Phase 2 Study to Test Therapeutic Potential of Samelisant for Narcolepsy Type 1

Ramakrishna Nirogi, PhD

Details behind a new phase 2 study testing samelisant (Suven Life Sciences), a potent and selective histamine 3 receptor inverse agonist, in patients with narcolepsy type 1 (NT1) have been unveiled. Presented at the 2025 SLEEP Annual Meeting, held June 8-11, in Seattle, Washington, the placebo-controlled, double-blind, trial will inform the therapeutic utility of the agent as a potential treatment for cataplexy in patients with NT1.¹

Expected to include 129 patients with the disease, the study will comprise a 4-week prescreening period, followed by a titration period lasting 3 weeks, and concluding with a 5-week treatment period. The study, a randomized, parallel-group trial, will use change in weekly cataplexy rate at day 56 as the primary end point, with other secondary end points that include change in Clinical Global Impression Scale-Severity (CGI-S) score and Epworth Sleepiness Scale (ESS) score.

Led by Ramakrishna Nirogi, PhD, vice president of Suven Life Sciences, patients will also be evaluated on a number of exploratory end points, including change in CGI-Change (CGI-C), Patient Global Impression of Change (PGI-C), Narcolepsy Severity Scale (NSS) score, and 5-level EQ-5D version. During the titration period, patients will follow a titration schedule to gradually increase their dose of samelisant before entering the 5-week treatment period.

Data from preclinical findings helped inform the design behind this new study. In preclinical models of orexin knockout mice and orexin-B SAP lesioned rate, the agent produced a significant reduction in cataplectic like episodes. In addition, among orexin-B SAP lesioned rats, the medication showed a significant decrease in direct wake to REM sleep episodes.

Samelisant was also previously tested in a phase 2 proof-of-concept trial (NCT04072), with results presented at this year’s SLEEP meeting. The study, a 190-patient cohort trial, showed that treatment with samelisant resulted in a statistically significant decrease in the primary end point of ESS scores over a 14-dayperiod (P <.024). compared with those on placebo, samelisant-treated patients demonstrated a clinically meaningful reduction of –2.1 points in total score.²

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In addition to meeting its primary end point, samelisant-treated patients also demonstrated improvements in excessive daytime sleepiness on PGI-S and PGI-C scores. Above all, the agent, which works as a selective inverse agonist of histamine 3 receptors, was safe and well tolerated, with no serious adverse events or deaths reported in the trial.

Histamine H₃ receptors are presynaptic autoreceptors found in the brain, especially in regions that regulate arousal, such as the tuberomammillary nucleus. These receptors inhibit the release of histamine and other wake-promoting neurotransmitters (e.g., dopamine, norepinephrine, acetylcholine). Inverse agonists (not just antagonists) reduce the baseline inhibitory activity of H₃ receptors, leading to increased histamine release and heightened wakefulness.

In 2019, the FDA approved pitolisant (Wakix; Harmony Biosciences) as the first H3 receptor inverse agonist indicated for the treatment of narcolepsy. With the decision, it also become the first FDA-approved treatment for both excessive daytime sleepiness and cataplexy in narcolepsy that is not a scheduled controlled substance. Pitolisant’s original approval was based on the HARMONY 1 and HARMONY 1b trials, where treatment with the agent led to statistically significant improvements in excessive daytime sleepiness over a 3-week titration period and a 5-week stable dose phase.^3,4

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REFERENCES
1. Nirogi R, Goyal VK, Ravula J, et al. RATIONALE AND STUDY DESIGN OF SAMELISANT (SUVN-G3031) FOR THE TREATMENT OF CATAPLEXY IN TYPE 1 NARCOLEPSY PATIENTS. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, Washington. ABSTRACT 1285.
2. Nirogi R, Goyal VK, Ravula J, et al. SAMELISANT (SUVN-G3031) ALLEVIATES EXCESSIVE DAYTIME SLEEPINESS IN NARCOLEPSY: RESULTS FROM A PHASE-2 STUDY. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, Washington. Abstract 0845.
3. WAKIX represents the first and only non-scheduled treatment approved for patients with narcolepsy in the U.S. news release. Harmony Biosciences; August 15, 2019. Accessed June 11, 2025. finance.yahoo.com/news/harmony-biosciences-announces-fda-approval-120000845.html. Accessed June 11, 2025.
4. Harmony Biosciences presents 5-year data on pitolisant at international narcolepsy symposium. news release. Harmony Biosciences; September 11, 2018. Accessed June 11, 2025. harmonybiosci&shy;ences.com/newsroom/harmony-biosciences-presents-5-year-data-on-pitolisant-at-international.