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

ABSTRACT

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 ).