TY - JOUR
T1 - Gaboxadol in Fragile X Syndrome
T2 - A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study
AU - Budimirovic, Dejan B.
AU - Dominick, Kelli C.
AU - Gabis, Lidia V.
AU - Adams, Maxwell
AU - Adera, Mathews
AU - Huang, Linda
AU - Ventola, Pamela
AU - Tartaglia, Nicole R.
AU - Berry-Kravis, Elizabeth
N1 - Funding Information:
The authors wish to thank Jeannie Visootsak for her contributions to the study design, Ying Yan for undertaking the statistical analyses, and the ROCKET Study Sites at Children’s Hospital Colorado, Cincinnati Children’s Hospital Medical Center, Kennedy Krieger Institute/the Johns Hopkins Medical Institutions, Rush University Medical Center, Southwest Autism Research & Resource Center, Suburban Research Associates, University of California Davis MIND Institute, Vanderbilt University Medical Center, The Chaim Sheba Medical Center. Medical writing support was provided, under the direction of the authors, by Ashfield MedComms, an Ashfield Health company.
Funding Information:
This study was funded by Ovid Therapeutics, Inc. Medical writing and editorial supported was provided by Ashfield MedCo.
Publisher Copyright:
© Copyright © 2021 Budimirovic, Dominick, Gabis, Adams, Adera, Huang, Ventola, Tartaglia and Berry-Kravis.
PY - 2021/10/8
Y1 - 2021/10/8
N2 - 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.
AB - 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.
KW - FMR1
KW - GABA
KW - OV101
KW - efficacy
KW - fragile X syndrome
KW - gaboxadol
KW - randomized study
KW - safety
UR - http://www.scopus.com/inward/record.url?scp=85117781424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117781424&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.757825
DO - 10.3389/fphar.2021.757825
M3 - Article
C2 - 34690787
AN - SCOPUS:85117781424
SN - 1663-9812
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 757825
ER -