Treatment with an orexin agonist reduces microsleeps and improves wakefulness during MWT in people with NT1

Music City Center 

Excessive daytime sleepiness (EDS) is a hallmark symptom of narcolepsy type 1 (NT1). The Maintenance of Wakefulness Test (MWT) is used in clinical trials to assess treatment effects on EDS by measuring the ability to stay awake until persistent sleep occurs. Sleep onset latency, the primary MWT endpoint, does not capture the quality of this wakefulness. We explored alternative EDS endpoints using manually scored microsleeps (3-5 sec sleep episodes) and hypnodensity-based sleepiness scores from MWT data in a phase 2 randomized, placebo-controlled trial of oveporexton (TAK-861), an oral orexin receptor 2 agonist (NCT05687903). Participants with NT1 (n=112) were randomized to oveporexton (4 doses) or placebo. Four 40-minute MWTs were performed at baseline, Day 28, and Day 56. Generalized mixed-effects models analyzed microsleep rates and average sleepiness scores. Among participants with NT1, oveporexton significantly reduced microsleep rates by Day 28 and 56 (from ~6 to <2 microsleeps/10 min) and reduced sleepiness scores (p<0.005 vs baseline). Placebo-treated participants showed minimal changes. These findings demonstrate oveporexton's potential for treating EDS in people with NT1.