AUTHOR=Budimirovic Dejan B. , Dominick Kelli C. , Gabis Lidia V. , Adams Maxwell , Adera Mathews , Huang Linda , Ventola Pamela , Tartaglia Nicole R. , Berry-Kravis Elizabeth 

TITLE=Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.757825

DOI=10.3389/fphar.2021.757825

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a &gt;200-trinucleotide repeat expansion in the 5’ untranslated region of the fragile X mental retardation 1 (<italic>FMR1</italic>) 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 (GABA<sub>A</sub>) receptor <italic>δ</italic> subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a <italic>δ</italic>-subunit–selective, extrasynaptic GABA<sub>A</sub> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> 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 (<italic>n</italic> = 8), 5 mg BID (<italic>n</italic> = 8), or 5 mg TID (<italic>n</italic> = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (<italic>n</italic> = 4), headache (<italic>n</italic> = 3), diarrhea (<italic>n</italic> = 2), and irritability (<italic>n</italic> = 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.</p><p><bold>Conclusions:</bold> 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.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="http://www.ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.ClinicalTrials.gov</ext-link>, identifier: NCT03697161</p>