Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study
- PMID: 34690787
- PMCID: PMC8531725
- DOI: 10.3389/fphar.2021.757825
Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study
Abstract
Background: Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABAA) receptor δ subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a δ-subunit-selective, extrasynaptic GABAA receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS. Methods: This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors. Results: A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (n = 8), 5 mg BID (n = 8), or 5 mg TID (n = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (n = 4), headache (n = 3), diarrhea (n = 2), and irritability (n = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement. Conclusions: Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03697161.
Keywords: FMR1; GABAA; OV101; efficacy; fragile X syndrome; gaboxadol; randomized study; safety.
Copyright © 2021 Budimirovic, Dominick, Gabis, Adams, Adera, Huang, Ventola, Tartaglia and Berry-Kravis.
Conflict of interest statement
Authors MA (4th author), MA (5th author), and LH were employed by the company Ovid Therapeutics, Inc. DB has received research funding from Akili, Alcobra, Forest, Lundbeck, Medgenics, Neuren, Ovid Therapeutics, Inc., Pfizer, Purdue, Roche, Seaside Therapeutics, Shire, Sunovion, Supernus, SyneuRX, and Zynerba Pharmaceuticals. All funds have been directed to the Kennedy Krieger Institute and Johns Hopkins medical institutions. KD has received research funding from the American Academy of Child and Adolescent Psychiatry, Roche, and Ovid Therapeutics Inc. All funds have been directed to Cincinnati Children’s Hospital Medical Center. NT has received research funding from Alcobra, Neuren, Novartis, Ovid Therapeutics, Inc., Roche, Seaside Therapeutics, and Zynerba. All funds have been directed to University of Colorado or CHCO in support of Fragile X and autism programs. EB-K has received research funding from Acadia, Alcobra, Anavex, Asuragen Inc., Biogen, BioMarin, Cydan, Fulcrum, GeneTx, GW, Ionis, Lumos, Marinus, Neuren, Neurotrope, Novartis, Orphazyme, Ovid, Roche, Seaside Therapeutics, Tetra Discovery Partners, Ultragenyx, Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, Yamo, and Zynerba. All funds have been directed to Rush University Medical Center in support of rare disease programs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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