Key Takeaways of the TAK-861-2001 Trial
- Clinically Meaningful Efficacy: In the Phase II TAK-861-2001 trial, oveporexton significantly improved average sleep latency, reduced daytime sleepiness, and decreased cataplexy frequency in patients with narcolepsy type 1 (NT1), with effects exceeding those of currently approved therapies.
- Favorable Safety Profile: Unlike earlier OX2R-selective agonists, oveporexton showed no hepatotoxicity and had a manageable adverse event profile, with most side effects—such as insomnia and urinary urgency—being mild to moderate.
- Promising First-in-Class Potential: As a highly selective oral OX2R agonist, oveporexton may become a first-in-class therapy targeting the root cause of NT1, restoring orexin signaling and normalizing wakefulness in affected individuals.
Results from the Phase II TAK-861-2001 trial (NCT05687903) show the novel therapy oveporexton produced clinically meaningful improvements in wakefulness, daytime sleepiness, and cataplexy frequency in patients with narcolepsy type 1 (NT1).
Phase IIb Trial Explores Targeted Orexin Therapy for Narcolepsy Type 1
Findings from the study, published by The New England Journal of Medicine, indicate that oveporexton has superior efficacy compared to currently approved therapies while avoiding the hepatotoxicity linked to other OX2R-selective agonists, according to the authors.1,2
“[NT1] is a 24-hour disease making it very challenging to function and lead a healthy, productive life,” principal investigator Yves Dauvilliers, MD, director, Sleep-Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France, said in a press release. “Oveporexton is the leading investigational orexin receptor 2 agonist designed to address the underlying pathophysiology of NT1. The supporting data from Takeda’s Phase IIb trial demonstrated clinically meaningful improvements across the full spectrum of symptoms impacting people with NT1.”3
Mechanism of Action: Targeting Orexin Receptor 2
Patients with NT1 experience a significant loss of orexin-producing neurons, which causes low levels of orexin. This can subsequently lead to symptoms such as excessive daytime sleepiness, cataplexy, cognitive symptoms, disrupted nighttime sleep, hallucinations, and sleep paralysis.3
Oveporexton, a novel, highly selective oral OX2R agonist, was developed to cross the blood−brain barrier and has been found to improve wakefulness in sleep-deprived healthy adults in prior studies.
“Orexins act through two G-protein−coupled receptors, orexin receptor 1 and orexin receptor 2 (OX2R), with overlapping but distinct distributions within the brain,” the study authors wrote. “Although both receptors have roles in a range of physiological responses, OX2R has functions in wakefulness, rapid-eye-movement (REM) sleep, and prevention of cataplexy in animal models of narcolepsy.”1
TAK-861-2001 Study Overview: Design, Dosing, and Participant Demographics
The randomized, placebo-controlled TAK-861-2001 trial enrolled adults aged 18 to 70 years with a diagnosis of NT1 as per criteria of the International Classification of Sleep Disorders, Third Edition. Participants were randomly assigned via interactive response technology in a 1:1:1:1:1 ratio to receive once- or twice-daily oral oveporexton (n = 90) or matching placebo (n = 22).
Oveporexton was administered three hours apart at 8 am and 11 am for a duration of eight weeks. Patients in the oveporexton groups were randomly assigned to receive the drug at dose levels of 0.5 mg twice daily (n = 23), 2 mg twice daily (n = 21), 2 mg followed by 5 mg daily (n = 23), and 7 mg (n = 23) once daily.
The trial’s primary endpoint was mean change from baseline to week eight in average sleep latency on the Maintenance of Wakefulness Test (MWT), with secondary end points that included change from baseline to week eight in the Epworth Sleepiness Scale (ESS) total score, weekly cataplexy rate at week eight, and safety.
Efficacy Outcomes: Improvements in Wakefulness and Symptom Control
Results of the trial show the following:
- Patients across all dosing levels of oveporexton showed improvements in MWT compared to placebo, with mean changes from baseline to week eight in average sleep latency on the MWT at 12.5 in the 0.5 mg twice daily cohort; 23.5 in the 2 mg twice daily cohort; 25.4 in the 2 mg followed by 5 mg daily cohort; 15.0 in the 7 mg cohort; compared to −1.2 minutes with placebo (adjusted P≤0.001 for all comparisons vs. placebo).
- Mean changes in the ESS total score at week 8 were −8.9 in the 0.5 mg twice daily cohort; −13.8 in the 2 mg twice daily cohort; −12.8 in the 2 mg followed by 5 mg daily cohort; −11.3 in the 7 mg cohort; and −2.5 in the placebo cohort (adjusted P≤0.004 for all comparisons vs. placebo).
- Weekly incidence of cataplexy at week eight was 4.24 in the 0.5 mg twice daily cohort; 3.14 in the 2 mg twice daily cohort; 2.48 in the 2 mg followed by 5 mg daily cohort; 5.89 in the 7 mg cohort; and 8.76 in the placebo cohort (adjusted P<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo).
- The frequently reported adverse events associated with oveporexton were insomnia, reported by 48% of the participants; urinary urgency reported by 33% of participants; and urinary frequency reported by 32% of participants.
Comparison With Existing Narcolepsy Therapies
The study authors noted that dose-dependent improvements in patients administered oveporexton ranged from approximately 14 to 27 minutes for average sleep latency on the MWT, which is a significant improvement over the range of two to 12 minutes reported with currently available narcolepsy treatments.
“For people living with [NT1], going to work or attending school and managing everyday activities like driving, exercising or socializing with family and friends can become daunting challenges,” Sarah Sheikh, MD, MSc, BM, BCh, MRCP, head of the Neuroscience Therapeutic Area Unit and Global Development at Takeda, said in the release. “Our Phase IIb results suggest that restoring orexin signaling has the potential to help people with [NT1] 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.”3
References
1. Dauvilliers Y., et al. Oveporexton, an Oral Orexin Receptor 2–Selective Agonist, in Narcolepsy Type 1. N Engl J Med 2025;392:1905-1916. DOI: 10.1056/NEJMoa2405847. VOL. 392 NO. 19.
2. A Study of TAK-861 in Participants With Narcolepsy Type 1. ClinicalTrials.gov. Updated January 9, 2025. Accessed May 16, 2025. https://clinicaltrials.gov/study/NCT05687903
3. 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. News release. Takeda. https://www.businesswire.com/news/home/20250508841747/en/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
