Category: Recent News

Enrollment continues in RECONNECT, a confirmatory pivotal Phase 3 trial of Zygel™ in patients with Fragile X syndrome; topline results expected first-half 2024

European Commission granted orphan drug designation for cannabidiol, the active ingredient in Zygel, in 22q11.2 deletion syndrome

$50.6 million in cash and cash equivalents at December 31, 2022; Cash runway to mid-year 2024

Devon, PA, March 28, 2023 – Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today reported financial results for the fourth quarter and full year ended December 31, 2022, and provided an overview of recent operational highlights and a pipeline update.

“We remain focused on enrolling patients in our confirmatory pivotal Phase 3 RECONNECT trial, and expect topline results in the first half of 2024,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “We are committed to bringing the first pharmaceutical product indicated for the treatment of behavioral symptoms of Fragile X syndrome to market, and with a cash runway to mid-year 2024, we remain well-positioned on achieving that goal.”

Operational Highlights and Pipeline Update

Zygel in Fragile X Syndrome (FXS)

• The Company expects topline results from RECONNECT, a confirmatory pivotal Phase 3 trial of Zygel in patients with FXS, in the first half of 2024. The Company believes that the results from RECONNECT, if positive, will be sufficient to support the submission of a New Drug Application (NDA) in the U.S. and a Marketing Authorization Application (MAA) in Europe for Zygel in patients with FXS.
• Published data in the Journal of Neurodevelopmental Disorders describing the role of the endocannabinoid system and cannabidiol therapy in FXS. The review of evidence suggests a central role for the endocannabinoid system in neuronal development and cognitive function and in the pathogenesis of FXS, and the potential role of cannabidiol as a treatment for FXS. (Press Release).
• Published data from the Phase 3 CONNECT-FX study of Zygel in the Journal of Neurodevelopmental Disorders. The Phase 3 study demonstrated that patients with FXS who have a highly methylated FMR1 gene that were treated with Zygel showed a significant reduction in behavioral symptoms compared to those treated with placebo, and that Zygel was well tolerated. (Press Release).
• The Company announced that the U.S. Patent and Trademark Office (USPTO) issued a patent titled “Treatment of Fragile X Syndrome With Cannabidiol,” which includes claims directed to methods of treating FXS with cannabidiol. This new patent, which expires in 2038, is part of an expanding international intellectual property portfolio covering Zygel. (Press Release)

Zygel in 22q11.2 Deletion Syndrome (22q)

• Based on the positive Phase 2 INSPIRE trial data announced in June 2022 (Press Release), the Company held an initial meeting with the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2022 to obtain feedback on the Phase 2 data and regulatory pathway for Zygel in patients with 22q. The Company expects to continue its productive dialogue with the FDA on this topic and arrive at an acceptable trial design by the end of 2023. The Company currently plans to initiate a Phase 3 program in children and adolescents with 22q following topline results from RECONNECT.
• In November 2022, the Company announced that the European Commission granted orphan drug designation to cannabidiol, the active ingredient in Zygel, for the treatment of 22q.
• The Company presented positive long-term 38-week data from the Phase 2 INSPIRE trial with Zygel in children and adolescents with 22q at the 61^st Annual Meeting of the American College of Neuropsychopharmacology. The data showed that through 38-weeks of treatment, sustained, statistically significant improvements were seen in children and adolescents treated with Zygel in the Pediatric Anxiety Rating Scale (PARS-R), all five scales of the Anxiety, Depression and Mood Scale (ADAMS), and all five subscales of the Aberrant Behavior Checklist – Community (ABC-C). These results are consistent with the previously reported 14-week treatment data suggesting a positive risk-benefit profile for Zygel in improving anxiety-related and behavioral symptoms in children and adolescents with 22q when added to a stable standard of care. (Press Release).
• During the fourth quarter of 2022, the Company announced that the USPTO issued a patent titled “Treatment of 22q11.2 Deletion Syndrome With Cannabidiol,” which includes claims directed to methods of treating one or more behavioral symptoms of 22q with cannabidiol, and expires in 2040. (Press Release).

Fourth Quarter and Full Year 2022 Financial Results

Research and development expenses were $5.5 million for the fourth quarter of 2022, including stock-based compensation of $0.5 million. General and administrative expenses were $3.2 million in the fourth quarter of 2022, including stock-based compensation expense of $0.5 million. Net loss for the fourth quarter of 2022 was $8.0 million, with basic and diluted loss per share of $(0.18).

Research and development expenses were $21.1 million for full year 2022, including stock-based compensation of $2.0 million. General and administrative expenses were $14.2 million for full year 2022, including stock-based compensation expense of $2.4 million. Net loss for full year 2022 was $35.0 million, with basic and diluted loss per share of $(0.82).

Financial Outlook

As of December 31, 2022, cash and cash equivalents were $50.6 million, compared to $67.8 million as of December 31, 2021. On March 13, 2023, the Company issued a statement confirming that it does not hold cash deposits or securities at Silicon Valley Bank.

On May 11, 2021, the Company entered into a Controlled Equity Offering^SM Sales Agreement (2021 Sales Agreement), with Cantor Fitzgerald & Co., Canaccord Genuity, LLC, H.C. Wainwright & Co. LLC and Ladenburg Thalmann & Co. Inc., as sales agents, pursuant to which the Company may sell, from time to time, up to $75.0 million of its common stock. During the year ended December 31, 2022, the Company sold and issued 4,608,274 shares of its common stock under the 2021 Sales Agreement in the open market resulting in gross proceeds of $6.2 million and net proceeds of $5.8 million, after deducting commissions and offering expenses. From January 1, 2023 through March 22, 2023, the Company sold and issued 1,179,077 shares of its common stock under the 2021 Sales Agreement in the open market resulting in gross proceeds of $0.7 million and net proceeds of $0.6 million, after deducting commissions and offering expenses.

On July 21, 2022, the Company entered into a Purchase Agreement and registration rights agreement for up to $20 million with Lincoln Park Capital Fund, LLC (LPC), a Chicago-based institutional investor. During the year ended December 31, 2022, the Company sold and issued 350,000 shares of its common stock under the 2022 Purchase Agreement with LPC in the open market resulting in gross proceeds of $0.3 million and net proceeds of $0.2 million, after deducting offering expenses. From January 1, 2023 through March 22, 2023, the Company sold and issued 1,950,000 shares of its common stock under the Purchase Agreement, resulting in gross and net proceeds of $1.0 million.

Management believes that the Company’s cash and cash equivalents are sufficient to fund operations and capital requirements into mid-year 2024. Top-line results from the Company’s confirmatory pivotal Phase 3 RECONNECT trial of Zygel in patients with FXS are expected in the first half of 2024.

About Zygel

Zygel is the first and only pharmaceutically-manufactured cannabidiol formulated as a patent-protected permeation-enhanced clear gel, designed to provide 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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About Zynerba Pharmaceuticals, Inc.

Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome and 22q11.2 deletion syndrome. 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 PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS
		(unaudited)
		Three months ended December 31,								Year ended December 31,
			2022				2021				2022				2021
Operating expenses:
Research and development		$	5,467,516			$	5,022,360			$	21,099,666			$	21,424,489
General and administrative			3,218,463				3,814,077				14,151,874				15,345,901
Total operating expenses			8,685,979				8,836,437				35,251,540				36,770,390
Loss from operations			(8,685,979	)			(8,836,437	)			(35,251,540	)			(36,770,390	)
Other income (expense):
Interest income			407,270				4,433				846,860				21,047
Foreign exchange gain (loss)			262,677				16,938				(631,126	)			(559,681	)
Total other income (expense)			669,947				21,371				215,734				(538,634	)
Net loss		$	(8,016,032	)		$	(8,815,066	)		$	(35,035,806	)		$	(37,309,024	)
Net loss per share – basic and diluted		$	(0.18	)		$	(0.22	)		$	(0.82	)		$	(0.95	)
Basic and diluted weighted average shares outstanding			45,127,998				40,227,715				42,662,770				39,259,495
Non-cash stock-based compensation included above:
Research and development		$	472,447			$	384,304			$	1,972,894			$	2,827,971
General and administrative			549,155				657,097				2,358,833				2,982,609
Total		$	1,021,602			$	1,041,401			$	4,331,727			$	5,810,580

ZYNERBA PHARMACEUTICALS, INC. CONSOLIDATED BALANCE SHEETS
		December 31, 2022				December 31, 2021
Assets
Current assets:
Cash and cash equivalents		$	50,640,993			$	67,808,000
Incentive and tax receivables			1,225,383				9,580,468
Prepaid expenses and other current assets			2,908,731				2,831,392
Total current assets			54,775,107				80,219,860
Property and equipment, net			409,572				385,833
Right-of-use assets			336,215				565,814
Total assets		$	55,520,894			$	81,171,507
Liabilities and Stockholders’ Equity
Current liabilities:
Accounts payable		$	1,942,830			$	1,798,813
Accrued expenses			7,014,882				7,896,598
Lease liabilities			214,901				209,068
Total current liabilities			9,172,613				9,904,479
Lease liabilities, long-term			119,524				353,694
Total liabilities			9,292,137				10,258,173
Stockholders’ equity:
Common stock			47,896				41,218
Additional paid-in capital			320,698,146				310,353,595
Accumulated deficit			(274,517,285	)			(239,481,479	)
Total stockholders’ equity			46,228,757				70,913,334
Total liabilities and stockholders’ equity		$	55,520,894			$	81,171,507

Zynerba Contacts

Jim Fickenscher, CFO and VP Corporate Development
Zynerba Pharmaceuticals
484.581.7483
fickenscherj@zynerba.com

Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

 

 

Devon, PA, March 13, 2023 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today issued a statement confirming that it does not hold cash deposits or securities at Silicon Valley Bank.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome and 22q11.2 deletion syndrome. 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

Devon, PA, March 7, 2023  — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that Armando Anido, Chairman and Chief Executive Officer of Zynerba Pharmaceuticals, will present at the virtual Oppenheimer 33rd Annual Healthcare Conference on Monday, March 13, 2023, at 4:40 p.m. ET, and host investor meetings.

Investors interested in arranging a virtual meeting with the Company’s management during the conference should contact the Oppenheimer conference coordinator. A webcast of the presentation will be available under the Events & Webcasts tab of the Investors section of the Zynerba website at www.zynerba.com as well as an archived webcast of the presentation that will be available on-demand for 60 days following the event.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome and 22q11.2 deletion syndrome. 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

Devon, PA, March 1, 2023 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that Armando Anido, Chairman and Chief Executive Officer of Zynerba Pharmaceuticals, will present at Cowen’s 43^rd Annual Health Care Conference on Wednesday, March 8, 2023, at 2:50 p.m. ET, and host investor meetings. The conference is being held at the Boston Marriott Copley Place in Boston, Mass.

Investors interested in arranging a meeting with the Company’s management during the conference should contact the Cowen conference coordinator. An archived webcast of the presentation will be available on-demand for 60 days following the event under the Events & Webcasts tab of the Investors section of the Zynerba website at www.zynerba.com.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome and 22q11.2 deletion syndrome. 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

Comprehensive data review suggests a central role for the endocannabinoid system (ECS) in neuronal development, cognitive function and in the pathogenesis of Fragile X syndrome (FXS)

Cannabidiol may help restore the function of the ECS in FXS patients according to review of data

Consistent with the proposed mechanisms of action of cannabidiol in FXS, Zygel™ showed a significant reduction in behavioral symptoms, in patients with ≥90% methylation of the FMR1 gene, compared to those treated with placebo in the CONNECT-FX clinical study

Devon, PA, January 11, 2023 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announces the publication of a paper entitled, “Role of the Endocannabinoid System in Fragile X Syndrome: Potential Mechanisms for Benefit From Cannabidiol Treatment,” in the Journal of Neurodevelopmental Disorders. The review of evidence suggests a central role for the endocannabinoid system (ECS) in neuronal development and cognitive function and in the pathogenesis of Fragile X syndrome (FXS), and the potential role of cannabidiol as a treatment for FXS. The article can be accessed online at the Journal of Neurodevelopmental Disorders at https://rdcu.be/c25fu.

“This publication describes the potential of Zygel as a treatment for Fragile X syndrome based on the central role the endocannabinoid system plays in neuronal development and function,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “The proposed mechanisms of action of cannabidiol are supported by the results from our Phase 3 CONNECT-FX trial in patients with Fragile X syndrome with greater than or equal to 90% methylation of the FMR1 gene, benefited from treatment with Zygel. These findings bolster our confidence in the design of the ongoing, confirmatory, pivotal Phase 3 RECONNECT trial.”

FXS is caused by deficiency or absence of the FMR1 protein, FMRP. The absence of FMRP disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS helps maintain neuronal function and signaling and is thought to be disrupted in FXS. Cannabidiol may help restore the function of the ECS in FXS according to a review of data to date. Cannabidiol may also act as an agonist on serotonin 5HT_1A and other receptors which may contribute to beneficial effects in people with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the Phase 3 CONNECT-FX trial, Zygel was associated with improvements in measures of social avoidance, irritability and social interaction, particularly in patients showing ≥90% methylation of the FMR1 gene. Results from the CONNECT-FX study of Zygel for the treatment of behavioral symptoms in children and adolescents with FXS can be accessed online at the Journal of Neurodevelopmental Disorders at https://rdcu.be/c0sKz.

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About Fragile X Syndrome (FXS)
Fragile X syndrome is a rare genetic developmental disability that is the leading known cause of both inherited intellectual disability and autism spectrum disorder, affecting 1 in 4,000 males and 1 in 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 about 78,000 people suffering with FXS, approximately 60% of whom have complete methylation of the FMR1 gene.

FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including important effects on the endocannabinoid system, and most critically, codes for a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity. The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat. In most neurotypical people, the FMR1 gene correctly codes for the FMRP protein. As a result, FMRP is produced at levels that enable control over behaviors like social avoidance and anxiety. In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function. Methylation of the FMR1 gene also plays a role in determining functionality of the gene. For patients with complete methylation, no FMRP is produced. With no FMRP, the systems and processes that are modulated by FMRP become dysregulated.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders. We are committed to improving the lives of patients and their families living with severe, chronic health conditions including Fragile X syndrome and 22q11.2 deletion syndrome. 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.

Investor Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

Media Contact
Andrea Cohen
Sam Brown Healthcare Communications
Cell: 917.209.7163
andreacohen@sambrown.com

RECONNECT initial screening visits are being adversely impacted by environmental factors, such as the “Tripledemic” (high rates of RSV, influenza and COVID-19); topline results now expected first half of 2024

Cash runway extended to mid-year 2024 due to prioritization of resources on the completion of the RECONNECT trial

Devon, PA, December 21, 2022 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that the Company is revising its target for announcing topline results from the pivotal Phase 3 RECONNECT trial of Zygel in Fragile X syndrome (FXS). The Company now expects topline results in the first half of 2024, rather than the second half of 2023.

The impact of environmental factors including unusually high rates of RSV (respiratory syncytial virus) and influenza and the continued impact of COVID-19 among children, adolescents, family members, and investigational center personnel, has resulted in higher than expected cancellations of initial screening visits at the investigational centers which has led to slower than anticipated enrollment. Despite these issues, clinical investigators at the 27 sites in the U.S., Australia, the UK and Ireland remain committed to completing the trial.

“Though we are still striving to report topline results by the end of 2023, when we look at the current and projected impact of the Tripledemic, we believe that the first half of 2024 is a more reasonable timeframe to have topline results from RECONNECT,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “We have also prioritized our corporate business plans to focus almost exclusively on completing RECONNECT and now expect we have cash into mid-year 2024.”

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About RECONNECT
RECONNECT is a randomized, double-blind, placebo-controlled, multiple-center efficacy and safety trial of Zygel administered as a transdermal gel to children and adolescents ages 3 through 17 with Fragile X syndrome. For more information regarding participation visit www.fragilexhelp.com.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan 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.

About Fragile X Syndrome (FXS)
Fragile X syndrome is a rare genetic developmental disability that is the leading known cause of both inherited intellectual disability and autism spectrum disorder, affecting 1 in 4,000 males and 1 in 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 about 78,000 people suffering with FXS, approximately 60% of whom have complete methylation of the FMR1 gene.

FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including important effects on the endocannabinoid system, and most critically, codes for a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity. The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat. In most neurotypical people, the FMR1 gene correctly codes for the FMRP protein. As a result, FMRP is produced at levels that enable control over behaviors like social avoidance and anxiety. In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function. Methylation of the FMR1 gene also plays a role in determining functionality of the gene. For patients with complete methylation, no FMRP is produced. With no FMRP, the systems and processes that are modulated by FMRP become dysregulated.

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 Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

Zygel™ achieved statistically significant and clinically meaningful improvements from baseline in multiple efficacy assessments and was generally well-tolerated through 38 weeks of treatment

Devon, PA, December 5, 2022 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, presented positive long-term 38-week data from the Phase 2 INSPIRE trial with Zygel in children and adolescents with 22q11.2 deletion syndrome (22q). The data were presented in a poster at the 61^st Annual Meeting of the American College of Neuropsychopharmacology, being held December 4-7, 2022 in Phoenix, Arizona. A copy of the poster is available on the Zynerba corporate website at www.zynerba.com/publications.

The poster, titled, “An Open-Label Tolerability and Efficacy Study of ZYN002 (Cannabidiol) Administered as a Transdermal Gel to Children and Adolescents with 22q11.2 Deletion Syndrome (INSPIRE),” shows that through 38-weeks of treatment, statistically significant improvements were seen in children and adolescents treated with Zygel in the Pediatric Anxiety Rating Scale (PARS-R), all five scales of the Anxiety, Depression and Mood Scale (ADAMS), and all five subscales of the Aberrant Behavior Checklist – Community (ABC-C). These results are consistent with the previously reported 14-week treatment data suggesting a positive risk-benefit profile for Zygel in improving anxiety-related and behavioral symptoms in children and adolescents with 22q when added to a stable standard of care.

“The 38-week data from the Phase 2 INSPIRE trial suggest children and adolescents with 22q who received Zygel over a longer term continued to show improvement in anxiety-related and behavioral symptoms,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “These data provide additional support and reinforce our belief in the potential of Zygel for the treatment of anxiety and behavioral symptoms in children and adolescents with 22q.”

The INSPIRE trial enrolled 20 patients in the U.S. and Australia. Seventeen of the 20 patients completed week 14 (Period 1). Patients with a ≥35% improvement in the ABC-C irritability subscale were allowed to continue treatment for an additional 24 weeks. Thirteen patients continued treatment, with 12 patients completing week 38 (Period 2). At the end of both Period 1 and Period 2, statistically significant improvements from baseline were seen in the PARS-R, all five subscales of the ADAMS, and all five subscales of the ABC-C.

Zygel was generally well tolerated, and the safety profile was consistent with data from previous Zygel clinical trials. Over the 38-week treatment period, three patients reported treatment-related adverse events which were all mild application site adverse events. Three patients experienced serious adverse events unrelated to Zygel and one patient discontinued due to an adverse event unrelated to Zygel.

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan 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 Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

Devon, PA, November 29, 2022  — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced the presentation of a poster at the 61^st Annual Meeting of the American College of Neuropsychopharmacology, being held December 4-7, 2022 in Phoenix, Ariz. A copy of the poster will be made available on the Zynerba corporate website following the presentation at www.zynerba.com/publications.

Poster Presentation Details
Title:	An Open-Label Tolerability and Efficacy Study of ZYN002 (Cannabidiol) Administered as a Transdermal Gel to Children and Adolescents with 22q11.2 Deletion Syndrome (INSPIRE)
Date available:	Available online beginning December 5, 2022 for entirety of conference
Live presentation:	In-person presentation, Poster Session III, December 7, 2022, 5:30 p.m. – 7:30 p.m. MST
Location:	JW Marriott Desert Ridge Resort and Spa, Phoenix, Ariz.

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan 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 Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

Study finds patients with Fragile X who have a highly methylated FMR1 gene that were treated with Zygel showed a significant reduction in behavioral symptoms compared to those treated with placebo

Topline results from follow-on RECONNECT confirmatory pivotal Phase 3 trial of Zygel in patients with a completely methylated FMR1 gene expected in second half 2023

Devon, PA, November 28, 2022 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that the results from the Phase 3 CONNECT-FX study of Zygel for the treatment of behavioral symptoms in children and adolescents with Fragile X syndrome (FXS) were published in the Journal of Neurodevelopmental Disorders.

The paper titled, “A Randomized, Controlled Trial of ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents with Fragile X Syndrome (CONNECT-FX),” details how Zygel was well tolerated in patients with FXS and demonstrated efficacy with a favorable benefit risk profile in patients with ≥90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. The article can be accessed online at the Journal of Neurodevelopmental Disorders at https://rdcu.be/c0sKz.

“Children with Fragile X syndrome are dramatically impacted by debilitating behavioral and emotional challenges, including anxiety, social avoidance, irritability, inattention and aggression,” said Elizabeth Berry-Kravis, M.D., Ph.D., Professor, Department of Pediatrics and Neurological Sciences, Rush University Medical Center. “The results from CONNECT-FX offer hope for children with FXS and their caregivers as additional treatment options are needed for children who continue to struggle with this condition.”

CONNECT-FX was a randomized, double-blind, multinational, 14-week study to evaluate the efficacy and safety of Zygel in children and adolescents aged 3 to 17 years. A total of 212 patients were randomized to 12 weeks of Zygel (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The trial was conducted at 21 investigational centers in the U.S., Australia and New Zealand. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-C_FXS) SA subscale in the full cohort of patients with full mutation FXS, regardless of the FMR1 gene methylation status. Ad hoc analyses assessed efficacy in patients with ≥90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.

Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥90% methylation of FMR1 (nominal p=0.020), representing 80% of the overall study population. This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and Isolation, Irritable and Disruptive Behaviors, and Social Interactions (nominal p-values: p=0.038, p=0.028, and p=0.002, respectively). Similar results were seen in patients with 100% methylation of FMR1, representing 65% of the study population. Zygel was generally well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (Zygel: 6.4%; placebo: 1.0%).

“CONNECT-FX provided evidence that a biologically identifiable and clinically responsive population of patients with FXS, who are defined by both full mutation and greater than or equal to 90% methylation of the FMR1 gene, benefited from treatment with Zygel,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “Given these findings, our follow-on pivotal Phase 3 trial, RECONNECT, is underway to confirm the results observed in this population. We believe having patients with complete methylation of their FMR1 gene as the primary analysis population improves our chance of success and we look forward to topline results from RECONNECT in the second half of 2023 and believe the results, if positive, will be sufficient to support the submission of a New Drug Application in the U.S. and Marketing Authorization Application in the EU for Zygel in patients with FXS.”

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

About Fragile X Syndrome (FXS)
Fragile X syndrome is a rare genetic developmental disability that is the leading known cause of both inherited intellectual disability and autism spectrum disorder, affecting 1 in 4,000 males and 1 in 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 about 78,000 people suffering with FXS, approximately 60% of whom have complete methylation of the FMR1 gene.

FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including important effects on the endocannabinoid system, and most critically, codes for a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity. The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat. In most neurotypical people, the FMR1 gene correctly codes for the FMRP protein. As a result, FMRP is produced at levels that enable control over behaviors like social avoidance and anxiety. In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function. Methylation of the FMR1 gene also plays a role in determining functionality of the gene. For patients with complete methylation, no FMRP is produced. With no FMRP, the systems and processes that are modulated by FMRP become dysregulated.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan 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.

Investor Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com

Media Contact
Laura Morgan
Sam Brown Inc.
Cell: 951.333.9110
lauramorgan@sambrown.com

Devon, PA, November 15, 2022 — Zynerba Pharmaceuticals, Inc. (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that the European Commission (EC) has granted orphan drug designation to cannabidiol, the active ingredient in its transdermal gel, Zygel™, for the treatment of 22q11.2 deletion syndrome (22q).

“We are pleased to have been granted orphan drug designation in the U.S. and now the EU, which we believe reflects the unmet medical need for new therapies to treat 22q,” said Armando Anido, Chairman and Chief Executive Officer of Zynerba. “Orphan drug designation is another important step forward in advancing Zygel as a potential new treatment option for patients with 22q.”

Orphan drug designation is granted to medicines that treat, prevent or diagnose a life-threatening or chronically debilitating rare disease, with a prevalence in the European Union (EU) of not more than 5 in 10,000, and with either no currently approved method of diagnosis, prevention or treatment or with significant benefit to those affected by the disease. The designation provides certain benefits to Zynerba, including 10-year EU market exclusivity upon regulatory approval, if received, reductions in European Medicines Agency application fees, and access to protocol assistance.

The Company believes there are approximately 112,000 patients with 22q in the EU and approximately 129,000 in Europe including the United Kingdom.

Zygel was previously granted orphan drug designation by the EC for the treatment of Fragile X syndrome (FXS) and by U.S. Food and Drug Administration (FDA) for the treatment of FXS and 22q. Additionally, the FDA has granted Fast Track designation for Zygel for the treatment of behavioral symptoms associated with FXS.

In June 2022, the Company announced positive topline results from the exploratory, open label Phase 2 INSPIRE trial of Zygel in children and adolescents with 22q (Press Release). Based on the positive Phase 2 data, the Company requested and has been granted an initial meeting with the FDA before the end of 2022 to obtain feedback on the Phase 2 data and regulatory pathway for Zygel in patients with 22q.

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 in the treatment of FXS and the treatment of 22q. Additionally, Zygel has been designated a Fast Track development program for treatment of behavioral symptoms of FXS.

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. In addition, Zynerba believes that there are approximately 112,000 patients with 22q in the EU and approximately 129,000 in Europe if the United Kingdom is included.

About Zynerba Pharmaceuticals, Inc.
Zynerba Pharmaceuticals is the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan 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 Contact
Peter Vozzo
ICR Westwicke
Office: 443.213.0505
Cell: 443.377.4767
Peter.Vozzo@Westwicke.com