A Pivotal Study of ZYN002 Cannabidiol (CBD) Transdermal Gel in Children and Adolescents With Fragile X Syndrome [CONNECT-FX (ZYN2-CL-016)]

Abstract

Background: ZYN002 is a pharmaceutically manufactured transdermal cannabidiol gel. CONNECT-FX was a randomized, double-blind, placebo-controlled study to evaluate efficacy and safety of ZYN002 in patients 3 to 17 years with full FMR1 gene mutation. Methods: Patients were randomized to ZYN002 or placebo for 12 weeks. The primary endpoint was change from baseline in the Aberrant Behavior Checklist–Community FXS Specific (ABC‒CFXS) Social Avoidance subscale. Key secondary endpoints included change from baseline in the ABC‒CFXS Irritability and Socially Unresponsive/Lethargic subscales and Clinical Global Impression, Improvement (CGI-I). A pre-planned ad hoc analysis was conducted in patients with ≥90% methylation of the FMR1 gene. Safety assessments included adverse events, laboratory tests, and electrocardiograms. Results: 212 patients were randomized. Mean age was 9.7 years; 75% were male. Improvements in ABC-CFXS Social Avoidance, Irritability, and Socially Unresponsive/Lethargic scores and the CGI-I, while greater for ZYN002 than placebo, were not significant in the full population. Patients with ≥90% methylation (n=169) showed a significant improvement in ABC-CFXS Social Avoidance (p=0.020) and significantly more patients had a clinically meaningful change in Social Avoidance (OR 2.04, P=.031) and Irritability (OR 2.17, P=.036). ZYN002 was well tolerated. Adverse events were mild to moderate severity; application site pain was the most common treatment-related event (placebo 1%; ZYN002 6.4%). No serious or severe events occurred. No other clinically relevant abnormalities occurred, including liver function. Conclusions: ZYN002 was well tolerated and demonstrated significant improvement in behavioral symptoms of FXS in patients with ≥90% methylation of the FMR1 gene, representing a biologically defined population within FXS. Supported By: Zynerba Pharmaceuticals Keywords: Fragile X syndrome, Cannabidiol, CBD, Social Avoidance, IrritabilityL20115630342021-04-13 <br />