Zygel, CBD Gel, to Enter Pivotal Trial in Patients With Severe Symptoms

Zynerba Pharmaceuticals announced plans to open a pivotal clinical trial next year for its cannabidiol (CBD) gel Zygel in fragile X syndrome patients with severe symptoms, a group that showed improvements in a previous Phase 2/3 study.  

According to the company, positive trial results would support a request for the regulatory approval of Zygel in treating fragile X.

“We believe that Zygel has the potential to meaningfully relieve the behavioral symptoms of the most impacted individuals with Fragile X syndrome,” Armando Anido, chairman and CEO of Zynerba, said in a press release.

The company expects to finalize the study design with input from the U.S. Food and Drug Administration (FDA) by June, with the trial commencing before the year’s end.  

“We are thankful for our ongoing constructive dialogue with the FDA on our path forward to NDA [new drug application] submission. Completing the development of Zygel in FXS and preparing for a successful launch will be the primary focus of the Company,” Anido added.

Fragile X is caused by increased methylation of the FMR1 gene, a DNA modification that silences gene activity and prevents the production of the FMRP protein. Higher methylation levels of FMR1 correspond with more severe symptoms.

Zynerba announced earlier that it would be meeting with the FDA to discuss the potential for Zygel’s approval based on results of the Phase 2/3 CONNECT-FX (NCT03614663) clinical trial.

In this 14-week study, 212 children with fragile X, ages 3 to 17, were randomly assigned to twice-daily doses of either Zygel or a placebo, both administered as a gel applied to the skin of the upper arm or shoulder. 

Although the trial did not meet its primary goal of easing behavioral abnormalities overall, a subset of patients saw significant improvements. Among 167 children with full methylation of FMR1 (at least 90% methylated) and more severe behavioral symptoms, Zygel led to a median improvement (reduction) of 40% in social avoidance behaviors, compared with a 21.1% improvement in the placebo group.

“The results reported in the analysis of children with a highly methylated FMR1 gene are a source of considerable hope for the patients and their families who are impacted by Fragile X syndrome,” said Linda Sorensen, executive director of the National Fragile X Foundation.

Zygel is designed to deliver CBD — a compound found in the cannabis plant that does not produce a “high” — directly into the bloodstream. CBD is thought to affect the endocannabinoid system, which is associated with some of the behavioral abnormalities that characterize fragile X.

Zynerba also announced its development plan for Zygel as a treatment for other conditions, including again enrolling patients for the Phase 2 INSPIRE trial in children and adolescents with DiGeorge syndrome (paused due to the ongoing pandemic), and a discussion with the FDA of results from the Phase 2 BRIGHT trial in children and adolescents with moderate-to-severe autism spectrum disorder.