0746 Acute Effects on Sleep Parameters Following Single Doses of E2086 in Patients with Narcolepsy Type 1

Abstract Introduction Sleep architecture is abnormal in narcolepsy, a disorder associated with daytime sleepiness, nocturnal sleep disruption, and profound impacts on REM sleep. We evaluated the effects of an orexin-receptor agonist (new class of potential narcolepsy treatments) on sleep architecture. Methods E2086-A001-101, a multicenter, randomized, double-blind, double-dummy, single-dose, 5-period crossover study, evaluated 3 doses of E2086 (5mg, 10mg, 25mg) compared with placebo (PBO) and modafinil 200mg (not reported here) in adults with verified narcolepsy type 1. Participants received study drug within an hour of waketime and underwent a nocturnal polysomnogram (approximately 12 hours post-dose). Sleep stages were scored according to standard criteria. To compare the doses of E2086 with PBO, a mixed-model analysis was performed with sleep stage parameter as the dependent variable, treatment, period, and sequence treated as fixed effects, and participant treated as a random effect. Two-sided 95% CIs were calculated for the differences of the least squares means of the doses versus PBO. Results Of 22 participants randomized, 19 were completers (ie, received all 5 treatments and had efficacy data). Latency to persistent sleep was significantly longer with 10mg (P=0.0332) and 25mg (P=0.0001) versus PBO. Wake after sleep onset was significantly higher with 25mg (P=0.0005) versus PBO, and sleep efficiency was lower with 10mg (P=0.0031) and 25mg (P< 0.0001) versus PBO. Total sleep time was significantly shorter with 10mg (P=0.0044) and 25mg (P< 0.0001) versus PBO. All doses were associated with significantly longer REM latency versus PBO (5mg P=0.0477; 10mg P< 0.0001; 25mg P< 0.0001) and decreased duration of REM sleep versus PBO (5mg P=0.0002; 10mg P< 0.0001; 25mg P< 0.0001). Total non-REM sleep was not different from PBO except with 25mg (lower; P=0.0004). E2086 was generally well tolerated; most adverse events were mild or moderate in severity. Conclusion These data suggest that E2086 alters REM sleep physiology, a core finding of narcolepsy, in a dose-dependent manner. These findings and reports of insomnia with other orexin-receptor agonists in development suggest the need to develop appropriate dose strengths to minimize any adverse impact on sleep parameters. Support (if any) Eisai Inc.