Zygel Cannabidiol Gel Tolerated Well Up to 21 Months, Trial Data Show

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Zygel, an experimental cannabidiol gel that Zynerba Pharmaceuticals is developing to help normalize behaviors in people with fragile X syndrome, continues to be well tolerated up to a median treatment length of 21 months, according to new data from the open-label extension of the Phase 2/3 CONNECT-FX trial.

Results were shared in the presentation “ZYN002 Cannabidiol Transdermal Gel Efficacy and Safety: Recent Clinical Research Advances in the Treatment of Autism and Fragile X Syndrome” at the BRAIN Foundation Synchrony 2021 Symposium.

CONNECT-FX (NCT03614663) enrolled 212 children with fragile X, ages 3 to 17, who were given Zygel (110 patients) or a placebo (102 patients) daily for 14 weeks. The trial’s main goal was to assess the effect of treatment on the Aberrant Behavior Checklist-Community FXS (ABC-CFXS), a caregiver-reported measure of abnormal behaviors.

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The trial failed to meet its main goal. Top-line data announced in 2020 showed that, compared with placebo, Zygel did not significantly reduce social avoidance behaviors (measured with the ABC-CFXS social avoidance subscale) in the overall trial participants.

However, further analyses showed that the treatment may have benefited patients with a fully methylated FMR1 gene. Methylation is a type of chemical modification that basically “turns off” genes, and alterations in the FMR1 gene cause fragile X.

Participants who completed CONNECT-FX had the option to enroll in an extension study, which is evaluating the long-term safety and effectiveness of Zygel. The study includes 240 children, including a few from other trials or who were ineligible for participation in CONNECT-FX. The extension study is open-label; all participants are treated with Zygel.

Over a median treatment length of 21 months, just under two-thirds of the participants have reported any adverse events (side effects), and the vast majority of those — 97.7% — were mild to moderate in severity. The most common adverse event deemed likely related to treatment was application site pain, reported in 6.6% of participants.

There have been seven serious adverse events reported in six participants, but none of these were deemed likely to be related to treatment.

Among participants with full FMR1 methylation who had available data, about 70% had an improvement of at least three points in social avoidance scores on the ABC-CFXS. Within a few weeks of entering the extension study, this rate was similar regardless of whether patients had been on Zygel or placebo in the original trial.

Zynerba now is running a Phase 3 trial called RECONNECT (NCT04977986). The study is recruiting about 200 children with fragile X, ages 3 to 17; about 80% of participants will have full FMR1 methylation. Enrollment is ongoing at locations in the U.S. and Australia, with additional locations expected to open in the U.K. and Ireland.

Participants in RECONNECT will be randomized to receive either Zygel or placebo. The study’s main goal is to assess changes in ABC-CFXS scores after 18 weeks of treatment.

Zynerba expects trial results in the second half of next year.

The company announced in a recent press release that it had received written scientific advice from the European Medicines Agency (EMA) providing clarity, guidance, and requirements to submit an application for Zynerba approval as a treatment for fragile X. Based on the EMA’s advice, Zynerba believes that it will meet these requirements once it completes its current development program for the investigational therapy.