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|Item 2.02||Results of Operations and Financial Condition|
On November 15, 2021, Zynerba Pharmaceuticals, Inc. (the “Company”) issued a press release announcing its financial results and operational highlights for the third quarter ended September 30, 2021. 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, 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, except as expressly set forth by specific reference in such filing.
Item 8.01 Other Events
Attached as Exhibit 99.2 is a presentation, including certain financial information that the Company will post on its website on November 15, 2021 and may use from time to time in presentations or discussions with investors, analysts or other parties.
|Item 9.01||Financial Statements and Exhibits|
|99.1||Press Release, dated November 15, 2021*|
|99.2||Zynerba Pharmaceuticals, Inc. Presentation**|
|104||The cover page from this current report on Form 8-K, formatted in Inline XBRL|
* Furnished herewith
** Filed herewith
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 15, 2021
|ZYNERBA PHARMACEUTICALS, INC.|
|By:||/s/ Suzanne Hanlon|
|Name: Suzanne Hanlon|
|Title: Secretary, Vice President and General Counsel|
Zynerba Pharmaceuticals Reports Third Quarter 2021 Financial Results
and Operational Highlights
– Initiated RECONNECT, a confirmatory pivotal Phase 3 trial of Zygel™ in patients with Fragile X
Syndrome (FXS); topline results expected second-half 2023 –
– Cash runway well into the first half of 2024; $75.6 million at September 30, 2021 –
DEVON, Pa., November 15, 2021 – Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for rare and near-rare neuropsychiatric disorders, today reported financial results for the third quarter ended September 30, 2021, and provided an overview of recent operational highlights and a pipeline update.
“We remain focused on enrolling patients into our confirmatory pivotal Phase 3 RECONNECT trial in children and adolescents with Fragile X Syndrome,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “If the results from RECONNECT are positive, Zygel has the potential to become the first FDA approved treatment option for the significant unmet medical need that affects FXS patients and their families.”
Third Quarter 2021 and Recent Highlights and Zygel Pipeline Update
Zygel in Fragile X Syndrome (FXS)
|§||Zynerba initiated a pivotal, multinational randomized, double-blind, placebo-controlled, multiple-center, efficacy and safety (RECONNECT) Phase 3 trial during the third quarter of 2021. The RECONNECT trial is designed to evaluate the efficacy and safety of Zygel (cannabidiol formulated in a transdermal gel) in children and adolescents with FXS. The trial is planned to confirm the positive results observed in a population of responders in the Company’s CONNECT-FX trial. (Press Release)|
|§||RECONNECT is an 18-week trial that is expected to enroll approximately 200 children and adolescents, aged three through 17 years, at approximately 25 clinical sites in the United States, Australia, the UK and Ireland. Approximately 160 of the patients enrolled will have complete (100%) methylation of their FMR1 gene and approximately 40 patients will have partial methylation of their FMR1 gene. Patients will be randomized 1:1 to either Zygel or placebo. Randomization will be stratified by gender, methylation status and weight.|
|§||The primary endpoint for the trial will be the change from baseline to the end of the treatment period in the Aberrant Behavior Checklist-Community FXS Specific (ABC-CFXS) Social Avoidance subscale in patients who have complete methylation of their FMR1 gene. The ABC-CFXS Social Avoidance subscale is the same primary endpoint used in the CONNECT-FX trial. The Company believes that the results from RECONNECT, if positive, will be sufficient to support the submission of a New Drug Application for Zygel in patients with FXS.|
|§||Presented data at the American Academy of Child and Adolescent Psychiatry (AACAP) Annual Meeting demonstrating that more patients on Zygel attained and maintained clinically meaningful improvement in social avoidance as compared to placebo-treated patients during the double-blind treatment phase of CONNECT-FX. In addition, patients who received blinded Zygel in CONNECT-FX continued to improve on open-label Zygel with approximately two-thirds of patients achieving sustained meaningful improvement in social avoidance at 16 weeks and 24 weeks on Zygel.|
|§||Presented data at the 2021 National Organization for Rare Disorders (NORD) Rare Diseases and Orphan Products Breakthrough Summit describing the design of the Phase 3 RECONNECT trial of Zygel in children and adolescents with FXS based on learnings from CONNECT-FX.|
Zygel in Autism Spectrum Disorder (ASD)
|§||Presented data at The Society for the Study of Behavioural Phenotypes (SSBP) Conference 2021 demonstrating that through 38 weeks of treatment, the Phase 2 BRIGHT trial suggests initial evidence of a positive benefit-risk profile for Zygel when administered in addition to stable standard of care in children and adolescents with moderate-to-severe ASD. Furthermore, in patients who completed the 38-week treatment period in BRIGHT, statistically significant improvements compared to baseline were sustained in all efficacy measures of ASD compared to baseline. (Press Release)|
Zygel in 22q11.2 Deletion Syndrome (22q)
|§||The Company continues to screen patients for the 14-week open-label Phase 2 INSPIRE trial in children and adolescents with genetically confirmed 22q.|
Zygel in Developmental and Epileptic Encephalopathies (DEE)
|§||Published results from the Company’s open-label Phase 2 BELIEVE study in the Journal of the American Medical Association (JAMA) Network Open. The article describes the positive results from BELIEVE, the first trial of a non-oral formulation of cannabidiol in children and adolescents with DEEs, and concludes that Zygel was safe, well tolerated, and was associated with reductions in focal impaired awareness seizures (FIAS) and tonic-clonic seizure (TCS) frequency and disease burden. (Press Release)|
Zynerba will provide an update on its development path forward in ASD, 22q and DEE by the end of 2021.
|§||In November 2021, Stephen O’Quinn, Pharm.D. was appointed as the Vice President, Medical Affairs. Dr. O’Quinn is a senior pharmaceutical executive with more than 30 years of experience in clinical development, medical affairs and commercialization of medicines in multiple therapy areas, including neurology and psychiatry. Dr. O’Quinn spent over 20 years with GlaxoSmithKline in senior leadership roles. He most recently served as a consultant to pharmaceutical clients, including Zynerba Pharmaceuticals, supporting clinical development and medical affairs activities. Dr. O’Quinn earned a Doctor of Pharmacy, with highest honors, from the University of North Carolina at Chapel Hill. He completed a post-doctoral fellowship in Cardiovascular Pharmacotherapy with the UNC School of Pharmacy and Division of Cardiology. He also completed marketing and executive leadership training at The Wharton School of the University of Pennsylvania.|
Third Quarter 2021 Financial Results
Research and development expenses were $6.3 million for the third quarter of 2021, including stock-based compensation of $0.8 million. General and administrative expenses were $3.9 million in the third quarter of 2021, including stock-based compensation expense of $0.8 million. The net loss for the third quarter of 2021 was $10.6 million, with basic and diluted loss per share of $(0.26).
As of September 30, 2021, cash and cash equivalents were $75.6 million, compared to $59.2 million as of December 31, 2020. Management believes that the Company’s cash and cash equivalents as of September 30, 2021 are sufficient to fund operations and capital requirements well into the first half of 2024.
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, autism spectrum disorder, 22q11.2 deletion syndrome, and a heterogeneous group of rare and ultra-rare epilepsies known as developmental and epileptic encephalopathies. 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 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 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 timing and outcome of current and future legal proceedings; and 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. 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 PHARMACEUTICALS, INC.
CONSOLIDATED STATEMENTS OF OPERATIONS
|Three months ended September 30,||Nine months ended September 30,|
|Research and development||$||6,341,171||$||5,805,948||$||16,402,129||$||30,038,582|
|General and administrative||3,869,481||3,425,831||11,531,824||11,834,434|
|Total operating expenses||10,210,652||9,231,779||27,933,953||41,873,016|
|Loss from operations||(10,210,652||)||(9,231,779||)||(27,933,953||)||(41,873,016||)|
|Other income (expense):|
|Foreign exchange (loss) gain||(376,637||)||172,467||(576,619||)||(85,171||)|
|Total other expense||(371,599||)||183,248||(560,005||)||153,895|
|Net loss per share - basic and diluted||$||(0.26||)||$||(0.31||)||$||(0.73||)||$||(1.59||)|
|Basic and diluted weighted average shares outstanding||40,092,128||29,243,375||38,933,209||26,258,626|
|Non-cash stock-based compensation included above:|
|Research and development||$||818,390||$||544,909||$||2,443,667||$||1,590,285|
|General and administrative||751,603||717,716||2,325,512||2,343,125|
ZYNERBA PHARMACEUTICALS, INC.
CONSOLIDATED BALANCE SHEETS
|September 30, 2021||December 31, 2020|
|Cash and cash equivalents||$||75,642,498||$||59,157,187|
|Incentive and tax receivables||8,535,607||9,042,586|
|Prepaid expenses and other current assets||3,880,014||5,166,401|
|Total current assets||88,058,119||73,366,174|
|Property and equipment, net||447,728||585,403|
|Incentive and tax receivables||868,083||—|
|Liabilities and Stockholders' Equity|
|Total current liabilities||10,897,934||13,913,248|
|Lease liabilities, long-term||411,237||—|
|Additional paid-in capital||309,312,130||262,286,008|
|Total stockholders' equity||78,686,999||60,143,528|
|Total liabilities and stockholders' equity||$||89,996,170||$||74,056,776|
Jim Fickenscher, CFO and VP Corporate Development
Corporate Overview November 2021
Forward - Looking Statements 2 © 2020 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. 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 INCLUDING RECONNECT TRIAL 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; THE COMPANY’S PLANNED RECONNECT TRIAL MAY NOT BE DETERMINED TO BE SUFFICIENT TO SUPPORT AN NDA SUBMISSION; 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; AND 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 .
Zynerba Pharmaceuticals (NASDAQ: ZYNE) 3 A Rare/Near - Rare Neuropsychiatric Company • Deep pipeline targeting high unmet medical needs; translating into multi - billion dollar market opportunity with Zygel Ʀ (Cannabidiol Gel) • Focused on completing development of Zygel in Fragile X syndrome (FXS) • Confirmatory RECONNECT pivotal trial initiated September 2021, with topline results expected 2H 2023 • Company guidance on path forward in three additional neuropsychiatric indications by end of 2021 following evaluation and prioritization of development plans: • Autism spectrum disorder (ASD) – Phase 2 complete • 22q11.2 deletion syndrome (22q) – Phase 2 ongoing • Developmental and epileptic encephalopathies (DEE) – Phase 2 complete • Experienced team with development and commercial expertise in transdermal delivery, orphan diseases, neurology, and psychiatry • Cash runway expected to be sufficient to fund operations and capital requirements well into 1H 2024
Deep Clinical Pipeline & Near - term Milestones 4 Zygel Cannabidiol Gel *Orphan Drug and Fast Track designation **Orphan Drug designation Expected Milestones Topline results expected 2H 2023 Company guidance on path forward by end of 2021 Screening of patients has resumed; timing for top line results TBD when enrollment complete Finalize target syndrome selection in 2021 Indication Preclinical Phase 1 Phase 2 Fragile X Syndrome (FXS)* Pivotal BRIGHT: Topline data released BELIEVE: Data published 9/3/21 in JAMA Network Open Developmental and Epileptic Encephalopathies (DEE) Autism Spectrum Disorder (ASD) INSPIRE: Ongoing RECONNECT: Pivotal confirmatory trial initiated 22q Deletion Syndrome (22q)**
Neuropsych Indications Differentiated Formulation delivers Cannabidiol through the epidermis and into the circulatory system Zygel (ZYN002) Cannabidiol Gel 5 Unique Mechanism of Action First & only patent - protected (2038), permeation - enhanced, pharmaceutically - produced cannabidiol gel Transdermal Cannabidiol modulates multiple receptors and mediates numerous pathways, including the endocannabinoid pathway Potential utility in rare / near - rare neuropsychiatric conditions
6 • Rare genetic developmental disability • Leading known cause of both inherited intellectual disability and ASD • No approved drugs indicated for FXS • Symptoms linked to deficiencies in the endocannabinoid system (ECS) • Mutation impacts FMR1 gene and causes ECS dysregulation, causing core cognitive, social, and behavioral symptoms of FXS • Easily identified mutation manifests as multiple CGG repeats in FMR1 (full mutation = >200 repeats) • U.S. patents provide IP protection to 2038 • FMR1 gene codes for production of FMRP* which is vital to synapse development • Methylation of FMR1 also plays a role in determining functionality of the gene • When methylation of FMR1 silences the gene, no FMRP is produced: Systems and processes affected by FMRP become dysregulated • ~60% of patients are believed to fall into the completely methylated category Fragile X Syndrome (FXS) *FMR Protein; RNA - binding protein that helps regulate synaptic development and plasticity Role of FMR1 Methylation FXS FXS is routinely diagnosed by assessing (1) CGG repeats and (2) methylation status ~ 40K U.S. patients with complete methylation ~70K U.S. patients with full mutation FXS
CONNECT - FX Trial Design 7 C linical study O f Ca NN abidiol in Childr E n and Adoles C en T s with F ragile X (CONNECT - FX) Zygel (n=110; 72 *) 250 mg daily 500 mg daily (weight - based dose) Placebo (n=102; 65 *) Mirrored Zygel administration 14 weeks Three through 17 years of age Open label extension (OLE) DBPC: Complete 48 months: Ongoing Patients randomized (1:1) to receive either Zygel or placebo * Patients with complete methylation of their FMR1 gene (137 total ~ 65% of trial population)
CONNECT - FX 8 • Primary endpoint: • Change from baseline to end of treatment in ABC - C FXS Social Avoidance subscale • Key secondary endpoints: • Change from baseline to end of the treatment in • ABC - C FXS Irritability subscale score • ABC - C FXS Socially Unresponsive/Lethargic subscale score • Improvement in Clinical Global Impression (CGI - I) at end of treatment, anchored to FXS behaviors • Aligned with FDA’s ‘Voice of the Patient’ Guidance • Captured qualitative data on clinical relevance of FXS behaviors Endpoints and Data Collected
9 9 CONNECT - FX Results: Complete FMR1 Methylation Consistent Improvements Observed with Zygel vs. Placebo Caregiver reported behavioral change Clinician reported improvements in behavior Clinically meaningful improvements in behavior Primary endpoint Caregiver Global Impression of Change Any Improvement Zygel vs placebo 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) Clinically meaningful improvement on drug Significantly more pts achieved a clinically meaningful change Zygel vs placebo Social Avoidance (≥ 3 points) 56% vs 37% ( p =0.030*) Irritability (≥ 9 points) 37% vs 26% ( p =0.232) Clinical Global Impression of Improvement (anchored)** Any Improvement Zygel vs placebo 50% vs 36% ( p =0.128) ABC - C FXS Social Avoidance subscale 40% median percent improvement in socially avoidant behaviors ( p =0.027*) * Statistically significant ** Not specific to Social Avoidance N=136 patients with complete methylation
CONNECT - FX: Safety 10 • Zygel was very well tolerated • No serious or severe adverse events reported during the trial • All treatment - emergent adverse events (TEAEs; any event, whether unrelated or related to study drug) were mild or moderate • Most common treatment - related TEAE: application site pain • Zygel: 6.4%; placebo: 1.0% • Seven total psychiatric disorder TEAEs; 5 were in placebo group • Laboratory values for chemistry and hematology comparable between placebo and Zygel groups; no clinically relevant abnormalities in either group • No clinically significant changes to liver function tests
Trial Design 11 R andomiz e d, Double - Blind, Pla c ebo - C on trolled, Multiple - Ce n ter, Effica c y and Safe t y Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with Fragile X Syndrome 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 18 weeks Three through 17 years of age Open label extension (OLE) DBPC: Initiated 24 months: Planned Patients randomized (1:1) to receive either Zygel or placebo * Patients with complete methylation of FMR1 gene
Primary endpoint • Change from baseline to end of treatment in ABC - C FXS Social Avoidance subscale in patients who have complete (100%) methylation of the FMR1 gene Secondary endpoints • Change from baseline to end of treatment in: • ABC - C FXS Irritability subscale in patients who have complete methylation • ABC - C FXS 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 12 Trial Design
Key study design elements • 18 week trial design will allow us to evaluate improvement in behavioral symptoms over time • Added a third dosing group of 750 mg for individuals >50 kg to maintain appropriate dosing levels for patients • Made trial more patient and family friendly than CONNECT – FX trial – virtual visits, fewer assessments administered, reduced frequency of lab and ECG tests, provided each family an electronic tablet for recording of assessments and skin diaries 13 Trial Design
14 • Near - rare disorder • Symptoms include irritability; anxiety, restricted, repetitive patterns of behavior; impairments in social communication; deficits in verbal and non - verbal communication; deficits in developing, understanding and maintaining relationships • Most diagnosed after age 4; can be diagnosed as early as age 2 ௗ • Significant unmet medical need • Accelerating rate of diagnosis but only two FDA approved products; both atypical antipsychotics • Neither address the key symptoms of social impairment and anxiety • Results from clinical trials of Zygel suggest spectrum of activity against core behaviors • Newer studies suggest ASD is linked to disruption of the ECS • Altered anandamide signaling may contribute to ASD - related social and communication impairments • ECS system modulates many cellular functions and molecular pathways altered in ASD • Cannabidiol may modulate the EC system and improve certain autism - related behaviors • Evidence suggests that cannabidiol may improve social avoidance and anxiety Autism Spectrum Disorder (ASD) Rationale for Developing Zygel in ASD ASD U.S. patents provide IP protection to 2038 ~1M U.S. children and adolescents with ASD
BRIGHT Phase 2 Trial in ASD 15 Open - La B el Tole R ab I lity and Efficacy Study of ZYN002 Administered as a Transdermal G el to C H ildren and Adolescen T s with Autism Spectrum Disorder 37 pts with moderate - to - severe ASD enrolled Three through 17 years of age Screening Zygel 14 Weeks Weight based dosing: 14 weeks: COMPLETE 250 mg to 500 mg daily • Aberrant Behavior Checklist (ABC - C) • Parent Rated Anxiety Scale – Autism Spectrum Disorder (PRAS - ASD) • Autism Parenting Stress Index • Autism Impact Measure (AIM) 24 Weeks Open label extension • Clinical Global Impression – Improvement (CGI - I) and Severity (CGI - S) • Qualitative Caregiver Reported Behavioral Problems Survey Efficacy assessments (primary efficacy assessment = week 14 vs baseline)
16 16 Results of BRIGHT Phase 2 Trial Autism symptom frequency and impact Parental stress Qualitative caregiver assessments Severity of anxiety Primary efficacy objective ABC - C subscales % improvement Irritability: 39.1% ( p <0.0001*) Inappropriate Speech: 42.5% ( p =0.0002*) Stereotypy: 39.1% ( p <0.0001*) Social Withdrawal: 36.4% ( p <0.0001*) Hyperactivity: 35.6% ( p <0.0001*) Qualitative Caregiver Behavioral Problems Survey % Improvements Behavioral: 69% improved Social: 63% improved Emotional: 72% improved Autism Parenting Stress Index Mean improvement of 38.9% ( p<0.0001 *) Parent Rated Anxiety Scale for ASD (PRAS - ASD) Mean improvement of 46% ( p <0.0001*) * Statistically significant Autism Impact Measure (AIM) % improvement Atypical behavior: 34.1% ( p <0.001*) Communication: 19.7% ( p <0.001*) Peer interaction: 19.8% ( p <0.001*) Repetitive behavior: 32.1% ( p <0.0001*) Social reciprocity: 10.7% ( p =0.0053*) Statistically Significant Results at Week 14 Compared to Baseline Full data available in May 26, 2020 and October 15, 2020 press releases
17 *Lower values reflect improvement in each ABC - C subscale. Mean Scores and Percent Improvement Through Week 38* 31.6 7.4 12.7 27.6 36.1 14.3 4.0 6.2 14.0 19.5 13.3 3.8 4.8 10.9 16.8 0 10 20 30 40 Irritability Inappropriate Speech Stereotypy Social Withdrawal Hyperactivity Baseline Week 14 Week 38 ABC - C Subscale Score 61.2% ( P <0.0001) 59.6% ( P <0.0001) 53.4% ( P <0.0001) 56.1% ( P <0.0001) 50.5% ( P< 0.0001) n=18 BRIGHT Phase 2 Trial in ASD Statistically Significant Improvements from Baseline In All ABC - C Subscale Scores Sustained Through Week 38 1 1 18 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.
• Well tolerated and consistent with previously released data at week 14 and week 38, compared to baseline • Approximately half the patients experienced a treatment - emergent adverse event (TEAE; any event, whether unrelated or related to study drug): 49% through week 14 and 54% at week 38 • Most were mild and transient • Only 14% and 19% of patients experienced a treatment - related AE at week 14 and week 38, respectively • All application site - related at week 14 • Most application site - related and 1 each of sleep disorder, increased appetite and pollakiuria at week 38 • No severe or serious AEs reported during the 38 - week trial 18 Well Tolerated Safety Profile in BRIGHT Trial in ASD
Next Steps in ASD Program 19 • In 1H 2021, Zynerba discussed data supporting the potential efficacy of Zygel in ASD, including the results of the Phase 2 BRIGHT trial, with the FDA to determine the regulatory path forward • Positive guidance from FDA included agreement on utilizing the irritability subscale of the Aberrant Behavior Checklist – Community (ABC - C) as the primary endpoint to support an indication for the treatment of irritability in ASD • Company guidance on path forward by end of 2021 • Present additional data at future medical meetings
20 • Rare disorder; most common contiguous gene deletion syndrome • Midline condition with abnormalities affecting palate, face, heart and other organs; surgically corrected in infancy • Neuropsychiatric illnesses (anxiety disorders, ASD) and learning disabilities common • 22q associated with increased anxiety, withdrawn behavior and social interaction problems • Early onset of neuropsychiatric symptoms disrupts development and quality of life, and heightens risk of later psychotic disorders • 25 - fold increased risk of developing schizophrenia • No drugs currently approved to treat 22q • Overlapping target symptoms in FXS and ASD have been shown to respond to Zygel in trials to date • Cannabidiol may treat neuropsychiatric symptoms due to activity as: • Modulator of endocannabinoid system • Agonist at serotonin 1A receptors • Antagonist at GPR55 receptors • Phase 2 trial underway in pediatric and adolescent patients with 22q • Enrollment delayed due to COVID - 19 restrictions in Australia; screening has resumed in March 2021 and an additional clinical site in US has been initiated; topline results timeline to be announced following completion of enrollment 22q11.2 Deletion Syndrome (22q) Rationale for Developing Zygel in 22q 22q Orphan Drug designation for treatment of 22q ~81K U.S. patients with 22q
INSPIRE Phase 2 Trial in 22q 21 Target: 20 patients Six through 17 years of age Screening Zygel 14 Weeks Weight based dosing: 14 Weeks 250 mg to 500 mg daily Efficacy assessments (week 14 vs baseline) include: • Aberrant Behavior Checklist - Community (ABC - C) • Anxiety, Depression and Mood Scale (ADAMS) • Qualitative Caregiver Reported Behavioral Problem Survey • Clinical Global Impression – Severity and Improvement Assessing the I mpact of Zygel (Tra ns dermal Cannabidiol Gel) on P ediatr i c Behavio r al and E motional Symptoms of 22q11.2 Deletion Syndrome 24 Weeks Open label extension
22 • Group of rare / ultra rare childhood - onset epilepsies with impaired or regressed developmental progress • Cognitive impairment, psychiatric problems, and behavioral disturbances are phenotypic • Medically fragile population • Comorbidities include cerebral palsy, chronic respiratory infections, gait disturbances, movement disorders, scoliosis, and feeding problems • Includes wheelchair bound individuals, feeding tubes • Most common and debilitating seizure types: • Focal impaired - awareness (FIAS) – complex partial • Focal to bilateral tonic - clonic and generalized tonic - clonic (TCS) – convulsive seizures (CS) • Strong positive data observed in open label BELIEVE trial • Due to the heterogeneity of DEE patients, FDA suggests pursuing individual syndromes rather than considering DEE as a single condition • Evaluation of potential target indication(s) is ongoing • Expect to finalize target syndrome selection in 2021 in one or more DEE syndromes • Company guidance on path forward by end of 2021 Developmental and Epileptic Encephalopathies (DEE) Developing Zygel in DEE DEE
BELIEVE Phase 2 Trial in DEE 23 Open La B el Study to Assess the Safety and E fficacy of ZYN002 Administered as a Transderma L Gel to Ch I ldren and Adol E scents with De V elopmental and E pileptic Encephalopathy 48 patients enrolled Three through 17 years of age Screening Maintenance 22 Weeks Titration 4 Weeks Open label extension Weight based dosing: Six months: COMPLETE Six months Zygel 250 mg to 1000 mg daily
24 24 Results of BELIEVE Phase 2 Trial Clinically Meaningful Improvements in FIAS / TCS and QoL vs. Baseline ≥35% and ≥50% responders Reductions in seizures in patients with ASD Improved Sleep Qualitative assessments Primary efficacy objective Median % Reductions in Seizures Month 3 (n=33): 44% Month 6 (n=29): 51% Month 9 (n=18): 60% Month 12 (n=18): 73% ELDQOL Statistically significant reductions in subscale scores for seizure severity, behavior, and mood ( p <0.01) Median % Reductions in Seizures: Comorbid ASD Month 3 (n=10): 45% Month 6 (n=10): 59% Month 9 (n=8): 67% Month 12 (n=8): 74% % of patients with ≥35% and ≥50% Reductions in FIAS and TCS ≥35% reductions Month 3: 58% Month 6: 62% Month 12: 89% Sleep Disturbance Scale for Children (SDSC) % Improvement Statistically significant improvements observed in Total Score: 36%; p =0.012 Disorders of initiating/maintaining sleep: 22%; p =0.006 Disorders of arousal/nightmares: 100%; p =0.031 Sleep wake transition disorder: 31%; p =0.030 ≥50% reductions Month 3: 46% Month 6: 55% Month 12: 83% Full data available in September 18, 2019 and December 4, 2020 press releases Caregiver Feedback Verbatim feedback included improved vitality, concentration and cognition, and school improvement
25 • Tolerability profile consistent with the safety database for Zygel • Most treatment - emergent adverse events (TEAEs) (any event, whether unrelated or related to study drug) were mild or moderate • Two SAEs deemed possibly drug - related (LRTI and status epilepticus) • No drug - related clinically significant changes in vital signs, ECGs, or laboratory findings BELIEVE Safety Zygel Well Tolerated over 12 months: No Safety Signal Identified
BELIEVE Phase 2 Trial in DEE 26 Results Published in JAMA Network Open , September 3, 2021 • The authors concluded that Zygel was safe, well tolerated, and was associated with reductions in focal impaired awareness seizures (FIAS) and tonic - clonic seizure (TCS) frequency and disease burden • The authors further noted: • Incidence of adverse events likely due to high baseline rate of complex morbidities & seizure severity, and to the relatively long trial duration • Low rate of GI AEs potential benefit of transdermal delivery • Study findings highlight important benefits beyond seizure reduction that improve overall quality of life for patients and families “ Safety and tolerability of transdermal cannabidiol gel in children with developmental and epileptic encephalopathies: A nonrandomized controlled trial ” 1 1 https ://protect - us.mimecast.com/s/0nw7CQWN6DsJj1nMIxLa2a?domain=jamanetwork.com
Financial Strength 27 • Clean balance sheet • No debt, 41.2M shares outstanding (as of November 11, 2021) • Cash and cash equivalent position of $ 75.6M as of September 30, 2021 • Cash runway expected to be sufficient to fund operations and capital requirements well into the first half of 2024
Deep Clinical Pipeline & Near - term Milestones 28 Zygel Cannabidiol Gel *Orphan Drug and Fast Track designation **Orphan Drug designation Expected Milestones Topline results expected 2H 2023 Company guidance on path forward by end of 2021 Screening of patients has resumed; timing for top line results TBD when enrollment complete Finalize target syndrome selection in 2021 Indication Preclinical Phase 1 Phase 2 Fragile X Syndrome (FXS)* Pivotal BRIGHT: Topline data released BELIEVE: Data published 9/3/21 in JAMA Network Open Developmental and Epileptic Encephalopathies (DEE) Autism Spectrum Disorder (ASD) INSPIRE: Ongoing RECONNECT: Pivotal confirmatory trial initiated 22q Deletion Syndrome (22q)**
Corporate Overview November 2021