An open-label study of the efficacy, safety and tolerability of oral BTD-001 in adults with idiopathic hypersomnia or narcolepsy type 2

Introduction: Recent research suggests that an endogenous agent in the central nervous system of idiopathic hypersomnia (IH) and narcolepsy type-2 (Na-2) patients acts as a GABA agonist and may be a key driver of debilitation. We assessed the efficacy and safety of BTD-001, a GABAA receptor (GABAAR) antagonist in IH and Na-2 in a pilot clinical study. Materials and methods: This study enrolled 3 IH and 2 Na-2 patientseone male and four femalesewhose excessive daytime sleepiness had been: 1) refractory to treatment with conventional wake promoting agents; as well as 2) responsive to previous therapies (clarithromycin (N=4) or flumazenil (N=2)) intended to antagonize GABAARs into an open label study consisting of three phases. The first was a 7-day washout phase beginning with discontinuation of treatment for IH or Na-2 (GABA antagonist and any concomitant stimulant or wakefulness-promoting agent). This was followed by a 14-day BTD-001 dose escalation phase with low dose BID for 7 days then high dose BID for 7 days. The third phase consisted of a 7-day washout beginning upon discontinuation of BTD-001. The primary exploratory measure was change on the Epworth Sleepiness Scale (ESS). Other secondary measures included Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), Short Form Health Survey (SF-36) and Multidimensional Fatigue Inventory (MFI). Results: BTD-001 treatment resulted in improvements compared to no treatment in all subjects as reported on the ESS, FOSQ, and SF-36. The Investigator rated all 5 subjects to be improved versus no therapy on both low and high dose BID BTD-001. Median improvement on ESS was 11 points for high dose BID BTD-001 compared to no treatment. One Na-2 subject reported complete relief of symptoms based on ESS while treated with high dose BTD-001. All subjects reported improvement on the FOSQ, SF-36 and MFI. Three of the five subjects reported better outcomes on FOSQ, SF-36 Composite Score 9 (Physical) and MFI and 4 out of 5 on the SF-36 Composite Score 10 (Mental) while receiving high dose BTD-001 as compared to their other GABA antagonist therapy. For the FOSQ, the most consistent benefit was in the domain of vigilance, though individuals reported increases in activity, general productivity, social outcomes and intimate relationships. For the SF-36 the most consistent benefits were on vitality and role limitations due to physical health. BTD-001 at low and high doses twice daily was well tolerated by all 5 subjects. Conclusions: The findings support further investigation of BTD-001 as a potential therapeutic for IH and Na-2.