Zygel, Cannabidiol Gel Now in Phase 3 Trial, Named Orphan Drug in EU

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by Lindsey Shapiro PhD |

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The European Commission has granted orphan drug designation to Zygel, Zynerba Pharmaceuticals’ cannabidiol (CBD) transdermal gel candidate to treat for behavioral symptoms in people with fragile X syndrome.

Orphan designation is assigned to promising therapies for life-threatening, rare diseases affecting fewer than 5 in every 10,000 people in the European Union and lacking effective treatments.

It carries benefits that include financial incentives, access to clinical protocol assistance, and 10 years of market exclusivity if approved.

A Phase 3 trial of Zygel, called RECONNECT (NCT04977986), is currently recruiting up to 204 children and adolescents, ages 3 to 17. Most of these patients need to have a complete methylation of FMR1, the gene mutated in fragile X. A full methylation of FMR1 is associated with a total absence of the FMRP protein and greater disease severity.

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Those enrolled will be randomized to 18 weeks of treatment with Zygel, as a clear gel applied to the skin, or to a placebo gel. Trial enrollment is underway at locations in the U.S. and Australia, with sites in the U.K. and Ireland expected to open soon. Top-line results are expected in late 2023.

The commission’s decision follows a similar orphan designation from U.S. Food and Drug Administration (FDA) for Zygel in treating fragile X. The FDA also gave the potential therapy fast track status, which helps to speed its development.

“Orphan drug designation by the [European Commission] is another important milestone for Zygel,” Armando Anido, chairman and CEO of Zynerba, said in a press release. “It underscores the urgent, unmet medical need for patients diagnosed with Fragile X syndrome, and will benefit us as we continue to advance our clinical programs and prepare to bring Zygel to market.”

Zygel is designed to deliver CBD into the bloodstream through the skin, as a gel applied to the shoulder or upper arm. CBD is a non-psychoactive compound found in the cannabis plant that acts on the body’s endocannabinoid system.

Imbalances in this system have been reported in fragile X, and may underlie some of the disease’s characteristic behavioral symptoms. In aiming to restore balance to the endocannabinoid system, Zygel might ease these symptoms in patients.

A previous Phase 2/3 trial, CONNECT-FX (NCT03614663), failed to show significant benefit with Zygel’s use across the 212 children enrolled for social avoidance. Changes in this common behavioral problem in fragile X was the study’s main outcome measure.

Further analyses, however, indicated clinically meaningful reductions in social avoidance behaviors in a subset of patients with a fully methylated FMR1 gene compared with a placebo group.

Methylation is a chemical modification that can “turn off,” or silence, genes. Alterations to FMR1, including methylation, are the underlying cause of fragile X syndrome, and about 60% of all patients are thought to have complete FMR1 methylation. These patients typically have more severe disease.

Data from a long-term and open-label extension study (NCT03802799), in 240 patients from CONNECT-FX and other trials, further supported benefits of Zygel treatment in those with full FMR1 methylation.

Results after a median 21 months of treatment also indicated that Zygel is generally safe. Just under two-thirds of participants reported side effects, most of which were mild or moderate. The most common deemed likely related to treatment was application site pain, reported in 6.6% of participants.

RECONNECT’s main goal is changes in behavioral symptoms from the study’s start to 21 weeks of treatment, compared with placebo, as measured using the Aberrant Behavior Checklist-Community FXS (ABC-CFXS) — a caregiver-reported assessment of abnormal behaviors.

About 160 of its enrolled patients will need to have a complete methylation of FMR1, the company has reported.

This Phase 3 trial is considered pivotal and confirmatory, meaning that Zynerba intends to use trial results, if successful, to support requests for approval.