A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

Abstract

Background Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. Design CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. Methods Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. Results A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). 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). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). Conclusions In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. Trial registration The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

Effects of AFQ056 on language learning in fragile X syndrome

“…As is the case for many drugs acting on the central nervous system, there may be subpopulations of individuals with FXS that are drug responders, as predicted by FMR1 mutation type, FMRP levels, electrophysiological parameters, or other biomarker responses, given that these parameters can predict clinical phenotype ( 42 ). There are precedents for subgroup responses in other trials ( 43 ) based on mutation type, and further analyses to evaluate these types of responses will be forthcoming.…”

A holistic approach to fragile X syndrome integrated guidance for person‐centred care

“…One study of sertraline, an SSRI often used for anxiety, was found possibly to be helpful in 2–6‐year‐olds with FXS, although the study did not consider anxiety per se (Hess et al, 2016). Cannabidiol is also a potentially promising treatment for anxiety (Berry‐Kravis et al, 2022), although at the present time Phase III trial results are awaited. Broadly speaking though, treatment choices for anxiety are based on evidence from the general population and other populations with intellectual disability/autism.…”

“…promising treatment for anxiety(Berry-Kravis et al, 2022), although at the present time Phase III trial results are awaited. Broadly speaking though, treatment choices for anxiety are based on evidence from the general population and other populations with intellectual disability/autism.…”

Medicinal Cannabis for Paediatric Developmental, Behavioural and Mental Health Disorders

“…However, pre-planned analyses were conducted in patients with at least 90% methylation of the FMR1 gene, associated with the most severe phenotype. In this subgroup, statistically significant improvements in social avoidance were seen in the CBD group relative to the placebo, and similarly in the caregivers’ global impression of change ratings [ 45 ]. Treatment-emergent adverse events were all considered mild or moderate, most commonly application site pain.…”