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FDA Accepts sNDA, Grants Priority Review to Fenfluramine for Lennox-Gastaut Syndrome

After demonstrating a significant effect in reducing the frequency of drop seizures, fenfluramine aims to build on its previous indication in rare epileptic disorders, as it is currently approved to treat Dravet syndrome.

According to a new announcement, the FDA has accepted for filing and granted priority review designation to Zogenix’s fenfluramine (Fintepla) to treat seizures associated with Lennox-Gastaut syndrome (LGS). The FDA will look to complete the review within the 6-month window, with a prescription user drug fee act (PDUFA) date of March 25, 2022.1

The application, submitted in September 2021, was backed by data from the phase 3 Study 1601 (NCT03355209), which showed that treatment with fenfluramine at a dose of 0.7 mg/kg/day was superior to placebo in reducing the monthly drop seizure frequency (MDSF; P = .0012). Additional long-term safety and effectiveness data in ongoing open-label extension trials were also included in the submission.

"This is a critically important milestone for our FINTEPLA development program in LGS and brings us one step closer to a potential new treatment option for this rare and difficult to treat childhood developmental and epileptic encephalopathy,” Gail Farfel, PhD, executive vice president and chief development officer, Zogenix, said in a statement.1 "We look forward to working closely with the FDA to potentially bring FINTEPLA for the treatment of seizures associated with LGS to market as quickly as possible."

READ MORE: Investigational Dravet Syndrome Agent STK-001 Demonstrates Safety in Phase 1/2a

If approved, this would be the second indication for fenfluramine, after originally being greenlight by the FDA in June 2020 to treat seizures associated with Dravet syndrome in patients 2 years of age and older.

In total, those in Study 1601 who were treated with fenfluramine 0.7 mg/kg/day achieved a –19.9% estimated median difference (ESM) from placebo in MDSF from baseline, which was comparable to the magnitude demonstrated in all other completed LGS randomized controlled trials (range, –14.8% to –21.6%).2

The same dose group also showed statistically significant improvements compared with placebo on several secondary efficacy end points. This included the proportion of patients with a clinically meaningful reduction, defined as at least 50% in drop seizure frequency, which occurred in 25.3% of patients on fenfluramine compared with 10.3% on placebo (P = .0165).

Overall, the therapy’s safety profile was well-tolerated and similar to what had been previously observed in studies of DS. The incidence of patients experiencing an adverse event was 89.7% in the 0.7 mg/kg/day group, 76.4% in the 0.2 mg/kg/day group, and 79.3% in the placebo group.

Although the ESM in MDSF from baseline in the cohort of patients treated with fenfluramine 0.2 mg/kg/day (n = 89) did not reach statistical significance (–10.5%; P = .09), investigators and caregivers rated patients “much improved” or “very much improved” on clinical global impression of improvement (CGI-I) for both doses compared with placebo. Tonic-clonic seizures, which were documented in 43% of the patient population, were reduced by 45.7% (= .007) and 58.2% (<.0001) with treatment of fenfluramine 0.7 mg/kg and 0.2 mg/kg per day, respectively.

REFERENCES
1. Zogenix announces US FDA acceptance for priority review of supplemental new drug application for fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome. News release. Zogenix. December 1, 2021. Accessed December 1, 2021. https://finance.yahoo.com/news/zogenix-announces-u-fda-acceptance-130000785.html
2. Knupp K, Sullivan J, Nickels K, et al. Efficacy and safety of fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized, double-blind, placebo-controlled clinical trial. Presented at AES 2020 Annual Meeting; December 4–8, 2020. Abstract 852.