Oveporexton Improves Wakefulness and Cataplexy in Narcolepsy Type 1

Oveporexton (Orzeyful; Takeda), an oral orexin receptor 2 (OX2R) agonist, significantly improved wakefulness, daytime sleepiness, and cataplexy over 12 weeks in people with narcolepsy type 1 (NT1), according to 2 phase 3 trials published in The New England Journal of Medicine.¹ Adverse events were more common with the drug than with placebo, most often increased urinary frequency and transient insomnia.

The findings supported the drug’s recent approval by the FDA for the treatment of NT1 (narcolepsy with cataplexy) in adults.² The agency's decision, announced August 5, 2026, positions oveporexton as the first therapy indicated to address the underlying orexin deficiency that drives NT1, rather than managing its symptoms individually.

Oveporexton Phase 3 Trial Design in Narcolepsy Type 1

The FirstLight (TAK-861-3001; NCT06470828) and RadiantLight (TAK-861-3002; NCT06505031) trials were multicenter, double-blind, placebo-controlled studies that enrolled 168 and 105 participants aged 16 to 70 years, respectively.¹ FirstLight randomized participants 3:3:2 to twice-daily oveporexton 1 mg, oveporexton 2 mg, or placebo. RadiantLight randomized participants 2:1 to twice-daily oveporexton 2 mg or placebo.

The primary end point was change from baseline to week 12 in mean sleep latency on the Maintenance of Wakefulness Test (MWT), with 20 minutes or more considered normal. Key secondary end points were change in Epworth Sleepiness Scale (ESS) total score and weekly cataplexy rate.

In FirstLight, mean sleep latency increased by 14.3 minutes with 1 mg and 17.6 minutes with 2 mg compared with a 0.4-minute decrease with placebo. In RadiantLight, it rose by 19.8 minutes with 2 mg and fell by 0.8 minutes with placebo (adjusted P < .001 for all comparisons).

At week 12, sleep latency reached 20 minutes or more in 48% of the 1-mg group, 56% of the 2-mg group, and 6% of the placebo group in FirstLight. In RadiantLight, 69% of the 2-mg group reached that threshold compared with no placebo participants.

Oveporexton Reduces Daytime Sleepiness and Cataplexy

Mean ESS scores fell by 9.7 points with 1 mg and 11.8 points with 2 mg in FirstLight compared with 1.5 points with placebo. In RadiantLight, scores fell by 11.0 points with 2 mg and 1.7 points with placebo. A normal score of 10 or lower was reached by 67% to 84% of oveporexton recipients vs 12% to 17% of placebo recipients.

Median weekly cataplexy rates declined by 82.6% with 1 mg and 79.0% with 2 mg in FirstLight vs 27.7% with placebo. In RadiantLight, the decline was 88.8% with 2 mg vs 39.1% with placebo (adjusted P < .001). Median cataplexy-free days per week rose from 0 at baseline to between 3.8 and 5.1 with oveporexton. Improvements appeared at the earliest assessments, at week 2 for cataplexy, week 4 for ESS, and week 8 for MWT.

Oveporexton Adverse Events and Safety Findings

Adverse events occurred in 86% to 89% of oveporexton recipients and 43% to 54% of placebo recipients. Increased urinary frequency affected 53% to 61% of the oveporexton groups vs 3% to 7% with placebo. Insomnia affected 53% to 58% vs 0% to 3%.

Most events were mild to moderate, began within 2 days of starting treatment, and did not lead to medical intervention. Most insomnia resolved within 1 week, and about half of urinary events resolved by week 12.

Six participants discontinued because of adverse events, 5 of them receiving oveporexton. These included 2 participants in RadiantLight with rhabdomyolysis attributed to intense exercise. Two serious adverse events occurred with oveporexton, ureterolithiasis and chest pain, and neither was considered related to treatment. Elevated liver-function values occurred in 3% to 4% of oveporexton recipients, none considered treatment-related, with no cases meeting Hy's law criteria. Ambulatory monitoring showed no clinically significant changes in heart rate or blood pressure.

“These two phase 3 trials showed consistent, clinically meaningful reductions in symptoms with oveporexton, an oral OX2R agonist, in persons with narcolepsy type 1, thus confirming findings from a previous phase 2 trial,” the authors wrote.

Study Limitations and Long-Term Extension

The authors noted that participants had predominantly moderate to severe symptoms, so generalizability may be limited. The requirement for at least 4 cataplexy episodes per week precluded evaluation in people with low-frequency cataplexy. They also acknowledged that the rapid onset of efficacy created a potential risk of functional unblinding, which they said the objective MWT and maintained blinding mitigated.

The trials lasted 12 weeks. A long-term extension study is underway, and more than 95% of participants who completed the trials chose to enroll. Takeda Development Center Americas funded the trials, and employees of the company were among the authors.

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. 2026;395(12):1166-1179. doi:10.1056/NEJMoa2601598
2. Grossi G. FDA approves first orexin agonist for narcolepsy type 1. AJMC^®. August 21, 2026. Accessed September 29, 2026. https://www.ajmc.com/view/fda-approves-first-orexin-agonist-narcolepsy-type-1