Phase 3 NEJM Data Highlights Oveporexton's Symptom Improvement in Narcolepsy Type 1

Takeda has announced that data from the phase 3 FirstLight (NCT06470828) and RadiantLight (NCT06505031) trials of oveporexton (Orzeyful), an oral orexin receptor 2 (OX2R) agonist recently FDA-approved for adults with narcolepsy type 1 (NT1), were published in the New England Journal of Medicine. Findings from the studies showed improvements across multiple manifestations of NT1, including wakefulness, daytime sleepiness, cataplexy, disease severity, and quality of life.^1,2

“People living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life,” FirstLight principal investigator and study author Emmanuel Mignot, MD, PhD, Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University, said in a statement.² “The newly published Phase 3 data reinforce the potential of oveporexton to transform how we approach narcolepsy type 1 in clinical practice, shifting from managing individual symptoms to treating the disease itself.”

Study Overview

FirstLight and RadiantLight were multicenter, double-blind, placebo-controlled trials conducted across North America, Europe, Asia, and Australia in participants aged 16 to 70 years with NT1. In FirstLight, 168 participants were randomized 3:3:2 to oveporexton 1 mg twice daily, 2 mg twice daily, or placebo; in RadiantLight, 105 participants were randomized 2:1 to oveporexton 2 mg twice daily or placebo.

Both trials ran for 12 weeks, with the primary end point defined as change from baseline in mean sleep latency on the 40-minute Maintenance of Wakefulness Test (MWT). Key secondary end points included change in Epworth Sleepiness Scale (ESS) total score and weekly cataplexy rate at week 12.

“Leveraging the extensive research we conducted on the impact of narcolepsy type 1, we designed our comprehensive Phase 3 program to reflect the complexity of the disease and the experiences of those living with it,” Sarah Sheikh, MSc, BM, BCh, MRCP, Head, Neuroscience Therapeutic Area Unit and Global Development at Takeda, said in a statement.² “The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment. We are grateful to the patients, caregivers and healthcare providers who have participated in our studies and are thrilled to bring the first orexin agonist to the community.”

Key Findings

Across both trials, oveporexton produced mean MWT sleep latency improvements ranging from 14.3 to 19.8 minutes, compared with −0.4 to −0.8 minutes with placebo (adjusted P <.001 for all comparisons). At week 12, 48% to 69% of oveporexton-treated participants achieved a sleep latency of 20 minutes or more, in the normal range for healthy adults, compared with 0% to 6% of placebo recipients.

ESS total scores improved by 9.7 to 11.8 points with oveporexton versus 1.5 to 1.7 points with placebo, and 67% to 84% of treated participants reached a normative ESS score of 10 or less by week 12. Median weekly cataplexy rates fell by 79.0% to 88.8% with oveporexton, compared with 27.7% to 39.1% with placebo, with incidence rate ratios versus placebo ranging from 0.13 to 0.38 (P <.001 for all comparisons). Improvements across all efficacy measures were apparent at the earliest assessment time points (week 2 for cataplexy, week 4 for ESS, week 8 for MWT).

READ MORE: Favorable Phase 1 Data for Orexin-2 Agonist BP-205, Broader Pipeline Progress Headline Harmony’s Q2 Update

Adverse events (AEs) occurred in 86% to 89% of oveporexton-treated participants versus 43% to 54% with placebo, most commonly increased urinary frequency and transient insomnia, effects the study authors characterized as consistent with the known class profile of OX2R agonists. Most AEs were mild to moderate, began in the first 2 days of treatment, and did not prompt medical intervention; insomnia events largely resolved in a week without affecting daytime functioning. Two participants receiving 2 mg oveporexton in RadiantLight developed rhabdomyolysis attributed to intense exercise; no drug-induced hepatotoxicity or clinically significant cardiovascular changes were observed.

Clinical Context and Indications

NT1 is a chronic neurologic disorder associated with deficient orexin signaling.³ Its clinical manifestations include excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, hallucinations, and cognitive symptoms. Together, these daytime and nighttime symptoms can interfere with education, employment, and social functioning.

Oveporexton selectively activates OX2R, aiming to restore signaling impaired by orexin deficiency and thereby promote wakefulness while reducing rapid eye movement sleep–related phenomena such as cataplexy.⁴ The drug is currently indicated in the United States and Japan for adults with NT1; China has approved it for adults and adolescents aged 16 years or older, according to Takeda.¹

Expert Insight

Sara Sarkey, PhD, vice president of Neuroscience and Vaccines at Takeda, has been involved in the company's neuroscience portfolio as orexin-directed therapeutics have advanced from a longstanding biologic concept toward clinical application. Following the FDA decision, Sarkey sat down with NeurologyLive^® to provide her perspective on what the approval may mean for the treatment of NT1.

In the interview, Sarkey discusses how directly addressing orexin deficiency could change expectations for clinicians and patients accustomed to managing NT1 symptom by symptom. She also considers the broader implications of treating a 24-hour disorder, the substantial adaptations patients often make around their symptoms, and why treatment goals may increasingly extend beyond conventional symptom measures toward everyday functioning and quality of life.

Click here to view more of our narcolepsy coverage.

REFERENCES
1. Dauvilliers Y, Mignot E, Antczak J, et al. Oveporexton for Narcolepsy Type 1 - Results from Two Phase 3 Trials. N Engl J Med. Published online September 9, 2026. doi:10.1056/NEJMoa2601598
2. New England Journal of Medicine Publishes Data from Phase 3 Studies Demonstrating Oveporexton (ORZEYFUL) Improved the Full Range of Narcolepsy Type 1 Symptoms and Quality of Life. News release. Takeda. September 9, 2026. Accessed September 11, 2026. https://www.takeda.com/newsroom/newsreleases/2026/nejm-oveporexton-narcolepsy-data/
3. Barateau L, Pizza F, Plazzi G, Dauvilliers Y. Narcolepsy. J Sleep Res. 2022;31(4):e13631. doi:10.1111/jsr.13631
4. Dauvilliers Y, Plazzi G, Mignot E, et al. Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1. N Engl J Med. 2025;392(19):1905-1916. doi:10.1056/NEJMoa2405847