The U.S. Food and Drug Administration (FDA) and Zynerba Pharmaceuticals will meet later this year to discuss the results of the CONNECT-FX trial and next steps regarding a potential regulatory approval of the experimental cannabidiol (CBD) gel Zygel for fragile X syndrome, according to the company.
If approved, use of Zygel would include children and adolescents with fragile X and a fully methylated FMR1 gene, a biochemical modification that “turns genes off” and leads to no production of the FMRP protein. A full methylation is associated with greater disease severity.
“The meeting with the FDA will be an important milestone for patients and their families who live with the debilitating behavioral impact of Fragile X,” Armando Anido, chairman and CEO of Zynerba, said in a press release.
“We look forward to discussing the pivotal data and the regulatory path for potential approval in FMet [fully methylated FMR1 gene] patients with the FDA in the fourth quarter of this year,” he said.
Also, Zynerba has been granted a patent — number 10,758,497 and titled “Treatment of Fragile X Syndrome with Cannabidiol” — from the U.S. Patent and Trademark Office (USPTO) covering the use of 250 mg or 500 mg of man-made or purified cannabidiol for a person in need of the therapy. The patent, which expires in 2038, is part of the company’s intellectual property portfolio that includes Zygel.
Zygel is designed to deliver CBD into the bloodstream through the skin. The gel is applied to the shoulder or upper arm. CBD, a compound found in the cannabis plant, but that does not produce a “high.” It is thought to modulate the endocannabinoid system, where imbalances have been suggested to underlie certain behavioral abnormalities in fragile X.
The investigational therapy was evaluated in the pivotal Phase 2/3 CONNECT-FX clinical trial (NCT03614663), which was completed recently in the U.S., Australia, and New Zealand.
In total, the Zynerba-funded study evaluated 212 children with fragile X (majority boys), ages 3 to 17. Participants were assigned randomly to receive either Zygel or a placebo every day for 14 weeks.
The trial failed to meet its primary goal, as Zygel-treated patients showed no differences relative to a placebo group on the Social Avoidance subscale of the Aberrant Behavior Checklist — Community FXS (ABC-C). Also, no significant differences were seen in key secondary ABC-C subscales assessing irritability and social unresponsiveness.
However, an analysis focused on 169 participants with greater disease severity — they had a full methylation in the FMR1 gene — revealed that Zygel led to significant benefits in the Social Avoidance subscale after 12 weeks. While Zygel-treated participants had a 40% median improvement, those on a placebo showed a 21.1% median improvement.
Likewise, caregivers reported fewer behavioral problems after treatment with Zygel over 12 weeks compared to the placebo. Specifically, more caregivers of patients on Zygel found improvements in social avoidance, social interactions, and irritable/disruptive behaviors than those in the placebo group.
No new safety concerns were identified in the study.
“Our ongoing evaluation of the pivotal CONNECT-FX data continues to clarify the impact that Zygel achieved in the most severely impacted children and adolescents with FXS, as well as the excellent tolerability profile,” Anido said.
Zynerba also has concluded a series of meetings with the FDA to discuss the clinical development of Zygel for developmental and epileptic encephalopathies (DEE), which is an umbrella term for a diverse group of rare and ultra-rare epilepsy syndromes that manifest with seizures and behavioral abnormalities. The agency recommends Zynerba to address individual syndromes rather than considering DEE as a single condition.
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