FDA approves Orzeyful, first orexin-targeted treatment for narcolepsy type 1

FDA has approved Orzeyful (oveporexton) for adults with narcolepsy type 1, introducing the first treatment designed to restore the orexin signaling that is deficient in the disorder.

The new mechanism distinguishes Orzeyful from existing narcolepsy treatments, which primarily manage individual manifestations such as excessive daytime sleepiness or cataplexy. Narcolepsy type 1 results from the loss of brain cells that produce orexin, a chemical messenger involved in regulating wakefulness, sleep, and muscle tone. Orzeyful activates orexin 2 receptors, effectively replacing part of that missing signal.

That approach allowed a single medication to improve multiple daytime and nighttime manifestations of narcolepsy type 1 in clinical trials, including wakefulness, excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and disrupted nighttime sleep. The oral drug is taken twice daily.

Approval was supported by two randomized, placebo-controlled 12-week studies involving 273 adults. Across both trials, patients receiving the approved 2-mg dose had improved ability to remain awake compared with placebo, along with less daytime sleepiness, fewer cataplexy episodes, and improvement across other symptoms of the disorder.

The new mechanism also brings a distinct adverse-effect profile. The most common adverse effects included insomnia, urinary frequency and urgency, and increased salivation. In pooled phase 3 data, insomnia occurred in 60% of patients receiving 2 mg twice daily versus 1% with placebo, while urinary frequency occurred in 58% versus 5%. Asymptomatic creatine phosphokinase elevations greater than five times the upper limit of normal occurred in 11% of Orzeyful-treated patients versus 5% with placebo. The drug is contraindicated with strong CYP3A inhibitors.

Orzeyful will become available through specialty pharmacies after the DEA determines its controlled-substance schedule, a decision Takeda expects within 90 days.

“Until now, people have managed narcolepsy type 1 with treatments that target symptom relief,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford University and principal US investigator in the Orzeyful phase 3 program. “As the first approved orexin therapy to treat the broad spectrum of the disease, Orzeyful can enable a different kind of conversation in the doctor’s office about treatment options.”

Source: U.S. Food and Drug Administration. (2026 Aug 5). FDA approves first drug to treat the full range of narcolepsy type 1 symptoms