that affect daily life. Children with 22q also experience withdrawn behavior, ADHD, cognitive impairment, and autism spectrum disorder that affect communication and social interaction. Later in life, they are at an increased risk of developing mental illnesses such as schizophrenia. It is estimated that 22q occurs in between one in 3,000 and one in 6,000 live births, suggesting that there are approximately 83,000 people living with 22q in the U.S.

 

About Zygel

 

Zygel is the first and only pharmaceutically-manufactured cannabidiol formulated as a patent-protected permeation-enhanced clear gel, designed to provide controlled drug delivery into the bloodstream transdermally (i.e. through the skin). Recent studies suggest that cannabidiol may modulate the endocannabinoid system and improve certain behavioral symptoms associated with neuropsychiatric conditions. Zygel is an investigational drug product in development for the potential treatment of behavioral symptoms associated with Fragile X syndrome (FXS), 22q11.2 deletion syndrome (22q) and autism spectrum disorder (ASD). The Company has received orphan drug designation for cannabidiol, the active ingredient in Zygel, from the FDA and the European Commission for the treatment of FXS and by the FDA for the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

 

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About Fragile X Syndrome (FXS)

 

FXS is a rare genetic developmental disability that is the leading known cause of both inherited intellectual disability and autism spectrum disorder, affecting 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females. It is the most common inherited intellectual disability in males and a significant cause of intellectual disability in females, and the leading genetic cause of autism spectrum disorder (ASD). The disorder negatively affects synaptic function, plasticity and neuronal connections, and results in a spectrum of intellectual disabilities and behavioral symptoms, such as social avoidance and irritability. In the U.S., there are approximately 78,000 people suffering with FXS, and approximately 121,000 in the EU and UK. We believe that approximately 60% of all patients with FXS have complete methylation of their FMR1 gene.

 

About Zynerba Pharmaceuticals, Inc.

 

Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for rare and near-rare neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome, 22q11.2 deletion syndrome and autism spectrum disorder. Learn more at www.zynerba.com and follow us on Twitter at @ZynerbaPharma.  

 

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. 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 Company’s cash and cash equivalents may not be sufficient to support its operating plan for as long as anticipated; the Company’s expectations, projections and estimates regarding expenses, future revenue, capital requirements, incentive and other tax credit eligibility, collectability and timing, and availability of and the need for additional financing; the Company’s ability to obtain additional funding to support its clinical development programs; the results, cost and timing of the Company’s clinical development programs, including any delays to such clinical trials relating to enrollment or site initiation; clinical results for the Company’s product candidates may not be replicated or continue to occur in additional trials and may not otherwise support further development in a specified indication or at all; actions or advice of the U.S. Food and Drug Administration, the European Medicines Agency and other foreign regulatory agencies may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional clinical trials; the Company’s ability to obtain and maintain regulatory approval for its product candidates, and the labeling under any such approval; the Company’s reliance on third parties to assist in conducting pre-clinical and clinical trials for its product candidates; delays, interruptions or failures in the manufacture and supply of the Company’s product candidates 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; the Company’s expectations regarding its ability to obtain and adequately maintain sufficient intellectual property protection for its product candidates; the extent to which health epidemics and other outbreaks of communicable diseases, including COVID-19, could disrupt our operations or adversely affect our business and financial conditions; and the extent to which inflation or global instability, including political instability, may disrupt our business operations or our financial condition. 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.

 

Zynerba Contacts

 

Peter Vozzo

ICR Westwicke

Office: 443.213.0505

Cell: 443.377.4767

Peter.Vozzo@Westwicke.com

 

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Exhibit 99.2

 

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© 2022 Zynerba Pharmaceuticals, Inc. All rights reserved. NASDAQ ZYNE Advancing Science. Improving Connections. Next-Generation Transdermal Cannabinoid Therapeutics June 2022

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Forward-Looking Statements The statements in this presentation may include forward-looking statements within the meaning of the private securities litigation reform act of 1995. 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, including the following: the company’s cash and cash equivalents may not be sufficient to support its operating plan for as long as anticipated; the results, cost and timing of the company’s clinical development programs, including any delays to such clinical trials relating to enrollment or site initiation; clinical results for the company’s product candidates may not be replicated or continue to occur in the company’s ongoing or planned clinical trials in FXS, 22q, or ASD, or in any additional trials, and may not otherwise support further development in a specified indication or at all; the company’s planned reconnect trial may not be determined to be sufficient to support a submission for regulatory approval, including an nda or maa; actions or advice of the U.S. Food and drug administration and foreign regulatory agencies may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional clinical trials; the company’s ability to obtain and maintain regulatory approval for its product candidates, and the labeling under any such approval; the company’s expectations regarding its ability to obtain and adequately maintain sufficient intellectual property protection for its product candidates. 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. June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 2 © 2022 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba and Zygel are trademarks of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners. trademarks are property of their respective owners.

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A different and exciting approach to Cannabidiol

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An Orphan-Focused Neuropsychiatric, Biopharmaceutical Company June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 4 Permeation-enhanced Patent-protected through 2038 Pharmaceutically manufactured; THC free FIRST AND ONLY TRANSDERMAL CANNABIDIOL GEL One Phase 3 clinical program ongoing Two additional indications are Phase 3 ready LATE-STAGE PIPELINE Leadership expertise in transdermal delivery, rare diseases and specialty markets Clean balance sheet and cash runway to end of 2023 / early 2024 POSITIONED FOR SUCCESS A different and exciting approach to Cannabidiol

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Benefits of Our Approach to Cannabidiol June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 5 FDA regulated Consistency of production Purity of ingredients No THC – not a scheduled drug by U.S. DEA Scalable production process PHARMACEUTICAL MANUFACTURING PHARMACEUTICAL DISPENSARY Ease of application for caregivers of patients with behavioral issues Minimizes GI side effects and reduces risk for liver toxicity Lower risk for drug/drug interactions Avoids conversion to THC in stomach TRANSDERMAL DELIVERY

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Clinical Development Programs Fragile X Syndrome FXS 22q Deletion Syndrome 22q Autism Spectrum Disorder ASD

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Overlap of Symptoms Across Conditions June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 7 Anxiety Seeks Isolation Social Avoidance Lack of Interaction Attention Deficits Irritability FXS 22q ASD

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Fragile X Syndrome (FXS) Focused Clinical Pipeline June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 8 Preclinical Phase 1 Phase 2 Pivotal Market 22q Deletion Syndrome (22q) Autism Spectrum Disorder (ASD) Regulatory Filing U.S. Orphan Drug and Fast Track designations; EU Orphan Drug designation U.S. Orphan Drug designation ZygelTM (ZYN002 Cannabidiol Gel)

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• Zygel safety database across all clinical studies includes data from over 900 volunteers and patients • Majority of treatment-emergent AEs (TEAE) were mild or moderate • Most common Zygel-related TEAE are application site events, the majority of which were mild and transient • No clinically significant changes in vital signs or ECGs • No Zygel-related clinically significant changes in laboratory values, including liver function tests June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 9 Well-Tolerated Safety Profile

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Fragile X Syndrome

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~78K U.S. PATIENTS What is Fragile X Syndrome (FXS) June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 11 • Leading known cause of inherited intellectual disability and autism spectrum disorder • Mutation of the FMR1 gene causes endocannabinoid system (ECS) dysregulation • Easily identified mutation manifests as multiple CGG repeats on FMR1 (full mutation >200 repeats) • Resulting in cognitive, social, and behavioral symptoms • Behavioral Symptoms linked to deficiencies in the ECS WITH FXS EU/UK PATIENTS ~121K

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Poised for Success in FXS June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 12 Largest clinical trial ever conducted in children with FXS Extensive safety database Patients on drug for up to five years Statistically significant outcomes in children with complete methylation Lessons Learned from Previous Trials Improve Probability of Success in RECONNECT Pivotal Trial

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Role of FMR1 Methylation in FXS June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 13 • FMR1 gene codes for production of FMRP* which is vital to synapse development • Methylation of the FMR1 gene plays a role in determining gene function • When methylation of the FMR1 gene silences the gene, no FMRP is produced: • Systems and processes affected by FMRP become dysregulated • ~60% of FXS patients are believed to be completely methylated • Completely methylated patients are the most severely impacted ~47K U.S. PATIENTS WITH COMPLETE METHYLATION EU/UK PATIENTS ~73K *RNA-binding protein that helps regulate synaptic development and plasticity

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CONNECT-FX Trial Key Learning: Results with complete methylation of FMR1 gene Consistent Improvements Observed with Zygel vs. Placebo in Patients with Complete Methylation June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 14 PRIMARY ENDPOINT CAREGIVER REPORTED BEHAVIOR CHANGE CLINICIAN REPORTED BEHAVIOR IMPROVEMENTS CLINICALLY MEANINGFUL BEHAVIOR IMPROVEMENTS ABC-CFXS Social Avoidance Subscale Caregiver Global Impression of Change (ZYGEL vs Placebo) Clinical Global Impression of Improvement (anchored)** More Patients Achieved Meaningful Change (ZYGEL vs Placebo) Ad hoc analysis of 136 patients with complete methylation *Statistically significant , **Not specific to Social Avoidance 40% median percent improvement in socially avoidant behaviors (p=0.027*) SOCIAL INTERACTION 63% vs 37% (p=0.005*) IRRITABLE/DISRUPTIVE BEHAVIORS 54% vs 33% (p=0.027*) SOCIAL AVOIDANCE/ISOLATION 58% vs 46% (p=0.195) OVERALL BEHAVIOR 61% vs 46% (p=0.100) ANY IMPROVEMENT Zygel vs placebo 50% vs 36% (p=0.128) SOCIAL AVOIDANCE (≥ 3 POINTS) 56% vs 37% (p=0.030*) IRRITABILITY (≥ 9 POINTS) 37% vs 26% (p=0.232)

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Change in ABC-CFXS Social Avoidance June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 15 Clinically Meaningful Changea Achieved and Maintained in Patients with Complete Methylation of FMR1 Geneb 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Cumulative Percentage of Patients Month Zygel (n=47) Placebo (n=49) Switch from Placebo to Zygel CONNECT-FX Double-Blindc Open-Label Extension Patients on Zygel a. Meaningful change in Social Avoidance: ≥3-point improvement from baseline; maintained for ≥ 2 consecutive visits b. Patients matching primary efficacy population in RECONNECT c. ZYN2-CL-016 (CONNECT-FX)

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Design Optimized from CONNECT-FX Trial June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 16 More patient and family friendly Extending trial to 18-weeks Increased dosing option for individuals >50 kg Successful completion of Phase 3 pivotal trial expected to satisfy requirements for an NDA submission in the U.S. and a marketing authorization application in the EU. Primary endpoint: Patients with complete methylation

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Confirmatory Pivotal Trial Design June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 17 Double-Blind, Placebo-Controlled Study: Initiated 18 weeks 3 to 17 years old Moderate-to-Severe FXS Zygel (n~100; 80*) 250 mg daily (≤30kg) 500 mg daily (>30kg) 750 mg daily (>50kg) (weight-based dose) Placebo (n~100; 80*) Mirrors Zygel administration *Patients with complete methylation of FMR1 gene Patients randomized (1:1) to receive either Zygel or placebo Open Label Extension (OLE): Ongoing 24 months All patients receive Zygel

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Trial Objectives June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 18 Change from baseline to end of treatment in ABC-CFXS Social Avoidance subscale in patients who have complete (100%) methylation of their FMR1 gene • Change from baseline to end of treatment in: • ABC-CFXS Irritability subscale in patients who have complete methylation • ABC-CFXS Social Avoidance subscale among all randomized patients (complete and partial methylation) • Percent of patients: • Any improvement on the Caregiver Global Impression of Change (CaGI-C) for Social Interactions among patients with complete methylation • Rated as improved on the Clinical Global Impression-Improvement (CGI-I) scale among patients with complete methylation SECONDARY ENDPOINTS PRIMARY ENDPOINT

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Next Steps in FXS June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 19 Continued RECONNECT pivotal trial enrollment Topline results expected in 2H 2023

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22q11.2 Deletion Syndrome (22q) Image courtesy Positive Exposure © 2016 Positive Exposure. All rights reserved. www.PositiveExposure.org. Eliza, living with 22q11.2 deletion syndrome

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What is 22q11.2 Deletion Syndrome (22q)? June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 21 • Rare disorder and second most common genetic disorder, behind Down syndrome • Midline condition with abnormalities affecting palate, face, heart and other organs; surgically corrected in infancy • Neuropsychiatric illnesses and learning disabilities common • Early onset of neuropsychiatric symptoms disrupts development and quality of life, and heightens risk of later psychotic disorders • No drugs currently approved WITH 22q U.S. PATIENTS ~83K

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U.S. ORPHAN DRUG DESIGNATION GRANTED FOR TREATMENT OF 22q Rationale for Zygel in 22q June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 22 • Overlapping symptoms with FXS and ASD • Associated with increased anxiety, irritability, social withdrawal and social interaction problems • Cannabidiol may treat neuropsychiatric symptoms due to activity as: • Modulator of ECS • Agonist at serotonin1A receptors • Antagonist at GPR55 receptors

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INSPIRE Phase 2 Trial Design June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 23 Period 1: Completed 14 weeks 4 to 15 years old With 22q11.2 Deletion Syndrome Zygel (n = 20) 250 mg daily (≤35kg) 500 mg daily (>35kg) (weight-based dose) Period 2: Ongoing 24 weeks Efficacy assessments include: (week 14 vs baseline) • Anxiety, Depression and Mood Scale (ADAMS) • Aberrant Behavior Checklist-Community (ABC-C) • Pediatric Anxiety Rating Scale-Revised (PARS-R) • Clinical Global Impression — Severity and Improvement (n = 13 of 17 Completers)

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• Statistically significant improvements at 14 weeks of treatment compared to baseline for multiple efficacy assessments: • The total score and all five subscales of the Anxiety, Depression and Mood Scale (ADAMS) • All five subscales of the Aberrant Behavior Checklist – Community (ABC-C) • Pediatric Anxiety Rating Scale - Revised (PARS – R) • The majority of patients showed clinically meaningful improvements at week 14 as demonstrated by the Clinical Global Impression – Improvement (CGI-I) • Seventy-five percent of patients were rated by the clinicians as “improved”, “much improved” or “very much improved” • Nearly two-thirds (62.5%) of the patients being “much improved” or “very much improved” • Zygel was shown to be well tolerated, and the safety profile was consistent with previously released data from other Zygel clinical trials • Three patients reported treatment related adverse events which were all mild application site adverse events • One patient discontinued treatment due to adverse events not related to Zygel May 2022 Zynerba Corporate Template 24 Positive Top Line Results from INSPIRE Trial

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ADAMS and ABC-C Results June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 25 ABC -C Subscale Baseline Week 14 Change from Baseline Mean % Improvement p Value Median % Improvement Social Withdrawal 14.4 7.9 -6.4 27.6% 0.0110 46.4% Inappropriate Speech 4.2 2.4 -1.8 18.3% 0.0166 50.0% Stereotypic Behavior 3.9 1.6 -2.3 52.1% 0.0155 58.3% Irritability 18.4 10.0 -8.4 36.3% 0.0055 39.6% Hyperactivity 18.1 10.4 -7.6 16.5% 0.0091 38.1% ADAMS Subscale Baseline Week 14 Change from Baseline Mean % Improvement p Value Median % Improvement Total Score 36.1 17.7 -18.4 45.3% 0.0005 43.0% General Anxiety 10.4 5.1 -5.4 43.6% 0.0005 48.8% Depressed Mood 7.6 3.4 -4.3 50.3% 0.0033 52.8% Social Avoidance 8.7 4.3 -4.4 41.3% 0.0084 50.5% Obsessive / Compulsive Behavior 3.0 1.1 -1.9 64.0% 0.0037 66.7% Manic / Hyperactive Behavior 7.6 4.4 -3.1 38.2% 0.0032 27.4%

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Next Steps in 22q June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 26 Discuss regulatory pathway with FDA Initiate Phase 3 program after FDA discussions and RECONNECT top line results

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Autism Spectrum Disorder

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Rationale for Zygel in Autism Spectrum Disorder (ASD) June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 28 • Results from FXS trials suggested spectrum of activity against behaviors also seen in ASD: irritability, social avoidance and anxiety • Studies suggested ASD is linked to disruption of the ECS • Altered anandamide* signaling may contribute to ASD-related social and communication impairments • The ECS modulates many cellular functions and molecular pathways altered in ASD • Cannabidiol may modulate the ECS and improve certain autism-related behaviors WITH ASD U.S. CHILDREN AND ADOLESCENTS ~1.4M * Anandamide is one of two primary endocannabinoids

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BRIGHT Open-label Phase 2 Trial Design June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 29 Period 1 14 weeks 3 to 16 years old Moderate-to-Severe ASD Zygel (n = 37) 250 mg daily (≤35kg) 500 mg daily (>35kg) (weight-based dose) Period 2 24 weeks 18 Patients with ≥ 35% improvement in Irritability at week 14 continued on Zygel

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BRIGHT Phase 2 Trial Results: Period 1 Statistically Significant Results at Week 14 Compared to Baseline (Completers in Efficacy Population n=28†) June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 30 † n=26 for ABC-C inappropriate speech; *Statistically significant; Full data available in May 26, 2020 and October 15, 2020 press releases Irritability: 39% (p<0.0001*) Inappropriate Speech: 43% (p=0.0002*) Stereotypy: 39% (p<0.0001*) Social Withdrawal: 36% (p<0.0001*) Hyperactivity: 36% (p<0.0001*) Atypical behavior: 34% (p<0.001*) Communication: 20% (p<0.001*) Peer interaction: 20% (p<0.001*) Repetitive behavior: 33% (p<0.001*) Social reciprocity: 11% (p=0.0053*) Mean improvement:39% (p<0.0001*) Behavioral: 69% improved Social: 63% improved Emotional: 72% improved Mean improvement: 46% (p<0.0001*) Aberrant Behavior Checklist — Community (ABC-C) subscales % improvement Qualitative Caregiver Behavioral Problems Survey % Improvements Autism Parenting Stress Index Autism Impact Measure (AIM) % improvement Parent Rated Anxiety Scale for ASD (PRAS-ASD)

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50% (P<0.0001) 61% (P<0.0001) 60% (P<0.0001) 53% (P<0.0001) 56% (P<0.0001) 0 5 10 15 20 25 30 35 40 Irritability Inappropriate Speech Stereotypy Social Withdrawal Hyperactivity ABC -C Subscale Score Mean Scores Baseline Week 14 Week 38 BRIGHT Period 2 Results: Statistically Significant Improvements from Baseline Sustained through Week 381 June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 31 ABC-C Irritability: Primary Endpoint to Support NDA Filing n=18 Lower values reflect improvement in each ABC-C subscale. *Same primary endpoint utilized in pivotal trials for two existing FDA approved ASD treatments 118 of 27 patients that completed week 14 demonstrated ≥35% improvement in the ABC-C at week 14 and were allowed to continue treatment for additional 24 weeks.

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Next Steps in ASD June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 32 Submit Investigational New Drug (IND) application specific to ASD with finalized clinical protocol ASD is now third in priority and initiation of phase 3 program is deferred at this time

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Positioned for Success

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Leadership June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 34 Armando Anido Chairman of the Board and CEO Terri B. Sebree President Jim Fickenscher CFO and VP, Corporate Development Paul Kirsch VP, Regulatory Affairs and Quality Assurance Joe Apostolico VP, Human Resources Terry Hurst GM, Zynerba Pharmaceuticals Pty Ltd (Australia) Stephen O’Quinn, PharmD VP, Medical Affairs Albert P. Parker Chief Legal Officer Brian Rosenberger VP, Commercial and Business Development Nancy Tich, Ph.D. VP, Clinical Ray Mannion VP, Manufacturing Carol O’Neill VP, Development

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Financial Strength June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 35 CASH AND CASH EQUIVALENTS $69.7M as of March 31, 2022; expected to be sufficient to fund operations and capital requirements to the end of 2023/early 2024 BALANCE SHEET CLEAN No debt, 43.6M shares outstanding (as of May 11, 2022)

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A Year of Clinical Progress Ahead June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 36 Fragile X Syndrome (FXS) Autism Spectrum Disorder (ASD) 22q Deletion Syndrome (22q) U.S. Orphan Drug and Fast Track designations; EU Orphan Drug designation U.S. Orphan Drug designation Pivotal trial results expected in 2H 2023 Finalize regulatory pathway with FDA; Initiate phase 3 after RECONNECT top line results Submit IND with finalized clinical protocol; initiation of phase 3 program deferred

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• Launch Zygel for FXS into a $1.9B+ U.S. market opportunity • Establish a fully integrated organization with U.S. commercial presence • Preparing for EU approval in FXS • Advance 22q and ASD Ph3 programs towards completion • Leaders in transdermal cannabidiol delivery • Late-stage clinical company with multiple CNS programs, all in areas of high unmet need • Launch Zygel in FXS via strategic partners in EU and other Territories • Launch Zygel into additional multi-billion $ market of 22q • Optimize Zygel growth with additional synergistic indications • Accelerate further growth through complimentary asset licensing and acquisition …and Beyond Zynerba Today… …in 2025 Zynerba Vision for Future Growth June 2022 Zynerba Pharmaceuticals | Advancing Science. Improving Connections. 37 • Launch Zygel for FXS into a $1.9B+ U.S. market opportunity • Establish a fully integrated organization with U.S. commercial presence • Prepare for EU approval in FXS • Advance 22q Ph3 program towards completion

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A different and exciting approach to Cannabidiol

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