Oveporexton for Narcolepsy Type 1 — Results from Two Phase 3 Trials

BACKGROUND: Narcolepsy type 1 is characterized by excessive daytime sleepiness, cataplexy, disrupted sleep, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, reduced symptoms of narcolepsy type 1 in a previous phase 2 trial. METHODS: We conducted two phase 3, randomized, placebo-controlled trials evaluating the efficacy and safety of oveporexton over a period of 12 weeks. Participants 16 to 70 years of age with narcolepsy type 1 were randomly assigned in a 3:3:2 ratio to receive twice-daily oveporexton (1 mg or 2 mg) or placebo in the First Light trial and in a 2:1 ratio to receive twice-daily oveporexton (2 mg) or placebo in the Radiant Light trial. The primary end point was the change from baseline to week 12 in mean sleep latency (the ability to stay awake under soporific conditions) on the Maintenance of Wakefulness Test (MWT; range, 0 to 40 minutes; normal, ≥20). Key secondary end points included the change from baseline to week 12 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, <10) and the weekly cataplexy rate at week 12. RESULTS: A total of 168 participants were enrolled in the First Light trial and 105 in the Radiant Light trial. Mean changes from baseline to week 12 in mean sleep latency on the MWT ranged from 14.3 to 19.8 minutes with oveporexton, as compared with -0.4 to -0.8 minutes with placebo (adjusted P<0.001 for all comparisons vs. placebo). Mean changes in the ESS total score ranged from -9.7 to -11.8 with oveporexton, as compared with -1.5 to -1.7 with placebo (adjusted P<0.001 for all comparisons vs. placebo). Median percent reductions in the weekly cataplexy rate ranged from 79.0 to 88.8% with oveporexton, as compared with 27.7 to 39.1% with placebo (adjusted P<0.001 for all comparisons vs. placebo). Adverse events occurred in 86 to 89% of the participants with oveporexton, as compared with 43 to 54% with placebo; the most common adverse events were increased urinary frequency and transient insomnia, which occurred in a majority of participants receiving oveporexton. CONCLUSIONS: Over a period of 12 weeks, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy in participants with narcolepsy type 1. Increased urinary frequency and transient insomnia were common side effects. (Funded by Takeda Development Center Americas; the First Light and Radiant Light ClinicalTrials.gov numbers, NCT06470828 and NCT06505031.).