Takeda has released the results of its phase 3 FirstLight (NCT06470828) and RadiantLight (NCT06505031) trials, which investigated the efficacy of oveporexton, an oral orexin receptor 2 (OX2R) agonist, in adults with narcolepsy type 1 (NT1). The findings, published in the New England Journal of Medicine, demonstrate significant improvements in various symptoms of NT1, including wakefulness, daytime sleepiness, cataplexy, disease severity, and quality of life.
Study Design and Methodology
The FirstLight and RadiantLight trials were multicenter, double-blind, placebo-controlled studies conducted in North America, Europe, Asia, and Australia, involving participants aged 16 to 70 years with NT1. In the FirstLight trial, 168 participants were randomly assigned to receive either oveporexton 1 mg twice daily, 2 mg twice daily, or a placebo, while the RadiantLight trial involved 105 participants who received either oveporexton 2 mg twice daily or a placebo.
Both trials lasted for 12 weeks, with the primary endpoint being the change in mean sleep latency on the 40-minute Maintenance of Wakefulness Test (MWT) from baseline. Secondary endpoints included changes in the Epworth Sleepiness Scale (ESS) total score and weekly cataplexy rate at week 12.
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Key Results from the Trials
The results of the trials show that oveporexton led to significant improvements in mean MWT sleep latency, ranging from 14.3 to 19.8 minutes, compared to −0.4 to −0.8 minutes with the placebo (adjusted P <.001 for all comparisons). At week 12, 48% to 69% of participants who received oveporexton achieved a sleep latency of 20 minutes or more, which is within the normal range for healthy adults, compared to 0% to 6% of participants who received the placebo.
The ESS total scores improved by 9.7 to 11.8 points with oveporexton, compared to 1.5 to 1.7 points with the placebo. Additionally, 67% to 84% of participants who received oveporexton achieved a normative ESS score of 10 or less by week 12. The median weekly cataplexy rates decreased by 79.0% to 88.8% with oveporexton, compared to 27.7% to 39.1% with the placebo, with incidence rate ratios versus the placebo ranging from 0.13 to 0.38 (P <.001 for all comparisons).
Adverse events (AEs) occurred in 86% to 89% of participants who received oveporexton, compared to 43% to 54% of those who received the placebo. The most common AEs were increased urinary frequency and transient insomnia, which were consistent with the known class profile of OX2R agonists. Most AEs were mild to moderate and did not require medical intervention. Two participants who received 2 mg oveporexton in the RadiantLight trial developed rhabdomyolysis due to intense exercise, but no drug-induced hepatotoxicity or clinically significant cardiovascular changes were observed.
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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 discussed the potential implications of the approval for the treatment of NT1, including how directly addressing orexin deficiency could change expectations for clinicians and patients accustomed to managing NT1 symptoms. She also considered the broader implications of treating a 24-hour disorder and the potential for treatment goals to extend beyond conventional symptom measures toward everyday functioning and quality of life.
Expert Perspective on Orexin Deficiency
According to Barateau L, Pizza F, Plazzi G, and Dauvilliers Y, narcolepsy is a chronic neurologic disorder associated with deficient orexin signaling, which can lead to excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep paralysis, hallucinations, and cognitive symptoms. These symptoms can interfere with education, employment, and social functioning.
Indications and Mechanism of Action
Oveporexton selectively activates OX2R, aiming to restore signaling impaired by orexin deficiency and promote wakefulness while reducing rapid eye movement sleep-related phenomena such as cataplexy. The drug is currently indicated in the United States and Japan for adults with NT1, and China has approved it for adults and adolescents aged 16 years or older, according to Takeda.