Zygel Improves Caregiver Impressions of Behavioral Symptoms in Some Fragile X Children

Zygel Improves Caregiver Impressions of Behavioral Symptoms in Some Fragile X Children
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The experimental cannabidiol (CBD) gel Zygel eased behavioral problems in children with fragile X syndrome and benefited those with greater disease severity according to their caregivers, new clinical trial data show.

The data were presented virtually at the 17th NFXF International Fragile X Conference Research Roundup by Zynerba Pharmaceuticals, which is developing Zygel. The presentation, “Zygel (ZYN002) Development Program in Fragile X Syndrome,” was given July 22, which was National Fragile X Awareness Day.

Zygel was designed to deliver CBD into the bloodstream through the skin after being applied to the upper arm or shoulder. CBD is a compound found in the cannabis plant that is not psychoactive, meaning it does not produce a “high.” CBD is believed to modulate the endocannabinoid system, where abnormalities have been linked with common behavioral abnormalities in fragile X. Among other effects, CBD also may regulate serotonin signaling, which is associated with anxiety.

The investigational therapy was evaluated in the Phase 2/3 clinical trial CONNECT-FX (NCT03614663), which was conducted at 21 clinical sites in the U.S., Australia, and New Zealand. The Zynerba-funded study evaluated 212 children with fragile X. Participants ranged in age from 3 to 17, and about three quarters were boys. They were assigned randomly to receive either Zygel or a placebo every day for 14 weeks.

The trial failed to meet its primary goal, as the Zygel and placebo groups did not differ on the Social Avoidance subscale of the Aberrant Behavior Checklist — Community FXS (ABC-C). Also, no significant differences were seen in key secondary ABC-C subscales assessing irritability and social unresponsiveness.

Fragile X is caused by genetic abnormalities that lead to increased methylation of the FMR1 gene, a biochemical modification that “turns genes off” and leads to no production of the FMRP protein.

Of the CONNECT-FX participants, 169 had at least 90% methylation of the FMR1 gene, which is regarded as full methylation and is associated with greater disease severity. Among this group, top-line results showed significant improvements in the social avoidance subscale with Zygel, compared to placebo.

The new data addressed caregiver perceptions of potential improvements among participants with full methylation.

When they entered the trial, their caregivers completed a survey to describe what they perceived as the patients’ most important behavioral challenges. The most commonly cited challenges were anxiety (66.3%), socially avoidant behaviors such as elopement (22%) and seeking isolation from others (22%), and disruptive behaviors such as aggression (41.9%), and temper tantrums (32.9%).

Caregivers were surveyed again at the end of the 12-week treatment period. They were asked to rate four behaviors — namely social avoidance, problems with social interaction, irritable/disruptive behavior, and overall behavior — on a seven-point scale, ranging from “much worse” to “much better” relative to the start of the study.

The proportion of caregivers who rated improvement — “a little better,” “moderately better,” or “much better” — was significantly higher for participants given Zygel, compared to placebo, for social avoidance (57.2% vs. 39.2%), social interactions (63.1% vs. 36.5%), and irritable/disruptive behaviors (46.4% vs. 28.4%).

Caregivers of patients receiving Zygel also rated improvement for overall behavior higher than those of boys taking the placebo, but the difference was not statistically significant.

Across all four domains, most caregivers who reported improvements said the behaviors were “a little better.”

“We believe that the caregiver data … further support the statistically significant improvement we achieved in the primary endpoint [goal] of social avoidance in patients with full methylation of their FMR1 gene,” Joseph M. Palumbo, MD, Zynerba’s chief medical officer, said in a press release. “We look forward to discussing these and other data with the U.S. Food and Drug Administration as soon as possible regarding a potential regulatory path forward.”

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
Total Posts: 12
José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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