What Do Orexin-2 Receptor Agonists Mean for Psychiatry?

David Plante, MD, PhD, discussed 2 posters at ASCP examining alixorexton, an orexin-2 receptor agonist under development for narcolepsy and related disorders.

Plante began by explaining the pathophysiology of type 1 narcolepsy, which is caused by loss of orexin-containing neurons in the lateral hypothalamus.¹ Orexin is a neuropeptide neurotransmitter critical for stabilizing sleep-wake transitions, and its deficiency produces the hallmark symptoms of type 1 narcolepsy: severe excessive daytime sleepiness, cataplexy, hypnagogic and hypnopompic hallucinations, sleep paralysis, and disrupted nocturnal sleep.² Alixorexton is a potent, highly selective orexin-2 receptor agonist designed to restore wakefulness-promoting signaling in this population.

The first poster presented primary results from VIBRANCE-1, a phase 2 randomized controlled trial of alixorexton in type 1 narcolepsy. The study evaluated once-daily doses of 4, 6, and 8 mg. The primary outcome was the maintenance of wakefulness test (MWT), an objective measure of a patient's ability to remain awake under soporific conditions. All 3 doses produced MWT improvements exceeding 20 minutes—substantially larger than the 2- to 10-minute improvements typically observed with stimulant medications—and moved scores into a range consistent with healthy controls. Subjective sleepiness, measured with the Epworth Sleepiness Scale, also improved markedly across all doses. The compound was well tolerated; no serious treatment-emergent adverse events were reported, and adverse effects were predominantly mild to moderate, including transient insomnia and urinary symptoms consistent with a class effect for orexin agonists.

Notably, alixorexton also produced significant improvements on the British Columbia Cognitive Complaints Inventory and the PROMIS Fatigue Severity Rating at all doses—domains not typically assessed as primary endpoints in narcolepsy trials. Plante highlighted these findings as opening the door to broader psychiatric and neurological applications. A second pipeline poster presented preclinical data from an animal model of attention-deficit hyperactivity disorder (ADHD) using a 5-choice serial reaction time task, in which an orexin-2 receptor agonist reduced impulsivity and improved sustained attention, both with and without a concomitant nonstimulant ADHD medication. Early phase 1 trials in healthy volunteers and individuals with ADHD are underway. Plante also identified excessive daytime sleepiness and fatigue in conditions such as multiple sclerosis and Parkinson's disease as additional candidate indications, characterizing orexin-2 receptor agonism as a promising bridge between sleep medicine and psychiatry.

Dr Plante is associate professor of psychiatry at the University of Wisconsin–Madison.

References

1. Rauf R, Asif S, AlSaafeen A, et al. Orexin deficiency in narcolepsy: molecular mechanisms, clinical phenotypes, and emerging therapeutic frontiers. Brain Behav. 2025;15(10):e70984.

2. Symptoms of narcolepsy. Division of Sleep Medicine Harvard Medical School. Accessed June 10, 2026. https://sleep.hms.harvard.edu/education-training/public-education/sleep-and-health-education-program/sleep-health-education-3