Once-daily drug eases daytime sleepiness in type 1 narcolepsy in trial
Use of oral therapy also cuts episodes of sudden muscle weakness
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A mid-stage clinical trial tested the oral therapy alixorexton in people with narcolepsy type 1. (Image from iStock)
Once-daily dosing with alixorexton, being developed by Alkermes, outperformed a placebo at helping adults with type 1 narcolepsy (NT1) stay awake longer and feel less sleepy during the day — while also reducing the number of sudden, uncontrollable episodes of muscle weakness called cataplexy that mark the sleep-related disorder.
Those are the findings of a now-completed Phase 2 clinical trial, dubbed Vibrance-1 (NCT06358950), in which the main goal was to watch for changes in how long it took patients to fall asleep during a monitored wakefulness test. The researchers also found alixorexton to be generally safe and well tolerated, supporting testing in a Phase 3 clinical program called Brilliance.
“Alixorexton demonstrated substantial and clinically meaningful benefits across multiple dimensions of narcolepsy type 1,” Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, said in a company press release, which also noted “improvements in patient-reported outcomes related to disease severity, fatigue, cognition and health-related quality of life.”
According to Hopkinson, “these findings highlight the potential of alixorexton to address a broad range of symptoms that continue to burden patients despite currently available therapies.”
The study detailing these results, titled “Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial,” was published in the journal The Lancet Neurology.
NT1 is a type of narcolepsy that leads to excessive daytime sleepiness, called EDS, and cataplexy. It is linked to the loss of nerve cells that produce orexin, a signaling chemical in the brain that helps keep people awake. Its loss disrupts the normal sleep-wake cycle, causing the condition’s symptoms.
Alixorexton is designed to activate the orexin 2 receptor (OX2R), the protein that orexin normally interacts with to send signals. By mimicking orexin, alixorexton is expected to reduce symptoms such as cataplexy and EDS. Alkermes is testing the experimental therapy for both NT1 and narcolepsy type 2 (NT2), another type of the disorder for which alixorexton was found to have benefits.
Vibrance-1 tested oral drug alixorexton at 3 doses
Vibrance-1 involved 92 adults diagnosed with NT1, who had a mean age of 33.5. After a two-week washout period to allow ongoing narcolepsy medications to leave the body, the participants were randomly assigned to receive either oral tablets of alixorexton — at doses of 4 mg, 6 mg, or 8 mg — or a placebo, taken once daily for six weeks. Nearly two-thirds of patients (62%) were women.
The trial’s main measure was mean sleep latency (MSL), which is the average amount of time a person can stay awake before falling asleep, as assessed by the Maintenance of Wakefulness Test (MWT). This is a standardized test that monitors wakefulness in a quiet setting; a longer sleep latency indicates a better ability to stay awake.
After six weeks, those on the placebo stayed awake for a mean of 2.3 minutes. Those treated with alixorexton stayed awake significantly longer: for a mean of 24 minutes with the 4 mg dose, 25.9 minutes with the 6 mg dose, and 28.2 minutes with the 8 mg dose. Compared with the placebo, the improvement was 22.2, 24.1, and 26 minutes, respectively, the data showed.
Secondary measures included changes in the Epworth Sleepiness Scale (ESS) score after six weeks. Reductions in daytime sleepiness were seen as early as week two of treatment with alixorexton. After six weeks, the improvement was 6.4 points at 4 mg, 8.7 points at 6 mg, and 8.3 points at 8 mg of alixorexton, compared with the placebo.
Along with a generally well-tolerated profile, alixorexton demonstrated improvements across a broad range of symptoms that affect daily functioning, including cataplexy.
Taking alixorexton also resulted in a significant reduction in the weekly cataplexy rate, a measure of how frequently such episodes occur. At week six, the median number of episodes was 7.6 in the patient group given the placebo. Among the individuals treated with alixorexton, this number was lower: 3.8 at the 4 mg dose, 1 at the 6 mg dose, and 2.5 at the 8 mg dose.
“Along with a generally well-tolerated profile, alixorexton demonstrated improvements across a broad range of symptoms that affect daily functioning, including cataplexy,” said Giuseppe Plazzi, MD, PhD, director of the Narcolepsy Center at the Institute of Neurological Sciences in Bologna, Italy, and one of the investigators in the clinical trial. Improvements were also noted in cognition and fatigue, Plazzi noted.
No serious adverse events linked to treatment
The most common treatment-emergent side effects were unusually frequent or urgent urination, insomnia (difficulty sleeping), increased production of saliva, blurred vision, and excessive sweating. These side effects were considered consistent with the expected effects of activating OX2R.
Overall, according to the researchers, “alixorexton treatment was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity, and no serious treatment-emergent adverse events.”
The team noted that the findings support the two Phase 3 clinical trials now underway: Briliance NT1 (NCT07540897) and Brilliance NT2 (NCT07502443). Those large trials, which are testing the therapy candidate against a placebo, are both scheduled to wrap up in 2027.
“With the global Brilliance phase 3 program now underway in both narcolepsy type 1 and type 2, we are excited to continue advancing alixorexton in this next stage of development,” Hopkinson said.
He noted that “the totality of evidence generated across the Vibrance phase 2 program in narcolepsy has reinforced our confidence in alixorexton’s potential.”
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