NEJM Publishes Phase 3 Data for Takeda's Oveporexton, the First Approved Orexin Agonist for Narcolepsy Type 1
核心洞察
Takeda's oveporexton (ORZEYFUL (搜索)) Phase 3 results were published in the New England Journal of Medicine, showing statistically significant improvements across all primary and secondary endpoints in narcolepsy type 1 (搜索).
The FirstLight and RadiantLight trials enrolled 168 and 105 adults respectively across 19 countries, testing twice-daily 1 mg and 2 mg doses versus placebo over 12 weeks.
Median weekly cataplexy rates fell 79.0% to 88.8% with oveporexton versus 27.7% to 39.1% with placebo, with p-values below 0.001 across efficacy measures.
Takeda announced that the New England Journal of Medicine has published results from two Phase 3 studies evaluating oveporexton (ORZEYFUL (搜索)), an oral orexin receptor 2 (搜索) (OX2R (搜索)) agonist, in adults with narcolepsy type 1 (搜索) (NT1). The publication follows the FDA's August 2026 approval of ORZEYFUL, making it the first approved orexin (搜索) therapy for adults with NT1 and, according to Takeda, the first and only medicine designed to treat the underlying cause of the disease rather than its individual symptoms.
The data come from the global FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002) studies, conducted across 19 countries. Both trials met their primary and secondary endpoints, demonstrating consistent, clinically meaningful and statistically significant improvements versus placebo in wakefulness, sleepiness, cataplexy, disease severity and quality of life across doses at Week 12, with p-values of <0.001. Improvements were observed at the earliest assessed timepoint for each measure and were sustained throughout the studies.
Trial Design and Patient Population
FirstLight enrolled 168 participants randomized to one of three dosing arms — twice-daily 2 mg, twice-daily 1 mg, or placebo — while RadiantLight enrolled 105 participants randomized to twice-daily 2 mg or placebo. The 14 primary and secondary endpoints assessed the effect of oveporexton on broad disease impact compared with placebo over 12 weeks. More than 95% of participants who completed the studies enrolled in the ongoing long-term extension study.
NT1 is a chronic, rare neurological disease driven by orexin (搜索) deficiency, caused by loss of orexin-producing neurons. Patients experience a range of daytime and nighttime symptoms including excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), disrupted nighttime sleep, sleep paralysis, hallucinations and cognitive symptoms. The persistent, 24-hour nature of the disease can severely impact work, education and social interactions.
Cataplexy and Disease Severity Outcomes
At Week 12, median percent reductions in weekly cataplexy rate ranged from 79.0% to 88.8% with oveporexton versus 27.7% to 39.1% with placebo. Oveporexton improved disease severity across all domains of the Narcolepsy Severity Scale (NSS-CT), including excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis across both doses, and in the disrupted nighttime sleep domain with the 2 mg dose. More than 70% of treated participants reported the lowest severity level on the NSS-CT (mild; score 0–14) across doses.
Nearly all treated participants (97%) reported improvements in overall narcolepsy symptoms as assessed by the self-rated Patient Global Impression of Change (PGI-C) scale. All dose groups achieved normative thresholds for wakefulness on the Maintenance of Wakefulness Test (MWT; ≥20 minutes) and on the Epworth Sleepiness Scale (ESS; score ≤10). Most participants reached or exceeded normal thresholds for quality-of-life outcomes measured by the 36-Item Short Form Survey (SF-36; secondary endpoint) and EuroQol-5 Dimensions 5-Levels (EQ-5D-5L; exploratory endpoint).
"People living with narcolepsy type 1 (搜索) face persistent symptoms across the day and night, which can impact many aspects of daily life," said Emmanuel Mignot, M.D., Ph.D., principal investigator for the FirstLight Phase 3 study. "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."
Safety and Tolerability Profile
Oveporexton was generally well tolerated, with a safety profile consistent with earlier clinical studies. The most commonly reported treatment-emergent adverse events across both studies were transient insomnia, urinary urgency, urinary frequency and excessive saliva. Most events were mild to moderate in intensity, started within two days of treatment and did not require medical intervention. Most insomnia events resolved within one week and did not impair daytime functioning, unlike traditional insomnia symptoms. Approximately half of urinary events resolved by Week 12, and unresolved events were all mild or moderate in severity.
In pooled Phase 3 data, insomnia developed in 60%, 55% and 1% of patients in the ORZEYFUL (搜索) 2 mg twice daily, 1 mg twice daily and placebo groups, respectively. Urinary frequency developed in 58%, 53% and 5%, and urinary urgency in 16%, 15% and 1%, respectively. Takeda notes these lower urinary tract symptoms are consistent with the drug's mechanism of action through OX2R (搜索) agonism on central micturition pathways. Asymptomatic creatine phosphokinase elevations >5x ULN were observed in 11% (21/196) of oveporexton-treated patients versus 5% (4/76) of placebo-treated patients; two cases involved markedly elevated CPK and transaminase levels, and both patients discontinued treatment. None of the cases were associated with myoglobinuria or renal impairment.
ORZEYFUL (搜索) is contraindicated in patients taking strong CYP3A inhibitors, and concomitant use with strong or moderate CYP3A inhibitors increases oveporexton exposure. Use should be avoided in patients with severe hepatic impairment (Child-Pugh C) or severe renal impairment on dialysis (eGFR <15 mL/minute), as the drug has not been studied in these populations. The controlled substance schedule is to be determined after review by the Drug Enforcement Administration, and the prescribing information is subject to change pending DEA scheduling and final label publication.
Regulatory Status and Broader Orexin Portfolio
Oveporexton previously received Breakthrough Therapy designation from the FDA for excessive daytime sleepiness in NT1 and Sakigake designation in Japan. It is now approved in the United States and Japan for adults with NT1, and in China for adolescents aged 16 and older as well as adults. Additional regulatory submissions are underway.
"Leveraging the extensive research we conducted on the impact of narcolepsy type 1 (搜索), we designed our comprehensive Phase 3 program to reflect the complexity of the disease and the experiences of those living with it," said Sarah Sheikh, M.Sc., B.M., B.Ch., MRCP, Head, Neuroscience Therapeutic Area Unit and Global Development at Takeda. "The magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of oveporexton to redefine how people feel on treatment."
Takeda is also investigating other oral orexin (搜索) agonists, including TAK-360 for NT1, narcolepsy type 2 (搜索) (NT2) and idiopathic hypersomnia (搜索) (IH), as well as TAK-495 (搜索).