The U.S. Food and Drug Administration (FDA) has approved oveporexton, an oral orexin receptor 2 (OX2R) agonist, for the treatment of narcolepsy type 1 (NT1; narcolepsy with cataplexy) in adults. Oveporexton is the first FDA-approved orexin agonist and is designed to address the underlying orexin deficiency associated with NT1 rather than targeting individual symptoms alone.
NT1 is a rare, chronic neurological disorder caused by the loss of orexin-producing neurons in the brain. Orexin plays a central role in maintaining wakefulness and regulating rapid eye movement (REM) sleep. People with NT1 may experience excessive daytime sleepiness, cataplexy, cognitive difficulties, sleep paralysis, hallucinations and disrupted nighttime sleep. An estimated 120,000 people in the United States are affected.
The approval was supported by the global phase 3 FirstLight (TAK-861-3001; NCT06470828) and RadiantLight (TAK-861-3002; NCT06505031) studies. These randomized, double-blind, placebo-controlled studies evaluated oveporexton over 12 weeks in 273 adults with NT1 across 19 countries. FirstLight enrolled 168 participants who received oveporexton 1 mg twice daily, oveporexton 2 mg twice daily or placebo. RadiantLight enrolled 105 participants who received oveporexton 2 mg twice daily or placebo.
The primary endpoint in both studies was improvement in excessive daytime sleepiness as measured by the Maintenance of Wakefulness Test (MWT). Key secondary endpoints included the Epworth Sleepiness Scale (ESS) and Weekly Cataplexy Rate. Both studies met all primary and secondary endpoints, with statistically significant improvements compared with placebo across doses at week 12 (P < .001).
The majority of participants receiving oveporexton 2 mg twice daily achieved a mean sleep latency within the normative range of at least 20 minutes on the MWT, and nearly 85% achieved ESS scores comparable with those of healthy individuals. Oveporexton reduced the median weekly cataplexy rate by more than 80% across doses. Median cataplexy-free days increased from 0 days per week at baseline to 4 to 5 days per week at week 12.
Improvements were also reported across broader measures of disease severity and functioning. More than 70% of treated participants reported symptoms within the mild range on the Narcolepsy Severity Scale for Clinical Trials, and 97% reported improvement on the Patient Global Impression of Change. In subsequent analyses, approximately 70% of oveporexton-treated participants reported no significant cognitive difficulties, compared with approximately 15% of those receiving placebo. Improvements in daily functioning, quality of life and nighttime sleep were also observed.
Safety and Tolerability
Oveporexton was generally well tolerated in the phase 3 program. The most common adverse reactions were insomnia, urinary frequency, urinary urgency and salivary hypersecretion.
In pooled phase 3 studies, insomnia occurred in 60% of participants receiving 2 mg twice daily, 55% receiving 1 mg twice daily and 1% receiving placebo. Urinary frequency occurred in 58%, 53% and 5%, respectively, while urinary urgency occurred in 16%, 15% and 1%, respectively. Persistent insomnia that substantially affects daytime functioning or quality of life may require dosage reduction or discontinuation.
Asymptomatic creatine phosphokinase elevations greater than 5 times the upper limit of normal occurred in 11% of oveporexton-treated participants and 5% of placebo-treated participants. Patients should be advised to report unexplained muscle pain, weakness or dark urine.
Oveporexton is contraindicated in patients taking strong CYP3A inhibitors. Strong or moderate CYP3A inhibitors can increase oveporexton exposure, while CYP3A inducers may decrease its effectiveness. Use should be avoided in patients with severe hepatic impairment or severe renal impairment requiring dialysis.
Oveporexton has the potential for abuse and misuse. Its controlled-substance classification is under review by the Drug Enforcement Administration. Takeda expects to make the medication available through a specialty pharmacy after the scheduling process is completed.
References:
Takeda Pharmaceutical Company Limited. Oveporexton phase 3 program results presented at World Sleep 2025. September 8, 2025. https://www.takeda.com/newsroom/newsreleases/2025/takeda-orexin-data-oveporexton-phase-3-narcolepsy-world-sleep-2025/
Takeda Pharmaceutical Company Limited. Oveporexton phase 3 results examining daily functioning, cognition and nighttime sleep. June 15, 2026. https://www.takeda.com/newsroom/newsreleases/2026/oveporexton-phase-3-narcolepsy-type-1/