Targeting Orexin 2 Receptors in Idiopathic Hypersomnia and Narcolepsy: A Randomised Phase 1b Proof‐Of‐Concept Study of Alixorexton

Idiopathic hypersomnia (IH) and narcolepsy type 2 (NT2) are central disorders of hypersomnolence characterised by excessive daytime sleepiness and substantial functional burden. Narcolepsy type 1 (NT1), defined by orexin deficiency, serves as an established biologic standard for evaluating therapies targeting the orexin system. Alixorexton (ALKS 2680) is a highly potent, oral, selective orexin 2 receptor (OX2R) agonist in clinical development for IH, NT2 and NT1. In this phase 1b, randomised, double-blind, placebo-controlled, four-way crossover study (ISRCTN98204977), adults aged 18-65 years with IH (n = 8), NT2 (n = 9) or NT1 (n = 10) received single oral doses of alixorexton (IH/NT2: 5, 12, 25 mg; NT1: 1, 3, 8 mg) and placebo across four treatment periods. The primary endpoint was safety and tolerability. Wakefulness was assessed by mean sleep latency on the Maintenance of Wakefulness Test (MWT) over 8 h post-dose and subjective alertness by the Karolinska Sleepiness Scale (KSS). Alixorexton was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate, with no serious TEAEs and no discontinuations due to TEAEs. In IH and NT2, alixorexton demonstrated statistically significant, clinically meaningful, dose-dependent increases in MWT sleep latency versus placebo and improved self-reported alertness. NT1 showed a similarly robust, dose-dependent response at lower doses, consistent with orexin-deficient biology. These findings support OX2R agonism as a therapeutic approach for central disorders of hypersomnolence, including conditions with uncertain orexin dysfunction and informed ongoing phase 2 evaluation in IH and narcolepsy. Trial Registration: A study in healthy subjects to see the effects of the test medicine ALKS 2680 in single- and multi-dose regimen; prospectively registered at ISRCTN on October 17, 2022 (identifier: ISRCTN98204977; URL: https://www.isrctn.com/ISRCTN98204977).