Oveporexton Improves Cognition in Narcolepsy Type 1

Oveporexton, an investigational agent for narcolepsy type 1 (NT1) that improved hallmark symptoms of sleep latency, excessive daytime sleepiness (EDS) and cataplexy in a phase 2 clinical trial, was found in secondary analysis² to have also improved measures of cognition.¹

"Cognitive symptoms—attention, memory, and executive function—are often overlooked in NT1, yet they can persist even beyond sleep-related challenges," study coauthor Brian Harel, PhD, JD, Takeda Development Center Americas, Cambridge, MA, remarked to Psychiatric Times.

"These symptoms are one of the most frequent and burdensome symptoms of the disorder and are not currently well addressed by current standard of care," Harel observed.

The 8-week, parallel-group, dose-finding controlled trial randomized participants to receive placebo or one of several oveporexton twice daily dose regimens. Each participant (18 to 70 years) had been diagnosed with NT1 in accordance with criteria of the International Classification of Sleep Disorders, 3rd edition, and confirmed by nocturnal polysomnography and a Multiple Sleep Latency Test within the previous 10 years.

Each participant was also determined to have orexin deficiency in the presence of catalepsy—either by a cerebrospinal fluid orexin-A (hypocretin-1) concentration of less than 110 pg/ml or a positive test for HLA genotype HLA-DQB1*06:02—and so were candidates for the investigational orexin receptor 2-selective agonist targeting that underlying mechanism of NT1.

The initial report of the trial described oveporexton effectiveness in improving sleep latency, EDS, and catalepsy. Cognitive tests which had been administered but not initially analyzed were the Psychomotor Vigilance Task (PVT), a test of sustained attention; the Continuous Paired Associated Learning (CPAL) test of memory; and measures of executive function on the International Digit Symbol Substitution Test-symbols version (IDSST-s) test of processing speed and the One Back test (ONB) of working memory.

Magnitude of Drug Effect

Harel and colleagues analyzed the data from 109 participants who remained in the study at week 8 and had completed all 4 cognitive tests, finding all treatment groups comparable at baseline testing. For the PVT, the investigators reported that the mean (SD) number of lapses increased after 8 weeks of placebo, but had decreased by 9.3 (16.30), 6.4 (17.12), 6.2 (13.29) and 1.7 (18.52) with twice daily oveporexton dosing of 0.5/0.5mg, 2/2mg, 2/5mg, and 7mg/0 (placebo), respectively. They noted that the magnitude of differences from placebo for each dosage treatment group was large, and that the effects were qualitatively similar in the 1-hour and 7-hour post-dose assessments.

For the CPAL, the number of errors made in learning the 8 pattern-location associations increased by 3.5 (38.31) in the placebo group, while there were substantial reductions with oveporexton. At testing after 8 weeks of treatment, the errors decreased by 22.4 (25.91), 15.9 (38.13), 13.2 (30.81), and 19.0 (28.06), with oveporexton doses of 0.5/0.5mg, 2/2mg, 2/5mg, and 7mg/0, respectively. The investigators rated the effect size differences from placebo as medium to large.

On the ONB, the placebo group's time to correct responses remained unchanged, but was shortened by 0.04 (0.09), 0.07 (0.16), 0.06 (0.08), and 0.04 (0.09) log10 ms with oveporexton doses of 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/0, respectively. These differences for each treatment group were also deemed medium and large in magnitude.

Changes in the mean number of correct responses on the IDSST-s increased in all groups, including placebo, which the investigators attributed, in part, to repeated application of the test. The increases in the active drug groups, however, did exceed those with placebo, by small to large magnitude.

Harel considered the questions of whether the changes in cognitive test measures are clinically significant, and if they might reflect general improvement in NT1 rather than drug-specific effect. Although acknowledging that the phase 2 trial had not formally assessed whether patients perceived a benefit to their cognitive function following treatment with oveporexton, he does find it likely, and indicated that they are pursuing that possibility further in phase 3.

"We saw improvements in cognitive symptoms at week 4 in the phase 2 trial. The effects were by convention large at week 8, which certainly suggests they were clinically meaningful," Harel commented. "We did assess this in phase 3 and found a substantial benefit to cognitive symptoms with oveporexton compared to placebo," he added.

Harel expects the improvements on the cognitive tests will be attributed to the oveporexton mechanism of action. "Since oveporexton is designed to address the underlying orexin deficiency that causes NT1 by restoring orexin signaling, we do believe the improvements we are seeing in cognitive symptoms are considered a drug-specific effect," he indicated.

"While other medicines may improve cognitive symptoms, they may not improve all aspects of the cognitive symptoms associated with NT1, and may not improve them to the same extent, and the improvements may simply be secondary to improvements in EDS," Harel said.

References
1. Dauvilliers Y, Plazzi G, Mignot E, et al. Oveporexton, an oral orexin receptor 2-selective agonist, in narcolepsy type 1. N Engl J Med. 2025; 392:1905-1915.

2. 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. 2026; 83(2):145-152.