Phase III CONNECT-FX study of Zygel in Fragile X Syndrome published in Journal of Neurodevelopmental Disorders

The paper titled, “A Randomized, Controlled Trial of ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents with Fragile X Syndrome (CONNECT-FX),” details how Zygel was well tolerated in patients with FXS and demonstrated efficacy with a favorable benefit risk profile in patients with at least 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. The article can be accessed online at the Journal of Neurodevelopmental Disorders at https://rdcu.be/c0sKz.

CONNECT-FX was a randomized, double-blind, multinational, 14-week study to evaluate the efficacy and safety of Zygel in children and adolescents aged 3 to 17 years. A total of 212 patients were randomized to 12 weeks of Zygel (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The trial was conducted at 21 investigational centers in the U.S., Australia and New Zealand. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) SA subscale in the full cohort of patients with full mutation FXS, regardless of the FMR1 gene methylation status. Ad hoc analyses assessed efficacy in patients with greater than 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.

Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with at least 90% methylation of FMR1 (nominal p=0.020), representing 80% of the overall study population. This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and Isolation, Irritable and Disruptive Behaviors, and Social Interactions (nominal p-values: p=0.038, p=0.028, and p=0.002, respectively). Similar results were seen in patients with 100% methylation of FMR1, representing 65% of the study population. Zygel was generally well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (Zygel: 6.4%; placebo: 1.0%).

See: "A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)." Elizabeth Berry-Kravis et al. Journal of Neurodevelopmental Disorders (2022) 14:56 https://doi.org/10.1186/s11689?022?09466?6