BALTIMORE — The investigational orexin receptor 2 agonist oveporexton (Takeda) improved cognition, daily functioning, and nighttime sleep in patients with narcolepsy type 1 (NT1).

Results from two phase 3 trials add to previously reported results showing that oveporexton (also known as TAK-861) significantly improved wakefulness, excessive daytime sleepiness, and cataplexy frequency, as reported by Medscape Medical News.

“Narcolepsy is a 24-hour disease” with symptoms affecting patients during the day and night, said Elena Koundourakis, PhD, who leads the orexin franchise development & neuroscience programs at Takeda.

These new data, she said, suggest restoring orexin signaling may improve “the full spectrum” of NT1 symptoms — not just excessive daytime sleepiness and cataplexy but also cognition, functioning, and nighttime sleep.

The findings from the FirstLight and RadiantLight trials were presented on June 15 at SLEEP 2026.

Beyond Wakefulness

The trials evaluated the efficacy, safety, and tolerability of twice daily oral oveporexton vs placebo in 273 patients with NT1 over 12 weeks. More than 95% of participants who completed the studies enrolled in the ongoing long-term extension trial.

Compared with placebo, oveporexton led to statistically significant improvements in cognitive symptoms (P < .001) as measured using objective neuropsychological tests of attention, executive function, and memory.

Patient-reported cognitive symptoms also improved substantially. On the Functional Impacts of Narcolepsy Instrument (FINI) Cognitive Function domain, approximately 70% of patients receiving oveporexton reported no significant cognitive difficulties at week 12, compared with roughly 15% of those receiving placebo.

Across both studies, oveporexton also led to significant improvements in daily functioning at 12 weeks compared to placebo (P < .001) across the six domains of the FINI.

Notably, more than two thirds of patients taking oveporexton reached or exceeded published normative thresholds across most functional domains, indicating functional scores comparable to those seen in healthy populations.

Exploratory analyses indicated that the drug improved multiple aspects of nighttime sleep, including hallucinations, sleep paralysis, and disturbed nighttime sleep. Researchers also reported that rapid eye movement sleep timing and patterns shifted toward those observed in healthy individuals.

Targeting Overlooked Symptoms

“Sleepiness is the symptom that gets the most attention, but the cognitive symptoms and trouble with daytime functioning are often the most debilitating both personally and professionally,” Andrew Spector, MD, professor of neurology, Duke University School of Medicine in Durham, North Carolina, who wasn’t involved in the studies, told Medscape Medical News.

“It’s exciting to see a potential new option to help patients with these frequently overlooked challenges,” Spector added.

Raman Malhotra, MD, professor of neurology and section chief of sleep medicine, Washington University in St. Louis, who also wasn’t involved, agreed.

Trouble with cognitive and daily functioning are “major issues for narcolepsy patients as they try to be an effective worker, student, family member, or friend,” he told Medscape Medical News.

“As a field, we have typically targeted symptoms of narcolepsy patients such as daytime sleepiness, cataplexy, and disrupted sleep without attempting to fix the underlying pathophysiological issue, which is orexin deficiency,” Malhotra noted.

“Any new therapy that we can provide our patients so they can have an improved quality of life is exciting and, looking at the data, I think this new class of medications has promise to do this,” he said.

The FDA has accepted Takeda’s New Drug Application for oveporexton for NT1 and granted priority review with a target action date in the third quarter of this year.

The studies were funded by Takeda. Multiple investigators reported having served as consultants, advisory, research, or employment relationships with Takeda and other companies developing narcolepsy therapies. Spector and Malhotra had no relevant disclosures.