New Phase 3 Data on Oveporexton for Narcolepsy Type 1

Newly published results from 2 phase 3 studies evaluating oveporexton (Orzeyful), an oral orexin receptor 2 (OX2R) agonist, in individuals with narcolepsy type 1 (NT1), show that treatment with oveporexton led to statistically significant improvements over placebo on all measures, including wakefulness, cataplexy, and quality of life.¹

The full results were published in the New England Journal of Medicine (NEJM). This is the first complete report of the primary and secondary efficacy, safety, and tolerability data underlying the drug's recent regulatory authorizations.²

Oveporexton selectively stimulates OX2R to restore signaling and address the underlying orexin deficiency that drives NT1, a chronic neurological disease marked by daytime and nighttime symptoms including excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, hallucinations, and cognitive symptoms. Rather than targeting individual symptoms, oveporexton is designed to correct the NT1's underlying biology, the first and only medicine to do so.

Trial Design

The NEJM data draw on the FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002) phase 3 studies. FirstLight randomly assigned 168 participants to twice-daily 2-mg or 1-mg oveporexton or placebo; RadiantLight randomly assigned 105 participants to twice-daily 2-mg oveporexton or placebo. Both studies were placebo-controlled and evaluated 14 primary and secondary endpoints over 12 weeks, capturing the oveporexton's effect on wakefulness, sleepiness, cataplexy, disease severity, and quality of life. More than 95% of participants who completed the trials enrolled in an ongoing long-term extension study.

Efficacy Results

Across both studies, oveporexton produced statistically significant improvements over placebo on all measures (P<0.001), with benefits apparent at the earliest assessed time point and sustained through week 12. Median weekly cataplexy rates fell 79.0% to 88.8% with oveporexton compared with 27.7% to 39.1% with placebo at week 12. Oveporexton improved disease severity across every domain of the Narcolepsy Severity Scale (NSS-CT)—including excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis—at both doses, plus the disrupted nighttime sleep domain at the 2-mg dose. More than 70% of treated participants reached the mildest NSS-CT severity tier (score 0-14). Nearly all treated participants (97%) reported improvement on the self-rated Patient Global Impression of Change scale, and all dose groups reached normative thresholds for wakefulness on the Maintenance of Wakefulness Test (≥20 minutes) and sleepiness on the Epworth Sleepiness Scale (≤10). Most participants also reached or exceeded normal quality-of-life thresholds on the 36-Item Short Form Survey and the EuroQol-5 Dimensions 5-Levels scale.

Safety Findings

The most commonly reported treatment-emergent adverse events were insomnia, urinary urgency, urinary frequency, and excessive saliva, consistent with prior clinical experience with oveporexton. Insomnia occurred in 60% of participants on the 2-mg dose and 55% on the 1-mg dose, vs 1% with placebo. Most episodes resolved within a week and did not impair daytime functioning. Urinary frequency occurred in 58% (2 mg) and 53% (1 mg) of treated participants vs 5% with placebo, with about half of events resolving by week 12; urinary urgency occurred in 16% and 15% of treated participants, respectively, vs 1% with placebo. Creatine phosphokinase elevations greater than 5 times the upper limit of normal occurred in 11% of participants taking oveporexton (21 of 196) compared with 5% of those on placebo (4 of 76). Most adverse events were mild to moderate, began within 2 days of starting treatment, and did not require medical intervention.

"People living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life," said Emmanuel Mignot, MD, PhD, the principal investigator for the FirstLight study. "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."

"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," said Sarah Sheikh, MSc, BM, BCh, MRCP, the head of the Neuroscience Therapeutic Area Unit and Global Development at Takeda. "The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment."

Future Directions

The publication follows the FDA's August 2026 approval of Orzeyful for NT1 in adults, which relied on topline results from the same 2 trials.³ With oveporexton now authorized in the United States, Japan, and China, Takeda said additional regulatory submissions are underway as the company works with health authorities to expand access for people with NT1.

References

1. 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. September 9, 2026. Accessed September 9, 2026. https://www.takeda.com/newsroom/newsreleases/2026/nejm-oveporexton-narcolepsy-data/

2. Dauvilliers Y, Mignot E, Antczak J, et al. Oveporexton for narcolepsy type 1: results from two phase 3 trials. N Engl J Med. 2026.

3. Walters J. FDA approves oveporexton for narcolepsy type 1, first drug to treat full range of NT1 symptoms. Psychiatric Times. August 5, 2026. https://www.psychiatrictimes.com/view/fda-approves-oveporexton-for-narcolepsy-type-1-first-drug-to-treat-full-range-of-nt1-symptoms