The New England Journal of Medicine Publishes Data from Phase 2b Trial of Oral Orexin Receptor 2 Agonist Oveporexton (TAK-861) in People with Narcolepsy Type 1

–Data Demonstrated Statistically Significant Improvements in Primary and Secondary Endpoints with Most Subjects Achieving Near Normal Ranges of Wakefulness and Clinically Meaningful Improvements Across the Broad Range of Symptoms Investigated–Oveporexton Found to be Generally Safe and Well Tolerated–Phase 3 Readout of Oveporexton Anticipated in 2025

Takeda (TSE: 4502/NYSE:TAK) today announced that the New England Journal of Medicine published data from the Phase 2b trial of oveporexton (TAK-861) in people with narcolepsy type 1 (NT1). Oveporexton is an investigational oral orexin receptor 2 (OX2R)-selective agonist designed to restore orexin signaling to address the underlying orexin deficiency that causes NT1. Results demonstrated significant improvement in objective and subjective measures of excessive daytime sleepiness (EDS), reductions in cataplexy events and clinically meaningful improvements in disease severity and quality of life across all doses tested compared to placebo through eight weeks of treatment.

NT1 is a severe, chronic neurological condition caused by a significant loss of orexin-producing neurons, resulting in low levels of orexin leading to EDS, cataplexy (sudden loss of muscle tone), cognitive symptoms, disrupted nighttime sleep, hallucinations that occur as one falls asleep or wakes up and sleep paralysis.These debilitating symptoms can markedly reduce an individual’s quality of life and severely impact job performance, academic achievement and personal relationships. Current standard of care includes polypharmacy to manage different symptoms, but none of these medicines target the underlying orexin deficiency that causes NT1.

“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.”

“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. We are working diligently to further investigate oveporexton and its potential to become the first-in-class, transformative therapeutic option for people living with NT1.”

TAK-861-2001 Phase 2b Trial in NT1

The TAK-861-2001 Phase 2b trial enrolled 112 adults aged 18−70 with NT1 globally. Participants were randomized equally to one of four dosing arms (twice-daily 0.5/0.5 mg, 2/2 mg, 2/5 mg or once-daily 7 mg) or placebo for 8 weeks. The primary and secondary endpoints from the study assessed the impact of oveporexton across subjective and objective measures of wakefulness and daytime sleepiness, cataplexy rates and safety compared to placebo.

Results from the Phase 2b trial showed:

• The primary endpoint demonstrated substantial increases in mean sleep latency on the Maintenance of Wakefulness Test (MWT), a key measure of wakefulness, with improvements across all doses compared to placebo (adjusted p ≤0.001 for all comparisons) sustained over 8 weeks. The mean sleep latency on the MWT reached values consistent with normative values seen in healthy individuals.
• Key secondary endpoints demonstrated significant reductions in Epworth Sleepiness Scale (ESS) scores, a measure of EDS, and reductions in Weekly Cataplexy Rate (WCR) across all doses compared to placebo and were sustained over 8 weeks.
• The Narcolepsy Severity Scale for Clinical Trials (NSS-CT), a self-assessment scale used to assess the severity, frequency and impact across narcolepsy symptoms, and the 36-item short-form (SF-36), used to assess quality of life, were evaluated as exploratory endpoints. NSS-CT domain scores indicated marked improvements across most domains (EDS, cataplexy, hypnagogic hallucinations and sleep paralysis) while clinically meaningful improvements in quality of life as assessed with the SF-36 questionnaire were observed with all oveporexton dose groups compared to placebo.
• The most commonly reported treatment-emergent adverse events (TEAEs) were insomnia (43%), increased urinary urgency (30%) and frequency (29%). Most TEAEs were mild to moderate in intensity, and most started within 1-2 days of treatment and were 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 (LTE) study, with many patients reaching one year or more of treatment.

Takeda is leading the field of orexin science with a multi-asset franchise. Oveporexton, the lead program in the franchise, is the first and only orexin agonist in Phase 3 trials. Takeda anticipates a data readout from the Phase 3 trials in calendar year 2025.

About Takeda’s Orexin Agonists for Sleep Wake-Disorders

Takeda is pioneering the field of orexin science with a multi-asset franchise offering tailored treatments. Orexin is a key regulator of the sleep-wake cycle and is involved in other essential functions, including respiration and metabolism. Oveporexton (TAK-861) is the leading investigational asset in this franchise and 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 progressing orexin agonists in patient populations with normal levels of orexin neuropeptides and other indications where orexin biology is implicated. This includes TAK-360, an oral OX2R agonist being investigated for narcolepsy type 2 and idiopathic hypersomnia, which received Fast Track designation from the FDA.

About Takeda

Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

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