0737 Efficacy and Safety of Oveporexton (TAK-861), an Oral Orexin Receptor 2 Agonist, for Narcolepsy Type 1 Treatment: A Pooled Analysis of Phase 3 Studies

Abstract Introduction Narcolepsy type 1 (NT1) is caused by a loss of orexin producing neurons in the hypothalamus. We report a pooled analysis of two randomized, double-blind, phase 3 studies (The First Light: NCT06470828; The Radiant Light: NCT06505031) that evaluated efficacy and safety of oveporexton (TAK-861), an oral orexin receptor 2-selective agonist. Methods Participants were 16–70 years with an International Classification of Sleep Disorders, Third Edition (ICSD-3) or ICSD-3-text revision diagnosis of NT1 supported by sleep tests or orexin cerebrospinal fluid concentrations ≤110 pg/mL; Epworth Sleepiness Scale (ESS) score ≥11; ≥4 partial/complete episodes of cataplexy/week. Participants were randomized to oveporexton 1mg (The First Light only), 2mg, or placebo, twice daily (3 hours apart) for 12 weeks, then either entered a long-term extension study or 4 weeks of follow-up. Primary endpoint: change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) at week 12. Secondary endpoints: change from baseline in ESS score at week 12, weekly cataplexy rate (WCR) at week 12, and treatment-emergent adverse events (TEAE). Results Overall, 273 participants (54.2% female) were randomized to oveporexton 1mg/1mg (n=61), 2mg/2mg (n=136), or placebo (n=76). Mean baseline age was 31.1 years, ESS score was 18.1, MWT mean sleep latency was 4.8 minutes and median baseline WCR was 26.0 attacks. At week 12, the least square mean differences from placebo (95% CI) for change from baseline in MWT mean sleep latency were 15.90 (12.65, 19.15) minutes (1mg/1mg oveporexton) and 19.16 (16.65, 21.68) minutes (2mg/2mg; both nominal P< 0.001), and in ESS total score −8.27 (−9.82, −6.73; 1mg/1mg) and −9.71 (−10.92, −8.50; 2mg/2mg; both nominal P< 0.001). Oveporexton decreased WCR at week 12 (incidence rate ratio [95% CI] vs placebo: 1mg/1mg, 0.28 [0.19,0.41], 2mg/2mg, 0.32 [0.23,0.45]; both nominal P< 0.001). The most common TEAEs with oveporexton were pollakiuria and insomnia; 6 participants (1mg/1mg oveporexton n=3; 2mg/2mg n=2; placebo n=1) had TEAEs leading to study drug discontinuation. 258 participants completed study treatment and 250 continued into the long-term extension. Conclusion In this pooled analysis, oveporexton treatment improved measures of wakefulness, sleepiness, and cataplexy frequency and was generally well tolerated. Support (if any) Funding by Takeda Development Center Americas, Inc.