Effects of Oveporexton, an Orexin Receptor 2–Selective Agonist, on Cognition in Narcolepsy Type 1

Importance: Cognitive symptoms negatively impact people with narcolepsy type 1 (NT1). While the effects of orexin receptor 2 (OX2R) agonists have been explored on diagnostic features of the disorder (excessive daytime sleepiness and cataplexy), effects on cognitive symptoms are not characterized. Objective: To explore the effects of oveporexton, an oral OX2R-selective agonist, on cognition in people with NT1. Design, Setting, and Participants: This is a secondary analysis of the TAK-861-2001 phase 2, 8-week, parallel-group, double-blind, placebo-controlled randomized clinical trial, conducted from January 2023 to December 2023, with a 4-week follow-up period. TAK-861-2001 was a multicenter study conducted in clinical settings. Eligible participants were 18 to 70 years of age, with an International Classification of Sleep Disorders, Third Edition diagnosis of NT1. Data analysis was performed from July 2024 to July 2025. Interventions: Participants were randomized 1:1:1:1:1 to twice-daily oral oveporexton or matching placebo, dosed 3 hours apart, in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks. Main Outcomes and Measures: Cognitive symptoms were assessed using the Psychomotor Vigilance Task (PVT) for attention, the Continuous Paired Associate Learning (CPAL) test for memory, and the One Back (ONB) test and International Digit Symbol Substitution Test-symbols (IDSST-s) for executive function. Results: Of 161 eligible individuals screened, 48 did not meet study inclusion criteria, 1 withdrew, and 112 were included in the study. Of 112 participants, mean (SD) age was 34.0 (11.5) years, and 58 participants (51.8%) were female. A total of 112 participants were randomized and received 1 or more doses of oveporexton (0.5/0.5 mg, n = 23; 2/2 mg, n = 21; 2/5 mg, n = 23; 7 mg, n = 23) or placebo (n = 22). Oveporexton improved attention, memory, and executive function over 8 weeks. Least-squares (LS) mean placebo-adjusted changes from baseline were -10.77 (95% CI, -16.74 to -4.79), -9.45 (95% CI, -15.66 to -3.24), -8.60 (95% CI, -14.84 to -2.36), and -8.69 (95% CI, -14.90 to -2.47) PVT lapses with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively. LS mean placebo-adjusted changes were -22.52 (95% CI, -34.95 to -10.10), -16.92 (95% CI, -30.12 to -3.71), -15.51 (95% CI, -28.82 to -2.21), and -17.59 (95% CI, -30.50 to -4.68) for CPAL errors; -0.05 (95% CI, -0.10 to -0.01), -0.07 (95% CI, -0.12 to -0.02), -0.07 (95% CI, -0.12 to -0.02), and -0.05 (95% CI, -0.10 to 0.00) units for ONB log10-transformed performance speed; and 4.72 (95% CI, -1.38 to 10.83), 7.33 (95% CI, 1.06-13.61), 7.85 (95% CI, 1.75-13.95), and 11.82 (95% CI, 5.75-17.89) for IDSST-s correct responses. Conclusions and Relevance: In this secondary analysis of the TAK-861-2001 randomized clinial trial, the OX2R agonist oveporexton improved NT1-associated cognitive symptoms in adults. Trial Registration: ClinicalTrials.gov Identifier: NCT05687903.