Effect of Oral Orexin Receptor 2 Agonist TAK-861 on the Severity of Symptoms in Individuals With Narcolepsy Type 1: Results From a Phase 2 Study

Introduction: Narcolepsy type 1 (NT1) involves excessive daytime sleepiness and cataplexy episodes and is defined by low orexin levels. TAK-861, an orexin receptor 2 agonist, showed wake-promoting effects and improvement of cataplexy-like symptoms in animal models.
Methods: Exploratory analysis of disease severity in NT1 patients was conducted from the randomized, double-blind, placebo-controlled, ph2 study (NCT05687903). Eligible participants were aged 18-70 (Japan: 16-70), with an Epworth sleepiness scale (ESS) >12; ≥4 partial/complete episodes of cataplexy/week. Participants were randomized to oral TAK-861 (0.5mg/0.5mg, 2mg/2mg, 2mg/5mg each 3 hours apart, or 7mg QD) or placebo. Exploratory endpoints included change from baseline to week 8 in Narcolepsy Severity Scale for Clinical Trials (NSS-CT) scores, and global impressions scales (CGI, PGI) at week 8. NSS-CT evaluates the severity, frequency, and impact of 5 narcolepsy symptoms. Efficacy and safety data were reported separately.
Results: 112 participants (mean age 34.0 years, 51.8% female, ESS score 18.5, NSS-CT score 30.7) were randomized to various doses of TAK-861 or placebo. TAK-861 achieved significant improvements in NSS-CT score (LS mean change from baseline to week 8: –18.2 [0.5mg/0.5mg], –21.0 [2mg/2mg], –21.1 [2mg/5mg], –17.2 [7mg]) with TAK-861 and –3.5 for placebo; all P < 0.001 vs placebo). At week 8, >70% of patients treated with TAK-861 were much/very much improved on the PGI and CGI. TAK-861 was generally well-tolerated with no treatment-related serious treatment-emergent adverse events (TEAEs) or discontinuations due to TEAEs.
Conclusion: In this study, patients taking TAK-861 showed significant and clinically meaningful improvements in NSS-CT, PGI, and CGI scores.