Physicians test new narcolepsy treatments by checking whether the drugs help people to fall asleep and stay asleep throughout the night.Credit: Lucia Graphus/Alamy
Earlier this month, the US Food and Drug Administration approved the first drug designed to treat the root cause of narcolepsy, a condition that affects millions of people by causing extreme sleepiness during the day and wakefulness at night.
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The success of the drug, called oveporexton and marketed as Orzeyful, is being celebrated by those who struggle with narcolepsy. “It’s the best thing that has ever happened to me,” says Tyler Chapman, who volunteered for one of the clinical trials that contributed to the drug’s approval. But it’s also being watched with anticipation by researchers, who see it as the first in a line of therapies for sleep disorders that are likely to be approved in the coming years.
These emerging treatments, known as orexin agonists, are exciting because they promise not just to alleviate symptoms of narcolepsy but also to target the disease’s biological cause — and might even have implications for other neuropsychiatric disorders. With this new strategy against narcolepsy, pharmaceutical companies have jumped at the chance to tap into a market that is projected to top US$6.4 billion annually by the early 2030s.
“This is a tremendously exciting time for patients and for clinicians and scientists who have been working towards this for many years,” says Barry Lubarsky, the vice-president of medical affairs at the pharmaceutical company Alkermes, which is based in Dublin, Ireland, and is developing its own narcolepsy treatment.
A chance to feel normal
For Chapman, a 19-year-old student at the University of Tennessee, Knoxville, the milestone is life changing. Chapman had long struggled with his condition, at times sleeping for 16 hours a day, struggling in school and relying heavily on coffee. When he laughed, it would sometimes trigger his body to collapse, even though he remained fully conscious — a symptom known as cataplexy. Instead of experiencing all that university life has to offer, Chapman says that he rarely went out.
That is, until he volunteered earlier this year for a clinical trial with Takeda Pharmaceuticals America in Cambridge, Massachusetts, to test a new class of narcolepsy drug. He had previously tried more than a dozen medications, including stimulants, but often experienced severe psychological side effects.
A new class of narcolepsy drug mimics the neuropeptide orexin. Shown here is one form of orexin that has 28 amino acids.Credit: Laguna Design/Science Photo Library
Now, he’s able to stay awake and alert for the entire day and to have restful sleep at night. “My quality of life is so much better,” he says. He and his mother are even planning a trip to the base camp of Mount Everest to celebrate.
Chapman’s challenges with managing his symptoms are not uncommon. Narcolepsy affects roughly 3 million people worldwide. Both forms of the disorder — type 1 and type 2 — cause daytime sleepiness, night-time alertness, sleep paralysis and hallucinations. Type 1, the form that Chapman has, is also marked by cataplexy.
For a long time, narcolepsy’s cause remained a mystery. But beginning in the late 1990s, researchers found that a peptide called orexin is often missing in the brains of people with type 1 narcolepsy1. Orexin is produced by roughly 70,000 neurons in the brain’s hypothalamus. These cells seem to die off in people with type 1 narcolepsy, and without the orexin that they produce, the brain is unable to regulate the sleep–wake cycle. Type 2 narcolepsy does not seem to be linked to a lack of orexin, and scientists are still investigating its cause.
A long road
Armed with this molecular knowledge, Takeda scientists scanned their massive database of chemical compounds and found one that mimicked orexin. In the brain, the compound stands in for orexin by activating the peptide’s receptors and thereby helps to stabilize a person’s wakefulness and sleep circuits. Takeda researchers first identified the candidate compound in 2011, but they spent years developing it into an oral pill and testing it.
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Takeda enrolled 273 people with type 1 narcolepsy in a pair of phase III clinical trials, giving them either a twice-daily dose of the oral medication or a placebo pill. Across both studies, people who received the drug were able to stay awake during the day and to fall, and stay, asleep at night. Participants who took Orzeyful also reported improvements in symptoms such as cataplexy, sleep paralysis and hallucinations.
By taking the drug, “patients become more or less like normal people”, says Emmanuel Mignot, a sleep medicine specialist at Stanford University in California. “Suddenly they really know what it is to be awake.” Mignot led Takeda’s late-stage trials and was a leader in the discovery of orexin’s link to the disorder.
