Long-term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome.

Milka Pringsheim, Michael D Lock, Tilman Polster, Elaine C Wirrell, Elizabeth A Thiele, Nicola Specchio, Orrin Devinsky, Katsumi Imai, Ingrid E Scheffer, Joseph Sullivan, Rima Nabbout, Stéphane Auvin, Lieven Lagae, Mélanie Langlois, Rebecca Zhang Roper, Amélie Lothe

Journal: Epilepsia 2025;66(6):1919-1932

PMID: 40072476

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Abstract

OBJECTIVE

We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults.

METHODS

Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults.

RESULTS

A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively.

SIGNIFICANCE

Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

Address: Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, University of Melbourne, Melbourne, Victoria, Australia.; Member of the European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, Institut Imagine, INSERM U1163, Université Paris Cité, Paris, France.; Member of the European Reference Network EpiCARE, University of Leuven, Leuven, Belgium.; NYU Langone Medical Center, New York City, New York, USA.; Member of the European Reference Network EpiCARE, APHP, Centre de Référence Epilepsies Rares, Hôpital Universitaire Robert-Debré, Paris, France.; Université Paris-Cité, INSERM Neuro Diderot, Paris, France.; Institut Universitaire de France (IUF), Paris, France.; Massachusetts General Hospital, Boston, Massachusetts, USA.; Mayo Clinic, Rochester, Minnesota, USA.; Krankenhaus Mara-Bethel Epilepsy Centre, Medical School OWL, Bielefeld University, Bielefeld, Germany.; Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Member of the European Reference Network EpiCARE, University Hospitals KU, Leuven, Belgium.; Schön Klinik Vogtareuth, Vogtareuth, Germany.; PMU Salzburg, Salzburg, Austria.; German Heart Centre, TUM, Munich, Germany.; NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.; Independent Statistical Consultant, Haiku, Hawaii, USA.; UCB, Colombes, France.; UCB, Slough, UK.; University of California San Francisco Weill Institute for Neurosciences, Benioff Children's Hospital, San Francisco, California, USA.

DOI: 10.1111/epi.18342

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MeSH Terms: Adolescent, Adult, Child, Female, Humans, Male, Young Adult, Anticonvulsants, Dioxolanes, Epilepsies, Myoclonic, Fenfluramine, Treatment Outcome, Child, Preschool