An-Sofie Schoonjans1, Fabienne Marchau2, Bernard P Paelinck3, Lieven Lagae4, Arnold Gammaitoni5, Milka Pringsheim6,7, Martin G Keane8, Berten Ceulemans1. 1. a Department of Paediatric Neurology , Antwerp University Hospital, University of Antwerp , Antwerp , Belgium. 2. b Department of Paediatric Cardiology , Antwerp University Hospital, University of Antwerp , Antwerp , Belgium. 3. c Department of Cardiology , Antwerp University Hospital, University of Antwerp , Antwerp , Belgium. 4. d Department of Development and Regeneration , Section of Paediatric Neurology, University Hospitals Gasthuisberg , Leuven , Belgium. 5. e Zogenix, Inc. , Emeryville , CA , USA. 6. f Department of Pediatric Cardiology , German Heart Centre Munich , Munich , Germany. 7. g Pediatric Neurology, Schön Klinik Vogtareuth , Vogtareuth , Germany. 8. h Temple University Hospital , Philadelphia , PA , USA.
Abstract
OBJECTIVE: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS. METHODS: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years. RESULTS: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10-20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period. CONCLUSIONS: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.
OBJECTIVE:Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS. METHODS: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years. RESULTS: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10-20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period. CONCLUSIONS: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.
Authors: Wyman W Lai; Bradley S Galer; Pierre C Wong; Gail Farfel; Milka Pringsheim; Martin G Keane; Anupam Agarwal Journal: Epilepsia Date: 2020-08-18 Impact factor: 5.864