0756 Phase-3 Clinical Development of Samelisant: Rationale and Study Design for Treating Excessive Daytime Sleepiness in Patients with Narcolepsy

Abstract Introduction Samelisant is a potent and selective histamine H₃ receptor inverse agonist that modulates the monoaminergic system, implicated in the regulation of sleep–wake cycle. In preclinical models of narcolepsy, Samelisant demonstrated robust wake-promoting and anticataplectic effects. The Phase-3 study is designed to evaluate the efficacy and safety of Samelisant for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy. Methods Samelisant was evaluated in orexin-knockout mice and orexin-B saporin (SAP) lesioned rats to characterize its effects on sleep–wake regulation and cataplexy using electroencephalography. Samelisant was subsequently investigated as monotherapy in a Phase-2 proof-of-concept study (NCT04072380) for the treatment of EDS in narcolepsy patients. Based on the strong preclinical findings and positive results from the Phase-2 study, a Phase-3 clinical study has been designed. Results In orexin-knockout mice, Samelisant significantly increased time spent in wakefulness and reduced cataplexy-like episodes. In orexin-B SAP-lesioned rats, Samelisant produced wake-promoting effects and significantly decreased direct wake-to-REM (DREM) transitions, a characteristic feature of narcolepsy. In the Phase-2 clinical study, Samelisant demonstrated a statistically significant and clinically meaningful improvement in EDS. At Day 14, Samelisant produced a 2.1-point reduction in Epworth Sleepiness Scale (ESS) total score compared with placebo (p< 0.024). Samelisant was generally safe and well tolerated in the study population. The proposed global Phase-3 study will be a randomized, double-blind, placebo-controlled, parallel-group study enrolling approximately 240 patients with a confirmed diagnosis of narcolepsy. Following a 4-week screening period, eligible participants will undergo 12-week treatment and a 4-week follow up period. The primary endpoint will be the change from Baseline in ESS total score at Week 12. Secondary endpoints will include changes from Baseline in Maintenance of Wakefulness Test (MWT) score, CGI-S, weekly rate of cataplexy (WRC) and Narcolepsy Severity Scale (NSS-CT) for NT1 at Week 12. Safety and tolerability will be assessed by adverse event incidence, vital signs, laboratory tests, ECGs, and suicidality. Conclusion The Phase-3 study is expected to begin in the first half of 2026. Outcomes from this study will provide insights into the therapeutic potential of Samelisant for the treatment of EDS in narcolepsy. Support (if any) None