medwireNews: The TAK-861-2001 trial has found that oveporexton treatment results in clinically meaningful improvements in wakefulness, daytime sleepiness, and cataplexy in patients with narcolepsy type 1.
Also, oveporexton was associated with mostly mild to moderate adverse events that resolved without medical intervention, and there were no hepatotoxic effects, note the investigators.
The phase 2, double-blind trial tested the efficacy and safety of the oral orexin receptor-2 selective agonist in 112 patients with type 1 narcolepsy. The participants had a baseline Epworth Sleepiness Scale (ESS) total score of more than 12 points, at least four episodes of partial or complete cataplexy per week during screening, and a high likelihood of orexin deficiency in the presence of cataplexy. The mean age of the participants was 34 years and 52% were women.
The participants were randomly assigned to receive once- or twice-daily oral oveporexton or matching placebo, administered 3 hours apart for 8 weeks: 0.5 mg twice daily (n=23), 2 mg twice daily (n=21), 2 mg and 5 mg daily (n=23), 7 mg once daily (n=23), or placebo twice daily (n=22).
Average sleep latency on the Maintenance of Wakefulness Test (MWT) improved significantly with oveporexton treatment, at all doses, from 3.6–5.6 minutes before treatment to 16.5–30.7 minutes after 8 weeks, with respective mean increases at each dose of 12.5, 23.5, 25.4, and 15.0 minutes, respectively.
By comparison, average sleep latency worsened among patients in the placebo group, decreasing from 6.1 minutes to 4.7 minutes at 8 weeks, giving a least squares mean improvement with oveporexton over placebo of 13.7–26.6 minutes.
After 8 weeks of treatment, 37–81% of participants receiving oveporexton had an average sleep latency on the MWT of 20 minutes or more, “the duration in healthy persons,” compared with 5% of participants in the placebo group, say Tina Olsson, from the Takeda Development Center Americas Inc in Cambridge, Massachusetts, USA, and colleagues. They add that such values were “reached by week 4, and the effect was maintained at week 8.”
Patients in the oveporxeton group also had significantly greater dose-dependent reductions in ESS total score after 8 weeks of treatment than those in the placebo group. Mean scores decreased from a respective 18.0–19.0 points and 18.6 points at baseline to 4.8–4.9 points and 16.0 points. At week 8, 67–95% of participants receiving oveporexton had an ESS total score of 10 points or lower, compared with 19% of participants in the placebo group.
The weekly incidence of cataplexy (assessed through completion of an electronic participant-reported outcome diary) decreased in both groups by week 8, but to a greater extent in those taking oveporxeton, from a mean 15.7–31.1 episodes to 2.1–10.1 episodes, compared with a mean decrease from 23.1 to 9.0 episodes in patients given placebo. The researchers note that the incidence rate ratios for cataplexy decreased with increasing oveporexton dose, with significant differences compared with placebo seen at doses of 2 mg twice daily and 2 mg and 5 mg daily.
Olsson and co-authors say that their findings were “supported by improvements in disease severity,” with Narcolepsy Severity Scale for Clinical Trial (NSS-CT) scores increasing by a mean of 28.7 points before to 33.5 points after 8 weeks of oveporexton treatment, compared with a decrease from 32.5 to 26.8 points with placebo. At week 8, a total of 65–91% of participants in the oveporexton arm reported only mild disease on the NSS-CT (0–14 points), compared with just 10% of those in the placebo arm.
The investigators also report that “clinically meaningful improvements in quality of life were observed with all oveporexton doses as compared with placebo.” These occurred at weeks 4 and 8 for the SF-36 mental component summary score, and at week 8 for the SF-36 physical component summary score.
Adverse events were experienced by 78% of 90 participants receiving oveporexton and 32% of 22 receiving placebo. The most common adverse events with oveporexton were insomnia, increased urinary urgency, and increased urinary frequency. Most cases of insomnia resolved within 1 week. Seven participants in the oveporexton arm had at least one severe adverse event (including a broken ankle unrelated to treatment). No hepatotoxic effects attributable to oveporexton were reported.
“Although the trial was not designed to compare the efficacy of oveporexton with that of other narcolepsy medications, dose-dependent improvements of nearly 14 to 27 minutes in average sleep latency on the MWT with oveporexton were markedly greater than mean improvements of 2 to 12 minutes observed with currently available narcolepsy medications,” say the researchers in The New England Journal of Medicine.
They conclude that “[t]o confirm these results, a phase 3 trial has been initiated, and a long-term extension study is ongoing.”
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