A pivotal study of zyn002 cannabidiol 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 randomised, doubleblind, placebo-controlled study to evaluate efficacy and safety of ZYN002 in patients 3-17 years with full mutation fragile X syndrome (FXS). Silencing of the FMR1 gene is now believed to require complete or near-complete methylation of the gene. Patients without silencing of the gene or significant mosaicism may represent a different population with higher levels of FMRP and perhaps mRNA. Methods: Patients were randomised 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, laboratories and electrocardiograms. Results: Two hundred twelve patients were randomised. 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, were not significant in the overall group. 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 = 0.031) and Irritability (OR 2.17, P = 0.036). 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 nor other relevant abnormalities occurred. Conclusion: ZYN002 was well tolerated and demonstrated significant improvement in behavioural symptoms of FXS in patients with ≥90% methylation of the FMR1 gene, representing a biological population within FXS most likely to have silencing of the FMR1 gene.L6358489792021-09-03 <br />