Alixorexton for Treatment of Narcolepsy Type 2: New Positive Phase 2 Data

Alkermes announced positive topline results from the Vibrance-2 dose-ranging phase 2 study evaluating alixorexton in patients with narcolepsy type 2 (NT2). Alixorexton, formerly referred to as ALKS 2680, is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in phase 2 development for the treatment of narcolepsy type 1 (NT1), NT2, and idiopathic hypersomnia (IH).¹

In Vibrance-2, participants with NT2 (n=93) were randomly assigned (1:1:1:1) to receive a once-daily dose of alixorexton (10 mg, 14 mg, or 18 mg) or placebo for 8 weeks. Once-daily alixorexton met the dual primary endpoints, demonstrating statistically significant and clinically meaningful improvements from baseline compared with placebo on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) at week 8.

On the MWT, alixorexton demonstrated clinically meaningful improvements from baseline in mean sleep latency compared to placebo at week 8 at all doses tested. Based on the prespecified analysis, the 14 mg and 18 mg doses achieved statistical significance (P<0.05 adjusted for multiplicity).

On the ESS, alixorexton demonstrated clinically meaningful improvements from baseline in excessive daytime sleepiness compared with placebo at week 8 at all doses tested. Based on the prespecified analysis, the 18 mg dose achieved statistical significance (P<0.05 adjusted for multiplicity).

"The alixorexton data from Vibrance-2 are the first demonstration in a large, randomized phase 2 study that an orexin 2 receptor agonist can drive clinically meaningful improvements in wakefulness and excessive daytime sleepiness in patients without known orexin deficiency, with a generally well tolerated profile. These data are exciting and represent an important breakthrough in advancing a potential new treatment option for patients living with narcolepsy type 2," said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the department of psychiatry and behavioral sciences at Stanford University and the director of the Stanford Center for Narcolepsy.

NT2, which is primarily characterized by excessive daytime sleepiness, has a heterogeneous patient population, with differences in symptom severity and treatment response.² This contrasts with NT1, in which orexin deficiency is well established. The pathophysiology of NT2 is less clearly defined than NT1 and is typically associated with normal orexin levels.³

Alixorexton was generally well tolerated across all doses tested throughout the 8-week, randomized, double-blind treatment period. Investigators found that most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, and no serious TEAEs were reported. There were no safety signals observed in hepatic and renal parameters, vital signs or ECGs, and there were no treatment-related clinically meaningful changes on ophthalmic exams in the alixorexton-treated group. The most common TEAEs were pollakiuria, insomnia, urinary urgency, dizziness, and headache. Approximately 95% of patients completed the 8-week double-blind portion of the trial and entered the ongoing, optional 5-week open-label extension.

"The positive topline results from Vibrance-2 mark a significant milestone for the narcolepsy patient community and for the alixorexton development program. In Vibrance-2, alixorexton achieved statistically significant and clinically meaningful improvements on the primary efficacy endpoints with a generally well-tolerated profile in this heterogeneous patient population. The results of this study provide critical insights that will inform our registrational program," said Craig Hopkinson, MD, the chief medical officer and executive vice president of research & development at Alkermes. "Alixorexton is the first and only oral orexin 2 receptor agonist to demonstrate efficacy in large randomized, double-blind, multi-week phase 2 studies across a range of once-daily doses in patients with narcolepsy type 1 and type 2. We are proud to lead the way in translating innovative science into a potential new treatment option for patients and look forward to moving alixorexton into phase 3 development as quickly as possible."

Results from Vibrance-2 and the preceding Vibrance-1 phase 2 study in patients with NT1 support the initiation of a global phase 3 program of alixorexton in patients with NT1 and NT2. Alkermes plans to initiate this alixorexton narcolepsy global phase 3 program in the first quarter of 2026. Additionally, Vibrance-3, a phase 2 study evaluating the safety and efficacy of alixorexton in adults with IH (NCT06843590), is currently enrolling.

Alkermes intends to present further detailed results from the Vibrance-2 phase 2 study, including exploratory patient-reported outcomes related to cognition and fatigue, at an upcoming meeting.

References

1. Alkermes announces positive topline results from Vibrance-2 phase 2 study of once-daily alixorexton in patients with narcolepsy type 2. News release. November 12, 2025. Accessed November 13, 2025. https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-positive-topline-results-vibrance-2-phase-2

2. Ruoff C, Rye D. The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality. Curr Med Res Opin. 2016;32(10):1611-1622.

3. Bassetti CLA, Adamantidis A, Burdakov D, et al. Narcolepsy – clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol. 2019;15(9):519-539.