Abstract Introduction Narcolepsy type 1 (NT1) is a rare, chronic neurological disorder of central hypersomnolence with sleep/wake instability caused by significant loss of orexin neurons. Sleep disruption is characterized using both objective components, derived from nocturnal polysomnography (PSG), and subjective components including dream-like hallucinations, sleep paralysis, and disturbed nighttime sleep, captured through patient questionnaires. Orexin agonists are new therapies treating NT1 by restoring orexin signaling. Using PSG and subjective reports, we assessed the impact of oveporexton, an orexin receptor 2-selective agonist, on sleep and PSG parameters in two randomized, placebo-controlled Phase 3 studies (The First Light FL: NCT06470828; The Radiant Light RL: NCT06505031). Methods Participants (16–70 years) with NT1 were randomized to receive oveporexton 1mg/1mg (FL only), oveporexton 2mg/2mg, or placebo, at least 3 hours apart (first dose 8AM). PSG was collected at baseline and end of treatment. Sleep was manually scored following AASM guidelines; selected metrics were computed by quarter-night. Subjective reports were captured using the Narcolepsy Severity Scale for Clinical Trials (NSS-CT). Exploratory endpoints were analyzed with mixed-effects models. Results reported as placebo-adjusted change from baseline. Results PSG data were collected from 157 FL participants (placebo: n=36, 1mg/1mg: n=57, 2mg/2mg: n=64) and 101 RL participants (placebo: n=34, 2mg/2mg: n=67). In all treatment groups across both studies, oveporexton normalized rapid eye movement (REM) sleep abnormalities. Specifically, REM sleep latency increased (all p 0.001), while first-quarter time spent in REM sleep decreased (all p 0.001) and NT1-specific REM transitions decreased. As a fraction of total sleep time, REM sleep decreased in oveporexton-treated groups (all p≤0.005, changes ranging from 4.0–5.1%) with corresponding increases in N2%. No significant changes occurred in N1% or N3%. Wake after sleep onset increased in the FL 1mg/1mg group (p=0.014) with no significant changes in other groups. Awakenings 5 minutes, considered clinically meaningful, were unchanged. Across all oveporexton-treated groups, hallucinations and sleep paralysis (NSS-CT) were significantly reduced (all p 0.001). Disturbed nighttime sleep (NSS-CT) was reduced in FL and RL 2mg/2mg groups (both p 0.05). Conclusion Treatment with oveporexton improves REM sleep architecture and sleep-related symptoms in participants with NT1 in two Phase 3 studies. Support (if any) Funded by Takeda Development Center Americas, Inc.
Barateau et al. (2026) studied this question.