When US regulators approved a treatment for narcolepsy in August, some researchers immediately predicted a bright future for the class of compounds it belongs to, known as orexin agonists. Much like blockbuster GLP-1 drugs, such as Ozempic, which were initially approved to treat diabetes but have since taken off as treatments for other conditions, these new drugs seem capable of much more than treating sleep disorders.

First-of-its-kind narcolepsy drug opens door to new therapies for the brain

“Diabetes was the tip of the iceberg for GLP-1s, and I’m convinced the same story will play out for orexin,” says Andrew Plump, president of research and development at Takeda, the Tokyo-based pharmaceutical company that developed the newly approved drug, called Orzeyful (oveporexton). “Our goal now is to unravel the science and understand what’s below the surface.”

This excitement comes on the heels of decades of research about orexins — peptides that are produced by the brain and that have a role in modulating metabolism, mood, appetite, memory and, most notably, sleep and wakefulness cycles. Now, scientists are racing to work out how best to apply what they have found in the clinic, exploring the use of orexin agonists in the treatment of attention deficit hyperactivity disorder (ADHD) and other conditions in which attention and alertness are dysregulated.

“Anyone who has gotten a poor night of sleep can tell you that it impacts nearly every aspect of their life,” says Luis de Lecea, a psychiatrist at Stanford University in California, who was among the first to identify orexins. “It is very rewarding to have a hand in something that has led to a drug that helps people.”

Dual discoveries

De Lecea was a budding scientist with a new laboratory at the Scripps Research Institute in San Diego, California, when, in the mid-1990s, he took on a daunting project: identifying proteins produced only in certain parts of the human brain. Groups at the institute were divvying up brain regions to study, and de Lecea chose the hypothalamus, an almond-sized region deep in the brain’s interior.

The team generated a list of hypothalamus-specific messenger RNAs — small chunks of genetic material that carry the instructions for making proteins. Sifting through the list, the scientists identified a pair of neuropeptides that they named hypocretin 1 and 2¹. Unbeknown to de Lecea, researchers in Texas had, around the same time, isolated the equivalent peptides in rats, dubbing them orexin A and B².

Neuroscientist Takeshi Sakurai was working in the lab of Masashi Yanagisawa, a molecular biologist then at the University of Texas Southwestern Medical Center in Dallas, when the group first identified the orexins. The researchers suspected that the peptides regulated feeding in rodents — the name comes from the Greek word orexis, meaning appetite — but when they artificially blocked orexin signalling, they found something unexpected.

Narcolepsy confirmed as autoimmune disease

“The animals sometimes abruptly collapsed,” says Sakurai, now at the University of Tsukuba in Japan. The behaviour bore a striking resemblance to a hallmark of narcolepsy type 1 in humans: a sudden, temporary loss of muscle control known as cataplexy. After further work, the team landed on a more complete understanding of the role of orexins. “Orexin does not simply wake us up, it keeps wakefulness stable,” he says.

Back in California, researchers were making more discoveries. Emmanuel Mignot, a sleep-medicine specialist at Stanford, and his colleagues were the first to identify a mutation in the gene that encodes orexin receptor 2 as the cause of canine narcolepsy³. In a study of people with narcolepsy type 1 who had died, Jerome Siegel, a neuroscientist at the University of California, Los Angeles, and his colleagues found that the brains of these people nearly always had a massive loss of the neurons that produce orexins⁴.

It’s a small population — just 70,000 cells among the hundreds of thousands in the hypothalamus — yet they seem to be crucial.

“Once those neurons are gone, the brain isn’t able to find a workaround,” Siegel says.

Turning knowledge into a drug

From the moment they first noted the link between orexins and sleep, Sakurai says he and his team recognized the therapeutic potential. In a few years, so did pharmaceutical companies.

The first investigations at Takeda began in the late 2000s as a pet project. One of the technicians there had a friend with narcolepsy type 1, and he began looking for a molecule that could bind to orexin receptors and restore a normal sleep–wake cycle.

When the technician scanned Takeda’s libraries for a molecule that met the criteria, only a single candidate, called TAK-925, came back. Going forward with it would be a risk, says Plump. “No chemist in their right mind would start a drug-discovery programme with a single hit.”

First orexin agonists address root cause of narcolepsy

Nevertheless, Takeda researchers gave it a try and the molecule performed well in animals. When the company launched the first human trial in 2017, the technician drove his friend to the study centre so that she could participate. He contacted Plump right away, saying that the drug seemed to work for her. “He could tell just from speaking with her,” Plump says.

Orzeyful, which has now received approval in three countries, builds on the foundation that TAK-925 and other early candidates set. The drug is a marked improvement on existing therapies that only mask symptoms of the disease and often come with severe side effects.

Mignot, who led Takeda’s late-stage trials says that people report that “after they take this drug, suddenly they really know what it is to be awake”.

The next GLP-1?

With the approval of Orzeyful, competitors are now racing to tap into a global market for narcolepsy drugs that analysts predict could top US$6.4 billion by 2031. Narcolepsy — both type 1 and type 2, which is not associated with a die-off of orexin-producing neurons — affects roughly three million people worldwide, and estimates suggest that many more cases go unreported or misdiagnosed.