Tripledemic Delaying Completion of Zygel Phase 3 Clinical Trial

Maker says timeline likely shifting to first half of 2024 for top-line results

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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A bell with the word Update on it is ringing with other small bells.

A tripledemic — high rates of respiratory syncytial virus, influenza, and COVID-19 — is slowing enrollment in the Phase 3 clinical trial testing Zygel, Zynerba Pharmaceuticals’ experimental cannabidiol gel, in children and adolescents with fragile X syndrome.

These environmental factors are causing unexpectedly higher cancellations of the initial screening visits, delaying the completion of the trial, called RECONNECT (NCT04977986).

“Though we are still striving to report topline results by the end of 2023, when we look at the current and projected impact of the Tripledemic, we believe that the first half of 2024 is a more reasonable timeframe to have topline results from RECONNECT,” Armando Anido, Zynerba’s chairman and chief executive officer, said in a company press release. “We have also prioritized our corporate business plans to focus almost exclusively on completing RECONNECT.”

The trial is recruiting up to 204 pediatric fragile X patients, ages 3 to 17, at 27 sites across the U.S., Australia, Ireland, and the U.K. Those interested in participating may apply through the RECONNECT website.

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Zygel delivers medicine into bloodstream as a gel applied to skin

Fragile X syndrome negatively impacts nerve cell communication and is marked by a spectrum of intellectual disabilities and behavioral symptoms, including social avoidance and irritability.

Zygel, also known as ZYN002, is designed to deliver cannabidiol (CBD) into the bloodstream through the skin as a gel applied to the shoulder or upper arm.

CBD is a nonpsychoactive compound found in the cannabis plant that is thought to modulate the brain’s endocannabinoid system, whose imbalance may relate to some behavioral abnormalities commonly seen in fragile X.

Thus, by restoring this system’s balance, Zygel is expected to help ease behavioral symptoms in these patients.

The experimental gel received orphan drug designation from the U.S. Food and Drug Administration (FDA) and the European Commission for treating behavioral symptoms in people with fragile X.  The FDA also granted the therapy fast track status for the same indication.

These designations are meant to accelerate the therapy’s clinical development and regulatory review.

Previous trial showed significant reduction in behavioral symptoms

In the previous Phase 2/3 CONNECT-FX trial (NCT03614663), Zygel led to a significant reduction in behavioral symptoms relative to a placebo only in a subgroup of fragile X patients with fully methylated FMR1, the gene mutated in the disease. Full study’s results were published late November in a peer reviewed journal.

Methylation is a chemical modification that turns off a gene. For patients with complete methylation of FMR1, who are thought to account for about 60% of cases, no FMRP protein is produced, and greater disease severity is found.

These results supported the launch of the Phase 3 RECONNECT trial to confirm the therapy’s benefits in pediatric fragile X patients, mostly carrying a full methylated gene. About 160 of its planned 204 participants need to have a complete methylation of FMR1, the company has reported.

Patients will be randomly assigned to receive either weight-based doses of Zygel or a placebo gel for about 4.5 months. The trial’s main goal is to evaluate whether Zygel can significantly ease behavioral problems, as assessed by the Aberrant Behavior Checklist-Community FXS Specific (ABC-CFXS) Social Avoidance subscale.

The ABC-CFXS is a validated measure of fragile X behavioral symptoms, covering social avoidance, irritability, hyperactivity, and inappropriate speech.

If positive, RECONNECT data will support Zynerba’s filing of an application seeking of Zygel’s approval for easing fragile X behavioral symptoms.

Interim data from an open-label extension study (NCT03802799) that includes patients who have participated in previous Zygel trials, such as CONNECT-FX, supported the therapy’s long-term safety and effectiveness. Again, greatest reductions in behavioral symptoms were observed for those with complete methylation of FMR1.