A New Narcolepsy Drug Could Change How We Understand Sleep

Julie Flygare builds her days around a handful of good hours. She guards her mornings for work, plans her afternoons around naps, and often turns down evening social plans.

The 43-year-old Los Angeles resident has narcolepsy type 1 with cataplexy, a chronic neurological disorder that disrupts sleep and wakefulness and can cause sudden muscle weakness triggered by strong emotions. Even with treatment, she sometimes needs to pull over to nap on short drives.

“It affects every decision of every day,” says Flygare, president and CEO of Project Sleep, a nonprofit organization dedicated to raising awareness about sleep health and disorders. “There are so few hours of goodness.”

Narcolepsy—which has two main forms, type 1 and type 2—affects an estimated one in 2,000 Americans, according to the National Institutes of Health. Now, a new drug could change how doctors treat its most well-understood form. In August, the U.S. Food and Drug Administration approved Orzeyful, known generically as oveporexton, the first drug designed to restore a missing brain signal that helps keep people awake. Orzeyful is expected to become available in November, once the DEA completes its scheduling.

Unlike existing treatments, which primarily address individual symptoms, Orzeyful targets a central feature of narcolepsy type 1: the loss of signaling from brain cells that produce orexins (also known as hypocretins), chemical messengers that help stabilize wakefulness and sleep. The advance is the culmination of decades of research into how the brain controls these states—and what happens when the boundaries between them break down.

For more than a century after doctors first documented narcolepsy in the 1870s, its biological roots remained elusive. A breakthrough came in 1998, when two research teams independently discovered a pair of chemical messengers, known as hypocretins and orexins, produced by a small group of neurons in the hypothalamus. Researchers soon linked orexin deficiency to narcolepsy type 1 in humans.

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Though relatively few in number, these neurons play an outsized role in sustaining wakefulness. When these cells are lost, other brain systems cannot fully compensate, says Luis de Lecea, a Stanford University neuroscientist and professor of psychiatry and behavioral sciences who helped discover the neuropeptides.

“And that makes these neurons very special,” de Lecea says. He describes orexin as “the Rosetta Stone of the language of sleep” because studying it has helped researchers decipher how the brain coordinates wakefulness.

Orexin does more than promote alertness; it helps keep sleep and wakefulness stable. Patrick M. Fuller, professor of neurological surgery at the University of California, Davis School of Medicine, compares the brain’s sleep and wake systems to opposite ends of a seesaw, with orexin acting like a finger in the middle that steadies it.

“In the absence of orexin, that switch becomes unstable,” says Fuller. “And both wakefulness and sleep become fragmented.”

Research is beginning to reveal how orexin keeps that switch stable. In a 2022 mouse study, Fuller’s team found that orexin-producing neurons indirectly inhibit sleep-promoting cells in the brain’s preoptic region. In other words, orexin may help sustain wakefulness not only by activating the brain’s arousal systems, but also by keeping sleep-promoting circuits in check.

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Why orexin-producing neurons disappear remains an area of active research. More than 90 percent of people with narcolepsy type 1 carry a gene variant called HLA-DQB1*06:02, which increases susceptibility to narcolepsy. People carry the variant from birth, but the onset of narcolepsy symptoms often presents in adolescence or early adulthood, says Thomas E. Scammell, professor of neurology at Harvard University and sleep neurologist at Beth Israel Deaconess Medical Center.

Researchers suspect that, in genetically susceptible people, an immune response to an infection such as the flu may mistakenly target orexin-producing neurons, damaging or destroying them.

The loss of these neurons is generally considered permanent. A study of brain tissue suggests that people with narcolepsy type 1 have 85 to 95 percent fewer orexin-producing neurons than people without the disorder. When orexin is missing, wakefulness becomes fragmented, and features of rapid eye movement (REM) sleep—a stage associated with vivid dreaming and temporary muscle paralysis—can appear at the wrong time, says Fuller.

For Flygare, those blurred boundaries felt terrifyingly real. At 21, she thought a burglar had broken into her apartment, but she couldn’t move her body. Later, she realized no one had broken in. She had experienced a hypnagogic hallucination along with sleep paralysis—a lived example of how awareness, dreaming, and muscle control can become disconnected when orexin is missing.

“It’s like being in this weird land between dreaming and reality,” says Flygare. “And those boundaries have kind of gone haywire.”

In people living with narcolepsy, loss of muscle control can also intrude into waking life. Cataplexy is like sleep paralysis that occurs during wakefulness, says Scammell. The muscle-paralysis pathways can be triggered suddenly, causing weakness or even collapse.

“It’s triggered by strong emotions like laughing at a joke,” says Scammell.

Researchers think emotional signals passing through the amygdala activate brainstem circuits that normally paralyze muscles during REM sleep. Orexins usually help keep those circuits in check while we are awake.

Orexins activate neurons in the brain through two receptors called OX1 and OX2. The latter plays a larger role in sustaining wakefulness and regulating REM sleep, says Scammell.

Even when orexin-producing neurons are lost, these receptors remain largely intact. That discovery has opened the door to a new kind of treatment. Rather than replacing the lost neurons, Orzeyful activates the OX2 receptor, helping restore the signaling needed to sustain wakefulness.

In two clinical trials involving 273 participants, people taking the drug showed substantial improvements in their ability to stay awake during the day. After 12 weeks, the treatment groups also experienced median reductions of 79 to 89 percent in the frequency of cataplexy episodes, compared with reductions of roughly 28 to 39 percent in the placebo groups.

Still, the new medication has limitations. Orzeyful does not closely reproduce orexin’s daily timing, says Scammell, and activates only the OX2 receptor type. Natural orexins act through both OX1 and OX2. Better wakefulness also does not mean fully restored nighttime sleep, Fuller adds, so some patients may still need other treatments.

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The implications of orexin research could extend beyond narcolepsy type 1. Scientists are investigating whether drugs that activate orexin receptors could also help people with other disorders characterized by excessive daytime sleepiness, including narcolepsy type 2 and idiopathic hypersomnia.

De Lecea sees broader possibilities. Activating orexin receptors could raise someone’s general level of alertness even if they aren’t deficient in orexin, he says. That raises the possibility of using these drugs to treat other conditions, including chronic fatigue and ADHD, although research into these applications is still in its early stages. His lab is also studying how the body tells the brain to sleep and the connections that carry those messages.

“The ultimate goal is to really optimize and control the brain states because by doing so, you can really treat and understand and treat many neuropsychiatric disorders,” says de Lecea.

For Flygare, the goal is simpler. She looks forward to trying Orzeyful when it becomes available, hoping it could reduce the cataplexy episodes she experiences while playing her favorite sport, tennis.

“It would be really nice to have [narcolepsy] be a little bit more in the background,” says Flygare.