Zygel continues to improve youngsters’ behavior, long-term data show

Zynerba shares interim analysis of CBD gel's open-label extension trial

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term treatment with Zygel, Zynerba Pharmaceuticals’ experimental cannabidiol (CBD) gel, is tolerated well and leads to clinically meaningful behavioral improvements in children and adolescents with fragile X syndrome.

That’s according to an interim analysis of nearly four years of data from the open-label extension (OLE) study ZYN2-CL-017 (NCT03802799).

Children with complete methylation of their FMR1 gene — a DNA modification linked to more severe disease — saw the greatest benefits, achieving significant reductions in social avoidance behaviors that were sustained for at least two years in the OLE.

These findings were presented by Zynerba in the poster “Long-term Safety and Sustained Efficacy of ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents with Fragile X Syndrome (ZYN2-CL-017),” at the 55th Gatlinburg Conference, held April 10-13 in Kansas City, Missouri.

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Meanwhile, the confirmatory Phase 3 RECONNECT trial (NCT04977986) is recruiting up to 204 fragile X patients, ages 3-22 years, at sites in the U.S., Australia, Ireland, and the U.K. Most participants will have a fully methylated FMR1 gene.

“New interim results from the open-label extension trial continue to support the long-term safety and sustained effectiveness of Zygel in children and adolescents with Fragile X syndrome (FXS), with the greatest improvements seen in those with complete methylation of their FMR1 gene, the population for the primary efficacy analysis in our pivotal RECONNECT trial,”  Armando Anido, chairman and CEO of Zynerba, said in a press release.

Fragile X syndrome is caused by mutations in the FMR1 gene, which is responsible for producing the FMRP protein that’s important for nerve cell function. These mutations are associated with FMR1 methylation, a type of chemical modification that “silences” the gene and causes it to produce less FMRP protein.

Full methylation of the FMR1 gene is linked to a complete absence of FMRP, and thus, more severe disease.

Zygel, also known as ZYN002, is designed to deliver CBD into the bloodstream when administered on the skin of the shoulder or upper arm. CBD is the main non-psychoactive compound derived from the cannabis plant; it modulates the body’s endocannabinoid system.

Endocannabinoid signaling

Disruptions to this system are thought to underlie some of the behavioral symptoms seen in fragile X patients. Zynerba believes the treatment may restore more normal endocannabinoid signaling and ease patients’ behavioral symptoms.

The open-label extension study was designed to evaluate the long-term safety and effectiveness of Zygel in fragile X patients, ages 3-17 years, who participated in the placebo-controlled Phase 2/3 CONNECT-FX (NCT03614663) or the open-label Phase 2 FAB-C (ZYN2-CL-009) trials.

In the extension trial, all participants are being given Zygel, at a dose of 250 or 500 mg per day based on the person’s weight.

The presentation concerned findings from 240 participants with up to 45 months (nearly four years) of treatment in the OLE, as of a cut-off date of Jan. 23. Patients had a mean age of 9.7 years at study’s start, and 183 (76.3%) were boys and 57 (23.8%) were girls.

For patients who participated in the ZYN2-CL-009 trial, Zygel treatment duration totaled a median of 74 months (about six years).

Consistent with a previous interim analysis, Zygel was found to be generally safe and tolerated well over a median of 20 months of treatment (about 1.5 years). Treatment-related adverse events were reported in 13.3% of patients, with the most common being application site pain (6.7%), which was typically mild and temporary.

Changing social avoidance

The study’s main efficacy goal is to assess changes in social avoidance — a behavioral abnormality common in fragile X patients — through the Social Avoidance subscale of the Aberrant Behavior Checklist-Community FXS (ABC-C FXS), a caregiver-reported assessment of abnormal behaviors in fragile X.

Reductions in social avoidance were observed across the entire study group, with the greatest improvements seen among the subset of patients from CONNECT-FX who had complete FMR1 methylation.

Specifically, these patients experienced significant and clinically meaningful reductions in the social avoidance subscale, indicating less social avoidance, that were sustained for up to two years in the OLE.

Similar reductions were observed in the irritability subscale of the ABC-C FXS, according to Zynerba.

Previous data from the CONNECT-FX trial similarly found evidence that Zygel led to reductions in social avoidance behaviors among participants with at least 90% FMR1 methylation.

The company believes these findings support the design of the ongoing RECONNECT trial, which is set to evaluate the effects of Zynerba treatment in patients with complete FMR1 methylation, but also will include patients with partial methylation.

Participants will be assigned randomly to receive either Zygel or a placebo for 18 weeks (about 4.5 months). The study’s main goal is to assess ABC-C FXS score changes in patients with a fully-methylated FMR1 gene.

Top-line data from RECONNECT initially were expected later this year, but recruitment delays have pushed the timeline to the first half of 2024.