‘Potent’ oral therapy found to boost wakefulness in adults with narcolepsy

In a small early clinical trial, single doses of the oral therapy alixorexton were found to be generally well tolerated and to improve wakefulness — both objective and self-reported — in adults with narcolepsy types 1 and 2.

“We observed similarly robust wake-promoting effects” with the treatment candidate in both narcolepsy types, albeit at different doses, the researchers reported, adding that the findings supported alixorexton’s mechanism of action “as a therapeutic approach.”

These and other positive results from subsequent clinical trials have led to alixorexton’s advancement into late-stage clinical testing. The experimental therapy is now being evaluated versus a placebo among people with both types of narcolepsy in three global Phase 3 trials.

Two of them — Brilliance NT1 (NCT07455383) and Brilliance NT1–304 (NCT07540897) — are testing alixorexton for narcolepsy type 1, and collectively are recruiting an estimated 300 adults. Evaluating the therapy for narcolepsy type 2 is Brilliance NT2 (NCT07502443), which is enrolling approximately 176 adults. All three are slated to run through the middle of next year.

In the earlier Phase 1b trial (ISRCTN98204977), conducted in Australia and the U.S., alixorexton was found to be “highly potent” and showed “dose-dependent improvements in objective wakefulness … and self-reported alertness,” according to researchers.

Their study, “Targeting Orexin 2 Receptors in Idiopathic Hypersomnia and Narcolepsy: A Randomised Phase 1b Proof-of-Concept Study of Alixorexton,” was published in the Journal of Sleep Research. Funding for the study came from Alkermes, the treatment’s developer. Six of the study’s 11 authors are employed by the Massachusetts-based company.

Recommended Reading

July 23, 2026 by Margarida Maia, PhD

Power naps and routines can make a difference when you have narcolepsy

Narcolepsy is a rare condition characterized by its hallmark symptom of uncontrollable sleepiness during the daytime. It is divided into two main types: narcolepsy type 1, which features sudden episodes of muscle weakness known as cataplexy, and narcolepsy type 2, which does not involve cataplexy but still causes significant daytime sleepiness.

In type 1 narcolepsy, the disease is caused by the near-complete loss of nerve cells that produce orexin, a brain chemical that helps regulate wakefulness and stable sleep-wake transitions. The role of orexin in narcolepsy type 2 is less clear, though researchers believe that boosting orexin signaling may still improve wakefulness in some patients.

Small trial tested alixorexton in narcolepsy types 1 and 2

Alixorexton, also known as ALKS 2680, is an oral therapy candidate being developed by Alkermes to activate orexin 2 receptors, the proteins at the surface of cells that are activated by orexin. It has been granted breakthrough therapy status in the U.S. for the treatment of narcolepsy type 1, which is meant to accelerate its clinical development and regulatory review.

The Phase 1b trial (ISRCTN98204977), sponsored by Alkermes, evaluated the safety, tolerability, and wake-promoting effects of alixorexton versus a placebo in adults with three conditions: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia, which is marked by excessive daytime sleepiness. This condition often results in severe sleep inertia and long, unrefreshing sleep.

Altogether, the study enrolled 10 adults with narcolepsy type 1, nine with type 2, and eight with hypersomnia. The type 1 patients had a mean age of 25.6 and 60% were women. Those with type 2 had a mean age of 36 and among them, 56% were women. The vast majority of those with hypersomnia (88%) were women; their mean age overall was 35.3.

Each person was randomly assigned to one of four treatment sequences, receiving the placebo and three single oral doses of alixorexton across four separate treatment periods. That allowed all of the participants to serve as their own comparison.

The narcolepsy type 1 group received lower alixorexton doses (1, 3, and 8 mg), while the other two groups received 5, 12, and 25 mg. There were washout periods between treatment periods to reduce the risk that effects from one dose would carry over into the next period.

The study’s main goal was to evaluate the therapy’s safety and tolerability. Alixorexton was generally well tolerated, with all adverse events reported being mild or moderate in severity. There were no serious adverse events, deaths or discontinuations due to adverse events.

Common treatment-related adverse events were insomnia, frequent urination, and dizziness. No clinically meaningful laboratory or cardiovascular safety signals were identified.

Recommended Reading

July 21, 2026 by Steve Bryson PhD

Sleep and wake patterns may help distinguish narcolepsy types

Highest dose of treatment led to greatest self-reported alertness

To test efficacy, the researchers used two assessments: the Maintenance of Wakefulness Test (MWT), which evaluates how long a person can remain awake in a quiet setting, and the Karolinska Sleepiness Scale, a self-reported measure of alertness.

The team found that alixorexton produced dose-dependent, significant improvements in wakefulness in both narcolepsy groups.

In the type 1 group, mean sleep latency — the exact amount of time it takes to transition from full wakefulness to actually falling asleep — on the MWT increased from 4.4 min with the placebo to 24.8 minutes with 1 mg alixorexton, 29.5 minutes with 3 mg and 35.9 minutes with 8 mg. In narcolepsy type 2 patients, average sleep latency rose from 14.3 minutes with the placebo to 26 minutes with 5 mg alixorexton, 32.9 minutes with 12 mg, and 35.4 minutes with 25 mg.

Self-reported alertness also improved after alixorexton, with the strongest effects being observed with the highest dose in each patient group. In addition, people with narcolepsy type 1 saw the largest benefits, with a clear dose-dependent response, the researchers noted.

The findings supported “continued clinical evaluation of alixorexton” and “informed dose selection for [subsequent] Phase 2 studies,” the researchers wrote. Those next studies were Vibrance-1 (NCT06358950) in narcolepsy type 1, and Vibrance-2 (NCT06555783) in narcolepsy type 2.

In both trials, data showed that alixorexton outperformed a placebo in reducing daytime sleepiness. Data from the studies’ open-label, extension phase demonstrated that long-term alixorexton treatment was associated with greater wakefulness, less fatigue, and better cognitive function.