Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist, as a potential treatment for narcolepsy: a phase-2 drug evaluation

INTRODUCTION: Narcolepsy is a debilitating chronic neurological disorder, and currently, there is no cure. Activation of the histaminergic system through the blockade of histamine 3 (H3) autoreceptors promotes wakefulness. Blockade of H3 heteroreceptors modulates adrenergic, serotonergic, cholinergic, and dopaminergic systems. These properties of H3 receptors may offer therapeutic options for managing the symptoms of narcolepsy. Samelisant is an investigational H3 receptor inverse agonist/antagonist being developed for the treatment of hypersomnia disorders. AREAS COVERED: This review includes an evaluation of the nonclinical and clinical profiles of samelisant. EXPERT OPINION: Samelisant's inverse agonism property at the H3 receptor may be ideal for addressing challenges associated with the constitutive activity. A key distinguishing feature of samelisant is its cleaner drug-drug interaction and cardiovascular safety profile compared to existing treatments. This is particularly important for women of childbearing potential, considering the known interactions of current treatments (e.g. pitolisant and modafinil) with hormonal contraceptives, as well as the common occurrence of polypharmacy and comorbidities in narcolepsy. Additionally, as samelisant may act downstream of orexinergic pathways, it presents an opportunity to complement orexin-based therapies. The potential of samelisant in combination with other narcolepsy treatments represents an important area for future research.