Samelisant is a potent and selective histamine 3 (H₃) receptor inverse agonist. Studies using orexin knockout mice have revealed its impressive wake-promoting and anticataplectic effects, suggesting it could be a promising treatment for narcolepsy.

To evaluate the efficacy and safety of Samelisant for the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy.

Samelisant was assessed in a Phase 2 proof-of-concept (POC) study as a monotherapy targeting EDS in patients with narcolepsy (NCT04072380). Patients diagnosed with narcolepsy as per ICSD-3 criteria with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean Maintenance of Wakefulness Test (MWT) time of <12 min were eligible. A total of 190 patients were randomized into one of three treatment arms (Samelisant 2 mg, Samelisant 4 mg and Placebo) in 1:1:1 ratio. Each subject received either placebo or Samelisant once daily for 2 weeks. The primary efficacy endpoint was a change in ESS score from baseline to Day 14. Secondary endpoints were changes in MWT, Clinical Global Impression – Severity (CGI-S), Patient Global Impression of Change (PGI-C), and Clinical Global Impression of Change (CGI-C) scores from baseline to Day 14.

The study met the prespecified primary endpoint. Samelisant demonstrated a statistically significant reduction in EDS measured by ESS total score when compared to placebo on Day 14 (p<0.024). Improvement observed in the primary endpoint was supported by a statistically significant improvement on the secondary endpoints like CGI-S, PGI-C, and CGI-C. Samelisant was safe and well tolerated.

Samelisant could be a potential new therapy for the management of EDS and cataplexy in patients with narcolepsy.  A Phase-3 study for the treatment of EDS in narcolepsy and a Phase-2 POC study for the treatment of cataplexy in narcolepsy are being planned.