Abstract
Objective: To assess safety and tolerability of a single dose of ERX-963 (IV flumazenil) vs placebo in myotonic dystrophy type 1 (DM1) individuals with daytime sleepiness.
Background: DM1 is a polynucleotide repeat disorder with multisystemic and central nervous system manifestations. CNS manifestations include daytime sleepiness and fatigue. It has been proposed that the dysregulation of the GABA-A neurotransmitter system or increased prevalence of GABA-A receptor subunits could play a role in CNS sleepiness and fatigue. Flumazenil, a selective benzodiazepine binding site antagonist has been reported to be effective for the therapy of idiopathic hypersomnia (IH) (Trotti-2016). Open-label treatment of IH patients using flumazenil administered by various delivery routes showed sustained clinical benefit in 39% of IH patients.
Design/Methods: 12 participants with adult onset DM1, excessive daytime sleepiness (Epworth scale > 11 or sleep duration < 10 hr day) and if present, optimally treated mod/severe sleep apnea, were enrolled. Cohort 1 (n=7) was randomly assigned to 1 mg ERX-963 vs placebo at visit 1 and the crossover treatment at visit 2; Cohort 2 (n=5) was randomized to 2 mg ERX-963 vs placebo. Outcome measures include: pharmacokinetic sampling, Stanford Sleepiness Scale (SSS), Psychomotor Vigilance Test (PVT) and one-back working memory test performed at baseline and every 30 min over 3 hr, continuous EEG, and Patient and Clinician Global Impression of Improvement (PGI-I, CGI-I).
Results: Both 1 mg and 2 mg doses of ERX-963 were safe and well tolerated. There was no significant difference between ERX-963 and placebo at any of the post-dose time points in SSS or PVT, nor in PGI-I or CGI-I.
Conclusions: While ERX-963 at 1 mg and 2 mg was safe, there was no evidence of efficacy in measures of sleepiness or vigilance with this dose and administration regimen.
Disclosure: Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Expansion Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viking Therapeutics. Dr. Sampson has received research support from Marigold Foundation. Eric Wang has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Expansion Therapeutics. Eric Wang has received stock or an ownership interest from Expansion Therapeutics. The institution of Eric Wang has received research support from Expansion Therapeutics. Eric Wang has received intellectual property interests from a discovery or technology relating to health care. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia Therapeutics. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapy. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Muscular Dystrophy Association. The institution of Dr. Day has received research support from Audentes. The institution of Dr. Day has received research support from Novartis Gene Therapy. The institution of Dr. Day has received research support from Biogen. The institution of Dr. Day has received research support from Cytokinetics. The institution of Dr. Day has received research support from Roche/Genentech. The institution of Dr. Day has received research support from Sanofi/Genzyme. The institution of Dr. Day has received research support from Sarepta. The institution of Dr. Day has received research support from Scholar Rock. Dr. Day has received intellectual property interests from a discovery or technology relating to health care. Dr. Gutmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Gutmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. The institution of Dr. Gutmann has received research support from NIH. The institution of Dr. Gutmann has received research support from CMTA. Dr. Gutmann has received publishing royalties from a publication relating to health care. Edward Mezerhane has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceuticals. Edward Mezerhane has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony Biosciences . Edward Mezerhane has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Edward Mezerhane has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Harmony Biosciences. Anita Seto has received personal compensation for serving as an employee of Expansion Therapeutics. Anita Seto has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for miRagen Therapeutics. Anita Seto has received stock or an ownership interest from Expansion Therapeutics. Elliot Ehrich has nothing to disclose.
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