Summary: Alkermes’ alixorexton met all primary and key secondary endpoints in a phase 2 trial for narcolepsy type 1, showing dose-dependent improvements in wakefulness and symptom severity, with a favorable safety profile, supporting its advancement to phase 3.

Key takeaways:

• Alixorexton (formerly ALKS 2680), an oral orexin-2 receptor agonist, met the primary endpoint in Vibrance-1 by significantly improving mean sleep latency on the MWT across all doses (p<0.0001).
• The drug also achieved significant and clinically meaningful improvements in excessive daytime sleepiness, cataplexy (at 6 mg), cognition, fatigue, and overall narcolepsy severity.
• All doses led to normative wakefulness (mean sleep latency >20 minutes) and patient-reported outcomes indicated broad symptomatic relief.
• Alixorexton was generally well tolerated, with no serious adverse events and no dose-related safety signals in liver, kidney, or ophthalmic assessments.
• Over 95% of participants continued into the open-label extension; Alkermes plans to initiate a global phase 3 program and present data at World Sleep Congress 2025.

Alkermes plc 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). 

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

 In Vibrance-1, alixorexton met the primary endpoint across all doses tested, demonstrating statistically significant, clinically meaningful, and dose-dependent improvements from baseline compared to placebo in wakefulness on the Maintenance of Wakefulness Test (MWT). 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 to placebo on patient-reported outcomes related to excessive daytime sleepiness and other key symptoms, such as fatigue and cognition. Alixorexton was generally well tolerated at all doses tested. These data support rapid initiation of a global phase 3 program of alixorexton in patients with NT1.

The results “highlight the breadth of benefit that alixorexton may provide across multiple facets of narcolepsy,” says neurologist Giuseppe Plazzi, MD, PhD, director of the Narcolepsy Center at the IRCCS of the Neurological Sciences of Bologna and a professor of Childhood Neuropsychiatry at the University of Modena and Reggio Emilia, in a release.”There is a clear and pressing need for new therapies for narcolepsy type 1, as patients continue to face a range of persistent symptoms that disrupt their day-to-day lives.”

Craig Hopkinson, MD, chief medical officer and executive vice president, research & development at Alkermes, says in a release, “Based on the positive outcomes across multiple symptoms important to patients, we are moving forward expeditiously to initiate a global phase 3 program….These positive topline data represent an important stride forward for the alixorexton development program and Alkermes’ broader portfolio of orexin 2 receptor agonists.”

Vibrance-1 is a global, randomized, double-blind, placebo-controlled, multiple-dose phase 2 study conducted in patients with NT1 (n=92). Patients were randomized (1:1:1:1) to receive a once-daily dose of alixorexton (4 mg, 6 mg, or 8 mg) or placebo for six weeks.

Primary Endpoint

• Maintenance of Wakefulness Test: Across all doses tested, alixorexton demonstrated statistically significant, clinically meaningful and dose-dependent improvements from baseline in mean sleep latency compared to placebo at week six (p<0.0001 at all doses).

Key Secondary Endpoints

• Epworth Sleepiness Scale: At all doses tested, alixorexton drove statistically significant and clinically meaningful improvements from baseline in excessive daytime sleepiness compared to placebo on the Epworth Sleepiness Scale at week six (p<0.0001 at all doses).
• Weekly Cataplexy Rates: Alixorexton numerically improved weekly cataplexy rates across all doses compared to placebo at week six and achieved statistical significance at the 6 mg dose (p=0.005).

Exploratory Patient-Reported Outcome Measures

Alixorexton demonstrated consistent and clinically meaningful improvements across patient-reported outcome measures of symptoms important to patients including (reported p-values are nominal):

• Narcolepsy Severity Scale: Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in narcolepsy symptom severity as compared to placebo at week six (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 to placebo at week six (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 to placebo at week six (p<0.01 at all doses).

Alixorexton was generally well tolerated across all doses tested in the randomized double-blind period of the Vibrance-1 study. 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 patients 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 patients who participated in the six-week double-blind portion of the trial entered into the seven-week open-label extension, which is ongoing.

Alkermes plans to present detailed safety and efficacy results from the Vibrance-1 phase 2 study in an oral presentation at the upcoming World Sleep Congress, taking place Sept 2025 in Singapore. Vibrance-2 and Vibrance-3, phase 2 studies evaluating the safety and efficacy of alixorexton in adults with NT2 (NCT06555783) and IH (NCT06843590), respectively, are ongoing.

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