A Stratified Analysis of Efficacy and Safety of Fenfluramine in Patients with Dravet Syndrome
Abstract number :
1.401
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1018
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Rima Nabbout, MD, PhD – Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
Stéphane Auvin, MD, PhD, FAES – Paris-Cité University & Robert-Debré University Hospital, Paris, France
Berten Ceulemans, MD, PhD – University of Antwerp
J. Helen Cross, MBChB, PhD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital
Orrin Devinsky, MD – NYU Grossman School of Medicine
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
M. Scott Perry, MD – Jane and John Justin Institute for Mind Health, Neurosciences Center, Cook Children's Medical Center
Rocío Sánchez-Carpintero, MD, PhD – Clínica Universidad de Navarra
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Nicola Specchio, MD, PhD – Bambino Gesu’ Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE
Adam Strzelczyk, MD, MHBA, FEAN – Goethe-University Frankfurt
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Elaine Wirrell, MD – Mayo Clinic
Diego Morita, MD – UCB Biosciences, Inc.
Mélanie Langlois, PhD – UCB Pharma S.A.
Patrick Healy, MS – UCB, Inc.
Amélie Lothe, PhD – UCB Pharma S.A.
Lieven Lagae, MD, PhD, FRCP – Member of the European Reference Network EpiCARE, University of Leuven
Rationale: Dravet syndrome (DS) is a rare, drug-resistant, developmental and epileptic encephalopathy characterized by frequent seizures and motor, behavioral, and cognitive impairments. Fenfluramine (FFA) 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.
Here, three pivotal phase 3, double-blind, placebo-controlled, randomized clinical trials (RCTs) were pooled and stratified by baseline characteristics not originally reported.
Methods: Patients with DS, 2-18 years of age, 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 across the 3 pooled studies.1-3 Pooled data were stratified by age at FFA initiation (< 4y and ≥4y), severity (number of failed ASMs: 1-3, 4-6, and 7+), and SCN1A pathogenic variant status (+ or -). Demographics, baseline characteristics, and safety were reported. Median percentage change in monthly convulsive seizure frequency (MCSF), median longest interval of convulsive seizure-free days, and proportion of patients with clinically meaningful improvement (much or very much improved) on Clinical Global Impression—Improvement (CGI-I) scores (caregiver and investigator) were assessed.
Results: Across the RCTs, 348 patients were included; 216 were treated with FFA (0.2FFA, n=85; 0.4FFA+STP, n=43; 0.7FFA, n=88) and 132 with placebo. Most patients (83.7%-89.4% across groups) were ≥4y and the majority (70.6%-81.4%) was SCN1A+. Many patients failed 4-6 (31.8%-48.8%) or 7+ ASMs (34.8%-57.6%); however, no patients treated with 0.4FFA+STP failed 7+ ASMs.
TEAE rates were similar across groups (81.8% [placebo]–97.7% [0.4FFA+STP]; Table 1). Highest dose groups (0.4FFA+STP and 0.7FFA) experienced the greatest percentage MCSF reduction (Fig 1A) and increase in median convulsive seizure-free days (Fig 1B) relative to placebo. In patients treated with 0.4FFA+STP, MCSF reductions were highest in patients < 4y, with 4-6 failed ASMs, or who were SCN1A-. FFA treatment was associated with increased frequency in clinically meaningful improvement on CGI-I scores relative to placebo (Fig 1C and 1D). While CGI-I scores were consistent across stratified groups, patients who failed only 1-3 ASMs prior to the trial had greater frequency of clinically meaningful improvement on investigator CGI-I scores.
Conclusions: FFA is associated with improved seizure and non-seizure outcomes relative to placebo, regardless of age, severity, or SCN1A status. Results should be interpreted with caution due to sample size. Inferential analyses of stratified groups in larger populations may provide a better understanding of the increased benefits seen with different DS populations, synergies with concomitant medications, and FFA doses.
References
1. Lagae L, et al. Lancet. 2019;394(10216):2243-54.
2. Nabbout R, et al. JAMA Neurol. 2020;77(3):300-8.
3. Sullivan J, et al. Epilepsia. 2023;64(10):2653-66.
Funding: UCB Pharma
Anti-seizure Medications