A first-of-its-kind drug for the sleep disorder narcolepsy was approved last month by the US Food & Drug Administration (FDA), offering a new treatment for people who live with the debilitating fog of sleepiness, and which is being described by experts as transformative, reports The New York Times.
Developed by Takeda Pharmaceutical, the pill – Orzeyful – marks a long-sought success in the quest to mimic an essential brain peptide called orexin, which is missing in people with type 1 narcolepsy. About 120 000 people in the United States suffer from this type of narcolepsy, which causes pervasive sleepiness and episodes of cataplexy.
Other companies, including Alkermes and Eli Lilly, are chasing close behind.
To test narcolepsy treatments, doctors use a “maintenance of wakefulness test” in which a person sits in a dim room for 40 minutes.
“You have to stay awake. You cannot read, you cannot watch TV, you cannot talk,” said Dr Emmanuel Mignot, a sleep researcher at Stanford and one of the leaders of the trial testing Orzeyful. “For a normal person, it’s already tough; for a person with narcolepsy, it’s impossible.”
Before treatment, patients fell asleep within four to five minutes, according to a study published in The New England Journal of Medicine. In two late-stage trials, nearly 300 patients aged 16 to 70 received either Orzeyful or a placebo for 12 weeks.
On Orzeyful, they could stay awake for more than 20 minutes, about twice as long as currently available medications, said Dr Thomas Scammell, a sleep researcher at Beth Israel Deaconess Medical Centre in Boston.
Scammell, who was not involved in the study, said he thought that the drug could be “transformative”. Patients taking the drug have reported developing hobbies for the first time; dancing, playing ice hockey or spontaneously socialising.
Julie Flygare (42), diagnosed with the sleep disorder in 2007, during her second year of law school, said it interferes with memory, attention and weighs down everyday existence like a “heaviness on the skull”.
While taking her current medications, Flygare has four to six precious hours of wakefulness a day, and still needs a nap. Positive feelings, like, say, the joy of hitting a volley in tennis, trigger episodes of cataplexy; her muscles go slack and her grip on the racquet loosens.
Flygare participated in one of the trials testing Orzeyful and recalled that when she was dropped off at the site for her first visit, she had been unable to think clearly and could barely walk because she was off her medications. (It is necessary to have a “blank slate” to test the effects of a new drug.)
Later, when the same driver picked her up after she’d started the medication, she remembers making a joke – the kind of casual, offhand human interaction that would typically have triggered her cataplexy and made her knees buckle.
“The wakefulness had a different tone to it; it felt sunnier compared with my experience with stimulants,” said. Flygare, who has founded an NPO called Project Sleep that raises awareness of sleep disorders.
The organisation receives funding from drug companies, including Takeda, and last year, she served as a consultant to the company on patient perspectives in clinical trials.
Orzeyful is taken twice daily. It will not be available until the Drug Enforcement Administration determines its classification as a controlled substance, which is expected to occur by November.
Physicians are thrilled to have a new tool, but there remain many unknowns: how well will it work long-term? Will a drug that activates orexin receptors alter people’s risk for other neurological diseases?
In the beginning…
The long road to the new drug began more than two decades ago, when scientists first discovered that people with narcolepsy lacked orexin.
Orexins are produced by brain cells and work like a key fitting into a lock, by binding to two different receptors on the surface of cells in a region of the brain called the hypothalamus. Blocking the lock, like sticking a piece of tape over it, was a straightforward drug development problem and several insomnia treatments based on this idea have been approved.
But designing a key that opened the lock required more finesse.
“It’s hard,” said Andrew Plump, president of research and development at Takeda. The drug is an “agonist” that must activate the receptor by binding to it, imitating what naturally-occurring orexin does.
The second problem was that narcolepsy is rare. “They said our science is very interesting and exciting, but narcolepsy, after all, is one in several thousands – not very rare, but not very common,” said Dr Masashi Yanagisawa, a molecular biologist at the University of Tsukuba in Japan who led one of the teams that discovered orexin in 1998.
A Takeda scientist who had a friend with narcolepsy initiated the project by screening a vast library of molecules for promising hits. “We got one,” Plump said. “And nobody in their right mind would ever start a drug discovery programme with a single hit."
The scientist was so passionate that the work began, but it wasn’t a slam dunk. An early version needed to be administered by IV. Another candidate caused liver injury.
Other companies are following close behind. Beyond sleep, the approval sets off a race to develop a new class of medicines that show early hints of promise in a host of ailments, from ADHD to neurodegenerative diseases.
Alkermes has a similar drug in late-stage testing against narcolepsy. Blair Jackson, chief executive of the Dublin-based company, said it 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 company with similar drugs in the pipeline.
“Sleep is the low-hanging fruit,” said Luis de Lecea, a molecular biologist at Stanford and part of the team that also discovered orexin – though they called it hypocretin – in 1998. Narcolepsy patients lack orexin, but it also declines with Alzheimer’s disease, Parkinson’s disease, PTSD, and even normal ageing.
The road to hope
The two researchers behind Orzeyful, Yanagisawa and Mignot, have now won a prestigious Lasker Award – after their research in animals laid the groundwork for the new drug.
They said it took sleepy animals, serendipity and competition to begin to unravel its precise biology. In the late 1990s, Yanagisawa, then at the University of Texas Southwestern Medical Centre, discovered two brain chemicals in rodents that seemed to be instrumental in stimulating hunger.
He called them “orexins”, a play on “orexis” the Greek word for appetite.
At the same time, Mignot was hunting for the root cause of an inherited form of narcolepsy in Doberman pinschers, Labrador retrievers and Dachshunds.
In back-to-back studies published in the summer of 1999, these two lines of research unexpectedly converged, breaking open the neurobiology of sleep and identifying a root cause of narcolepsy.
Last week Yanagisawa, now at the University of Tsukuba in Japan, shared the Albert Lasker Basic Medical Research Award with Mignot for their work into the nature of sleep. The prizes are often called “America’s Nobel”.
“Their work has cracked open a molecular dissection of sleep regulation, reinforced the immune system’s involvement in human narcolepsy, and pointed toward new treatments for this illness and other sleep disturbances,” the Lasker citation said.
While the field is now a major target of pharmaceutical companies, their basic science research was supported largely by philanthropy and federal funding.
Thirty years ago, it was far from clear that these scientists were studying the same problem.
Yanagisawa was fascinated by basic science: there were dozens of receptors on the surface of brain cells whose functions were unknown. He wanted to decipher the function of these “orphan” receptors, and one of his first successes yielded short chains of amino acids, called peptides, that bound themselves to two brain receptors.
When researchers injected the peptides into rodents in large doses, they ate more. He called them orexins. (Simultaneously, this was when De Lecea’s group discovered the same brain chemicals and called them hypocretins.)
Next, they genetically tweaked mice to knock out the gene that carried the code for orexin, expecting the animals to be skinny and disinterested in food. To Yanagisawa’s disappointment, the mice looked normal, at least until scientists started videotaping them at night and reviewing hours of infrared footage.
That’s when they discovered that the mice were abruptly collapsing multiple times a night and plunging into brief bouts of REM sleep.
Mignot, on the other hand, had come at the research question from the opposite direction, hoping to find the root cause of narcolepsy.
In humans and dogs, narcolepsy not only causes excessive sleepiness, but episodes of cataplexy; positive emotions cause muscles to go slack. The dogs, Mignot found, lacked a particular receptor that was activated by the same brain peptide Yanagisawa had discovered.
“In two different species, this was such a dramatic and beautiful convergence, which makes everything in the story very convincing,” Yanagisawa said.
Study details
Oveporexton for Narcolepsy Type 1 – Results from Two Phase 3 Trials
Yves Dauvilliers, Emmanuel Mignot, Jakub Antczak et al.
Published in The New England Journal of Medicine on 9 September 2026
Abstract
Background
Narcolepsy type 1 is characterised by excessive daytime sleepiness, cataplexy, disrupted sleep, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Oveporexton (TAK-861), an oral orexin receptor 2−selective agonist, reduced symptoms of narcolepsy type 1 in a previous phase 2 trial.
Methods
We conducted two phase 3, randomised, placebo-controlled trials evaluating the efficacy and safety of oveporexton over a period of 12 weeks. Participants 16 to 70 with narcolepsy type 1 were randomly assigned in a 3:3:2 ratio to receive twice-daily oveporexton (1 mg or 2 mg) or placebo in the First Light trial and in a 2:1 ratio to receive twice-daily oveporexton (2 mg) or placebo in the Radiant Light trial. The primary end point was the change from baseline to week 12 in mean sleep latency (the ability to stay awake under soporific conditions) on the Maintenance of Wakefulness Test (MWT; range, 0 to 40 minutes; normal, ≥20). Key secondary end points included the change from baseline to week 12 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, <10) and the weekly cataplexy rate at week 12.
Results
A total of 168 participants were enrolled in the First Light trial and 105 in the Radiant Light trial. Mean changes from baseline to week 12 in mean sleep latency on the MWT ranged from 14.3 to 19.8 minutes with oveporexton, as compared with −0.4 to −0.8 minutes with placebo (adjusted P<0.001 for all comparisons vs. placebo). Mean changes in the ESS total score ranged from −9.7 to −11.8 with oveporexton, as compared with −1.5 to –1.7 with placebo (adjusted P<0.001 for all comparisons vs. placebo). Median percent reductions in the weekly cataplexy rate ranged from 79.0 to 88.8% with oveporexton, as compared with 27.7 to 39.1% with placebo (adjusted P<0.001 for all comparisons vs. placebo). Adverse events occurred in 86 to 89% of the participants with oveporexton, as compared with 43 to 54% with placebo; the most common adverse events were increased urinary frequency and transient insomnia, which occurred in a majority of participants receiving oveporexton.
Conclusions
Over a period of 12 weeks, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy in participants with narcolepsy type 1. Increased urinary frequency and transient insomnia were common side effects.
NEJM article – Oveporexton for Narcolepsy Type 1 — Results from Two Phase 3 Trials (Open access)
A New Drug Lifts the Fog of Sleepiness for Those With Narcolepsy (Restricted access)
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