FDA Approves Orexin Agonist Oveporexton for Narcolepsy Type 1

The FDA has approved Takeda's oveporexton, an oral orexin receptor 2 (OX2R)-selective agonist, for the treatment of narcolepsy type 1 (NT1) in adults. Marketed as Orzeyful, the therapeutic is considered the first medicine approved for NT1 as a unified disorder, addressing the condition's full symptom range, and the first to work by directly targeting the loss of orexin signaling that causes the disease.¹

“This is a historic moment for the narcolepsy community. The approval gives new hope to people living with type 1 narcolepsy, like myself, and and marks the beginning of a new era of orexin innovation,” Julie Flygare, JD, the president and CEO at Project Sleep, told NeurologyLive^®.

Mechanism and Unmet Need

NT1 is caused by the loss of orexin-producing neurons in the hypothalamus, a chemical messenger that regulates wakefulness, sleep, and muscle tone. Its loss produces a cluster of disabling symptoms, including excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and disrupted nighttime sleep. Existing therapies have relied on stimulants or sedatives to manage individual symptoms rather than acting on the underlying orexin system.

Rather than masking symptoms, oveporexton directly activates the same receptor that orexin would normally stimulate, restoring the missing signal; it is taken as an oral tablet twice daily.

“For too long, people with narcolepsy type 1 have had to manage a complex, lifelong neuropsychiatric condition with treatments that only address pieces of it,” Tiffany Farchione, MD, director of the Division of Psychiatry within the FDA's Center for Drug Evaluation and Research, said in a statement.¹ “This new drug is the first medicine that impacts the underlying biology of the disease, treating narcolepsy type 1 as a whole.”

Phase 3 Data Supporting Approval

The approval was based on 2 randomized, double-blind, placebo-controlled 12-week studies, FirstLight (NCT06470828) and RadiantLight (NCT06505031), enrolling a combined 273 adults with NT1. Across both trials, oveporexton at the 2 mg dose met its primary endpoint, showing statistically significant improvement in the ability to stay awake during the day as measured by the Maintenance Wakefulness Test, relative to placebo (P <.001 in both studies).^1,2

READ MORE: FDA Accepts NDA for Axsome Therapeutics’ AXS-12 for the Treatment of Cataplexy in Narcolepsy

Patients also showed significant improvements on secondary measures, including reduced Epworth Sleepiness Scale scores and a significant reduction in weekly cataplexy rate (both P <.001), along with meaningful improvement in sleep paralysis, hallucinations, and disrupted nighttime sleep.

“Takeda's groundbreaking efforts targeting the orexin receptor 2 in clinical studies led to positive Phase 3 results for oveporexton, bringing us a major step closer to having the first orexin therapy that addresses the underlying cause of narcolepsy type 1,” Emmanuel Mignot, MD, PhD, principal investigator for FirstLight and Craig Reynolds Professor of Sleep Medicine at Stanford University, said in a statement at the time of the released data.²

Supporting Phase 2b and Sleep Architecture Data

Earlier phase 2b data (NCT05687903), published in the New England Journal of Medicine, had shown dose-dependent improvement across 112 patients randomized to 1 of 4 oveporexton dosing arms or placebo over 8 weeks, with mean Maintenance Wakefulness Test changes ranging from 12.5 to 25.4 minutes across active arms compared with -1.2 minutes for placebo (adjusted P ≤.001 for all comparisons).³

A separate analysis of FirstLight and RadiantLight, presented at the 2026 SLEEP Annual Meeting, found that oveporexton also normalized objective measures of REM sleep architecture, including significantly prolonged REM latency and reduced early-night REM burden relative to placebo (P <.001 across active-dose groups), alongside significant reductions in patient-reported hallucinations and sleep paralysis.⁴

Safety and Access

The most common adverse effects (AEs) observed in the studies were insomnia, increased urinary frequency, urinary urgency, and increased saliva production, with a low rate of treatment discontinuation because of AEs. Of note, oveporexton should not be used with strong CYP3A inhibitors, and its safety and effectiveness have not been established in patients under 18 years of age.

The drug received Breakthrough Therapy Designation and Priority Review, and has been recommended for scheduling under the Controlled Substances Act; it will be lawful to market following a scheduling decision from the Drug Enforcement Administration.

Clinician Insight

During the 2026 SLEEP Annual Meeting, held June 14 to 17, in Baltimore, Maryland, NeurologyLive^® spoke with Elena Koundourakis, PhD, head of orexin franchise development and neuroscience programs at Takeda. In the clip below, Koundourakis outlined the design of the FirstLight and RadiantLight studies, walked through the correlation observed between objective and patient-reported cognitive measures, and detailed the newly presented nighttime sleep findings, including the shift toward more normalized REM sleep architecture on PSG.

REFERENCES
1. FDA Approves First Drug to Treat the Full Range of Narcolepsy Type 1 Symptoms. News release. US Food and Drug Administration. August 5, 2026. Accessed August 5, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-full-range-narcolepsy-type-1-symptoms
2. Takeda Announces Positive Results from Two Pivotal Phase 3 Studies of Oveporexton (TAK-861) in Narcolepsy Type 1. News release. Takeda. July 14, 2025. Accessed August 5, 2026. https://www.takeda.com/newsroom/newsreleases/2025/positive-results-phase-3-oveporexton-narcolepsy-type-1/
3. 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
4. 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, 2026; Baltimore, MD. Abstract 0723.