1171 Study Design and Rationale for a Phase-2 Study of Samelisant (SUVN-G3031) for the Treatment of Cataplexy in Patients with Type 1 Narcolepsy

Abstract Introduction Samelisant (SUVN-G3031) is a potent and selective histamine-3 receptor inverse agonist designed to modulate the histaminergic system, a key regulator of the brain’s sleep–wake cycle. Preclinical studies in narcolepsy-relevant animal models have shown that Samelisant produces significant anticataplectic and wake-promoting effects, supporting its potential as a therapeutic option for Type 1 narcolepsy (NT1). Methods Samelisant was evaluated in orexin-knockout mice and orexin-B saporin (SAP) –lesioned rats to assess its effects on cataplexy and sleep–wake regulation using electroencephalography (EEG). In orexin-knockout mice, Samelisant significantly reduced cataplexy-like episodes, and in orexin-B SAP–lesioned rats, it produced a significant decrease in direct wake-to-REM sleep (DREM) episodes. Based on these nonclinical findings, a Phase-2 proof-of-concept study is being planned to investigate Samelisant for the treatment of cataplexy in patients with NT1. Results This proposed study is a randomized, double-blind, placebo-controlled, parallel-group study will enroll approximately 129 patients with a confirmed diagnosis of Type 1 narcolepsy (NT1) according to ICSD-3-TR or DSM-5-TR criteria. Following a 4-week prescreening period, eligible participants will undergo a 3-week dose-titration phase, followed by 5 weeks of stable-dose treatment and 2-week follow-up period. The primary endpoint is the change from baseline in weekly cataplexy rate at Day 57. Secondary endpoints include changes from baseline in Clinical Global Impression–Severity (CGI-S), Epworth Sleepiness Scale (ESS) scores and evaluation of safety and tolerability. Exploratory endpoints include changes from baseline in Clinical Global Impression–Change (CGI-C), Patient Global Impression–Change (PGI-C), Narcolepsy Severity Scale (NSS), the EQ-5D-5L score and Sustained Attention to Response (SART) scores at Day 57. Conclusion Findings from animal models indicate that Samelisant may exert meaningful anticataplectic effects. The results of the planned Phase-2 study will inform the therapeutic potential of Samelisant for the treatment of cataplexy in patients with NT1. Support (if any)