Narcolepsy pill brings wakefulness to normal levels in two trials

Two phase 3 trials of oveporexton, the first approved drug that works by replacing the missing brain signal behind narcolepsy type 1, were published in the New England Journal of Medicine on 9 September 2026. In both, people taking the twice-daily tablet reached normal levels of wakefulness on standard tests, and cataplexy attacks fell by around 80% or more.

The drug, sold as Orzeyful by Takeda, was approved by the US Food and Drug Administration (FDA) on 5 August 2026 for adults with narcolepsy type 1. It is also approved in Japan and China.

What goes wrong in narcolepsy type 1

Narcolepsy type 1 (NT1) is a chronic, rare neurological condition. It is caused by the loss of brain cells that make orexin, sometimes called hypocretin, a chemical messenger that keeps us awake and stabilises the line between sleep and wakefulness.

Without orexin, people experience:

• excessive daytime sleepiness, often with sudden urges to sleep
• cataplexy, a sudden loss of muscle tone, often triggered by laughter or strong emotion
• disrupted night-time sleep
• sleep paralysis and vivid hallucinations when falling asleep or waking

Existing treatments, such as stimulants, sodium oxybate and pitolisant, manage individual symptoms. None replaces the orexin signal itself.

How oveporexton works

Oveporexton is an oral orexin receptor 2 agonist. In plain terms, it switches on the receptor that orexin would normally activate. Takeda describes it as treating the underlying cause of NT1, because it restores the signal that the brain can no longer produce.

The two trials

The NEJM paper, led by Yves Dauvilliers and Emmanuel Mignot, reports two 12-week, placebo-controlled studies:

• FirstLight enrolled 168 people, randomised to 2 mg twice daily, 1 mg twice daily or placebo
• RadiantLight enrolled 105 people, randomised to 2 mg twice daily or placebo

Together the trials tested 14 main and secondary measures. More than 95% of those who completed the studies chose to continue in a long-term extension.

The results

Takeda reports statistically significant improvements against placebo (P<0.001) across wakefulness, sleepiness, cataplexy, disease severity and quality of life, at every dose. The improvements appeared at the first time point measured and lasted through the 12 weeks.

Wakefulness and sleepiness. All dose groups reached normal thresholds on two standard tests:

• the Maintenance of Wakefulness Test, where staying awake for 20 minutes or more is considered normal
• the Epworth Sleepiness Scale, where a score of 10 or less is considered normal

That is notable because current medicines often improve sleepiness without bringing people into the normal range.

Cataplexy. At week 12, the median fall in weekly cataplexy attacks was 79.0% to 88.8% with oveporexton, against 27.7% to 39.1% with placebo, depending on the study and dose.

Overall severity. More than 70% of people on oveporexton reached the mildest level on the Narcolepsy Severity Scale. Improvements were seen across sleepiness, cataplexy, hallucinations and sleep paralysis at both doses, and in disrupted night-time sleep at the 2 mg dose.

How people felt. 97% of treated participants reported improvement in their overall narcolepsy symptoms. Most also reached or exceeded normal thresholds on two quality of life questionnaires.

"The newly published Phase 3 data reinforce the potential of oveporexton to transform how we approach narcolepsy type 1 in clinical practice, shifting from managing individual symptoms to treating the disease itself," said Mignot, principal investigator of FirstLight.

Side effects

The most common side effects were insomnia, needing to pass urine more often, urinary urgency and excess saliva. These are consistent with how the drug works, since orexin also acts on sleep and bladder pathways.

In pooled phase 3 data from the US prescribing information:

Takeda says most side effects were mild to moderate and began within two days of starting. Most insomnia resolved within a week and did not affect daytime functioning. About half of urinary symptoms had resolved by week 12, and the rest were mild or moderate.

Raised levels of creatine phosphokinase, a muscle enzyme, above five times the upper limit of normal were seen in 11% of people on oveporexton against 5% on placebo. These had no symptoms, but two people with markedly raised levels stopped treatment.

Oveporexton must not be taken with strong CYP3A inhibitors, a group of drugs that includes some antifungals and antibiotics, because they raise levels of the drug in the blood. The US label also notes potential for misuse, and controlled drug scheduling was still to be set by the Drug Enforcement Administration at the time of the release.

Points to keep in mind

• Short trials. Both studies ran for 12 weeks. The extension study will show whether benefits and side effects hold over years.
• Narcolepsy type 1 only. The approval and these trials cover NT1, where orexin is lost. People with narcolepsy type 2 or idiopathic hypersomnia were not studied here.
• Side effects are common. More than half of participants had insomnia or urinary frequency at first. For many these eased, but they need discussing before starting.
• Availability. We found no UK or EU approval at the time of writing. Takeda says further regulatory submissions are under way.

This article explains research findings and is not medical advice. Talk to your sleep specialist before changing any treatment.