Phase 2 VIBRANCE-2 Findings Further Support Orexin-Targeting Treatment Alixorexton in Narcolepsy

Newly announced data from the phase 2 VIBRANCE-2 trial (NCT06555783) showed that treatment with once-daily alixorexton, an investigational orexin 2 receptor (OX2R) agonist, was safe and led to statistically significant and clinically meaningful efficacy improvements in patients with narcolepsy type 2 (NT2). Overall, the drug met the study’s dual end points, further supporting its development in a phase 3 program for NT2 and narcolepsy type 1 (NT1).¹

VIBRANCE-2, a randomized, double-blind, placebo-controlled trial, featured 93 patients with NT2 who were randomly assigned to 1 of 3 doses of alixorexton (10 mg, 14 mg, or 18 mg) or placebo for an 8-week treatment period. At the conclusion of this time point, investigators reported clinically meaningful improvements in sleep latency, demonstrated through Maintenance of Wakefulness Test (MWT), at all doses. More specifically, those in the 14 mg and 18 mg groups demonstrated statistical significance (P <.05 adjusted for multiplicity).

Aside from MWT, the study also used change in sleepiness, measured through the Epworth Sleepiness Scale (ESS), as a dual end point. Here, results continued to support alixorexton’s efficacy, as treated patients in all dosed cohorts demonstrated clinically meaningful improvements from baseline. Based on the pre-specified analysis, the 18 mg dose achieved statistical significance (P <.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,” Emmanuel Mignot, MD, PhD, Craig Reynolds Professor of Sleep Medicine, Stanford University, and director of the Stanford Center for Narcolepsy, said in a statement.¹ "These data are exciting and represent an important breakthrough in advancing a potential new treatment option for patients living with narcolepsy type 2."

NT2, a chronic sleep disorder, is characterized by excessive daytime sleepiness without the cataplexy seen in NT1. Treatment for NT2 has been primarily through wake-promoting agents, such as modafinil or armodafinil, or newer therapies like solriamfetol (Sunosi) or pitolisant (Wakix). While NT2 is often viewed as milder than NT1, it can be equally debilitating.

In terms of safety, alixorexton was shown to be well tolerated through the study period, with most treatment-emergent adverse events (TEAEs) being mild to moderate in nature. Overall, there were no serious TEAEs reported, along with no new safety signals or treatment-related clinically meaningful changes on ophthalmic exams. Encouragingly, 95% of patients who completed the double-blind portion entered into the 5-week open-label extension, which is ongoing.

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"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,” Craig Hopkinson, MD, chief medical officer and executive vice president of Research & Development at Alkermes, said in a statement.¹

He added, "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."

Alixorexton, also known as ALKS 2680, previously showed efficacy in patients with NT1 through the phase 2 VIBRANCE-1 trial (NCT06358950). In this double-blind, placebo-controlled trial, treatment with the agent led to statistically significant, clinically meaningful, and dose-dependent improvements in MWT, the primary end point, after 6 weeks of treatment in all doses tested. Similar to VIBRANCE-2, investigators reported statistically significant enhancements in EDS via the ESS (P <.0001 at all doses), a key secondary end point.²

In VIBRANCE-1, a dose-ranging study, 92 patients were randomly assigned to alixorexton at 3 different doses of placebo, once daily for 6 weeks, with an optional 7-week, open-label study to follow once completed. Across 6 weeks, all alixorexton doses improved weekly cataplexy rates, with the 6-mg group reaching significance (P = .005). The agent also produced clinically meaningful gains on the Narcolepsy Severity Scale (P < .001) and the British Columbia Cognitive Complaints Inventory (P < .0001) across all doses.

The last trial of the clinical program is VIBRANCE-3, a phase 2 study testing alixorexton in patients with idiopathic hypersomnia (IH), another neurological disorder characterized by EDS. This study, which is currently enrolling, tests 3 different doses of alixorexton (10 mg, 14 mg, and 18 mg) over an 8-week treatment period, using change in ESS score as the primary outcome. Other secondary end points include change in Idiopathic Hypersomnia Severity Score and incidence of adverse events.³

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 12, 2025. https://www.prnewswire.com/news-releases/alkermes-announces-positive-topline-results-from-vibrance-2-phase-2-study-of-once-daily-alixorexton-in-patients-with-narcolepsy-type-2-302612355.html
2. Alkermes announces positive topline results from Vibrance-1 phase 2 study of once-daily Alixorexton in patients with narcolepsy type 1. News release. Alkermes. July 21, 2025. Accessed November 12, 2025. https://www.prnewswire.com/news-releases/alkermes-announces-positive-topline-results-from-vibrance-1-phase-2-study-of-once-daily-alixorexton-in-patients-with-narcolepsy-type-1-302509211.html
3. Alkermes Announces Initiation of Vibrance-3 Phase 2 Study Evaluating ALKS 2680 for the Treatment of Idiopathic Hypersomnia. News release. Alkermes. April 1, 2025. Accessed November 12, 2025. https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-initiation-vibrance-3-phase-2-study