Trial review confirms effectiveness of approved narcolepsy drug
Oral therapy shown in 2 late-stage trials to ease range of type 1 symptoms
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The approved medication Orzeyful was shown to outperform a placebo in treating narcolepsy type 1, a review study found. (Image from iStock)
A new review, by an international team of scientists, confirms what was found in two large, late-stage clinical trials: The now-approved narcolepsy drug Orzeyful (oveporexton) worked significantly better than a placebo in reducing measures of sleepiness and easing a wide range of other symptoms in people with type 1 narcolepsy (NT1).
The results from this pair of Phase 3 trials had formed the basis for Orzeyful’s recent approvals in the U.S. and Japan. Now, those findings have undergone peer review, the process in which scientists not involved in a trial go through the data.
The full peer-reviewed results were published in The New England Journal of Medicine, in a paper titled “Oveporexton for Narcolepsy Type 1 — Results from Two Phase 3 Trials.” The work was funded by Takeda Pharmaceuticals, the company that markets Orzeyful. Among the 38 researchers, 18 are employed by Takeda Development Center Americas in the U.S.
According to a company press release from Takeda, data from the trials show that Orzeyful “demonstrated significant and clinically meaningful improvements with the potential to redefine narcolepsy type 1 (NT1) care.”
Sarah Sheikh, head of the neuroscience therapeutic area unit and global development at Takeda, said “the magnitude of effect seen across the full range of symptoms evaluated reinforces the potential of [Orzeyful] to redefine how people feel on treatment.”
NT1, also called narcolepsy with cataplexy — a sudden, brief loss of muscle tone — is marked by low levels of orexin, a signaling chemical that helps regulate sleep and wakefulness. Orzeyful is designed to act as an agonist, or activator, for a specific protein receptor for orexin, essentially mimicking the function of this molecule to address the underlying cause of NT1.
Orzeyful tested in 1 trial at both approved doses
The new paper covers results from two trials: FirstLight (NCT06470828) and RadiantLight (NCT06505031). Collectively, these studies enrolled more than 270 people, ages 16 to 70, with NT1. In both studies, participants were given twice-daily Orzeyful or a placebo for about three months.
The FirstLight study tested two doses of Orzeyful (1 or 2 mg twice daily), while the RadiantLight study tested only the higher 2 mg dose. Both the lower and higher doses are now approved for use in the U.S.
“Leveraging the extensive research we conducted on the impact of narcolepsy type 1, we designed our comprehensive Phase 3 program to reflect the complexity of the disease and the experiences of those living with it,” Sheikh said.
In both trials, the main goal was to determine whether Orzeyful worked better than the placebo in prolonging mean sleep latency on the Maintenance of Wakefulness Test (MWT). The MWT basically measures how well people can stay awake in calm, quiet conditions. A result of 20 minutes or longer is considered normal; the test is ended after approximately 40 minutes if the person is still awake.
Over the course of both Phase 3 trials, mean sleep latency changed by less than one minute in patients given the placebo. However, for patients given Orzeyful, times increased: by 14.3 minutes for patients given the lower dose in FirstLight, and by 17.6 and 19.8 minutes for patients given the higher dose in FirstLight and RadiantLight.
By the end of the 12-week studies, most patients given the higher dose of Orzeyful had mean sleep latency times within normal ranges, as did about half of those given the lower dose of the medication. In both trials, Orzeyful’s improvements in sleep latency were evident at the first assessment done eight weeks after starting treatment.
In both trials, now-approved drug outperformed the placebo
Orzeyful treatment also outperformed the placebo at reducing scores on the Epworth Sleepiness Scale (ESS), a subjective measure of sleepiness. Among participants given the placebo, average ESS scores improved by fewer than two points. But for those on Orzeyful, scores improved significantly more — by nearly 10 points in participants given the lower dose in FirstLight, and by 11 points or more for patients on the higher dose. Improvements in ESS scores were observed as early as four weeks after the treatment’s start in both studies.
Data also showed that Orzeyful reduced rates of cataplexy, a symptom that marks NT1 but is usually not seen in narcolepsy type 2.
At week 12, the median reductions in weekly cataplexy rate ranged from 79% to 89% with Orzeyful versus a maximum of 39% with the placebo. The number of days without cataplexy increased from 0 to as many as 5.1 with the highest dose of the therapy, the data showed.
Scores on the Narcolepsy Severity Scale for Clinical Trials (NSS-CT), an overall measure of narcolepsy symptom severity, showed improvements with both doses of Orzeyful within about a month of starting treatment. By the end of the study, about three-quarters of patients given Orzeyful had NSS-CT scores within the range that typically indicates mild overall symptom severity. By contrast, no more than 1 in 4 patients given the placebo had NSS-CT scores in the mild range.
“The consistency of efficacy improvements across the two independent, placebo-controlled phase 3 trials suggests the potential for [Orzeyful] to address symptoms of narcolepsy type 1 across the disease spectrum,” the researchers wrote.
Patients on Orzeyful were also more likely than those given the placebo to report improvements in overall health status, including attention and quality of life, the researchers noted.
The newly published [trial review] data reinforce the potential of [Orzeyful] to transform how we approach narcolepsy type 1 in clinical practice, shifting from managing individual symptoms to treating the disease itself.
Safety data, meanwhile, showed that the therapy was generally tolerated well, with the most common side effects including temporary insomnia, urgent and/or frequent urination, and excessive salivation.
Emmanuel Mignot, MD, PhD, the principal investigator of the FirstLight study, noted that “people living with narcolepsy type 1 face persistent symptoms across the day and night, which can impact many aspects of daily life.”
According to Mignot, “the newly published Phase 3 data reinforce the potential of [Orzeyful] to transform how we approach narcolepsy type 1 in clinical practice, shifting from managing individual symptoms to treating the disease itself.”
Sheikh extended appreciation to everyone taking part in the two trials.
“We are grateful to the patients, caregivers and healthcare providers who have participated in our studies and are thrilled to bring the first orexin agonist to the community,” Sheikh said.
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