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Alixorexton, a selective orexin 2 receptor agonist, improves wakefulness in narcolepsy type 1

In a phase 2 randomized controlled trial, alixorexton (4, 6, or 8 mg once daily) significantly increased mean sleep latency on the Maintenance of Wakefulness Test compared to placebo at 6 weeks. Placebo-corrected improvements were 22.2, 24.1, and 26.0 minutes for the 4, 6, and 8 mg doses, respectively. The drug was generally well tolerated, with adverse events consistent with on-target OX2R agonism.

Last updated: Aug 26, 2026•1 RCTs•📖 Read as article →

Evidence Score

Evidence Score44/100
Human RCT★★☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

observational

Plazzi G, Grunstein RR, Mignot E, Lammers GJ, Plante DT, Buntinx E, Del Río Villegas R, Chen H, Lovett A, Doane MJ, Hopkinson C, Rege B, Himes J, Dauvilliers Y · The Lancet. Neurology (2026)

Participants: N/A
Duration: 6 weeks
Intervention: Alixorexton (oral OX2R agonist) at doses of 4 mg, 6 mg, or 8 mg once daily for 6 weeks
Outcome: Change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT); also safety and tolerability
Effect Size: Least-squares mean placebo-corrected change from baseline: 22.2 min (95% CI 17.2-27.2) for 4 mg, 24.1 min (19.0-29.1) for 6 mg, 26.0 min (21.0-31.0) for 8 mg
Population: Adults (aged 18-70 years) with narcolepsy type 1

Result:

PubMed: 42636845DOI: 10.1016/S1474-4422(26)00278-4

Mechanism Graph

Alixorexton binds to and activates orexin 2 receptors (OX2R) in the brain
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OX2R activation promotes wakefulness and suppresses rapid eye movement sleep
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This leads to increased alertness and reduced cataplexy in narcolepsy type 1
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Result: Significant improvement in mean sleep latency on MWT

Limitations

  • ⚠Phase 2 trial with relatively small sample size (n=92)
  • ⚠Short duration (6 weeks) and no long-term safety data
  • ⚠Open-label extension may introduce bias
  • ⚠No comparison with existing treatments (e.g., modafinil, pitolisant)

Frequently Asked Questions

What is alixorexton?▼

Alixorexton is an oral selective orexin 2 receptor agonist being investigated for narcolepsy type 1.

How effective is alixorexton for narcolepsy?▼

In this phase 2 trial, alixorexton improved mean sleep latency by about 22-26 minutes compared to placebo at 6 weeks, which is clinically meaningful.

What are the common side effects of alixorexton?▼

Common side effects (in ≥5% of patients) included frequent urination (pollakiuria), insomnia, increased salivation, urgency to urinate, blurred vision, and excessive sweating.

Is alixorexton approved for narcolepsy?▼

No, this is a phase 2 trial. Further phase 3 evaluation is needed before regulatory approval.

Products

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References

  1. 1.Plazzi G, Grunstein RR, Mignot E, Lammers GJ, Plante DT, Buntinx E, Del Río Villegas R, Chen H, Lovett A, Doane MJ, Hopkinson C, Rege B, Himes J, Dauvilliers Y. "Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.." The Lancet. Neurology, 2026. PMID: 42636845 DOI: 10.1016/S1474-4422(26)00278-4
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.