Oveporexton shows promise in improving wakefulness in narcolepsy type 1

Research led by Gui de Chauliac Hospital in Montpellier, France, and the University of Bologna in Italy reports that oveporexton improves wakefulness and reduces cataplexy episodes in patients with narcolepsy type 1. Findings suggest a potential therapeutic alternative to existing narcolepsy treatments without hepatotoxic effects associated with other treatment types.

Narcolepsy type 1 is a neurological disorder marked by excessive daytime sleepiness and episodes of muscle weakness known as cataplexy. Orexin, a neuropeptide crucial for regulating wakefulness and preventing rapid-eye-movement (REM) sleep transitions, is deficient in patients with narcolepsy type 1. Current treatments primarily address symptoms without targeting the underlying orexin system itself.

Previous efforts have successfully targeted orexin receptor 2 (OX2R) to restore wakefulness and reduce cataplexy in patients with OX2R-targeting drugs. Liver-related side effects have so far limited clinical use, and the need for safe OX2R-targeting agents remains.

In the study, “Oveporexton, an Oral Orexin Receptor 2–Selective Agonist, in Narcolepsy Type 1,” published in The New England Journal of Medicine, researchers conducted a Phase II, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of oveporexton in patients with narcolepsy type 1.

The trial included a total of 112 adults aged 18 to 70 from multiple international sites, including the United States, Europe, and Japan. Participants underwent randomization using interactive response technology to receive one of five dosing regimens administered orally over eight weeks: 0.5 mg twice daily, 2 mg twice daily, 2 mg followed by 5 mg daily, 7 mg once daily, or placebo.

Wakefulness was assessed using the Maintenance of Wakefulness Test (MWT), which measures the time it takes to fall asleep under soporific conditions.

Daytime sleepiness was quantified using the Epworth Sleepiness Scale (ESS), with higher scores indicating greater sleepiness. Cataplexy frequency was recorded through participant-reported diaries, with episodes averaged over two-week periods.

Participants receiving oveporexton demonstrated significant improvements in wakefulness and reductions in cataplexy episodes compared to those receiving placebo.

Average sleep latency on the Maintenance of Wakefulness Test (MWT) increased by 12.5 to 25.4 minutes across oveporexton dosing regimens, while the placebo group experienced a decrease of 1.2 minutes.

ESS scores decreased by 8.9 to 13.8 points among those receiving oveporexton, indicating reduced daytime sleepiness. The placebo group experienced a 2.5-point reduction.

Participants receiving placebo reported an average of 8.76 cataplexy episodes per week.

In comparison, the 0.5 mg twice-daily group averaged 4.24 episodes per week, the 2 mg twice-daily group averaged 3.14 episodes per week, and the 2 mg followed by 5 mg daily group averaged 2.48 episodes per week. Only the 2 mg twice-daily and 2 mg followed by 5 mg daily regimens demonstrated statistically significant reductions in cataplexy frequency, suggesting a dose-dependent effect in reducing cataplexy episodes.

Participants receiving oveporexton reported a high incidence of insomnia (48%), urinary urgency (33%), and urinary frequency (32%), though none of these adverse events led to treatment discontinuation. Significant improvements were observed in disease severity on the Narcolepsy Severity Scale for Clinical Trials (NSS-CT) and in quality-of-life scores on the 36-Item Short Form Survey (SF-36).

Researchers conclude that oveporexton significantly improved wakefulness, reduced daytime sleepiness, and lowered cataplexy frequency over the eight-week study period.

Unlike other orexin receptor agonists in development, oveporexton did not result in liver-related side effects, suggesting a potentially safer therapeutic profile for long-term use.

Further studies, including a Phase III trial and a long-term extension study, are ongoing to confirm the efficacy and safety of oveporexton.

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