Fenfluramine Provides Clinically Meaningful and Durable Improvement in Seizure Frequency in Patients with Dravet Syndrome Regardless of Age: “Real-World” Use in a European Early Access Program
Abstract number :
1.298
Submission category :
7. Anti-seizure Medications / 7C. Cohort Studies
Year :
2021
Submission ID :
1826539
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Amélie Lothe, PhD - Zogenix International Limited; Nicola Specchio - Rare and Complex Epilepsy Unit, Department of Neuroscience - Bambino Gesù Children’s Hospital IRCCS; Ángel Aledo-Serrano - Epilepsy Program, Department of Neurology - Ruber Internacional Hospital; Milka Pringsheim - Clinic for Neuropediatrics and Neurorehabilitation - Epilepsy Center for Children and Adolescents, Schön Klinik; Francesca Darra - Child Neuropsychiatry, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics - University of Verona; Thomas Mayer - Epilepsy Center Kleinwachau; Antonio Gil-Nagel - Epilepsy Program, Department of Neurology - Ruber Internacional Hospital; Tilman Polster - Mara Hospital, Bethel Epilepsy Center - Bielefeld University; Sameer Zuberi - Paediatric Neurosciences Research Group, Royal Hospital for Children & Institute of Health & Wellbeing - University of Glasgow; Amélie Lothe - Zogenix International; Arnold Gammaitoni - Zogenix, Inc.; Adam Strzelczyk - Epilepsy Center Frankfurt Rhine-Main - Goethe University Frankfurt
Rationale: Fenfluramine (FFA) has been shown in phase 3 clinical trials to substantially and significantly reduce convulsive seizure frequency in patients aged 2 to 18 years with Dravet syndrome (DS). The European Early Access Program (EEAP) enrolled DS patients aged 1 to 46 years, thus allowing an analysis of the effect of age on response to FFA in a “real-world” setting.
Methods: Patients with DS with insufficient seizure control despite available treatments were allowed pre-approval access to FFA through the EEAP. Contraindications for use of fenfluramine included valvular heart disease, pulmonary arterial hypertension (PAH), and administration of monoamine oxidase inhibitors within 14 days before starting FFA. In the EEAP, FFA was added to each patient’s anti-seizure medication (ASM) at 0.2 mg/kg/day given in 2 equivalent doses per day. After 7 days, the dose could be titrated based on effect and tolerability to a maximum dose of 0.7 mg/kg/day (maximum 26 mg/day) for patients not treated with stiripentol, or 0.4 mg/kg/day (maximum 17 mg/day) for patients also receiving stiripentol. To assess cardiac valve function and identify the possible development of PAH, echocardiograms were conducted prior to starting treatment with FFA and every 6 months thereafter for the first 2 years, and then once a year.
Results: A total of 149 patients from the EEAP at multiple centers in Germany, Italy, Spain, and UK have been included in this pooled analysis ( < 6 years old, n=63; 6 to 17 years old, n=62; ≥ 18 years old, n=24). Over 95% of patients in each group had a pathogenic or likely pathogenic variant in SCN1A, and 69% to 73% of patients in each group were treated with ≥ 3 ASMs. Stiripentol (STP) use was reported by 42% to 60% in each age group. FFA doses and treatment duration were similar in each age group (Table 1). FFA provided durable, consistent, clinically meaningful reduction in seizure frequency across all age groups, with 43% to 55% of patients experiencing a ≥ 75% reduction in seizure frequency after 12 months of treatment with FFA (Table 2). As of the most recent follow-up visit, the percentage of patients rated by their physician as “much” or “very much” improved was 70%, 56%, and 54% for the < 6-year-old, 6- to 17-year-old, and ≥ 18-year-old groups, respectively. FFA was generally well tolerated, with 8% to 18% of patients in the 3 age groups stopping treatment. A total of 35% to 63% of patients in each age group reported at least 1 adverse event. No cases of valvular heart disease or PAH were observed in any age group.
Anti-seizure Medications