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
Highlights
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder caused by a full-mutation expansion [>200 trinucleotide (CGG) repeats] in the promoter region of the fragile X mental retardation 1 (FMR1) gene
To ensure that the effects of OV101 were evaluated in a patient population with minimal fragile X mental retardation protein (FMRP) expression, females were excluded from the study
Other exclusion criteria included a history of uncontrolled seizure disorder or seizure episodes within 6 months of screening, a change in anticonvulsant pharmacotherapy within 3 months of screening, use of a GABAergic agent on a regular schedule, use of a cannabinoid derivative, a history of suicidal behavior, and any clinically significant medical condition or laboratory finding at screening that could interfere with study conduct/participation or pose an unacceptable risk
Summary
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder caused by a full-mutation expansion [>200 trinucleotide (CGG) repeats] in the promoter region of the fragile X mental retardation 1 (FMR1) gene. With an estimated prevalence of approximately 1 in 4,000 males and 1 in 6,000 females, FXS is the most common single-gene cause of intellectual disability (ID) and autism spectrum disorder (ASD) (Crawford et al, 2001; Tassone et al, 2012). Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200trinucleotide repeat expansion in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene. No drug is approved in the United States for the treatment of FXS
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