Oveporexton may ease daily life for people with narcolepsy type 1

Takeda’s experimental therapy oveporexton helped people with narcolepsy type 1 (NT1) improve measures of nighttime sleep, daily functioning, and cognitive symptoms.

That’s according to additional data from secondary and exploratory endpoints from two now-completed global Phase 3 studies, FirstLight (NCT06470828) and RadiantLight (NCT06505031), presented at SLEEP 2026, the annual meeting of the Associated Professional Sleep Societies, being held June 14-17 in Baltimore.

Previous results from the trials showed that oveporexton significantly reduced excessive daytime sleepiness and cataplexy, or sudden episodes of muscle weakness, two hallmark symptoms of NT1, while also improving disease severity and quality of life.

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Oveporexton may have broad benefits

According to Takeda, the new findings suggest oveporexton may improve a broad range of symptoms that affect people with NT1, extending its benefits beyond excessive daytime sleepiness and cataplexy. The company said the results further support the therapy’s potential to redefine the standard of care for the disease.

“Narcolepsy type 1 is not defined by a single symptom, which is why we designed a comprehensive Phase 3 program to evaluate the effect of oveporexton on the broad disease impact,” Sarah Sheikh, head of the neuroscience therapeutic area unit and global development at Takeda, said in a company press release. “We are grateful to the patients, caregivers and healthcare providers who have been a part of this journey.”

NT1 is caused by the loss of nerve cells that produce hypocretin, also known as orexin, a signaling molecule that’s important for regulating sleep-wake cycles, likely due to an autoimmune reaction. The resulting orexin deficiency causes excessive daytime sleepiness along with cataplexy, disrupted nighttime sleep, sleep paralysis (a temporary inability to move or speak during sleep-wake transitions), hallucinations, cognitive problems, and mood issues.

“Narcolepsy type 1 is a 24-hour disease driven by orexin deficiency, and while excessive daytime sleepiness and cataplexy are the most recognized symptoms, many people experience additional bothersome symptoms such as cognitive difficulties and disrupted nighttime sleep,” said Emmanuel Mignot, MD, PhD, principal investigator of the FirstLight study.

Phase 3 studies tested two doses

Oveporexton, formerly known as TAK-861, is an investigational oral therapy designed to restore orexin signaling. By binding to and activating orexin receptor 2, or OX2R, the therapy aims to address the broad spectrum of daytime and nighttime symptoms associated with NT1.

The two Phase 3 studies tested oveporexton over 12 weeks in people with NT1. FirstLight enrolled 168 participants who were randomly assigned to receive one of two doses of oveporexton — 1 mg or 2 mg twice daily — or a placebo. RadiantLight enrolled 105 participants who were randomly assigned to receive oveporexton at a dose of 2 mg twice daily or a placebo. More than 95% of participants who completed the studies enrolled in an ongoing long-term extension study.

Top-line results reported last year showed that oveporexton significantly reduced excessive daytime sleepiness and weekly cataplexy attacks compared with a placebo. Most participants receiving the 2 mg twice-daily dose achieved daytime wakefulness in the normal range, and close to 85% had excessive daytime sleepiness scores comparable to those of healthy individuals.

The therapy also significantly reduced overall disease severity, with more than 70% of participants reporting only mild symptoms after treatment, while also improving quality-of-life scores to the normal range. Oveporexton was generally well tolerated, with no treatment-related serious adverse events reported.

The new data showed that, across all doses, oveporexton significantly improved daily functioning compared with the placebo. Benefits were seen across all six areas measured by the Functional Impacts of Narcolepsy Instrument (FINI), including tiredness, cognitive functioning, cataplexy, social activities, everyday activities, and everyday responsibilities. Most participants reached or exceeded published benchmarks for typical daily functioning.

Oveporexton also eased cognitive symptoms associated with NT1. Benefits were seen on tests of attention, executive function, and memory, as well as on patient-reported measures. On the FINI cognitive function domain, about 70% of participants receiving oveporexton reported no significant cognitive difficulties, compared with about 15% of those given the placebo.

Nighttime sleep measures also improve

Exploratory analyses showed improvements in nighttime sleep. Across all doses, most participants reported no hallucinations or sleep paralysis, and most people receiving the 2 mg twice-daily dose experienced meaningful reductions in disrupted nighttime sleep. Researchers also found that the timing and pattern of REM sleep (a period of high brain activity and vivid dreaming) shifted toward those seen in healthy individuals.

“Oveporexton has demonstrated significant improvement across a broad range of NT1 symptoms, daily functioning and quality of life, with the potential to shift disease management beyond incremental symptom relief,” Mignot said.

The therapy is currently under review by the U.S. Food and Drug Administration (FDA), which has accepted Takeda’s application seeking approval of oveporexton for NT1 and granted it priority review. A decision is expected in the third quarter of this year. Regulatory applications are also under review in China and Japan, with additional submissions planned this year.

“With oveporexton under review by multiple regulatory agencies, we are on the cusp of bringing the first and only orexin agonist to the narcolepsy type 1 community, with the potential to redefine the standard of care if approved,” Sheikh said.