A new generation of drugs could transform the lives of people with narcolepsy and offer hope of future treatments for ADHD and depression.
Orexins help regulate wakefulness, as well as attention, motivation and the brain’s reward system. This month, the US Food and Drug Administration approved the first orexin agonist treatment for narcolepsy. Oveporexton (sold as Orzeyful) is designed to target the cause of the chronic sleep disorder, rather than treat the symptoms with stimulants.
But “the excitement is not just about narcolepsy”, said The Economist. Inspired by the success of drugs that mimic glucagon-like peptide-1 (GLP-1), developed to treat diabetes and later used for weight-loss in medication such as Ozempic, drugmakers are “betting” that orexins could “follow a similar path”, potentially leading to treatments for conditions that “burden hundreds of millions” of people.
What are orexins?
They are two peptides (chains of amino acids that act as messengers in the brain) that are involved in the body’s sleep-wake system. Specifically, they are neuropeptides. They act as neurotransmitters, or chemicals, that carry messages between neurons. They are involved with reward and motivation.
Named after the Greek word orexis (appetite), orexins were discovered in 1998 by two teams working independently in the US. The discovery turned “the long march to develop a new kind of sleeping pill into a sprint”, said The Guardian.
But their “true role emerged” in 1999, said The Economist. People with narcolepsy were found to lack the specialised neurons that produce orexins, causing “abnormally low levels”. That means the brain “loses the ability to control when the body sleeps”, said Time.
How do they work?
In 2011, researchers at Takeda, a Japanese pharmaceutical company, found a chemical compound that could block the orexin receptor, and so promote sleep. Orexin antagonists were developed as a treatment for insomnia, differing from conventional sleeping pills that induce sedation.
But “the bigger prize may lie not in blocking orexin’s signal, but restoring it”, said The Economist. The results of Takeda’s trials of oveporexton, published last year in The New England Journal of Medicine, “created a stir”. Volunteers were able to stay awake 12.5 to 25 minutes longer with the drug (depending on the dose) than without it.
The drug “activates the orexin pathway” and “restores the brain’s ability to remain alert”, said Time. Volunteers also had fewer episodes of cataplexy, or loss of muscle control, as well as other symptoms such as hallucinations and irregular sleep. There were “no serious adverse events related to treatment”, said the Smithsonian magazine.
“It’s really a complete revolution,” Emmanuel Mignot, a sleep-medicine professor who led Takeda’s final studies, told The Wall Street Journal. “The first time patients take it, it’s like the light switch.” One 19-year-old trial participant said: “It was the first time I felt somewhat alive in the last 10 years.” “It’s the best thing that has ever happened to me,” he told Nature.
What might the future hold?
In the US and Western Europe, narcolepsy affects about one in 2,000 people, but there is no cure. Existing drugs – “decades-old stimulants and sedatives” – only manage symptoms, said The Wall Street Journal. Oveporexton and its competitors are “designed to treat the disease as a whole”. Morgan Stanley estimates that orexin-based medicines for narcolepsy and other sleep disorders could generate $16 billion a year by 2035, according to SF Globe.
Takeda is testing orexin-targeting drugs for sleep apnea and chronic daytime sleepiness. Alkermes, an Irish biotech company, is testing an orexin drug for ADHD in adults. And this year Eli Lilly (of Mounjaro fame) bought Centessa, a biotech firm with an orexin agonist in trials, in a deal potentially worth up to $7.8 billion. New research has also revealed “the essential role of orexin neurons” in motivation, said BioTechniques.
The twice-daily oral drug Orzeyful could be “a boon for the roughly 120,000 people in the United States with narcolepsy type 1”, said the Smithsonian. But its success also “opens the door to the use of orexin-mimicking drugs for other conditions associated with low levels of the chemical”, such as ADHD and depression. “Orzeyful is just the beginning,” said Andy Plump, Takeda’s president of research and development.