Oveporexton Improves REM Sleep Architecture and Sleep-Related Symptoms in Phase 3 Narcolepsy Type 1 Studies

Newly presented findings from an analysis of 2 randomized, placebo-controlled phase 3 studies, The First Light (NCT06470828) and The Radiant Light (NCT06505031), showed that treatment with the investigational orexin receptor 2 agonist oveporexton (Takeda) was associated with improvements in REM sleep architecture and reductions in several sleep-related symptoms among patients with narcolepsy type 1 (NT1).¹

All told, the analysis of both studies showed that oveporexton normalized several objective measures of REM sleep abnormalities and also reduced patient-reported hallucinations, sleep paralysis, and disturbed nighttime sleep. Presented by lead author Lucie Barateau, MD, PhD, associate professor in the Sleep Unit of Montpellier University Hospital, at the 2026 SLEEP Annual Meeting, held June 14-17 in Baltimore, Maryland, these findings add to a growing body of evidence supporting orexin receptor agonism as a disease-targeted therapeutic strategy for NT1.

The analysis included participants aged 16 to 70 years with NT1 who were randomized to receive oveporexton or placebo. In The First Light study, participants received placebo (n = 36), oveporexton 1 mg/1 mg (n = 57), or oveporexton 2 mg/2 mg (n = 64), administered at least 3 hours apart beginning at 8 AM. In The Radiant Light trial, participants received placebo (n = 34) or oveporexton 2 mg/2 mg (n = 67). Sleep outcomes were assessed using overnight polysomnography (PSG) at baseline and end of treatment, while patient-reported symptoms were evaluated using the Narcolepsy Severity Scale for Clinical Trials (NSS-CT).

For context, NT1 is caused by the loss of hypothalamic orexin-producing neurons, resulting in deficient orexin signaling and instability of sleep-wake states.² Current therapies primarily target symptoms, including excessive daytime sleepiness and cataplexy, but do not directly address the underlying orexin deficiency. Oveporexton, formerly known as TAK-861, is designed to selectively activate the orexin receptor 2 pathway, potentially restoring physiologic wakefulness and sleep regulation.

Across both studies, treatment with oveporexton was associated with significant normalization of REM sleep abnormalities. REM sleep latency increased significantly in all active treatment groups compared with placebo (all P <.001), indicating a reduction in the tendency to enter REM sleep prematurely, a hallmark feature of narcolepsy. In addition, time spent in REM sleep during the first quarter of the night decreased significantly across all oveporexton-treated groups (all P <.001), whereas NT1-specific transitions into REM sleep were also reduced.

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Investigators observed a reduction in REM sleep as a proportion of total sleep time among patients receiving oveporexton, with placebo-adjusted decreases ranging from 4.0% to 5.1% (all P ≤.005). These changes were accompanied by corresponding increases in stage N2 sleep. No significant changes were reported in the proportions of N1 or N3 sleep, suggesting that treatment effects were primarily concentrated within REM-related sleep architecture.

Although wake after sleep onset increased significantly in the 1-mg treatment group in The First Light study (P = .014), no significant changes were observed in the higher-dose group or in The Radiant Light study. Importantly, the frequency of awakenings lasting longer than 5 minutes, considered a clinically meaningful measure of sleep disruption, remained unchanged across treatment groups.

Beyond objective PSG findings, participants receiving oveporexton reported significant improvements in several NT1-related symptoms. Hallucinations and sleep paralysis were significantly reduced across all active treatment groups in both studies (all P <.001). Disturbed nighttime sleep scores on the NSS-CT were also significantly improved in participants receiving the 2-mg dose in both trials (P <.05).

The findings provide additional evidence that restoration of orexin signaling may improve both daytime and nighttime manifestations of NT1. Notably, the observed effects extended beyond measures of wakefulness to include improvements in REM sleep regulation and symptom burden commonly associated with the disorder.

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REFERENCES
1. Barateau L, Gong Y, Dauvilliers Y. Effects of Treatment with Oveporexton, an Orexin Receptor 2 Agonist, on Sleep in People with Narcolepsy Type 1: Phase 3 Results. Presented at: 2026 SLEEP Annual Meeting; June 14-17; Baltimore, Maryland. Abstract 0723.
2. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499-511. doi:10.1016/S0140-6736(07)60237-2