Efficacy and Safety of TAK-861, an Oral Orexin Receptor 2 Agonist, in Individuals With Narcolepsy Type 1: Results From a Phase 2 Study

Introduction: Narcolepsy type 1 (NT1) involves excessive daytime sleepiness and cataplexy associated with low CSF orexin levels. TAK-861, an orexin receptor 2 agonist, showed wake-promoting effects and improvement of cataplexy-like symptoms in previously studied narcolepsy animal models.
Methods: This randomized, double-blind, placebo-controlled, Ph2 study (NCT05687903) evaluated the efficacy and safety of TAK-861 in participants with NT1. Eligible participants were aged 18-70 years (Japan: 16-70) with Epworth Sleepiness Scale (ESS) scores >12 and ≥4 partial/complete episodes of cataplexy/week. Participants were randomized to oral TAK-861 (0.5mg/0.5mg, 2mg/2mg, 2mg/5mg, each 3hrs apart, or 7mg QD) or placebo. Endpoints included change from baseline to week 8 in mean sleep onset latency on the Maintenance of Wakefulness Test (SOL-MWT), ESS, weekly cataplexy rate (WCR), and treatment-emergent adverse events (TEAEs).
Results: The study included 112 participants (baseline mean age 34 years; ESS 18.5; 51.8% female). LS mean (SE) changes from baseline to week 8 (SOL-MWT) were 12.49(2.13), 23.50(2.04), 25.42(2.07), 14.96(1.95), and –1.16(2.06) minutes, with 0.5mg/0.5mg, 2mg/2mg, 2mg/5mg, 7mg, and placebo, respectively (all P≤0.001 vs placebo). Statistically significant changes were achieved for all dose groups vs placebo in ESS, and for the 2mg/2mg and 2mg/5mg groups for WCR. 56.5%-91.3% of TAK-861 patients experienced TEAEs vs 31.8% receiving placebo. Most TEAEs were mild to moderate severity. Most common TEAEs were urinary urgency/frequency and insomnia. No treatment-related serious TEAEs or discontinuations due to TEAEs occurred during the study.
Conclusion: TAK-861 showed significant, clinically meaningful improvements in sleepiness and cataplexy frequency. TAK-861 was generally well tolerated in participants with NT1.