Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis

Joseph Sullivan, Nicola Specchio, Orrin Devinsky, Stéphane Auvin, M Scott Perry, Adam Strzelczyk, Antonio Gil-Nagel, David Dai, Bradley S Galer, Arnold R Gammaitoni, Joseph Sullivan, Nicola Specchio, Orrin Devinsky, Stéphane Auvin, M Scott Perry, Adam Strzelczyk, Antonio Gil-Nagel, David Dai, Bradley S Galer, Arnold R Gammaitoni

Abstract

Objective: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications.

Methods: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots.

Results: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue.

Significance: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.

Trial registration: ClinicalTrials.gov NCT02682927 NCT02826863 NCT02826898.

Keywords: Dravet syndrome; fenfluramine; seizure-free days; time-to-event analysis.

Conflict of interest statement

J.S. received research grants from Stoke, Marinus, Zogenix, and Biopharm; served as consultant/advisor for the Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharma, Asceneuron, Longboard Pharmaceuticals, Knopp Biosciences, and Neurocrine; has stock options in Epygenix; served as a reviewer for the Epilepsy Study Consortium; and received travel support from Zogenix. N.S. received consulting fees from Zogenix; received research support from LivaNova and Biomarin; and served as a paid consultant for LivaNova. O.D. received research funding from Novartis, PTC Therapeutics, Zogenix, and GW Pharma; and holds equity interest in Rettco, Pairnomix, Tilray, Papa & Barkley, California Cannabis Enterprises, Tevard Biosciences, Regel Biosciences, Script Biosciences, Silver Spike Capital, and Silver Spike SPAC. S.A. received personal fees from Arvelle, Biocodex, GW Pharma, and Xenon; received personal fees and nonfinancial support from Biomarin, GW Pharma, and Nutricia; received personal fees/grants from Eisai and UCB Pharma for work as an investigator; and received research support from Zogenix. M.S.P. received research support from Stoke, Encoded, Marinus, Ovid, and Zogenix; and received honoraria (speakers' bureaus, advisory/consulting roles) from Greenwich Biosciences, Biomarin, Zogenix, Neurelis, Encoded, and Stoke. A.S. received personal fees or grants from Arvelle Therapeutics, Desitin Arzneimittel, Eisai, GW Pharma, Marinus Pharmaceuticals, UCB Pharma, and Zogenix; and received honoraria for consulting and serving on advisory boards from Zogenix. A.G.‐N. received personal fees or research grants from Arvelle Therapeutics, Bial, Biocodex, Eisai, Esteve, GW Pharma, PTC Therapeutics, Stoke, UCB, and Zogenix. D.D. served as a paid consultant for Zogenix. B.S.G. and A.R.G. serve as employees with ownership interest in Zogenix.

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Kaplan–Meier analysis of days to reach baseline seizure count in patients receiving (A) fenfluramine (FFA) .7 mg/kg/day, FFA .2 mg/kg/day, or placebo in Study 1; or (B) FFA .4 mg/kg/day or placebo in Study 2. p values are versus placebo
FIGURE 2
FIGURE 2
Individual patient time to reach baseline seizure count by treatment group. (A) Study 1, fenfluramine (FFA) .7 mg/kg/day, FFA .2 mg/kg/day, or placebo. (B) Study 2, FFA .4 mg/kg/day or placebo. #Patient did not complete the trial. §Data censored due to substantial number (>10%) of missing diary days
FIGURE 3
FIGURE 3
Number of convulsive seizure‐free days per 28 days by treatment group and study. p values are versus placebo by an analysis of covariance model, with treatment group and age group as factors. Median number of convulsive seizures is per 28 days. FFA, fenfluramine

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