Abstract Introduction Narcolepsy is a chronic neurological sleep disorder marked by excessive daytime sleepiness (EDS), sudden sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. Existing therapies often present challenges, including side effects, limited efficacy, and need for complex combination regimens. Samelisant, a selective histamine-3 receptor inverse agonist, is a promising therapeutic option. In diverse animal models, Samelisant promoted wakefulness and reduced cataplexy, supporting its potential benefit in narcolepsy. Samelisant’s safety/tolerability have been established in healthy volunteers. Efficacy and safety of Samelisant was evaluated in narcolepsy patients with moderate to severe EDS. Methods Samelisant was evaluated as monotherapy in a Phase-2, proof-of-concept study conducted in the USA and Canada to assess its efficacy in treating EDS in patients with narcolepsy (NCT04072380). The study enrolled adults aged 18–65 years who met ICSD-3 diagnostic criteria for narcolepsy, had an Epworth Sleepiness Scale (ESS) score ≥12, and a mean Maintenance of Wakefulness Test (MWT) time 12 minutes. A total of 190 patients were randomized in a 1:1:1 ratio to receive placebo, Samelisant 2 mg, or Samelisant 4 mg once daily for 14 days. The primary endpoint was the change in total ESS score from Baseline to Day 14. Secondary and exploratory endpoints included changes in Clinical Global Impression–Severity (CGI-S), MWT, and Patient Global Impression–Change (PGI-C) scores over the same period. The safety and tolerability endpoints included incidence of adverse events, vital signs, electrocardiogram, laboratory and suicidality assessments, and was assessed throughout the study by the medical monitor and an independent data safety monitoring committee. Results The study met its pre-specified primary efficacy endpoint, with Samelisant demonstrating a statistically significant (p 0.024) and clinically meaningful reduction (-2.1 points) in ESS total score compared with placebo at Day 14. Samelisant treatment also produced significant improvements in EDS across clinician- and patient-reported outcome measures. Samelisant was generally safe and well tolerated, with no serious adverse events or deaths reported in narcolepsy patients. Conclusion Samelisant shows promise as a monotherapy for treating EDS in patients with narcolepsy. Building on these positive results, a global Phase-3 study is planned to begin in H1 2026. Support (if any)
Nirogi et al. (2026) studied this question.