0735 Effect of the Oral Orexin Receptor 2 Agonist Oveporexton (TAK-861) on Functional Impacts of Narcolepsy Type 1: Results from Two Phase 3 Studies

Abstract Introduction Narcolepsy type 1 (NT1), a central hypersomnolence disorder with deficiency of hypothalamic orexin signaling, affects functioning, quality of life, and work productivity. We evaluated the effect of oveporexton (TAK-861), an orexin receptor 2-selective agonist, on the Functional Impacts of Narcolepsy Instrument (FINI; comprised of 6 independent domains: Tiredness, Cognitive Functioning, Cataplexy, Social Activities, Everyday Activities, and Everyday Responsibilities) in two phase 3 trials in participants with NT1 (The First Light [FL]: NCT06470828 and The Radiant Light [RL]: NCT06505031). Methods Eligible participants were 16–70 years with a confirmed ICSD-3 NT1 diagnosis supported by polysomnography or orexin cerebrospinal fluid ≤110 pg/mL; participants had an Epworth Sleepiness Scale score ≥11 and ≥4 partial/complete cataplexy episodes/week. Participants received twice daily oral oveporexton 1 mg (The First Light only) or 2 mg, or placebo, ≥3 hours apart for 12 weeks. The FINI (secondary endpoint) is scored from 0 (best functioning) to 100 (worst functioning). Results Overall, 273 participants were randomized (FL, n=168; RL, n=105) to oveporexton 1mg/1mg (n=61), oveporexton 2mg/2mg (n=136), or placebo (n=76). Mean ages were 31.4 years (The First Light) and 30.7 years (The Radiant Light); 58.3% (n=98) and 47.6% (n=50) were female, respectively. Significant improvements versus placebo were observed for all FINI domains: Least square (LS) mean changes from baseline to Week 12 versus placebo for oveporexton were clinically meaningful across all FINI domains for both trials across all doses, all p< 0.001. Conclusion In two phase 3 trials, oveporexton consistently showed significant and clinically meaningful improvements in narcolepsy-specific functioning over placebo. Support (if any) Funded by Takeda Development Center Americas, Inc.