Long-term oral therapy benefits patients in narcolepsy trials

Long-term treatment with the experimental oral therapy alixorexton safely improved wakefulness, eased fatigue, and boosted cognition for people with narcolepsy in clinical trials, according to interim data announced by alixorexton’s developer, Alkermes.

“These long-term results represent a significant contribution to our understanding of alixorexton as a potential new treatment option for patients with narcolepsy,” Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, said in a company press release. “We are particularly encouraged by the durability of effect observed across multiple dimensions of the disease, including wakefulness, cognition and fatigue, together with a safety profile that continued to be generally well tolerated.”

Narcolepsy is marked by uncontrolled sleepiness during the daytime. Patients may also have other symptoms, including fatigue, cognitive problems, and cataplexy (a sudden loss of muscle tone). The condition has two main types, defined by differences in a sleep-regulating signaling molecule called orexin (also called hypocretin). People with type 1 narcolepsy (NT1) have abnormally low orexin levels, whereas people with type 2 narcolepsy (NT2) have normal levels of this signaling molecule.

Alixorexton, designed as a potential l treatment for both forms of narcolepsy, works by activating a receptor that normally responds to orexin.

The new data “underscore the importance of dosing flexibility to meet individual needs across narcolepsy patients with known orexin deficiency as well as patients with normal orexin tone,” Hopkinson said.

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Alixorexton was tested at various doses against a placebo in a pair of Phase 2 clinical trials, Vibrance-1 (NCT06358950) in NT1 and Vibrance-2 (NCT06555783) in NT2. In both trials, the main findings suggested that alixorexton outperformed a placebo at improving measures of daytime sleepiness. Three doses of the experimental drug were given in each trial: 4 mg, 6 mg and 8 mg in Vibrance-1, and 10 mg, 14 mg and 18 mg in Vibrance-2.

Following the placebo-controlled studies, participants had the option to enter into an ongoing open-label extension study in which all are being treated with alixorexton and monitored for long-term outcomes. The new analysis covers data out to about six months in the extension study — nine months of treatment for patients who received alixorexton in the original Phase 2 studies.

To assess sleepiness, researchers mainly looked at two measures: One, mean sleep latency (MSL), measures the time it takes someone to fall asleep for a daytime nap. An MSL of 20 minutes or longer is considered normal. The other is a patient-rated questionnaire called the Epworth Sleepiness Scale (ESS); a score of 10 or lower is considered normal.

As of data cutoff, 70 people with NT1 were still in the extension study. Available data showed that, at month six in the long-term study, MSL and ESS scores from all evaluable NT1 patients were generally within the normal range, with mean scores of 29 minutes for MSL and 7.5 points for ESS. Prior to starting on alixorexton, the mean MSL was about two or three minutes, and mean ESS scores were around 19 points.

Similar improvements were seen in people with NT2. Fifty-one NT2 patients were in the extension study at data cut-off. After six months in the extension study, mean MSL was approximately 18 minutes, and mean ESS was 8.9 points. Prior to starting alixorexton, mean MSL was two to five minutes, and mean ESS was about 18 points.

Patients also tended to report reduced fatigue and improved cognitive function. Prior to starting alixorexton, patients reported moderate fatigue and cognitive impairment; at the latest follow-up in the extension study, average scores were mostly within normal ranges.

“For people living with narcolepsy, symptom burden extends beyond excessive daytime sleepiness and can affect cognitive function and fatigue,” said Yves Dauvilliers, MD, PhD, director of the Sleep-Wake Disorders Center at the University of Montpellier in France. “It is exciting to see clinically meaningful improvements sustained across these important measures in this analysis of the long-term extension study of alixorexton in patients with narcolepsy type 1 and type 2.”

Long-term safety data have generally been positive, and no serious treatment-emergent adverse events have been reported in people with NT1 or NT2.

“The consistency of the data in up to nine months of treatment provides further evidence that alixorexton, across a range of doses, has the potential to address important aspects of disease burden of narcolepsy regardless of narcolepsy type 1 or type 2 diagnosis,” Dauvilliers said.

Alkermes is running a Phase 3 program to further test alixorexton. The Brilliance NT1 studies (NCT07455383 and NCT07540897) are recruiting participants with NT1 at sites in the U.S., Australia, Canada, and the Netherlands. Meanwhile, the Brilliance NT2 trial (NCT07502443) is recruiting people with NT2 at sites in the U.S. and Canada. Both Phase 3 trials are comparing alixorexton against a placebo, with the main goal of evaluating the medication’s effect on wakefulness after about three months.

“We are excited to continue advancing enrollment in the phase 3 Brilliance Studies,” Hopkinson said.