Summary: Takeda’s orexin agonist oveporexton shows promise in phase 2b narcolepsy trial and moves on to phase 3.
Key Takeaways:
- 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.
The New England Journal of Medicine has published data from Takeda’s phase 2b trial of oveporexton (TAK-861) in people with narcolepsy type 1 (NT1). Oveporexton is an investigational oral orexin receptor 2-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, 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.
Principal investigator Yves Dauvilliers, MD, director of the Sleep-Wake Disorders Center in the department of Neurology at Gui de Chauliac Hospital, Montpellier, France, says in a release: “The supporting data from Takeda’s Phase 2b trial demonstrated clinically meaningful improvements across the full spectrum of symptoms impacting people with NT1.”
Sarah Sheikh, MD, MSc, BM, BCh, MRCP, head of the neuroscience therapeutic area unit and global development at Takeda, says in a release, “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 ages 18 to 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), 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 scores and reductions in weekly cataplexy rate across all doses compared to placebo and were sustained over 8 weeks.
- The Narcolepsy Severity Scale for Clinical Trials and the 36-item short-form used to assess quality of life were evaluated as exploratory endpoints. Scores indicated marked improvements across most domains (excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis) while clinically meaningful improvements in quality of life as assessed with the short form questionnaire were observed with all oveporexton dose groups compared to placebo.
- The most commonly reported treatment-emergent adverse events were insomnia (43%) and increased urinary urgency (30%) and frequency (29%). Most treatment-emergent adverse events 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 study, with many patients reaching one year or more of treatment.
Oveporexton, the lead program in Takeda’s orexin science 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.
