The FDA is set to complete its review of FT218 by June 17, 2023, and Avadel has indicated its expectation that the investigational treatment for excessive daytime sleepiness and cataplexy in adults with narcolepsy will be approved.
According to a recent Securities filing from Avadel Pharmaceuticals, the FDA has issued a proposed final label and medication guide for the company’s investigational treatment for excessive daytime sleepiness and cataplexy in adults with narcolepsy, FT218. A portion of the new drug application (NDA) for the once-nightly sodium oxybate formulation relating to the REMS patent has been deemed inappropriate and has pushed the approval deadline to June 17, 2023, as a result.1
Avadel further stated that the FDA requested an added certification to the Risk Evaluation and Mitigation Strategy (REMS) patent but confirmed that no additional patent certifications were required. Approval for FT218 can occur sooner, but only if the REMS patent is delisted from the FDA’s Orange Book; or otherwise, if the patent is deemed invalid, not infringed, or otherwise unenforceable by a court; or if a court determines that FDA erred in requesting the certification.
“The Company believes in the potential of FT218 and its importance to the narcolepsy community. The Company is committed to pursuing all options for FT218 to realize its full value,” Avadel noted in the filing.
This is now the second time the agency has pushed back the therapy’s review. The NDA was originally accepted by the FDA in February 2021, at which time it set a Prescription Drug Use Fee Act action date of October 15, 2021. In October 2021, the FDA announced that the review process was still ongoing.2 At that time, Greg Divis, CEO, Avadel, said in a statement that the company had “addressed all questions received to date and remain confident that the package we have submitted satisfies all of the FDA’s requests. We have not been informed of any deficiencies in our application and remain fully committed to work closely with the FDA for the duration of its review of our NDA for FT218.”2
The application was supported by positive data from the phase 3 REST-ON study (NCT02720744), which was held under a special protocol assessment agreement with the FDA. In the study, investigators led by Clete A. Kushida, MD, PhD, director, Stanford Center for Human Sleep Research, randomized patients by narcolepsy type 1 or type 2.
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REST-ON included a total of 222 patients with narcolepsy, all of whom were 16 years or older. Patients were randomized 1:1 to receive uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g of FT218 or placebo over the course of a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period.The study met all 3 of its primary end points, which were change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacked within the 6-, 7.5-, and 9-g groups.3
Compared with placebo, FT218 treatment showed a significantly greater increase in sleep latency at week 3 for the 6-g dose group (8.1 vs 3.1 min, respectively; least-squares mean difference [LSMD], 4.98; 95% CI, 2.90-7.05; P <.001); at week 8 for the 7.5-g dose group (9.6 vs 3.3 min, respectively; LSMD, 6.21; 95% CI, 3.84-8.58; P <.001); and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min, respectively; LSMD, 6.13; 95% CI, 3.52-8.75; P <.001).3
Additionally, recently presented updated data at the virtual component of the 2022 American Academy of Neurology Annual Meeting, April 24-26, from the ongoing RESTORE study (NCT04451668) open-label extension suggested that patients have a preference for the once-nightly regimen of FT218.4,5 Those interim results included data from a cutoff date of February 16, 2022, a further 5 months from the data that were reported earlier in the month (cutoff of September 7, 2021). In total, 53 individuals who switched from twice-nightly dosing to once-nightly, and 92.5% (n = 49) of those reported preferring the new regimen 3 months after the switch. There were 93 participants who switched to FT218 had data collected on nocturnal adverse events (AEs), with data showing that 66.7% (n = 62) unintentionally missed their second dose of the prior twice-nightly regimen, after which 83.9% (n = 52) reported feeling worse the next day and 14% (n = 9) feeling the same.4,5
“Twice-nightly oxybates for narcolepsy require a challenging dosing regimen that disrupts nighttime sleep. The results from the nocturnal AEs questionnaire illustrate the burden that the second dose places on some patients, who already struggle with getting a full night of refreshing sleep,” presenting author Asim Roy, MD, medical director, Ohio Sleep Medicine Institute, said in a statement.5 “In my experience with patients in my practice, a once-at-bedtime option like FT218 would ease this burden and has the potential to be a major advance for the entire narcolepsy community.”