Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1
Yves Dauvilliers1,2, Giuseppe Plazzi3,4, Emmanuel Mignot5
1National Reference Network for Narcolepsy, Sleep and Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France.
Background:
Narcolepsy type 1 is a disorder of hypersomnolence caused by a loss of orexin neurons, which results in low orexin levels in the brain.
Methods:
In this phase 2, randomized, placebo-controlled trial, participants with narcolepsy type 1 received once- or twice-daily oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes; normal, ≥20). Secondary end points included the change from baseline to week 8 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, ≤10), the weekly cataplexy rate at week 8, and the occurrence of adverse events.
Results:
A total of 90 participants received oveporexton (0.5 mg twice daily, 23 participants; 2 mg twice daily, 21 participants; 2 mg followed by 5 mg daily, 23 participants; and 7 mg once daily, 23 participants), and 22 received placebo. The mean changes from baseline to week 8 in average sleep latency on the MWT were 12.5, 23.5, 25.4, 15.0, and -1.2 minutes, respectively (adjusted P≤0.001 for all comparisons vs. placebo). The mean changes in the ESS total score at week 8 were -8.9, -13.8, -12.8, -11.3, and -2.5, respectively (adjusted P≤0.004 for all comparisons vs. placebo). The weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, 5.89, and 8.76, respectively (adjusted P<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo). The most common adverse events associated with oveporexton were insomnia (in 48% of the participants; most cases resolved within 1 week), urinary urgency (in 33%), and urinary frequency (in 32%), without any hepatotoxic effects.
Conclusions:
In this phase 2 trial involving participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks. (Funded by Takeda Development Center Americas; TAK-861-2001 ClinicalTrials.gov number, NCT05687903.).
Insights
Oveporexton significantly improved wakefulness and reduced sleepiness and cataplexy in narcolepsy type 1 patients. This oral orexin receptor 2 agonist shows promise for treating this rare neurological disorder.
Area of Science:
- Neurology
- Sleep Medicine
- Pharmacology
Background:
- Narcolepsy type 1 is characterized by hypersomnolence due to the loss of orexin neurons and subsequent low orexin levels.
- Understanding the orexin system is crucial for developing targeted narcolepsy treatments.
Purpose of the Study:
- To evaluate the efficacy and safety of oveporexton (TAK-861), an orexin receptor 2-selective agonist, in patients with narcolepsy type 1.
- To assess the impact of different dosing regimens of oveporexton on key narcolepsy symptoms.
Main Methods:
- A phase 2, randomized, placebo-controlled trial was conducted.
- Participants received once- or twice-daily doses of oveporexton or a placebo.
- Primary endpoint: mean change in sleep latency on the Maintenance of Wakefulness Test (MWT) at 8 weeks.
Main Results:
- Oveporexton significantly improved sleep latency on the MWT compared to placebo across all tested doses (adjusted P≤0.001).
- Significant improvements were also observed in the Epworth Sleepiness Scale (ESS) scores (adjusted P≤0.004).
- Oveporexton reduced the weekly incidence of cataplexy for specific dosing regimens (adjusted P<0.05).
Conclusions:
- Oveporexton demonstrated significant efficacy in improving wakefulness, reducing sleepiness, and decreasing cataplexy in patients with narcolepsy type 1 over 8 weeks.
- The study supports oveporexton as a potential therapeutic agent for narcolepsy type 1.
- Common adverse events included insomnia, urinary urgency, and frequency, with no observed hepatotoxicity.
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