Oveporexton: The first-in-class orexin receptor 2 (OX2R) agonist approved for treatment of narcolepsy type 1 (NT1).

Abstract

Narcolepsy type 1 (NT1) is a chronic neurological disorder caused by selective loss of orexin-producing neurons, resulting in unstable sleep-wake regulation and characteristic symptoms including excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic or hypnopompic hallucinations, and disrupted nocturnal sleep. Current treatments mainly provide partial symptomatic relief and do not correct the underlying orexin deficiency, highlighting the need for mechanism-based therapies. Oveporexton (TAK-861), an orally administered selective orexin receptor 2 (OX2R) agonist developed by Takeda Pharmaceuticals, represents the first approved therapy targeting the orexin pathway in NT1. By activating preserved OX2R signaling, oveporexton restores wakefulness regulation and alleviates multiple core symptoms of NT1. Its approval was aided by two global phase 3 trials which demonstrated significant improvements in wakefulness and cataplexy compared with placebo. Although its long-term safety, accessibility, and real-world efficacy need to be evaluated further, oveporexton represents a major advance toward disease mechanism-based treatment for NT1.