Associate Professor, Department of Neurology University of Minnesota School of Medicine
Rationale: Angelman syndrome (AS), a complex genetic, neurodevelopmental condition with impaired expression of UBE3A that causes reduced tonic inhibition is thought to be mediated by reduced GABAergic tone resulting from accumulation of GAT1. AS commonly presents with epilepsy and EEG abnormalities (~ 84% prevalence), including increased delta and theta rhythmicity. Gaboxadol (OV101) is a highly selective extrasynaptic GABAA receptor agonist that restores deficits in tonic inhibition AS mouse models. STARS study (randomized, double-blinded, placebo-controlled) evaluated safety and tolerability of two dosing gaboxadol regimens and explored changes in EEG findings from baseline (BL) to Week 12 (Wk12). Methods: Eighty-eight subjects (13-49 years) with AS were randomized 1:1:1 to receive gaboxadol QD (placebo morning, 15mg evening); gaboxadol BID (10 mg morning, 15mg evening) or placebo BID. Safety and tolerability endpoints including seizures and EEG at BL and Wk12 were evaluated in 58 patients. Neurophysiological interpretations in the time domain were assessed visually for all EEGs by an American Board of Psychiatry and Neurology certified Neurophysiologist, including presence of increased delta or theta rhythmic activity. EEG spectral power was quantified in the delta (1-4 Hz) and theta (5-7 Hz) bands utilizing frequency analytical methods in a subset of patients. Results: Descriptive statistics were used due to the variability in BL data and absent or indeterminate readings. Visual analysis of the EEG for presence of abnormal delta rhythmicity revealed a differential response across treatment regimens. Specifically, absence of AS-related delta rhythmicity improved between BL and Wk12 in the QD group (from 29.2% to 40.7%), but somewhat worsened in the BID group (from 34.8% to 29.2%) and did not meaningfully change in the placebo group (from 52.2% to 54.2%). Similarly, abnormally excessive AS-related theta rhythmicity (defined as present >50% of the time) also improved in the QD group (decreased from 33% to 18.5%), worsened in the BID group (from 30.4% to 37.5%) and essentially unchanged in the placebo group (13% to 12.5%) from BL to Wk12. Visual EEG analysis findings at BL were further confirmed by quantitative EEG analysis. Differences in spectral power in patient groups divided based on the neurophysiological assessments were significant in delta frequency band (p=0.001) and showed a trend toward significance in the theta band (p=0.076). Only two subjects had seizure (one unrelated and the other possibly treatment related). Conclusions: Improvements in novel EEG markers seen in the both delta and theta frequencies of the QD dosing cohort of gaboxadol expand our understanding of electrophysiological significance of EEG change in AS. Observed changes in these EEG markers are consistent with the differential response in clinical improvement observed in the trial. Furthermore, given the high prevalence of epilepsy in AS, gaboxadol appears to be generally safe and well tolerated. Funding: Please list any funding that was received in support of this abstract.: This study was funded by Ovid Therapeutics Inc.