Secondary Analysis Finds Oveporexton Improves Cognitive Function in Adults With Narcolepsy Type 1

A secondary analysis of exploratory outcomes from a randomized phase 2 clinical trial (NCT05687903) reported moderate- to large-magnitude effects of oveporexton (TAK-861; Takeda Pharmaceuticals), an oral orexin receptor 2, on cognitive measures in adults with narcolepsy type 1 (NT1). Overall, these findings suggest that selective orexin receptor 2 (OX2R) agonism with oveporexton may improve cognitive symptoms in this patient population.¹

Published in JAMA Neurology, the aim of this analysis was to determine if overporexton treatment was associated with cognitive improvements such as attention, memory, or executive function, over 8 weeks of daily dosing. Cognitive symptoms were assessed using the Psychomotor Vigilance Task (PVT) for attention, the Continuous Paired Associate Learning (CPAL) test for memory, and the One Back (ONB) test and International Digit Symbol Substitution Test–symbols (IDSST-s) for executive function. This analysis differed from the initial phase 2 (TAK-861-2001; NCT05687903) trial where the cognitive benefits of overporexton were recorded but not considered for the trial’s primary or secondary endpoints.

Led by Gert Jan Lammers, MD, PhD, professor of neurology at the Leiden University Medical Centre in Leiden, Netherlands, study analyzed 112 participants (58 female [51.8%]; mean age of 34 [SD, 11.5] years) included in the phase 2 trial who were randomized 1:1:1:1:1 to twice-daily oral oveporexton or matching placebo. Participants were dosed 3 hours apart, in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks.

All told, results from the study indicated that oveporexton improved attention, memory, and executive function over 8 weeks. More specifically, least-squares (LS) mean placebo-adjusted changes from baseline in PVT lapses were −10.77 (95% CI, −16.74 to −4.79), −9.45 (95% CI, −15.66 to −3.24), −8.60 (95% CI, −14.84 to −2.36), and −8.69 (95% CI, −14.90 to −2.47) with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively. Corresponding LS mean placebo-adjusted changes for CPAL errors were −22.52 (95% CI, −34.95 to −10.10), −16.92 (95% CI, −30.12 to −3.71), −15.51 (95% CI, −28.82 to −2.21), and −17.59 (95% CI, −30.50 to −4.68).

Additional cognitive benefits were observed across measures of working memory, processing speed, and executive function. LS mean placebo-adjusted changes in ONB log₁₀-transformed performance speed were −0.05 (95% CI, −0.10 to −0.01), −0.07 (95% CI, −0.12 to −0.02), −0.07 (95% CI, −0.12 to −0.02), and −0.05 (95% CI, −0.10 to 0.00) units, respectively. Improvements in IDSST-s correct responses were 4.72 (95% CI, −1.38 to 10.83), 7.33 (95% CI, 1.06 to 13.61), 7.85 (95% CI, 1.75 to 13.95), and 11.82 (95% CI, 5.75 to 17.89) across the same dose groups.

The initial results of the phase 2 trial, presented at the 2025 SLEEP Annual Meeting, held June 8 to 11, in Seattle, Washington, showed that patients on oveporexton demonstrated significant reductions in microsleep rates and delayed the first occurrence of microsleep in patients with NT1. Study investigators concluded that these findings first highlighted the potential of overporexton as an effective treatment for daytime sleepiness in adults with NT1.²

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Results from the phase 2 trial indicated that across all overporexton treatment groups, microsleep rates prior to sleep onset decreased significantly from 6 microsleeps per 10 minutes at baseline to fewer than 2 per 10 minutes by 4 and 8 weeks. Additional findings revealed that all treatment groups experienced a statistically significant prolongation in time-to-first microsleep compared with baseline (P <.005).

In the phase 2 trial, researchers reported that the average microsleep duration, excluding participants who experienced no microsleeps, did not show significant change in any treatment arm. Furthermore, participants in the placebo group exhibited minimal changes in microsleep frequency and timing across sessions and study visits.

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REFERENCES
1. Lammers GJ, Plazzi G, Mignot E, et al. Effects of Oveporexton, an Orexin Receptor 2–Selective Agonist, on Cognition in Narcolepsy Type 1: A Secondary Analysis of a Randomized Clinical Trial. JAMA Neurol. Published online December 08, 2025. doi:10.1001/jamaneurol.2025.4825
2. Gong Y, Tracey B, Olsen M, et al. Treatment with an Orexin Agonist Reduces Microsleeps and Improves Wakefulness During MWT in People with NT1. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, WA. ABSTRACT 0847.