// NATURE NEWS — SPAZIO & SCIENZA
Will this sleep-disorder drug be the next big blockbuster?
Amanda Heidt is a freelance journalist in southeast Utah.
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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.”
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.