Zygel May Be Effective for Children with Severe Fragile X Symptoms, CONNECT-FX Trial Suggests

Zynerba Pharmaceuticals‘ Zygel failed to significantly ease behavioral symptoms in the overall group of children with fragile X syndrome (FXS) who took part in the CONNECT-FX trial, top-line results show.

However, significant benefits were detected in participants with more severe symptoms, indicating that the experimental cannabidiol (CBD) gel may be effective for certain individuals with fragile X.

“This study identified a key population of patients who might benefit from treatment of their behavioral symptoms of FXS with Zygel,” Randi J. Hagerman, MD, a CONNECT-FX investigator and professor at UC Davis School of Medicine, said in a press release. “Zygel has the potential to be an important therapeutic option for the most severely impacted patients with Fragile X.”

Zygel is intended to deliver CBD into the bloodstream through the skin after being applied to the shoulder or upper arm. CBD, a compound found in the cannabis plant that is not psychoactive — meaning it does not produce a “high” — is believed to modulate the endocannabinoid system; Abnormalities in this system may underlie some of the behavioral abnormalities common in fragile X.

The Phase 2/3 clinical trial CONNECT-FX (NCT03614663) was conducted at 21 clinical sites in the U.S., Australia, and New Zealand. Funded by Zynerba, the study evaluated 212 children with FXS, ages 3 to 17. Three-quarters of participants were boys.

Participants were assigned randomly to receive either Zygel (110 participants) or a placebo (102 participants) every day for 14 weeks — one sachet given every 12 hours to children weighing 35 kg (about 77 pounds) or less, and four sachets — two every 12 hours — to those weighing more 35 kg.

The trial’s primary outcome was the Social Avoidance subscale of the Aberrant Behavior Checklist — Community FXS (ABC-C). The ABC-C measures multiple abnormal behaviors that are common among people with fragile X, including social avoidance, irritability, hyperactivity, and inappropriate speech.

In the total study population, Zygel treatment did not significantly improve Social Avoidance scores on the ABC-C, relative to the placebo. Zygel treatment also did not significantly improve scores on other ABC-C subscales measuring irritability and social unresponsiveness, and it did not provide benefits on the Clinical Global Impression (CGI) assessment of behavior.

Fragile X is caused by a repeat expansion in the gene FMR1, leading to no production of the FMRP protein. Specifically, people with fragile X have more than 200 repeats of a short sequence of nucleotides (the “letters” of DNA), in contrast to the less than 40 repeats seen in healthy people. The expansion results in FMR1 methylation, a biochemical way for cells to “turn off” genes.

An analysis focused on the 169 participants who had at least 90% methylation (termed “full methylation”) in the FMR1 gene and thereby with greater disease severity showed that Zygel resulted in significant benefits in the Social Avoidance subscale of the ABC-C after 12 weeks. Zygel-treated participants had a mean decrease of 2.99 points (a 40% median improvement), while those given a placebo had a mean decrease of 1.99 points, which corresponds to a 21.1% median improvement.

Relative to placebo, Zygel treatment did not significantly improve other ABC-C subscale scores or CGI scores among participants with full methylation.

No new safety concerns were identified in the trial. Treatment with Zygel was well-tolerated. Fifteen participants (7%) experienced a treatment-related adverse event (side effect), 11 of whom were given Zygel and four placebo. The most commonly reported treatment-related adverse event was pain at the application site (6.4% for Zygel, 1% for placebo).

Overall, the results indicate that Zygel may be effective at lessening some behavioral symptoms in fragile X patients who have full methylation. Based on these findings, Zynerba is planning discussions with the U.S. Food and Drug Aministration (FDA) regarding a regulatory path forward for Zygel.

“The results from CONNECT-FX identified a significant patient population who responded well to Zygel and may provide us with a pathway towards licensure,” said Armando Anido, Zynerba’s chairman and CEO. “We intend to discuss the results of the study with the FDA as soon as possible.”