Orexin-2 Receptor Agonists in Narcolepsy After First-in-Class Approval: From Symptomatic Wake Promotion to Pharmacological Restoration of Orexin Signalling: A Narrative Review

Narcolepsy type 1 (NT1) is caused by loss of hypothalamic orexin (hypocretin) neurons and consequent deficiency of orexin signalling. Conventional pharmacotherapy improves excessive daytime sleepiness, cataplexy, or disturbed nocturnal sleep through downstream monoaminergic, histaminergic, or GABA-related mechanisms but does not correct the underlying neurochemical lesion. Selective orexin-2 receptor (OX2R) agonists act directly at the receptor normally engaged by the missing peptide. Danavorexton established proof of mechanism; firazorexton (TAK-994) confirmed oral efficacy but was discontinued for idiosyncratic hepatotoxicity; and oveporexton produced large, sustained improvements in wakefulness, sleepiness, cataplexy, and broader disease measures across two pivotal phase 3 trials, leading to its approval (August 2026) as the first OX2R agonist for NT1. This review appraises OX2R biology, oveporexton's clinical pharmacology, class safety versus molecule-specific toxicity, and the emerging pipeline, and argues that the class is best framed as functional restoration of orexin signalling rather than proven disease modification.