One Peptide has recently transformed medicine. Drugs based on glucagon-like peptide-1 (GLP-1), a hormone released by the gut after a meal, began as treatments for diabetes before proving remarkably good at helping people shed weight. They have since shown benefits in the fields of heart disease, kidney disease, sleep apnoea and other ailments. Drugmakers are now betting that two other peptides, the orexins, could follow a similar path for a variety of brain-related ailments.
Orexins are a pair of neurotransmitters—chemicals that carry messages between neurons. One of the main jobs of these particular neurotransmitters is to regulate wakefulness. And a new generation of drugs designed to mimic their effects is approaching the market.
On 5 August America’s drug regulator approved oveporexton, made by Takeda, a Japanese pharmaceutical firm, as the first orexin agonist (ie, molecule that stimulates the same cell-surface receptors) for narcolepsy, a disorder that leaves patients excessively sleepy by day and prone to nod off without warning.
Alkermes, an Irish biotech, is developing a competitor. Eli Lilly, whose fortunes GLP-1s have transformed, does not intend to miss another peptide boom. In June it bought Centessa, a biotech with an orexin drug in early trials, in a deal worth up to $7.8bn, depending on the trials’ success. Morgan Stanley, a bank, reckons orexin medicines could generate $16bn a year by 2035 from narcolepsy and related sleep disorders alone. The current crop of narcolepsy drugs, by contrast, has annual sales of some $3bn.
And the excitement is not just about narcolepsy, which is estimated to afflict one person in 2,000 in America. Orexins help coordinate sleep, attention, motivation and the brain’s reward system. Drugmakers hope orexin medicines could eventually treat depression, attention-deficit hyperactivity disorder (ADHD) and addiction, conditions that burden hundreds of millions of people.
Orexins were discovered nearly three decades ago by two teams working independently. In January 1998, Luis de Lecea and his colleagues at the Scripps Research Institute in La Jolla, California, found the peptides and called them hypocretins. Weeks later, a group led by Yanagisawa Masashi, of the University of Texas Southwestern Medical Centre in Dallas, reported that injecting the same peptides into rats’ brains made the animals eat more. They named the molecules orexins, from the Greek orexis, meaning appetite.
Orexins’ true role emerged the following year. Emmanuel Mignot, of Stanford University, was studying hereditary narcolepsy in Doberman pinschers and Labrador retrievers, dog breeds prone to sudden collapse mid-play. He showed that a mutation blocked the brain’s ability to respond to them. That same year, Dr Yanagisawa’s laboratory found that mice engineered to lack orexins repeatedly fell asleep and collapsed. Human confirmation followed: narcoleptic patients had lost the specialised neurons that produce orexins.
These neurons inhabit the hypothalamus, a brain region tucked behind the eyes. Once released, orexins lock, depending on their nature, onto one of two types of cell-surface receptors, OX1R and OX2R, in neighbouring neurons, switching them on. It is OX2R that is important for maintaining wakefulness. Its activation stimulates several wakefulness-promoting systems that rely on other neurotransmitters—norepinephrine, serotonin, dopamine and so on—and keeps them working together, rather like the conductor of an orchestra. OX1R is more involved with reward and motivation.
