Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1.

BACKGROUND 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.).