To date, pharmacological treatments in AS have relied on symptomatic strategies mainly unrelated to what is known about the neurobiology of the disorder. Experimental therapeutic trials with a variety of medicines (eg, minocycline; levodopa; pro-methylation dietary supplements) have been more targeted and biologically plausible but have likewise failed despite positive preliminary preclinical data.
Behavioral interventions, speech therapy, physical therapy, and occupational therapy may partially improve related symptoms in some children. Medication management typically focuses on controlling seizures, hyperactivity, and sleep disturbance. Yet, no established interventions exist and best clinical practices address behavior and sleep problems with only limited success.
With advances in genetic technology and improved access to testing, it is likely that more cases of AS will be identified in the future. Given the high unmet need, it is critical to develop novel and more targeted therapeutics to address the global developmental impact of AS. OV101 (gaboxadol) is a highly selective extrasynaptic GABAA receptor agonist which binds to the delta-subunit-containing extrasynaptic GABAA receptors.6 OV101 acts as an orthosteric agonist and restores deficits in tonic inhibition in mouse models of AS.7
Taking a genetics-first approach, Ovid Therapeutics recently completed the first industry-sponsored trial in AS. STARS was a Phase 2, 12-week, placebo-controlled, parallel group study in adolescents and adults with AS. The primary objectives were to evaluate the safety and tolerability of two different doses of OV101 in AS. Exploratory objectives included efficacy assessments on global clinical functioning, motor function, sleep, and behavior.
Results suggest that OV101 was generally safe and well-tolerated with improvement on measures of clinical global improvement, sleep, motor function, and behavior. Based on results from the Phase 2, a Phase 3 multi-site trial to demonstrate the efficacy of OV101 in treating symptoms of AS has been initiated.
• AS is a severe neurodevelopmental disorder that results from UBE3A mutations which cause loss of tonic GABAergic inhibition.
• There are currently no established treatments for AS that target the underlying biology of the condition.
• OV101 is a GABAA receptor agonist that may restore deficits in tonic inhibition and address the pathophysiology of AS.
• STARS was the first industry-sponsored Phase 2 trial in AS which demonstrated that OV101 is generally safe, well tolerated, and associated with global improvement in AS symptoms.
Dr Kolevzon is a child and adolescent psychiatrist and Professor of Psychiatry and Pediatrics at the Icahn School of Medicine at Mount Sinai in New York. He serves as the Director of Child and Adolescent Psychiatry for the Mount Sinai Health System and the Clinical Director of the Seaver Autism Center for Research and Treatment at Mount Sinai.
The author reports that he receives research support from AMO Pharma and acts as a consultant for Ovid Therapeutics; Takeda; Coronis Neurosciences; 5AM Ventures; LabCorp; and Sema4.
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