Interim Safety Analysis of an Ongoing Open-Label Extension Study of Fenfluramine for Dravet Syndrome
Abstract number :
3.412
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2232954
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Elaine Wirrell, MD – Mayo Clinic; Ingrid E. Scheffer, MBBS, PhD, FRS – Professor, Austin Health/University of Melbourne; Orrin Devinsky, MD – NYU Langone Medical Center; Elizabeth Thiele, MD, PhD – Massachusetts General Hospital; Stéphane Auvin, MD, PhD – Robert Debré University Hospital & Université Paris-Cité; Tilman Polster, MD – Bethel Epilepsy Centre, Krankenhaus Mara, Bielefeld University; Joseph Sullivan, MD – University of California San Francisco, Weill Institute for Neurosciences, Benioff Children’s Hospital; Milka Pringsheim, MD – Schön Klinik Vogtareuth; Michael Lock, PhD – Zogenix, Inc. (now a part of UCB), consultant; Katsumi Imai, MD – Shizuoka Institute of Epilepsy and Neurological Disorders; Amélie Lothe, PhD – Zogenix International (now a part of UCB); Shikha Polega, PharmD – Zogenix, Inc. (now a part of UCB)
This is a Late Breaking abstract
Rationale: Fenfluramine (FFA) is a dual-action serotonergic agent with sigma-1 receptor positive modulation indicated for the treatment of seizures associated with Dravet syndrome (DS) in patients ≥ 2 years old. Patients with DS from 3 randomized controlled trials were given the option to continue into an open-label extension (OLE) study. When treated with adjunctive FFA for up to 3 years in the OLE, patients demonstrated profound and sustained convulsive seizure reductions [Scheffer IE, et al. AES 2020: 978]. At 1 year in the OLE, improved everyday executive functioning was observed.[Bishop KI, et al. Epilepsy Behav. 2021;121(PtA):108024] Interim reports of the OLE study indicated FFA was generally well tolerated. Common, previously reported adverse events (AEs) included pyrexia, nasopharyngitis, and decreased appetite. Cardiovascular monitoring for up to 3 years revealed no cases of valvular heart disease or pulmonary arterial hypertension [Agarwal A, et al. Eur J Paediatr Neurol. 2022;39:35-39]. Here we report an updated safety evaluation of FFA treated DS patients enrolled in the OLE.
Methods: Patients with DS, aged 2-18 years, enrolled in the OLE (NCT02823145) and who received ≥ 1 dose of FFA were included. All patients were re-initiated with FFA at 0.2 mg/kg/day and titrated over 4 weeks based on seizure response and tolerability (maximum FFA dose without stiripentol: 26 mg/day, with stiripentol: 17 mg/day). Safety and efficacy assessments were conducted monthly for the first 3 months, followed by every 3 months thereafter. The incidence of treatment-emergent adverse events (TEAEs) was evaluated.
Results: A total of 343 patients were enrolled as of November 1, 2021, and received ≥ 1 dose of FFA; median treatment duration (exposure) was 827 days (range, 7-1280). Mean (SD) age at time of study entry was 9.1 (4.7) years (range, 2-19), and 46.1% were female. Nine patients (2.6%) discontinued treatment due to an AE. TEAEs reported in ≥ 15% of patients were pyrexia, nasopharyngitis, decreased blood glucose, decreased appetite, diarrhea, upper respiratory tract infection, and seizure (Table). Although 24.2% of patients reported decreased appetite, this did not correlate with weight loss. No patient has developed valvular heart disease or pulmonary arterial hypertension as determined by continued cardiac safety monitoring. Three patients (0.9%) died due to sudden unexpected death in epilepsy, which was considered unrelated to study drug.
Conclusions: Results of this interim safety analysis are consistent with past updates, highlighting that FFA is safe and well-tolerated. No new or unexpected safety signals were observed in this analysis period of over 3 years in patients with DS.
Funding: Zogenix, Inc. (now a part of UCB)
Anti-seizure Medications