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., Nov. 28, 2022 (GLOBE NEWSWIRE) —

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.

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