Cannabidiol Transdermal Gel for the Treatment of Fragile X Syndrome: Post hoc Responder Analysis and Pattern of Efficacy on domains of the Aberrant Behavior Checklist-FXS (ABC-CFXS)

Objective: This study evaluated the pattern of clinical efficacy of open-label ZYN002, experimental cannabidiol (CBD) transdermal gel, in the treatment of Fragile X Syndrome (FXS). Background: FXS is a neurodevelopmental condition characterized by repeat expansion in the FMR1 gene on the X chromosome. Previously, we documented open-label treatment with ZYN002 was well-tolerated and associated with improvement in behavioral symptoms and anxiety in patients with FXS. An improvement of at least 25% in individual domains of the Aberrant Behavior Checklist-FXS (ABC-CFXS) has been established as an important criterion in defining positive responder status in contemporary studies in FXS. The pattern of response to ZYN002 across multiple ABC-CFXS domains may help to predict its possible future clinical utility. Design/Methods: This 12-week, phase 2, open-label study assessed ZYN002 in participants aged 6–7 years, with full FMR1 mutation, who showed suboptimal clinical response to standard of care. We explored efficacy by assessing change on all ABC-CFXS domains (social avoidance, irritability, socially unresponsive/lethargic, hyperactivity, stereotypy, inappropriate speech), creating responder analyses and “radar charts” to visualize change in each ABC-CFXS domain. Results: Of the 20 enrolled participants, 18 completed the study. Maximal 25% responder rates on all domains of ABC-CFXS on any visit ranged from 77.8 – 83%. Maximal 50% responder rates on all domains of ABC-CFXS on any visit ranged from 55.6 – 77.8%. Baseline to endpoint “radar charts” showing all ABC-CFXS domains, with each domain independently represented its own normalized single axis, provided visual evidence of meaningful change Conclusions: The majority of FXS patients treated with open-label ZYN002 met an important criterion for response on the ABC-CFXS. Simultaneous visualization of change across all measured domains of the ABC-CFXS (“radar charts”) provided evidence of more global, multi-domain reduction in behavioral symptom burden, and may provide evidence to support the efficacy of ZYN002 CBD transdermal gel in FXS. Disclosure: Dr. Palumbo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zynerba Pharmaceuticals. Dr. Du has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zynerba Pharmaceuticals. Dr. Heussler has received research support from Zynerba Pharmaceuticals. Dr. Silove has received research support from Zynerba Pharmaceuticals. Dr. Cohen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zynerba Pharmaceuticals. Dr. Cohen has received research support from Zynerba Pharmaceuticals.