Alixorexton cuts daytime sleepiness, boosts cognition in NT2 trial

Alixorexton, an experimental oral therapy from Alkermes, reduced daytime sleepiness and fatigue while boosting wakefulness and cognitive function in the Phase 2 Vibrance-2 study for narcolepsy type 2 (NT2).

“People living with narcolepsy type 2 frequently experience a lengthy and challenging diagnostic journey, and many continue to live with significant symptom burden following diagnosis,” Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, said in a company press release. “The Vibrance-2 dataset reinforces our belief that alixorexton has the potential to deliver clinically meaningful benefits across key symptoms.”

Investigators presented updated Vibrance-2 data at SLEEP 2026, the annual meeting of the Associated Professional Sleep Societies.  The presentation was titled “Vibrance-2: A randomized Phase 2 study evaluating the efficacy and safety of the orexin 2 receptor agonist alixorexton in patients with narcolepsy type 2.”

The findings support the ongoing Phase 3 Brilliance NT2 trial (NCT07502443), a larger alixorexton study currently recruiting people with NT2. Alkermes is sponsoring two other Phase 3 trials, the Brilliance NT1 studies (NCT07455383 and NCT07540897), in people with narcolepsy type 1 (NT1).

Narcolepsy is a rare condition that causes uncontrollable sleepiness during the daytime. It can also lead to cognitive and mood symptoms. There are two main types: NT1 and NT2. NT1 is an autoimmune disorder characterized by deficits in the signaling molecule orexin (also called hypocretin), which helps regulate sleep and wakefulness. In NT2, orexin levels are usually normal, and the precise underlying causes remain unclear.

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Alkermes is testing alixorexton as a therapy for both narcolepsy types. The medication binds to the orexin 2 receptor, a process called orexin 2 receptor agonism that the company expects may increase wakefulness and ease other symptoms across disease types.

The Phase 2 Vibrance-2 trial (NCT06555783) tested the medication in 93 adults with NT2. The study ran alongside Vibrance-1 (NCT06358950), which tested the therapy in NT1.

Vibrance-2 participants were randomly assigned to receive a placebo or one of three doses of alixorexton (10 mg, 14 mg, or 18 mg). They took the assigned dosage daily for eight weeks, and could then continue in an optional five-week, open-label extension study.

One of the study’s main goals was to measure changes in the Maintenance of Wakefulness (MWT), which assesses how long one can stay awake in a quiet environment.

Across all doses of alixorexton, participants saw clinically meaningful increases in MWT time, indicating a greater capacity to stay awake. In the 14 mg and 18 mg dose groups, the mean MWT time increased from 6 minutes to 14 minutes — a statistically significant difference compared to the control group.

Investigators also used the Epworth Sleepiness Scale (ESS), a questionnaire assessing daytime sleepiness. Again, all alixorexton groups had clinically meaningful improvements. The mean ESS score indicated severe excessive daytime sleepiness before treatment, but most alixorexton participants had scores indicating normal or mildly elevated sleepiness after the study. This difference was statistically significant in the 18 mg group.

At week 13, during the open-label extension period, mean ESS scores across all alixorexton dose groups were within the normal range. Together, these results mean that the trial met both of its primary goals.

“Vibrance-2 was the first large clinical trial in patients with NT2 to demonstrate positive results with an orexin 2 receptor agonist,” the research team wrote in the SLEEP 2026 abstract.

A participant-reported fatigue measure also decreased significantly in the 14 mg and 18 mg dose groups. Improvements began as early as the second week of treatment and continued through the open-label extension period.

Cognitive function improved along a similar timeline, according to the British Columbia Cognitive Complaints Inventory. However, this change only reached statistical significance in the 18 mg dosage group.

“The Vibrance-2 results presented at SLEEP provide compelling evidence that alixorexton meaningfully improved measures of wakefulness, fatigue and cognition in patients with narcolepsy type 2,” said Richard K. Bogan, MD, principal of Bogan Sleep Consultants and associate clinical professor at the University of South Carolina. “As excitement builds around innovative, potential new treatments, these findings are particularly notable as the first orexin 2 receptor agonist to demonstrate such clinically meaningful benefits in patients with narcolepsy type 2, a population without known orexin deficiency.”

Most participants tolerated alixorexton well, and most reported safety events were mild or moderate, according to Alkermes. The most common events included frequent daytime urination, an increased urgency around urination, insomnia, dizziness, and headaches.

No potential safety concerns arose in laboratory tests of liver, kidney, heart, or eye function.

“Alongside positive Vibrance-1 data in narcolepsy type 1, these results underscore alixorexton’s potential to become an important new treatment option for patients with narcolepsy,” Bogan said.

Vibrance-1 investigators also presented positive findings at SLEEP 2026. The trial found that alixorexton was safe, decreased daily sleepiness, and improved quality of life in NT1 participants.

The Brilliance trials will follow up on the Vibrance program in larger groups of narcolepsy participants. They will test multiple alixorexton doses against a placebo, with daily dosing for 12 weeks.