A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy

Background: Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and sero-tonin 5-HT1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy vol-unteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cat-aplexy and alertness in subjects with narcolepsy-cataplexy.Methods: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulo-taront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment). Results: Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group.Conclusions: Acute and sustained treatment with ulotaront reduced nighttime REM duration and day-time SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a sta-tistical or clinically meaningful effect in narcolepsy-cataplexy. Registration: ClinicalTrials.gov identifier: NCT05015673.(c) 2023 Published by Elsevier B.V.