Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome

J Helen Cross,Bradley S Galer,Antonio Gil-Nagel,Orrin Devinsky,Berten Ceulemans,Lieven Lagae,An-Sofie Schoonjans,Elizabeth Donner,Elaine Wirrell,Sanjeev Kothare,Anupam Agarwal,Michael Lock,Arnold R Gammaitoni

doi:10.1016/j.seizure.2021.10.024

Abstract

PurposeTo assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). MethodsIn this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. ResultsA total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43−7) for persons with DS receiving standard-of-care. ConclusionAll-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk.Clinical Trial Registration: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.

Highlights

Dravet syndrome is a rare, severe, treatment-resistant developmental epileptic encephalopathy with onset in the first year of life in otherwise normal infants
sudden unexpected death in epilepsy (SUDEP) represents a large fraction of all epilepsy-related deaths, its incidence is likely underestimated because definitive postmortem signs or bio markers of SUDEP do not exist [9, 10]
We present a post hoc analysis examining all-cause and SUDEP mortality in patients with Dravet syndrome treated with FFA in phase 3 clinical trials, European (EU) and United States (US) Early Access programs (EAPs), and two cohorts of Dravet syndrome patients in Belgium who have been treated with FFA for up to 32 years and compare the findings with the expected incidence of mortality and SUDEP based on published literature

Summary

Introduction

Dravet syndrome is a rare, severe, treatment-resistant developmental epileptic encephalopathy with onset in the first year of life in otherwise normal infants. SUDEP represents a large fraction of all epilepsy-related deaths, its incidence is likely underestimated because definitive postmortem signs or bio markers of SUDEP do not exist [9, 10]. Both all-cause mortality and SUDEP rates are elevated in children with Dravet syndrome compared with children with pediatric epilepsy [7, 11]. Two major risk factors for SUDEP are frequency of generalized tonic-clonic seizure (GTCS) and failure to adequately control treatment-resistant seizures [12, 13], both of which are hallmarks of Dravet syndrome and likely contribute to the higher incidence of SUDEP in the disease [8, 14]

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