Awake to the possibilities: a ‘first in class’ narcolepsy drug could be transformational

On a summer Sunday afternoon in a quintessentially English village, a cricket match is being played on a green. Two batters are running between the wickets and enthusiastically try and get in an extra score as a second run looks possible. But, just before reaching their end and getting the end of their bat over the crease, one of the batters drops like a stone. He is fast asleep.

Our sleeping cricketer had become so excited by the thrill of the run that his body’s neural pathways became disrupted and his muscles temporarily paralysed.

This is typical of a scene when narcolepsy suddenly takes control of a person. The snoozing cricketer has type 1 of the chronic neurological disorder. Narcolepsy disrupts sleep and wake cycles. In narcolepsy type 1 (NT1), the disease also causes cataplexy, which is a sudden collapse in muscle utility, causing abrupt sleep. It is different from narcolepsy type 2 (NT2), which causes excessive daytime sleepiness but without cataplexy.

For patients with NT1, treatment so far has generally been a case of managing symptoms: stimulants that promote wakefulness, such as modafinil, and central nervous system depressants, such as sodium oxybate, which is derived from gamma-hydroxybutyrate. But hope is on the horizon for NT1 sufferers with the advent of oveporexton — a drug developed by Japanese pharmaceutical company Takeda and marketed under the name Orzeyful. Instead of tackling the symptoms, it is aimed at treating the cause of the disorder^​1,2​.

In August 2026, the US Food and Drug Administration (FDA) approved Orzeyful as a NT1 therapy^​3​, and Takeda is now looking to get it approved in the UK.

Tiffany Farchione, director of the division of psychiatry within the FDA’s Center for Drug Evaluation and Research, says: “This new drug is the first medicine that impacts the underlying biology of the disease, treating NT1 as a whole.”

Drug discovery

In the late 1990s, Emmanuel Mignot, a researcher working at Stanford University in California, United States, who is now an Craig Reynolds professor of sleep medicine at the university, started to look at sleep disorders, including narcolepsy. “When I started, this topic was really backwater,” he says.  

Mignot found that a specific gene was responsible for narcolepsy in dogs^​4​. He knew this was not the case in humans — as narcolepsy seemed to be triggered by an autoimmune response — but that gene found in dogs would hold clues. After a ten-year search, Mignot and his colleagues isolated that gene: hypocretin (orexin) receptor 2 gene or Hcrtr2. It controlled the production of neuropeptide orexin, and Mignot’s findings showed that narcolepsy was linked to disruptions in orexin production in the brain. Orexin has two receptors — the other is orexin receptor type 1 or HcrtR1, but he says that is less important.

This discovery gave medicinal chemists a clear target: to make drugs that could activate the orexin receptor and restore orexin production to the brain.

Rania Ward, principal pharmacist for sleep medicine at Queen Victoria Hospital in the UK, says: “We’ve identified this is a single pathway in the middle of our brain, in the hypothalamus, that works across the whole brain and controls wakefulness.”  

Subsequent work showed that when you inhibit this pathway, it leads to narcolepsy in animals, setting off the chain of events that led to a drug that can mimic the protein necessary for wakefulness.

Ward notes that oveporexton “is a first in class” drug. However, it was not the first orexin agonist Takeda has tried to market. Previous iterations did not pass safety trials because they led to liver failure^​5​.

Ward adds that oveporexton is a good example of how a drug is developed. “It has taken about 25 years, which is usual,” she says.

“This is how long it takes to get to market, and they’ve done it. They found the pathway, they found the protein, they’ve created an agonist, and they’re about to market it. And this is exciting because it’s the first targeted medication for narcolepsy, in so much as dealing with the actual pathway that’s responsible. All the other medicines are dealing with the associated pathways,” Ward continues.

Dream a little dream

To properly understand why narcolepsy is such a devastating condition, we need to look at the basics of sleep physiology. Sleep is defined by rapid eye-movement (REM). There are two types of sleep: non-REM and REM sleep. In non-REM sleep, “we have these big slow waves of rest”, Mignot says.

During REM sleep, however, the body is paralysed while the brain is active. The eyes move rapidly. “You are paralysed because otherwise you would be acting your dreams,” Mignot explains.

Patients with narcolepsy are both sleepy all the time, but they also go into abnormal REM sleep. Margot says: “They are half awake and half dreaming. So sometimes, for example, they fall asleep, [and] they start to have hallucinations because they are dreaming.”

“So, because they are dreaming immediately when they fall asleep, and also their dreams can be so vivid, sometimes they really think they are true,” he adds.^​6​

Orexin agonists can stop that abrupt REM sleep because orexin itself stops REM sleep from happening in a wakeful person^​7​. “These agonists are really miraculous for narcolepsy,” Mignot says. “People the first time they try [it], their body has not seen orexin for 20 years sometimes.”

He notes that the result is instantaneous, adding that in people with narcolepsy, the drug worked so well that it could almost be used as a diagnostic test.

Oveporexton, which is taken as a pill twice a day, isn’t perfect, Mignot cautions. “There are a couple of things we still don’t know [about it].”  He notes that after six months, the effect decreases in the evening.

“We have trouble finding the right regimen that makes people awake in the evening, and that’s normally when the orexin is the highest,” Mignot says, adding that this is down to the pharmacokinetics of the drug.

Patients also often need to urinate more often at night when on the drug, which Mignot describes as a side effect that is easily tolerated. However, he explains that of everyone who has been on the drug: “I don’t have a single patient that wanted to drop out.”

Charlotte Gurr

Maybe more to come

Takeda isn’t the only company developing the power of orexin agonists. There have been headlines suggesting that orexin agonists are going to be the brain’s ‘Ozempic moment’^​8​.

Centessa, a subsidiary of Eli Lilly, has three orexin agonists in their pipeline, with one of those in phase I and phase IIa clinical trials for NT1^​9​.

Biopharmaceutical company Alkermes, headquartered in Dublin, has an orexin 2 receptor agonist — alixorexton — in phase III clinical trials, says Craig Hopkinson, chief medical officer at Alkermes^​10​. “We are entering an exciting period in sleep medicine. Decades of research into the biology of sleep and wakefulness are beginning to translate into new therapeutic possibilities.”

Alkermes is also investigating orexin signalling for other sleep disorders. “Growing evidence suggests that enhancing orexin signalling may also benefit people living with NT2 and idiopathic hypersomnia, despite the biology of those disorders being less fully understood,” Hopkinson says^​11​.

Pharma company Lundbeck, headquartered in Copenhagen, is also in the game. Their orexin agonist Lu AH69593 is undergoing efficacy and safety investigations^​12​. The company is focused on patient experience.

Tarek Samad, global head of research and development at Lundbeck, says: “We understand that for people living with narcolepsy, the burden goes far beyond sleepiness. It can affect education, work, relationships, daily functioning and quality of life.”

“Those experiences help guide how we think about meaningful progress as Lu AH69593 advances through development; it must reflect the broader impact of sleep–wake instability on people’s lives,” he adds.

Potential UK approval

Drug development that leads to a marketable drug, of course, is contingent on approval. Following the FDA’s approval of Orzeyful as a NT1 therapy^​3​, Takeda announced that Orzeyful was also approved for sale in China and Japan on 13 October 2026.

In a press release published on 15 October 2026, Giles Platford, president of the international business unit at Takeda, said: “We’re excited at the potential to fundamentally change how NT1 is managed across Japan and China.”

In the UK, the National Institute for health and Care Excellence (NICE) is currently looking into whether it would be clinically worthwhile and cost effective to make the drug available on the NHS^​13​. NICE will have its first committee meeting about this on 9 February 2027, with a publication on its decision scheduled for 14 April 2027.

The Medicines and Healthcare products Regulatory Agency (MHRA) has told The Pharmaceutical Journal it cannot say whether Takeda has applied for marketing authorisation in the UK because it is “commercially sensitive”.

However, Takeda has confirmed to The Pharmaceutical Journal that it intends to seek regulatory authorisation from the MHRA in the UK. 

Ward explains that the UK has no regulatory path specific to sleep disorders. “There is no training pathway that is funded by NHS England to allow physicians to subspecialise in sleep,” she says. “You end up just falling into it, and that’s why the people involved in sleep services are numerous. You have psychiatrists, you have neurologists and you have respiratory physicians. You also have psychologists, and they mainly deal with insomnia.”

Ward adds that in the UK, “there’s no subspecialism that is called sleep medicine”.

So, real specialists in narcolepsy are thin on the ground. Ward says that she and colleagues are all feeding into NICE’s consultation on oveporexton.

Helen Strongman, trustee and director of Narcolepsy UK, notes that even MHRA approval and NICE authorisation won’t necessarily mean the end of suffering for all NT1 patients in the UK, as the length of time to diagnosis remains problematic.

“People first need a diagnosis, and people in our Charter survey waited an average of four to five years from first symptoms. They then need to be seen regularly by a specialist sleep service whose local NHS organisation has prescribing arrangements in place for the drug,” she says. “In our experience, gaps in these arrangements can prevent access or cause delays. Whether or not NICE recommends oveporexton, we will continue to advocate for access to new treatments that meet our community’s needs.”

Takeda, and other companies, are investigating where orexin neurotransmitters have other implications, and are also looking at how oveporexton might work in other disorders. Orexin agonists could potentially have a use in treating depression, where excessive sleep is often a symptom^​14​.

However, Mignot notes that for people without NT1, the drug is needed in a much larger dose to have any impact on sleep or wakefulness. In Parkinson’s disease, where dopamine is disrupted, he suggests that orexin agonists might help in treatments where dopamine-triggering stimulants fail, and researchers are investigating these links^​15​.

“I think it’s going to turn out to be a very important neurotransmitter in general,” Mignot says.

He now wants to experiment with giving orexin agonists — and then antagonists — to perhaps “switch on” and “switch off” sleep, with possible military applications.

But, for now, Ward is keen to see oveporexton come to the UK as a first step and has already started to tell her patients about it. She wants to see it become a first-line treatment, especially in young people, for NT1.

“The first two decades of life are so crucial, so vital. It’s the start of a person’s entire life and setting them up right at the beginning is so essential,” Ward says. “I am hoping that NICE will think about that when they come to [a] decision.”

Mignot remains as fascinated by narcolepsy as when he started back in the 1990s, but the field now has its first potential blockbuster drug and a potential pipeline of other related drugs coming through.

“These agonists are really miraculous for narcolepsy,” he says. “There’s no doubt, and it’s really transformative.”

Mignot adds: “I’m sure that there will be better formulations and even better drugs.”

And the journey to really unpick what other functions orexin is involved in now begins in earnest. “People are really starting to explore the effects of this drug in many other indications. I think that’s where it’s exciting. I think it’s going to turn out to be a very important neurotransmitter,” he explains.