FDA Approves Orzeyful (oveporexton), First Orexin Agonist for Narcolepsy Type 1
核心洞察
The FDA has approved Orzeyful (搜索) (oveporexton), the first drug designed to mimic orexin (搜索), the brain peptide missing in people with narcolepsy type 1 (搜索).
In two phase 3 trials, oveporexton roughly doubled sleep latency versus placebo and cut weekly cataplexy (搜索) rates by up to 88.8%.
Adverse events occurred in 86 to 89 percent of oveporexton-treated participants, most commonly increased urinary frequency and transient insomnia.
The US Food and Drug Administration (搜索) has approved Orzeyful (搜索) (oveporexton), the first drug designed to replace the brain peptide orexin (搜索) that is missing in people with narcolepsy type 1 (搜索), developer Takeda Pharmaceutical announced. The approval, granted last month, offers a new option for patients living with the disorder's pervasive sleepiness and cataplexy (搜索), and experts involved in the research have described the drug as potentially transformative.
About 120,000 people in the United States have narcolepsy type 1 (搜索), which causes excessive daytime sleepiness and episodes of cataplexy (搜索), in which positive emotions cause muscles to go slack. Diagnosis is frequently delayed: "There's a statistic that people with narcolepsy (搜索) are diagnosed about ten to fifteen years after onset of symptoms," said Dr. Matthew Davis, a neurologist and sleep expert. One patient, Richelle Topping, reported living with symptoms for 18 years before being diagnosed at age 33 in 2020.
Phase 3 Results in the New England Journal of Medicine
The approval rests on two phase 3, randomised, placebo-controlled trials, published in The New England Journal of Medicine on 9 September 2026 by Yves Dauvilliers, Emmanuel Mignot, Jakub Antczak and colleagues. The First Light trial enrolled 168 participants and the Radiant Light trial 105; participants aged 16 to 70 with narcolepsy type 1 (搜索) were randomly assigned to twice-daily oveporexton (1 mg or 2 mg) or placebo for 12 weeks. First Light used a 3:3:2 randomisation ratio and Radiant Light a 2:1 ratio for oveporexton 2 mg or placebo.
The primary end point was change from baseline to week 12 in mean sleep latency on the Maintenance of Wakefulness Test (MWT; range 0 to 40 minutes; normal ≥20). Mean changes ranged from 14.3 to 19.8 minutes with oveporexton versus −0.4 to −0.8 minutes with placebo (adjusted P<0.001 for all comparisons). On the Epworth Sleepiness Scale (range 0 to 24; normal <10), mean changes ranged from −9.7 to −11.8 with oveporexton versus −1.5 to −1.7 with placebo (adjusted P<0.001). Median percent reductions in weekly cataplexy (搜索) rate ranged from 79.0 to 88.8% with oveporexton versus 27.7 to 39.1% with placebo (adjusted P<0.001).
Adverse events occurred in 86 to 89% of participants receiving oveporexton versus 43 to 54% with placebo. The most common were increased urinary frequency and transient insomnia, which occurred in a majority of participants on the drug.
A Different Kind of Wakefulness
The MWT requires patients to sit in a dim room for 40 minutes without reading, watching television or talking. "For a normal person, it's already tough; for a person with narcolepsy (搜索), it's impossible," said Dr Emmanuel Mignot, a sleep researcher at Stanford and one of the trial leaders. Before treatment, patients fell asleep within four to five minutes, according to the NEJM study. On oveporexton, they could stay awake for more than 20 minutes — about twice as long as with currently available medications, according to Dr Thomas Scammell of Beth Israel Deaconess Medical Centre in Boston, who was not involved in the study.
Julie Flygare, 42, diagnosed in 2007 during her second year of law school, described the disorder as a "heaviness on the skull" that interferes with memory and attention. While taking her current medications she has four to six hours of wakefulness a day and still needs a nap. After starting oveporexton in a trial, she recalled making an offhand joke to a driver — the kind of casual interaction that would typically have triggered her cataplexy (搜索). "The wakefulness had a different tone to it; it felt sunnier compared with my experience with stimulants," she said. Flygare founded the nonprofit Project Sleep, which receives funding from drug companies including Takeda, and served as a consultant to the company last year on patient perspectives in clinical trials.
Two Decades of Basic Science
The drug's development traces to the discovery more than two decades ago that people with narcolepsy (搜索) lack orexin (搜索). Orexins bind to two receptors on cells in the hypothalamus. Blocking those receptors proved a straightforward drug development problem, and several insomnia treatments based on that approach have been approved; designing an agonist that activates the receptor required more finesse. "It's hard," said Andrew Plump, president of research and development at Takeda.
A Takeda scientist with a friend who had narcolepsy (搜索) initiated the project by screening a large molecule library. "We got one," Plump said. "And nobody in their right mind would ever start a drug discovery programme with a single hit." An early version required intravenous administration, and another candidate caused liver injury.
In the late 1990s, Dr Masashi Yanagisawa, then at the University of Texas Southwestern Medical Centre, identified two brain chemicals in rodents that appeared to stimulate hunger and named them orexins. Simultaneously, Luis de Lecea's group at Stanford found the same chemicals and called them hypocretins. Mignot was separately hunting the root cause of an inherited form of narcolepsy (搜索) in Doberman pinschers, Labrador retrievers and Dachshunds, and found the dogs lacked a receptor activated by the same peptide. In back-to-back studies published in the summer of 1999, the two lines of research converged. "In two different species, this was such a dramatic and beautiful convergence, which makes everything in the story very convincing," Yanagisawa said.
Yanagisawa, now at the University of Tsukuba in Japan, and Mignot shared the Albert Lasker Basic Medical Research Award for their work on the nature of sleep. "Their work has cracked open a molecular dissection of sleep regulation, reinforced the immune system's involvement in human narcolepsy (搜索), and pointed toward new treatments for this illness and other sleep disturbances," the Lasker citation said.
A Broader Race and Open Questions
Other companies are following close behind. Alkermes has a similar drug in late-stage testing against narcolepsy (搜索); chief executive Blair Jackson said the Dublin-based company has identified 19 areas within neuroscience where such drugs could have potential. Eli Lilly recently agreed to pay up to $7.8bn for Centessa Pharmaceuticals, a biotech with similar drugs in the pipeline.
"Sleep is the low-hanging fruit," said Luis de Lecea. Narcolepsy (搜索) patients lack orexin (搜索), but the peptide also declines with Alzheimer's disease (搜索), Parkinson's disease (搜索), PTSD (搜索) and even normal ageing, opening a race to develop a new class of medicines with early hints of promise from ADHD (搜索) to neurodegenerative diseases.
Orzeyful (搜索) is taken twice daily and will not be available until the Drug Enforcement Administration (搜索) determines its classification as a controlled substance, expected by November. Physicians remain enthusiastic but note unknowns: how well the drug will work long-term, and whether activating orexin (搜索) receptors alters risk for other neurological diseases. "I'm really excited to now have an option that treats the root cause instead of playing whack a mole with these different symptoms," Topping said.