Orexin-2 Receptor Agonists in Narcolepsy: Restoring the Missing Signal

Background/Objectives: Narcolepsy type 1 (NT1) results from loss of hypothalamic orexin neurons. Selective orexin-2 receptor (OX2R) agonists now permit direct receptor-level restoration of deficient signaling, but recent broad reviews do not fully integrate the post-approval, trial-specific efficacy, prescribing, and safety evidence. This review asks what benefits and risks are supported by current data, which toxicities appear class-related versus molecule-specific, and how OX2R agonism should be positioned clinically. Methods: We performed a targeted narrative review of peer-reviewed human studies, major guidelines, trial registries, and regulatory documents updated through 16 October 2026. Peer-reviewed trials and regulatory sources were prioritized; conference- or sponsor-reported data were used only when peer-reviewed evidence was unavailable and were identified as provisional. Results: In the pivotal phase 3 trials, oveporexton produced placebo-adjusted improvements in MWT sleep latency of 13.8–20.1 min, ESS reductions of 8.0–9.8 points, and weekly cataplexy incidence-rate ratios of 0.25–0.38. Clinically important safety considerations include insomnia, urinary frequency/urgency, CPK elevations, CYP3A interactions, and measurable abuse potential. Alixorexton phase 2 data support OX2R agonism as a developing drug class, whereas firazorexton illustrates molecule-specific hepatotoxic risk. Conclusions: OX2R agonists are best described as mechanism-based pharmacological restoration of orexin signaling, not proven disease-modifying therapy. Their comparative clinical position remains uncertain because head-to-head trials with established therapies are lacking.