To describe the study design of the pivotal Phase 3 NEPTUNE trial of gaboxadol (OV101) in Angelman syndrome (AS).

AS is a rare, genetic, neurodevelopmental condition caused by disruption of the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene and associated with increased uptake of GABA and reduced tonic inhibition. The clinical presentation of AS is heterogenous, and individuals may have motor, sleep, communication, and cognitive impairments, along with severe behavioral disturbances. Current therapies address symptoms but do not target the underlying mechanism affecting neuronal function.

Gaboxadol is a highly selective orthosteric agonist that activates the δ-containing subunit of extrasynaptic GABA_A receptors, potentially normalizing tonic inhibition. In the Phase 2 STARS trial, gaboxadol was demonstrated to be generally safe and well-tolerated with a significant effect on the Clinical Global Impressions-Improvement (CGI-I) efficacy outcome measure.

The pivotal Phase 3 NEPTUNE trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of gaboxadol in pediatric participants with AS (age, 4-14 years), after 12 weeks of treatment. The primary outcome measure will be the CGI-I-Angelman syndrome (CGI-I-AS), which is a clinical rating scale that detects the patient’s change in AS symptoms (improvement/worsening) after the initiation of treatment. Secondary measures will evaluate motor function, behavior, communication, and sleep, and include CGI-Severity-AS, Vineland Adaptive Behavior Scales 3rd Edition, actigraphy, and sleep diary. Furthermore, safety alone will be assessed in subjects 2-3 years old. 

The trial is ongoing and anticipated to be completed in 2H 2020.