Takeda Pharmaceutical Company announced today that the New England Journal of Medicine has published promising data from its Phase 2b trial of oveporexton (TAK-861) in patients with narcolepsy type 1 (NT1). The results demonstrate significant improvements across multiple symptoms of this debilitating neurological disorder.
The trial evaluated oveporexton, an investigational oral orexin receptor 2 (OX2R)-selective agonist designed to address the underlying orexin deficiency that causes NT1. Unlike current treatments that manage individual symptoms, oveporexton targets the root cause of the disease.
Significant Clinical Improvements Across Multiple Measures
The Phase 2b trial enrolled 112 adults aged 18-70 with NT1 globally. Participants were randomized to receive one of four dosing regimens (twice-daily 0.5/0.5 mg, 2/2 mg, 2/5 mg, or once-daily 7 mg) or placebo for 8 weeks.
Results showed substantial increases in mean sleep latency on the Maintenance of Wakefulness Test (MWT), a key objective measure of wakefulness, with statistically significant improvements across all doses compared to placebo (adjusted p ≤0.001). Notably, the mean sleep latency on the MWT reached values consistent with those seen in healthy individuals.
"Narcolepsy type 1 is a 24-hour disease making it very challenging to function and lead a healthy, productive life," said principal investigator Yves Dauvilliers, M.D., Director, Sleep-Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France. "Oveporexton is the leading investigational orexin receptor 2 agonist designed to address the underlying pathophysiology of NT1. The supporting data from Takeda's Phase 2b trial demonstrated clinically meaningful improvements across the full spectrum of symptoms impacting people with NT1."
Key secondary endpoints also showed significant improvements, including reductions in Epworth Sleepiness Scale (ESS) scores, a measure of excessive daytime sleepiness (EDS), and reductions in Weekly Cataplexy Rate (WCR) across all doses compared to placebo. These improvements were sustained throughout the 8-week treatment period.
Addressing the Underlying Cause of Narcolepsy Type 1
NT1 is a severe, chronic neurological condition caused by a significant loss of orexin-producing neurons. This deficiency leads to excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), cognitive symptoms, disrupted nighttime sleep, hallucinations, and sleep paralysis. These symptoms can significantly impact quality of life, job performance, academic achievement, and personal relationships.
Current standard of care typically involves multiple medications to manage different symptoms, but none target the underlying orexin deficiency that causes NT1.
"For people living with narcolepsy type 1, going to work or attending school and managing everyday activities like driving, exercising or socializing with family and friends can become daunting challenges," said Sarah Sheikh, M.D., M.Sc., B.M., B.Ch., MRCP, Head of the Neuroscience Therapeutic Area Unit and Global Development at Takeda. "Our Phase 2b results suggest that restoring orexin signaling has the potential to help people with narcolepsy type 1 achieve near normal ranges of wakefulness as seen in healthy individuals while also positively impacting the broader spectrum of the disease."
Improvements in Disease Severity and Quality of Life
The trial also evaluated exploratory endpoints including the Narcolepsy Severity Scale for Clinical Trials (NSS-CT) and the 36-item short-form (SF-36) quality of life assessment. NSS-CT domain scores indicated marked improvements across most domains, including excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis.
Clinically meaningful improvements in quality of life, as assessed with the SF-36 questionnaire, were observed with all oveporexton dose groups compared to placebo.
Safety Profile and Ongoing Research
The most commonly reported treatment-emergent adverse events were insomnia (43%), increased urinary urgency (30%), and frequency (29%). Most adverse events were mild to moderate in intensity, typically starting within 1-2 days of treatment and proving transient. No cases of hepatotoxicity or visual disturbances were reported.
The majority of participants (95%) who completed the trial enrolled in the long-term extension study, with many patients reaching one year or more of treatment.
Leading the Field in Orexin Science
Takeda is pioneering the field of orexin science with a multi-asset franchise. Oveporexton, the lead program in this franchise, is the first and only orexin agonist in Phase 3 trials. The drug has received Breakthrough Therapy designation for the treatment of excessive daytime sleepiness in narcolepsy type 1 from the U.S. Food and Drug Administration (FDA) and Center for Drug Evaluation of China's National Medical Products Administration.
The company is also developing TAK-360, an oral OX2R agonist being investigated for narcolepsy type 2 and idiopathic hypersomnia, which has received Fast Track designation from the FDA.
Takeda anticipates a data readout from the Phase 3 trials of oveporexton in calendar year 2025, potentially bringing this first-in-class therapeutic option closer to patients with NT1.
