Abstract Rationale Narcolepsy type 1 (NT1) is a rare, chronic neurological disorder caused by loss of orexin-producing neurons in the hypothalamus, resulting in excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, and hallucinations. We report findings from a phase 3 study of oveporexton (TAK-861), an investigational orexin receptor 2-selective agonist, in individuals with NT1. Methods The Radiant Light (TAK-861-3002; NCT06505031) was a double-blind, placebo-controlled, phase 3 trial where participants were randomized 2:1 to receive oral oveporexton 2 mg or placebo twice daily ≥3 hours apart for 12 weeks. Inclusion criteria included: age 16-70 years; International Classification of Sleep Disorders, Third Edition (ICSD-3), or ICSD-3-text revision diagnosis of NT1 supported by polysomnography, multiple sleep latency testing, or cerebrospinal fluid orexin ≤110 pg/mL; Epworth Sleepiness Scale (ESS) score of ≥ 11; and ≥4 partial/complete episodes of cataplexy/week. Primary endpoint was change from baseline (CFB) in mean sleep latency on Maintenance of Wakefulness Test (MWT) at week 12. Secondary endpoints: CFB in ESS total score at week 12, weekly cataplexy rate (WCR) at week 12, Narcolepsy Severity Scale for Clinical Trials (NSS-CT), 36-item Short-Form survey (SF-36) Mental (MCS) and Physical Component Summary (PCS) scores, and occurrence of treatment-emergent adverse events (TEAEs). Results Seventy participants were randomized to oveporexton 2mg/2mg and 35 to placebo. At baseline, mean age was 30.7 years; MWT mean sleep latency was 4.5 minutes and ESS total score, 17.5; median WCR was 23.5 and mean NSS-CT total score, 31.1. Mean baseline SF-36 scores were: MCS, 38.3–38.9; PCS, 48.8–50.5. At week 12, oveporexton significantly increased MWT mean sleep latency versus placebo: least-squares (LS) mean difference 95% CI, 20.09 16.57, 23.61 minutes, P0.001. Significant improvements versus placebo were observed in ESS total score (LS mean CFB 95% CI: −9.53 −11.10, −7.97, P0.001), WCR (incidence rate ratio 95% CI: 0.25 0.15, 0.42, P0.001), NSS-CT total score (LS mean CFB 95% CI: −18.11 −21.25, −14.96, P0.001), and SF-36 component summary scores (LS mean CFB: MCS, 9.32, P0.001; PCS, 5.01, P0.001). Sixty (85.7%) participants on oveporexton experienced TEAEs versus 15 (42.9%) on placebo; no serious TEAEs occurred. Most TEAEs with oveporexton were urinary frequency (43 61.4%), insomnia (40 57.1%), and urinary urgency (10 14.3%). Overall, 101 (96.2%) completed study treatment, of which 100 (99.0%) enrolled in the long-term extension. Conclusions Oveporexton treatment resulted in clinically meaningful and significant improvements in excessive daytime sleepiness, cataplexy frequency, and disease severity compared to placebo, and was generally well tolerated. This abstract is funded by: Takeda Development Center Americas, Inc.
Bogan et al. (Fri,) studied this question.