SLEEP 2026 | Evolving understanding of orexin deficiency in narcolepsy type 1 and the impact of orexin agonists

We’ve known now for some time that narcolepsy type 1 is caused by a destruction, presumably an autoimmune destruction, of the orexin-secreting neurons in the hypothalamus. And orexin is a neurotransmitter that’s critically important not only in maintaining alertness during the day, but also stabilizing REM sleep at night. And it facilitates and interacts with the other wake-promoting pathways in the brain. And so this translates into the phenotype of narcolepsy type 1, which is difficulty maintaining alertness during the day, lapses into sleep, whether it’s sleep attacks or naps, but also disrupted nighttime sleep, and in many patients, sleep paralysis, hallucinations, and lucid dreaming. We’re in a time now where orexin agonists have been developed and have been tested in humans and are now advancing into various types of Phase III trials where we see early data supporting that these treatments may not only improve alertness and reduce cataplexy. And by that, I mean sort of treating the symptoms, symptomatically treating, which is what we’ve done for decades and decades. But more than that, because we know now that these medications improve quality of life, improve functional impairments, and also improve specific aspects of cognition. So it’s very reasonable to think about this as a transition, you know, maybe a transformative change in care from treating the symptoms, which is really all we were able to do in the past. Not that that wasn’t important and effective. And with many agents that are on the market, we are quite successful in improving symptoms. But perhaps by replacing orexin in people with narcolepsy type 1, where orexin deficiency is the root cause of the problem, we can restore function in a way that we couldn’t imagine in the past.

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