Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study

Abstract

Purpose: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS).; Method: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range.; Results: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study.; Conclusions: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants.; Clinicaltrials: GOV: NCT04106557.; Competing Interests: Declaration of competing interest Christopher Keary: has received compensation from Ovid Therapeutics and Biogen for consulting and research funding from Ovid Therapeutics. Lynne Bird: has received compensation from Ovid Therapeutics, F. Hoffman-LaRoche, Biogen and Ionis for consulting, and research funding from Ovid Therapeutics, F. Hoffman-LaRoche, Biogen and Ionis. Marie-Claire de Wit: has received compensation from Roche, Ionis, GW Pharma for scientific advice committees (all compensation paid to the University Hospital). Shivkumar Hatti: has received compensation from Ovid for scientific advisory board meetings. Gali Heimer: has received compensation from Ovid Therapeutics and Biogen-Ionis for participation in advisory boards. Helen Heussler: had received compensation for conducting research from Ovid therapeutics, Zynerba Pharmaceuticals, GW pharma and Axial Biotherapeutics, and for participation in advisory boards from Zynerba Pharmaceuticals and Axial Biotherapeutics (all paid to the Centre for Clinical Trials in Rare Neurodevelopmental Disorders, Queensland Children's Hospital, Brisbane, Queensland, Australia). Alexander Kolevzon: has received compensation from Ovid Therapeutics, Acadia, Alkermes, Ritrova Therapeutics, Jaguar therapeutics, GW Pharmaceuticals, Neuren Pharmaceuticals, and Scioto Biosciences. Cesar Ochoa-Lubinoff: has received compensation from Ovid Therapeutics for consulting. Wen-Hann Tan: has received research support and/or compensation for consulting from Ovid Therapeutics, F. Hoffman-LaRoche, Biogen, and Ionis. Adera Matthews, Ying Yan, and Maxwell Adams are current or former employees of Ovid Therapeutics and may hold stock or stock options. (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)