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Samelisant Shows Potential as a Treatment for Excessive Daytime Sleepiness in Parkinson Disease
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Preclinical findings show the potential of samelisant, a potent and orally active Histamine H3 receptor inverse agonist, as a potential treatment for patients with Parkinson disease who experience excessive daytime sleepiness.
Ramakrishna Nirogi, PhD
Recent findings presented at the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, from the study investigating samelisant (SUVN-G3031; Suven Life Sciences) suggests that the potent and selective histamine 3 receptor inverse agonist may be a potential treatment for patients with Parkinson disease (PD) who experience excessive daytime sleepiness (EDS).1,2
In the preclinical study, hemiparkinsonian animals demonstrated a decrease in wake and an increase in sleep time. Notably, post-samelisant (10 and 30 mg/kg, orally) treatment showed a significant increase in cumulative wake time during the first 3 hours. In comparison, treatment with quinpirole showed a decrease in wake and an increase in sleep time in hemiparkinsonian rats. Also, samelisant in the quinpirole-treated hemiparkinsonian rats showed a dose–dependent increase in wake with a decrease in rapid eye movement (REM) and non-REM sleep periods.
"Samelisant exhibited desired pharmacokinetic properties and favorable brain penetration in rodents. Preclinical studies demonstrated samelisant produced wake promoting and anticataplectic effects in orexin knockout mice," lead author Ramakrishna Nirogi, PhD, the vice president of Suven Life Sciences, and colleagues wrote.1 "Additionally samelisant modulated neurotransmitters like histamine in brain indicating neurochemical basis for wake promoting effects. EDS estimated to affect 20% to 50% of patients with PD. Although nontreated PD patients exhibit EDS and sleep attacks, it is often associated with use of dopamine (DA) agonists, especially the recent nonergot DA D2/3 agonists."
Male Wistar rats were induced with hemiparkinsonism by injection of 6-OHDA (12 µg/4 µL) unilaterally into the medial forebrain bundle. There was also a telemetric device implanted to monitor electroencephalography (EEG) and electromyography (EMG) activity in the rats. Prior to the initiation of the EEG recordings, the animals were allowed to recover for 3 weeks.
Before the administration of samelisant, the basal EEG was recorded for 1 hour and then post-treatment EEG acquisition was recorded for 6 hours. Following a washout period of 1 week, the animals received the quinpirole (30 µg/kg, intraperitoneal injection) after samelisant treatment where EEG acquisition was continued for 6 hours. The recordings of the EEG were processed for the different sleep stages using NeuroScore and sleep sign software (DSI, MN, USA).
Based on phase 1 study results, samelisant demonstrated wake-promoting activity in orexin knockout mice, an animal model of narcolepsy, and also showed a similar trend in healthy human subjects.1 For more context, samelisant has successfully completed preclinical in vitro and in vivo efficacy studies under the US investigational new drug application (IND), which supports the neurochemical studies, pharmacokinetic studies, safety studies, and phase 1 clinical studies.
Currently, a phase 2 double-blind, placebo-controlled, parallel-group, multicenter study(NCT04072380) is evaluating the safety, tolerability, pharmacokinetics, and efficacy of 2-mg and 4-mg samelisant compared with placebo in patients with narcolepsy both with and without cataplexy for EDS.2 Approximately 190 adult patients from 58 clinical trial sites across the United States and Canada were randomly assigned on a ratio of 1:1:1 to 2-mg samelisant, 4-mg samelisant, or placebo. The end points are the change from baseline in the mean Maintenance of Wakefulness Test score and in the mean total Epworth Sleepiness Scale score at day 14. Readout for the study is anticipated to come in August 2023, as the study has completed its enrollment.
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