Positive Phase 2 Data: Alixorexton for the Treatment of Adults With Narcolepsy Type 1

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Alkermes today announced positive topline results from the randomized double-blind treatment period of the Vibrance-1 phase 2 study evaluating alixorexton in patients with narcolepsy type 1 (NT1). Treatment with alixorexton led to statistically significant and dose-dependent improvements in sleep latency among patients with NT1.¹

Alixorexton, formerly referred to as ALKS 2680, is a novel, investigational, oral orexin 2 receptor (OX2R) agonist in phase 2 development as a once-daily treatment for NT1, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

Vibrance-1 is a phase 2, randomized, double-blind, dose-range-finding, placebo-controlled study evaluating the safety and efficacy of alixorexton in adults with NT1. Participants (n=92) were randomly assigned (1:1:1:1) to receive 1 of 3 doses of alixorexton (4 mg, 6 mg, or 8 mg) or placebo to be taken once-daily for 6 weeks. The primary endpoint assessed whether participants receiving alixorexton experienced an improvement in wakefulness compared with participants taking placebo, as measured by the change from baseline in mean sleep latency on the maintenance of wakefulness test (MWT) at week 6. Secondary endpoints included change from baseline in Epworth Sleepiness Scale (ESS) score and mean weekly cataplexy rate (WCR) at week 6, and incidence of adverse events. Investigators also assessed several patient-reported outcome measures, which evaluated the effect of alixorexton on participants' disease severity, fatigue, and cognition. All participants in the double-blind portion of the study were eligible to continue to a 7-week open-label safety extension portion of the study, followed by a long-term safety study.

Alixorexton met the primary endpoint across all doses tested, demonstrating statistically significant, clinically meaningful, and dose-dependent improvements from baseline compared with placebo in wakefulness on the MWT (P<0.0001 at all doses). In addition to achieving normative wakefulness across all dose groups on the MWT (mean sleep latency >20 minutes), once-daily alixorexton demonstrated robust and clinically meaningful improvements compared with placebo on patient-reported outcomes related to excessive daytime sleepiness (P<0.0001 at all doses). Additionally, alixorexton numerically improved weekly cataplexy rates across all doses compared with placebo at week 6 and achieved statistical significance at the 6 mg dose (P=0.005).

"These compelling results demonstrated that once-daily alixorexton normalized wakefulness and excessive daytime sleepiness scores in highly symptomatic patients with NT1 with a generally well tolerated profile across all doses tested. In addition, the initial data from patient-reported outcome measures related to fatigue and cognition are truly exciting and highlight the breadth of benefit that alixorexton may provide across multiple facets of narcolepsy. There is a clear and pressing need for new therapies for NT1, as patients continue to face a range of persistent symptoms that disrupt their day-to-day lives," said Giuseppe Plazzi, MD, PhD, a neurologist and the director of the Narcolepsy Center at the IRCCS of the Neurological Sciences of Bologna and Professor of Childhood Neuropsychiatry at the University of Modena and Reggio Emilia. "These exciting data underscore the transformative potential of orexin 2 receptor agonists for the treatment of NT1 and highlight the differentiated features of alixorexton."

The additional exploratory patient-reported outcome measures assessed by investigators included:

• Narcolepsy Severity Scale: Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in narcolepsy symptom severity as compared with placebo at week 6 (P<0.001 at all doses).
• British Columbia Cognitive Complaints Inventory: Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in cognitive complaints compared with placebo at week 6 (P<0.0001 at all doses).
• PROMIS (Patient-Reported Outcomes Measurement Information System)-Fatigue: Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in fatigue as compared with placebo at week 6 (P<0.01 at all doses).

Alixorexton was generally well tolerated at all doses tested. No treatment-emergent serious adverse events were reported. Most treatment-emergent adverse events were mild to moderate in severity and were generally consistent with the events observed across the alixorexton phase 1 program in healthy volunteers and participants with NT1, NT2, and IH. There were no treatment-related safety signals observed in hepatic and renal parameters, vital signs, or ophthalmic exams. More than 95% of the participants who participated in the 6-week double-blind portion of the trial also entered the 7-week open-label extension, which is currently ongoing.

Alkermes will present detailed safety and efficacy results from the Vibrance-1 phase 2 study in a presentation at the upcoming World Sleep Congress in Singapore on September 5-10, 2025. The phase 2 studies Vibrance-2 and Vibrance-3 evaluating the safety and efficacy of alixorexton in adults with NT2 (NCT06555783) and IH (NCT06843590), are currently ongoing.²

"Data from Vibrance-1 further characterize the clinical profile of alixorexton across a range of once-daily doses in a multiweek study in patients with narcolepsy type 1. Based on the positive outcomes across multiple symptoms important to patients, we are moving forward expeditiously to initiate a global phase 3 program. We look forward to sharing detailed data from Vibrance-1 at the World Sleep meeting in September," said Craig Hopkinson, MD, the chief medical officer and executive vice president of Research & Development at Alkermes. "These positive topline data represent an important stride forward for the alixorexton development program and Alkermes' broader portfolio of orexin 2 receptor agonists. Alkermes is at the forefront of development in this exciting potential therapeutic category, and these data support our hypothesis that the therapeutic potential of orexin 2 receptor agonists extends beyond improvements in wakefulness to other symptoms such as fatigue and cognition in narcolepsy."

References

1. Alkermes announces positive topline results from Vibrance-1 phase 2 study of once-daily alixorexton in patients with narcolepsy type 1. News release. July 21, 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

2. Alkermes announces initiation of Vibrance-2 phase 2 study evaluating ALKS 2680 for the treatment of narcolepsy type 2. News release. August 22, 2024. Accessed July 21, 2025. https://www.prnewswire.com/news-releases/alkermes-announces-initiation-of-vibrance-2-phase-2-study-evaluating-alks-2680-for-the-treatment-of-narcolepsy-type-2-302227858.html