Oveporexton Met Primary, Key Secondary End Points in Phase 3 Studies

The New England Journal of Medicine published full results from the FirstLight (NCT06470828) and RadiantLight (NCT06505031) phase 3 trials of oveporexton (Orzeyful), the oral orexin receptor 2 agonist the FDA approved in August as the first treatment aimed at the underlying cause of narcolepsy type 1. The 2 randomized, double-blind, placebo-controlled trials enrolled a combined 273 participants and measured changes in objective wakefulness, daytime sleepiness, and cataplexy over 12 weeks.¹

Investigators reported that oveporexton met its primary and key secondary end points in both studies, with improvements appearing as early as the first post-baseline assessment and continuing through week 12.¹

Trial Design and Populations

FirstLight randomized 168 participants, 16 to 70 years of age, in a 3:3:2 ratio to twice daily oveporexton at 1 mg, twice daily oveporexton at 2 mg, or a placebo. RadiantLight randomized 105 participants in a 2:1 ratio to twice daily oveporexton at 2 mg or placebo. Eligible participants had a diagnosis of NT1 confirmed by polysomnography or cerebrospinal fluid orexin testing, an Epworth Sleepiness Scale (ESS) score of 11 or higher, and at least 4 cataplexy episodes per week.¹

A total of 157 of 168 FirstLight participants and 101 of 105 RadiantLight participants completed the 12-week regimen. More than 95% of participants who completed either trial enrolled in an ongoing long-term extension study.^1,2

Efficacy Across Wakefulness, Sleepiness, and Cataplexy

On the primary endpoint, mean sleep latency on the Maintenance of Wakefulness Test improved by 14.3 to 19.8 minutes with oveporexton, compared with a change of −0.4 to −0.8 minutes with placebo (P < .001 for all comparisons). By week 12, sleep latency reached the normal threshold of 20 minutes or more in 48% of participants on the 1-mg dose, 56% on the 2-mg dose in FirstLight, and 69% on the 2-mg dose in RadiantLight, versus 6% and 0% of the respective placebo groups.¹

ESS total scores fell by 9.7 to 11.8 points with oveporexton compared with 1.5 to 1.7 points with placebo. The weekly cataplexy rate dropped by a median of 79.0% to 88.8% with oveporexton, compared with 27.7% to 39.1% with placebo, and the median number of cataplexy-free days per week rose from 0 at baseline to 3.8 to 5.1 days with oveporexton.¹

"People living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life," Emmanuel Mignot, MD, PhD, principal investigator for the FirstLight study, said in a news release.² "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."

Quality of Life and Disease Severity Gains

Scores on the Narcolepsy Severity Scale for Clinical Trials fell from a baseline range of 30.4 to 31.9 down to 9.6 to 12.1 with oveporexton, compared with 27.2 to 27.9 with placebo, exceeding the scale's clinically meaningful threshold of 8 points. At week 12, 75% to 76% of oveporexton-treated participants had scores indicating mild NT1 symptoms, versus 9% to 25% of the placebo groups.¹

On the Patient Global Impression of Change scale, 74% of participants on the 1-mg dose and 97% on the 2-mg dose in FirstLight reported feeling "much improved" or "very much improved," compared with 22% on placebo. In RadiantLight, 91% of the oveporexton group reported the same, versus 15% on placebo. Least-squares mean changes in SF-36 mental and physical component scores also improved significantly versus placebo in both trials.¹

"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," Sarah Sheikh, MSc, BM, BCh, MRCP, head of Takeda's Neuroscience Therapeutic Area Unit and Global Development, said in the release.² "The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment."

Safety Findings and Pharmacist-Relevant Monitoring

Adverse events occurred in 86% to 89% of oveporexton-treated participants across the two trials, compared with 43% to 54% of placebo groups. The most common adverse events were increased urinary frequency and transient insomnia, occurring in a majority of oveporexton-treated participants. Most began within 2 days of treatment initiation, were mild to moderate, and did not require medical intervention. Most insomnia episodes resolved within a week without affecting daytime functioning, and about half of urinary events had resolved by week 12.¹

Pooled phase 3 safety data cited in Takeda's label information put these rates more precisely: insomnia developed in 60% of participants on the 2-mg dose and 55% on the 1-mg dose, versus 1% on placebo; urinary frequency occurred in 58% and 53%, versus 5% on placebo; and urinary urgency occurred in 16% and 15%, versus 1% on placebo.²

Two serious adverse events—ureterolithiasis and chest pain, neither considered treatment-related—occurred in FirstLight. In RadiantLight, 2 participants developed rhabdomyolysis tied to intense exercise and asymptomatic aminotransferase increases and discontinued the trial as a result. Investigators did not consider the events related to the trial regimen.¹

Asymptomatic creatine phosphokinase elevations greater than 5 times the upper limit of normal occurred in 11% of pooled oveporexton-treated participants versus 5% of those on placebo.² Elevated liver-function tests occurred in 3% to 4% of oveporexton participants across the two trials. None were considered related to treatment, and no cases met Hy's law criteria for drug-induced liver injury. Investigators reported no clinically significant changes in heart rate or blood pressure and no evidence of weight gain with oveporexton relative to placebo.¹

The trial authors noted that participants had predominantly moderate-to-severe NT1 symptoms at baseline, which may limit generalizability to patients with milder disease.¹

Because oveporexton's efficacy became apparent to some participants during treatment, the authors acknowledged a risk of functional unblinding, though they noted that the objective Maintenance of Wakefulness Test and maintained blinding of investigators and the sponsor helped mitigate this risk. The requirement of at least four cataplexy episodes per week for enrollment also means the trials did not evaluate efficacy in patients with low-frequency cataplexy, and both trials were limited to 12 weeks, though a long-term extension study is underway.¹

What This Means for Pharmacists

Orzeyful carries a contraindication for use with strong CYP3A inhibitors, and both strong and moderate CYP3A inhibitors or inducers can meaningfully alter overporexton exposure—a consideration for pharmacists reviewing concomitant medications. The drug should be avoided in patients with severe hepatic impairment (Child-Pugh C) or severe renal impairment on dialysis.²

At the time of FDA approval in August, oveporexton’s controlled-substance schedule had not yet been finalized by the Drug Enforcement Administration, and the drug was expected to be distributed through specialty pharmacy channels once scheduling was complete.³

Given how commonly urinary frequency, urgency, and transient insomnia appeared in the trials, pharmacists counseling patients starting oveporexton may want to set expectations early. These effects typically emerge within the first days of treatment and, per the trial data, are self-limiting for most patients rather than signs the drug should be stopped.¹

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. Published online September 9, 2026. doi:10.1056/NEJMoa2601598

2. Takeda Pharmaceutical Company Limited. 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. Business Wire. September 9, 2026. Accessed September 10, 2026. https://www.businesswire.com/news/home/20260909425335/en/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

3. Gallagher A. FDA approves Orzeyful, first drug targeting underlying cause of narcolepsy. Drug Topics. August 6, 2026. Accessed September 10, 2026. https://www.drugtopics.com/view/fda-approves-orzeyful-first-drug-targeting-underlying-cause-of-narcolepsy