A Stratified Analysis of Efficacy and Safety of Fenfluramine in Patients With Dravet Syndrome
Rima Nabbout1, Joseph Sullivan2, Stéphane Auvin3, Berten Ceulemans4, J Helen Cross5, Orrin Devinsky6, Antonio Gil-Nagel7, Renzo Guerrini8, Kelly Knupp9, M Scott Perry10, Rocio Sanchez-Carpintero11, Ingrid Scheffer12, Nicola Specchio13, Adam Strzelczyk14, James Wheless15, Elaine Wirrell16, Diego Morita17, Mélanie Langlois17, Patrick Healy17, Amélie Lothe17, Lieven Lagae18
1Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité, 2University of California San Francisco Weill Institute for Neurosciences, Benioff Children’s Hospital, 3Service de Neurologie Pédiatrique & INSERM U1141, Robert Debré University Hospital, APHP, 4University of Antwerp, Antwerp University Hospital, 5UCL NIHR BRC Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, 6Comprehensive Epilepsy Center, NYU Langone Medical Center, 7Hospital Ruber Internacional, 8Meyer Children’s Hospital IRCCS, University of Florence, 9Children's Hospital Colorado, Anschutz Medical Campus, 10Cook Children’s Medical Center, 11Clinica Universidad de Navarra, Pediatric Neurology Unit, 12University of Melbourne, Austin Hospital and Royal Children’s Hospital, Florey and Murdoch Children’s Research Institutes, 13Member of European Reference Network EpiCARE, Bambino Gesú Children’s Hospital, IRCCS, 14Goethe University Frankfurt, Epilepsy Center Frankfurt Rhine-Main & University Hospital Frankfurt, 15University of Tennessee Health Science Center & Le Bonheur Children’s Hospital, 16Mayo Clinic/Dept of Child Neurology, 17UCB, 18Member of the European Reference Network EpiCARE, University of Leuven
Objective:
Data from three randomized clinical trials (RCTs) of fenfluramine (FFA) use in patients with Dravet syndrome (DS) were pooled and stratified by baseline characteristics not originally reported.
Background:
DS is a rare, drug-resistant, developmental and epileptic encephalopathy characterized by frequent seizures and motor, behavioral, and cognitive impairments. FFA was evaluated in three pivotal phase 3 RCTs and is approved for the treatment of seizures associated with DS in the United States, European Union, United Kingdom, Japan, and Israel in patients ≥2 years of age.
Design/Methods:
Patients (aged 2-18y) with DS treated with placebo, 0.2 or 0.7 mg/kg/d FFA (0.2FFA, 0.7FFA) without stiripentol (STP), or 0.4 mg/kg/d FFA with STP (0.4FFA+STP) were included. Data were stratified by FFA initiation age (<4y, ≥4y), severity (number of failed antiseizure medications [ASMs]: 1-3, 4-6, and 7+), and SCN1A pathogenic variant status (+ or -). Baseline characteristics, safety, median percentage change in monthly convulsive seizure frequency (MCSF), median longest interval of convulsive seizure-free days (SFDs), and Clinical Global Impression—Improvement (CGI-I) scores (caregiver and investigator) were assessed.
Results:
Among 348 patients, 216 were treated with FFA (0.2FFA, n=85; 0.4FFA+STP, n=43; 0.7FFA, n=88), 132 with placebo; 83.7%-89.4% were ≥4y and 70.6%-81.4% were SCN1A+. Many patients failed 4-6 (31.8%-48.8%) or 7+ ASMs (34.8%-57.6%); no patients treated with 0.4FFA+STP failed 7+ ASMs. Rates of treatment-emergent adverse events were similar across groups. In 0.4FFA+STP and 0.7FFA dose groups, MCSF reductions and longest interval of convulsive SFDs were high in patients <4y. CGI-I scores were consistently higher for patients treated with FFA versus placebo, regardless of stratification.
Conclusions:
FFA is associated with improved seizure and non-seizure outcomes relative to placebo, regardless of age, severity, or SCN1A status. Inferential analyses of stratified groups in larger populations may provide a better understanding of the benefits seen with different DS populations, concomitant medications, and FFA doses.
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