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Abstract Details

Evidence of pharmacodynamic tolerance during repeated daily gaboxadol exposure in individuals with Angelman syndrome
Child Neurology and Developmental Neurology
P13 - Poster Session 13 (5:30 PM-6:30 PM)
5-011

To evaluate the evidence from the Phase 2 STARS trial in patients with Angelman syndrome (AS) for the emergence of pharmacodynamic tolerance with multiple daily doses of gaboxadol (OV101).

Gaboxadol is a highly selective orthosteric agonist that activates the δ-containing subunit of extrasynaptic GABAA receptors. In the STARS trial, gaboxadol once daily (QD; 15 mg at bedtime) was demonstrated to be generally safe and well-tolerated. Significance was observed in the Clinical Global Impression-Improvement (CGI-I]) score after 12 weeks, which appeared to indicate an improvement in overall global function. In contrast, the CGI-I did not reach significance with gaboxadol twice daily (BID; 15 mg at bedtime, 10 mg morning), suggesting the development of pharmacodynamic tolerance.
Changes in the CGI-I and the Clinical Impressions of Nine Domains following gaboxadol QD or BID versus placebo were retrospectively evaluated using a mixed model repeated measures (MMRM) analysis. Sleep actigraphy was evaluated using MMRM in actigraphy-tolerant participants. 
In the Clinical Impressions of Nine Domains, gaboxadol QD demonstrated a significantly improved sleep domain versus placebo (P=0.0141 and BID, P=0.1407, respectively). QD dosing showed a progressive and durable improvement of sleep onset latency (SOL at 12 weeks, -25.7 min, P=0.0147) as assessed by actigraphy, as well as improved sleep efficiency and reduced total day-time sleep. While a transient reduction in SOL occurred within 1 week of BID dosing, this treatment did not significantly improve sleep parameters. 
The observed improvement in global function following QD, but not BID, were paralleled by improvements in sleep. The progressive and sustained QD dosing improvements in SOL contrasted the transient SOL reduction seen with BID dosing. These results support the emergence of pharmacodynamic tolerance with repeated, excessive daily exposure to gaboxadol in AS. Further studies examining extrasynaptic GABAA receptor modulation/desensitization following excessive gaboxadol exposure are warranted.
Authors/Disclosures
Tom Parry
PRESENTER 		Tom Parry has received personal compensation for serving as an employee of Ovid Therapeutics Inc. Tom Parry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingleheim. Tom Parry has received personal compensation in the range of $0-$499 for serving as a Grant Reviewer with NIH.
Amit Rakhit, MD (Ovid Therapeutics) No disclosure on file
No disclosure on file
No disclosure on file