Recently, a peptide has transformed medicine. Drugs based on glucagon-like peptide-1 (GLP-1), a hormone released by the gut after a meal, started as treatments for diabetes before proving especially effective in helping people lose weight. Since then, they have also shown benefits in treating heart, kidney diseases, sleep apnea, and other conditions. Now, pharmaceutical companies are betting that two other peptides, orexins, could follow a similar path in various brain-related diseases.
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Orexins are a pair of neurotransmitters, chemical substances that transmit messages between neurons. One of the main functions of these neurotransmitters is to regulate wakefulness. And a new generation of drugs designed to mimic their effects is about to hit the market.
On August 5, the U.S. drug regulator approved orexorexin, developed by Takeda, a Japanese pharmaceutical company, as the first orexin agonist (that is, a molecule that stimulates the same cell surface receptors) for narcolepsy, a disorder that causes excessive daytime sleepiness and makes patients fall asleep without warning. Alkermes, an Irish biotech, is developing a competing drug. Eli Lilly, whose fortune has changed thanks to GLP-1s, does not intend to miss another peptide boom. In June, it acquired Centessa, a biotech with an orexin drug in early trial phases, in a deal valued at up to $7.8 billion, depending on trial success. Morgan Stanley, a bank, estimates that orexin drugs could generate $16 billion annually by 2035 from narcolepsy and similar sleep disorders alone. In comparison, current narcolepsy drugs generate about $3 billion in annual sales.
In the future, orexins could serve as a basis to treat depression, ADHD, and addictions
And the excitement is not limited to narcolepsy, which is estimated to affect one in 2,000 people in the United States. Orexins help coordinate sleep, attention, motivation, and the brain’s reward system. Pharmaceutical companies hope that orexin-based drugs could, in the future, treat depression, attention deficit hyperactivity disorder (ADHD), and addictions, problems affecting hundreds of millions of people.
Orexins were discovered nearly thirty years ago by two teams working independently. In January 1998, Luis de Lecea and colleagues at the Scripps Research Institute in La Jolla, California, identified these peptides and named them hypocretins. Weeks later, a group led by Yanagisawa Masashi at the University of Texas Southwestern Medical Center in Dallas reported that injecting the same peptides into the brains of rats caused the animals to eat more. They called these molecules orexins, from the Greek orexis, meaning appetite.
The true role of orexins was revealed the following year. Emmanuel Mignot, from Stanford University, was studying hereditary narcolepsy in Dobermans and Labradors, dog breeds prone to suddenly collapsing while playing. He demonstrated that a mutation blocked the brain’s ability to respond to orexins. That same year, Yanagisawa’s lab discovered that mice engineered to lack orexins repeatedly fell asleep and collapsed. Shortly after, it was confirmed in humans: narcoleptic patients had lost the specialized neurons that produce orexins.
These neurons are located in the hypothalamus, a brain region behind the eyes. When released, orexins bind, depending on their type, to one of two receptor types on the cell surface, OX1R and OX2R, present in nearby neurons, and activate them. The OX2R receptor is key to maintaining wakefulness. Its activation stimulates several systems that promote alertness and depend on other neurotransmitters—noradrenaline, serotonin, dopamine, among others—and allows them all to work in coordination, like musicians in an orchestra following the conductor. The OX1R receptor is more involved in reward and motivation mechanisms.
Pharmaceutical labs first learned to deactivate the OX2R conductor. Orexin antagonists (which block the action of these molecules instead of mimicking them, thus promoting sleep) have been available since 2014 as treatments for insomnia. Their mechanism differs from conventional sleeping pills, which enhance GABA, one of the brain’s main inhibitory neurotransmitters.
Birgitte Kornum, an orexin expert at the University of Copenhagen, states that these types of pills induce sedation rather than natural sleep and usually lose effectiveness with continued use. In contrast, orexin antagonists reduce the brain’s alert signal, allowing systems that promote sleep to take control.
The big prize might not be in blocking the orexin signal, but in restoring it, as many sleep disorders are due to malfunctioning orexin signaling. The immediate application in mind is for narcolepsy type 1 (NT1), in which excessive daytime sleepiness is accompanied by cataplexy, a sudden loss of muscle control usually triggered by intense emotions. Later, narcolepsy type 2 (NT2), which lacks cataplexy, and idiopathic hypersomnia, another related type of excessive daytime sleepiness, are also targets for pharmaceutical companies.
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If there is insufficient orexin, a person can be fully awake and suddenly collapse
NT1 is caused by abnormally low levels of orexin that binds to OX2R. During the REM (rapid eye movement) phase of sleep, when dreams are most intense, the brain paralyzes the body to prevent it from acting out dreams. When a person is awake, this paralysis is kept at bay thanks to noradrenaline and serotonin, two neurotransmitters supported by orexin. If there is insufficient orexin, the paralysis circuit can activate even when the person is fully conscious. The person can be perfectly awake, for example in the middle of a laughing fit, and suddenly lose muscle control and collapse to the ground.
However, reactivating orexins is more difficult than deactivating them. An antagonist only needs to fit into a receptor to prevent an orexin from binding. An agonist, on the other hand, must reproduce the effect of a peptide that is many times greater than the drug molecule itself. Additionally, it must cross the blood-brain barrier, which protects the brain by blocking potentially harmful molecules.
Takeda’s first attempt, an agonist called firazorexin, initially showed good results but was discontinued in 2021 after causing liver damage in several patients. However, results published in May 2025 on orexorexin, its next-generation OX2R agonist, caused a stir. In an eight-week trial with 90 patients, volunteers sat in a dark room to see how long they could stay awake—a test known as the Maintenance of Wakefulness Test. Without orexorexin, many fell asleep within a minute. With the drug, they managed to stay awake between 12.5 and 25 minutes longer, depending on the dose, bringing many close to normal values. Cataplexy episodes were about one-third less frequent among those taking the drug compared to the placebo group. Side effects included insomnia and, in about one-third of patients, an uncomfortable need to urinate.
What distinguishes orexorexin is not only its effect but the way it achieves it. Existing treatments, including stimulants like methylphenidate and wakefulness-promoting drugs like modafinil, focus on controlling symptoms rather than the disease itself. These substances increase the activity of neurotransmitters such as dopamine and noradrenaline in various brain areas. While this can improve alertness, it can also cause anxiety, hypertension, and sleep difficulties. Some drugs also carry a risk of addiction.
Orexins act at an earlier stage. Instead of stimulating individual parts of the alert system, they help coordinate them. Yanagisawa states that orexin agonists should provide more natural and stable wakefulness, with fewer side effects and lower abuse potential than stimulants.
Regarding NT2 and idiopathic hypersomnia, Lilly’s orexin agonist, acquired through Centessa, is being tested against both conditions as well as NT1. Preliminary data are promising, although the sample size is small. In a trial with 55 patients, the drug improved wakefulness by more than 20 minutes in people with NT1 and by more than ten minutes in those with NT2.
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Pharmaceutical labs are investigating the effects of orexin agonists on more prevalent conditions. Alkermes is testing one in adults for ADHD treatment, although current medications are considered quite effective, based on the observation that an additional benefit in narcolepsy patients is improved attention, suggesting they could also be useful for ADHD. Others are exploring their use in treating sleep apnea, a much more common disorder.
There are also intriguing ideas about the role of the other receptor, OX1R, in motivation and the reward system, although research in this area is less advanced. Yanagisawa states that blocking OX1R seems promising for curbing cravings associated with addictions. Activating the receptor, rather than blocking it, is a more speculative line, but he believes enhancing orexin signaling in the brain’s reward circuits could help treat certain types of depression and even improve motivation.
These are clues, not proof, and rigorous trials will be needed before any drug reaches the market. Hunger and sleep, Skovronsky, Lilly’s chief scientific officer, argues, are both “major homeostatic mechanisms,” that is, systems that keep the body in balance. When they fail, diseases appear. The broad utility of GLP-1-based drugs has shown what can be achieved by targeting a complete regulatory system. Pharmaceutical companies hope that orexin-targeted therapies will have similar success.
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