Alixorexton is the company’s novel, investigational, oral, selective orexin 2 receptor agonist in phase 2 development for the treatment of narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.
Key takeaways:
- Alixorexton, an oral selective orexin-2 receptor agonist, produced clinically meaningful improvements on the MWT and ESS in patients with narcolepsy type 2 in the phase 2 Vibrance-2 trial.
- Higher doses (14 mg and 18 mg) met statistical significance on MWT, while the 18 mg dose met statistical significance on ESS after multiplicity adjustment.
- The investigational therapy was generally well-tolerated, with no serious adverse events and mostly mild to moderate effects such as pollakiuria, insomnia, and dizziness.
- The results suggest orexin-2 agonism may benefit NT2 patients despite typically normal orexin levels, an important mechanistic finding given the unclear pathophysiology of NT2.
- Combined Vibrance-1 (NT1) and Vibrance-2 (NT2) data support rapid movement into a global phase 3 program beginning in early 2026.
- A separate phase 2 study, Vibrance-3, is enrolling adults with idiopathic hypersomnia to evaluate alixorexton’s potential in that population.
Alkermes plc released 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 the company’s novel, investigational, oral, selective orexin 2 receptor agonist in phase 2 development for the treatment of narcolepsy type 1 (NT1), NT2, and idiopathic hypersomnia (IH).
In Vibrance-2, once-daily alixorexton met the dual primary endpoints, demonstrating statistically significant and clinically meaningful improvements from baseline compared to placebo on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) at week eight.
Alixorexton was generally well-tolerated at all doses tested. Results from Vibrance-2 and the previously announced Vibrance-1 phase 2 study in patients with NT1 support rapid initiation of a global phase 3 program of alixorexton in patients with NT1 and NT2.
In contrast to NT1, in which orexin deficiency is well established, the pathophysiology of NT2 remains less clearly defined and is typically associated with normal orexin levels.
In Vibrance-2, patients with NT2 (n=93) were randomized (1:1:1:1) to receive a once-daily dose of alixorexton (10 mg, 14 mg, or 18 mg) or placebo for eight weeks. Topline results include:
Dual Primary Endpoints
- MWT: Alixorexton demonstrated clinically meaningful improvements from baseline in mean sleep latency compared to placebo at week eight at all doses tested. Based on the pre-specified analysis, the 14 mg and 18 mg doses achieved statistical significance (p<0.05 adjusted for multiplicity).
- ESS: Alixorexton demonstrated clinically meaningful improvements from baseline in excessive daytime sleepiness compared to placebo on the ESS at week eight at all doses tested. Based on the pre-specified analysis, the 18 mg dose achieved statistical significance (p<0.05 adjusted for multiplicity).
Safety
- Alixorexton was generally well-tolerated across all doses tested throughout the eight-week, randomized, double-blind treatment period. Most treatment-emergent adverse events were mild to moderate in severity. No serious treatment-emergent adverse events 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 treatment-emergent adverse events were pollakiuria, insomnia, urinary urgency, dizziness, and headache.
- Approximately 95% of patients completed the eight-week double-blind portion of the trial and entered into the optional five-week open-label extension, which is ongoing.
“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,” says Emmanuel Mignot, MD, PhD, 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, in a release.
“The results of this study provide critical insights that will inform our registrational program,” says Craig Hopkinson, MD, chief medical officer and executive vice president of research & development at Alkermes, in a release. “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.”
Alkermes plans to present detailed results from the Vibrance-2 phase 2 study, including exploratory patient-reported outcomes related to cognition and fatigue, at a future scientific meeting.
Alkermes plans to initiate the alixorexton narcolepsy global phase 3 program in the first quarter of 2026. Vibrance-3, a phase 2 study evaluating the safety and efficacy of alixorexton in adults with IH, is currently enrolling.
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