Results of Double-blind, Placebo-controlled, Dose Range Finding, Crossover Study of Single Day Administration of ERX-963 (IV Flumazenil) in Adults with Myotonic Dystrophy Type 1
Jacinda Sampson1, Eric Wang2, John Day3, Laurie Gutmann4, Edward Mezerhane5, Anita Seto6, Elliot Ehrich6
1Department of Neurology, Stanford University, 2Molecular Genetics and Microbiology, University of Florida, 3Department of Neurology, Stanford University School of Medicine, 4Department of Neurology, University of Indiana, 5Sleep Medicine Specialists of South Florida, 6Expansion Therapeutics
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.