Dauvilliers, YvesYvesDauvilliersPlazzi, GiuseppeGiuseppePlazziMignot, EmmanuelEmmanuelMignotLammers, Gert JanGert JanLammersDel Río Villegas, RafaelRafaelDel Río VillegasKhatami, RaminRaminKhatamiTaniguchi, MitsutakaMitsutakaTaniguchiAbraham, AnsonAnsonAbrahamHang, YamingYamingHangKadali, HarishaHarishaKadaliLamberton, MartaMartaLambertonSheikh, SarahSarahSheikhStukalin, EllieEllieStukalinNeuwirth, RachelRachelNeuwirthSwick, Todd JTodd JSwickTanaka, ShinichiroShinichiroTanakavon Hehn, ChristianChristianvon Hehnvon Rosenstiel, PhilippPhilippvon RosenstielWang, HaoHaoWangCai, AliceAliceCaiNaylor, MelissaMelissaNaylorOlsson, TinaTinaOlsson2025-06-052025-06-052025-05-15https://boris-portal.unibe.ch/handle/20.500.12422/211724Background Narcolepsy type 1 is a disorder of hypersomnolence caused by a loss of orexin neurons, which results in low orexin levels in the brain.Methods In this phase 2, randomized, placebo-controlled trial, participants with narcolepsy type 1 received once- or twice-daily oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes; normal, ≥20). Secondary end points included the change from baseline to week 8 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, ≤10), the weekly cataplexy rate at week 8, and the occurrence of adverse events.Results A total of 90 participants received oveporexton (0.5 mg twice daily, 23 participants; 2 mg twice daily, 21 participants; 2 mg followed by 5 mg daily, 23 participants; and 7 mg once daily, 23 participants), and 22 received placebo. The mean changes from baseline to week 8 in average sleep latency on the MWT were 12.5, 23.5, 25.4, 15.0, and -1.2 minutes, respectively (adjusted P≤0.001 for all comparisons vs. placebo). The mean changes in the ESS total score at week 8 were -8.9, -13.8, -12.8, -11.3, and -2.5, respectively (adjusted P≤0.004 for all comparisons vs. placebo). The weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, 5.89, and 8.76, respectively (adjusted P<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo). The most common adverse events associated with oveporexton were insomnia (in 48% of the participants; most cases resolved within 1 week), urinary urgency (in 33%), and urinary frequency (in 32%), without any hepatotoxic effects.Conclusions In this phase 2 trial involving participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks. (Funded by Takeda Development Center Americas; TAK-861-2001 ClinicalTrials.gov number, NCT05687903.).enarticle10.48620/883774036737410.1056/NEJMoa2405847