Efficacy and safety of selective orexin 2 receptor agonists in narcolepsy type 1: a systematic review and meta-analysis of randomized controlled trials.

Abstract

Selective orexin 2 receptor (OX2R) agonists target the orexin deficiency underlying narcolepsy type 1, but their efficacy and safety across compounds have not been quantitatively synthesized. We searched PubMed, Embase, Web of Science, and Cochrane library from inception through September 10, 2026, for randomized, double-blind, placebo-controlled trials of oral OX2R agonists in narcolepsy type 1.The primary outcomes were Maintenance of Wakefulness Test sleep latency, Epworth Sleepiness Scale score, and weekly cataplexy rate. Safety analyses included all double-blind active regimens. Adjusted mean differences and incidence rate ratios were pooled using inverse-variance random-effects models with restricted maximum-likelihood estimation and Hartung-Knapp confidence intervals. Evidence certainty was assessed using GRADE. Five trials randomized 550 participants and evaluated TAK-994, oveporexton, or alixorexton over 6-12 weeks; the primary efficacy synthesis included 337 participants. Compared with placebo, OX2R agonists increased Maintenance of Wakefulness Test sleep latency by 22.7 min (95% CI 16.8-28.7; 95% prediction interval, 8.0-37.4; I2 = 74.4%; low-certainty evidence), reduced epworth sleepiness scale scores (mean difference, - 9.8 points; 95% CI - 10.9 to - 8.8; I2 = 0%; moderate-certainty evidence), and reduced weekly cataplexy rates by 69% (incidence rate ratio, 0.31; 95% CI 0.23-0.41; I2 = 0%; moderate-certainty evidence). Urinary frequency, insomnia, urinary urgency, and salivary hypersecretion were more frequent with treatment. The TAK-994 program was terminated after hepatotoxicity. Short-term OX2R agonist therapy improved wakefulness, sleepiness, and cataplexy in narcolepsy type 1. Limited trials, substantial MWT heterogeneity, and short follow-up constrain class-wide and long-term safety conclusions.

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