Objective: To evaluate safety and tolerability and exploratory efficacy endpoints for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS).

Methods: Gaboxadol is a highly selective orthosteric agonist that activates γ-subunit–containing extrasynaptic γ-aminobutyric acid type A (GABA_A) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd); gaboxadol 10 mg morning dose and 15 mg evening dose (bid); or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy endpoints included adapted Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression–Improvement (CGI-I) scales which documented the clinical severity at baseline and change after treatment, respectively.

Results: Eighty-eight individuals were randomized. Of 87 individuals (aged 13–45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006).

Conclusion: After 12 weeks of treatment, gaboxadol was found to be generally well tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies.