To evaluate the effect of Samelisant (SUVN-G3031) in behavioral and neurochemical animal models for its potential in the treatment of symptoms of narcolepsy

Samelisant is potent and selective H3R inverse agonist currently being evaluated as monotherapy in a Phase-2 trial for the treatment of narcolepsy with and without cataplexy (NCT04072380).

Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTPγS assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters. Orexin knockout male mice were implanted with telemetric device for simultaneous monitoring of sleep electroencephalography (EEG) and electromyography. Animals were allowed for surgical recovery of 3 weeks prior to EEG recording. Effect of Samelisant at 3 and 10 mg/kg, p.o. was evaluated during active period of animals.

Samelisant is an inverse agonist with equipotent binding affinity at human and rat histamine H3R and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in rat cortex whereas, it did not change dopamine levels in striatum and accumbens suggesting it does not have propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant significantly decreased number of cataplectic episodes in orexin knockout mice.

Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for its potential utility in the treatment of narcolepsy with and without cataplexy.