The first results of the Phase 3 REST-ON trial published earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met the three final co-primary efficacy criteria at all three doses. evaluated (6 g, 7.5 g and 9 g). Patients who received the drug showed significantly greater improvements in the wake maintenance test (MWT), improved overall clinical impression (CGI-I), and mean weekly cataplexy attacks compared with those who received placebo. .
New analyzes, focused on key secondary outcomes, showed that the three doses of the new agent were associated with significant improvements in sleep quality, the refreshing nature of sleep, sleep paralysis, nighttime sleep disorder, and scores. on the Epworth Drowsiness Scale (ESS). ).
Lead researcher Michael J. Thorpy, MD, director of the Sleep Vigil Disorders Center at Montefiore Medical Center in New York City, said in a statement that the results represent “the promise of a new strategy of potential treatment for doctors and patients “.
“I am particularly impressed with the consistency of the results as early as 3 weeks with only a 6 g dose,” he added.
Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients.
“The advantage of this drug is its formulation once a night, so patients don’t need to wake up at night and can actually sleep better,” he said. Medscape Medical News.
Thorpy presented the results of the study at the 2021 annual American Academy of Neurology (AAN) virtual annual meeting.
FT218 is currently under review by the U.S. Food and Drug Administration (FDA), which has set October 15 as the deadline for the Prescription Drug User Tariff Act.
Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and, as reported per Medscape Medical News, was expanded in 2005 to also treat excessive daytime sleepiness (EDS). This formulation is indicated for administration twice a night, and the second dose is taken 2.5 to 4 hours after the first.
“The need for a forced awakening to take the second dose … can result in non-compliance, which can lead to reduced efficacy and / or erroneous doses,” the researchers note.
FT218 is a modified release version of sodium oxybate. A single 6 g dose of the investigating agent “has shown a bioequivalent exposure to immediate release twice at night. [sodium oxybate] are given as a 3 g dose, ”the researchers write.
It also currently has the FDA orphan drug designation for the treatment of narcolepsy.
The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years of age or older who had type 1 or type 2 narcolepsy.
Patients received active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a 4-period forced dosing program of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.
Secondary outcome measures included ESS, sleep quality / refreshing nature of sleep on a visual analog scale, sleep paralysis, and hypnagogic hallucinations in a diary of sleep symptoms, nighttime sleep disturbed by measures polysomnographic and the number of excitations defined by the American Sleep Academy Medical Punctuation Manual.
Adverse event (AE) reports were collected from informed consent up to 7 days after the last dose received.
The results showed that, compared with placebo, the improvement in disturbed nighttime sleep from baseline was significantly greater for active treatment at 6 g at week 3 (mean difference between groups, -11; Pg <0.001), at 7.5 g at week 8 (mean difference, -17.7; Pg <0.001), and at 9 g at week 13 (mean difference, -22.6; Pg <.001).
The mean difference between the three doses and placebo for the reduction in the number of excitations was -11.3 (Pg <0.05), -19.4 (Pg <.001) and -23.7 (Pg <.001), respectively. And doses of 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 showed significant (Pg <.001) improvements versus placebo in ESS (mean difference, -2.1, -3.2, and -3.9, respectively).
All three doses also showed a significant improvement in sleep quality and the refreshing nature of sleep (Pg <.001 for all comparisons), as well as improving sleep paralysis (Pg = 0.04, Pg = 0.02 i Pg = 0.04, respectively).
There were no significant differences between FT218 and placebo to improve hypnagogic hallucinations.
Thorpy noted that the number of patients with basal hallucinations “was relatively small,” which may have led to this finding.
“If there was a much larger population with hallucinations, I suspect we would also have seen a statistically significant improvement,” he said.
Generally well tolerated
The researchers noted that FT218 was “generally well tolerated, and that the most common adverse reactions were known and established sodium oxybate adverse reactions.”
Seven major EAs were reported, including 5 in those assigned to active treatment. This included a case of insufficient control of diabetes, paresthesia, perirectal abscess, hypertensionand suicidal ideation. It was only considered that the case of suicidal ideation was a treatment-related AE.
The researchers point out that while they have not yet delved into subgroup analysis to look for differences between sex, age or race, they plan to do so in the future.
Overall, the results indicate that “FT218 is an effective agent not only for the main symptoms of drowsiness and cataplexy, but also for the quality of sleep at night,” Thorpy said.
Asked if he believes the FDA will approve the drug, he said it should be “simple” because it’s just a different formulation from an already approved agent.
“I really hope there are no problems in approving this drug,” Thorpy said.
Advantages “Sleep Architecture”
Commenting on the findings of Medscape Medical News, Logan Schneider, MD, co-director of the Stanford / VA Alzheimer’s Center and clinical assistant professor (affiliate) at Stanford Sleep Center in Redwood City, Calif., Said researchers’ focus on these side results was “really worth it.” .
Schneider, who was not involved in the research, noted that because the study only included patients with narcolepsy, the results cannot be extrapolated to groups that have other sleep disorders.
Still, “it’s worth expanding now beyond the two main life-threatening symptoms for me: daytime drowsiness and cataplexy. We should also address more about quality of life and other aspects of narcolepsy, including nighttime sleep disorders and sleep quality problems related to it, ”he said.
“Being able to address these issues and say,‘ I have a therapy that clearly helps the multidimensionality of our patients ’is very demanding,” Schneider noted.
He was also impressed with the various measures the researchers used, rather than relying solely on patient reports, “which are subject to memory difficulties. This was a good way to possibly quantify the underlying alteration as a diagnostic marker.” of sleep, as well as a possible marker of treatment to show how a therapy works. “
“It actually shows a beneficial effect on sleep architecture,” Schneider said.
The study was funded by Avadel Pharmaceuticals. Thorpy is a consultant / board member of Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences and Takeda Pharmaceutical. Schneider reports that he was an advisor and / or in the office of similar pharmaceutical speakers at Jazz Pharmaceuticals and Harmony Biosciences.
Annual Meeting of the American Academy of Neurology (AAN) 2021.
Filed April 17, 2021. Summary