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 serotonin 5-HT _1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy.
Methods: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront 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 daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy.
Registration: ClinicalTrials.gov identifier: NCT05015673.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steven T. Szabo, Seth C. Hopkins, Robert Lew, Antony Loebel, and Kenneth S. Koblan are employees of Sunovion Pharmaceuticals.Thomas Roth is a consultant for Jazz Pharmaceuticals, Takeda Pharmaceutical Co. Ltd., Merck & Co., Inc., and Avadel Pharmaceuticals.
(Copyright © 2023. Published by Elsevier B.V.)