0265 Samelisant (SUVN-G3031), a Histamine H3 Receptor Inverse Agonist in Animal Models of Narcolepsy

Abstract

Abstract Introduction Samelisant (SUVN-G3031) is a potent and selective H3 receptor (H3R) inverse agonist with hKi of 8.7 nM. It lacks measurable affinity against 70 other targets which includes GPCRs, ion channels, transporters, enzymes, peptides, steroids, second messengers, growth factors and prostaglandins. Samelisant exhibited desired pharmacokinetic properties and favorable brain penetration in preclinical species. Samelisant blocked R-α-methylhistamine induced dipsogenia in rats and increased tele-methylhistamine levels in brain and cerebrospinal fluid as well. Samelisant is currently being evaluated in a Phase-2 study as monotherapy for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods In brain microdialysis, samelisant was evaluated for its effects on modulation of neurotransmitters like histamine and norepinephrine in prefrontal cortex. In male orexin knockout mice, electroencephalography (EEG), electromyography and activity were monitored using telemetric device. Effects of samelisant on sleep/ wake profile and cataplexy episodes were evaluated during active period of animals. Animals were allowed three weeks of recovery from surgery prior to EEG recording. Results Samelisant significantly increased histamine, dopamine and norepinephrine levels in the prefrontal cortex. Samelisant did not change dopamine levels in the striatal and accumbal. These suggest that samelisant may not have propensity to induce abuse liability. Samelisant produced a significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. It also significantly decreased number of cataplectic episodes in orexin knockout mice. Conclusion The results from non-clinical studies presented here provide a strong evidence for the potential utility of samelisant for the treatment of EDS and cataplexy in patients with narcolepsy. Support (If Any) None