0051 Samelisant, a H3 Receptor Inverse Agonist for the Potential Treatment of Excessive Daytime Sleepiness in Parkinson’s Disease

Abstract

Abstract Introduction Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor (H3R) inverse agonist with hH3 Ki of 8.7 nM. 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. Additionally samelisant modulated neurotransmitters like histamine in brain indicating neurochemical basis for wake promoting effects. Excessive daytime sleepiness (EDS) estimated to affect 20-50% of patients with Parkinson’s disease (PD). Although non-treated PD patients exhibit EDS and sleep attacks, it is often associated with use of dopamine (DA) agonists, especially the recent non-ergot DA D2/3 agonists. Samelisant is currently being evaluated in a Phase-2 study as monotherapy for the treatment of EDS in patients with narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Hemiparkinsonism was induced in male Wistar rats by injecting 6-OHDA (12 µg/4 µL) unilaterally into the medial forebrain bundle, and telemetric device was implanted to monitor EEG, EMG and activity. Animals were allowed to recover for 3 weeks prior to initiating EEG recordings. Basal EEG was recorded for 1 hour prior to samelisant administration and EEG acquisition was continued for 6 hours post treatment. After a washout period of 1 week, rats were administered with the quinpirole (30 µg/kg, i.p.) followed by samelisant and EEG acquisition was continued for 6 hours. EEG recordings were processed for sleep stages using NeuroScore and sleep sign software (DSI, MN, USA). Results Hemiparkinsonian animals showed decrease in wake and increase in sleep time during dark phase. Treatment with samelisant (10 and 30 mg/kg, p.o.) produced significant increase in cumulative wake period during first 3 hours post treatment. Treatment with quinpirole in hemiparkinsonian rats produced decrease in wake and increase in sleep time. Treatment with samelisant produced dose- dependent increase in wake with decrease in REM and NREM periods in quinpirole treated hemiparkinsonian rats. Conclusion The results from current preclinical studies indicate that samelisant may have a potential utility for the treatment of excessive daytime sleepiness in PD patients. Support (if any)