Long-term Data on the Cardiovascular Safety Profile of Fenfluramine in the Treatment of Dravet Syndrome: Interim Analysis of an Open-label Safety Extension Study

Rationale: In two recently completed Phase 3 clinical trials, fenfluramine has demonstrated superior efficacy compared with placebo for the reduction of convulsive seizures in children and young adults (2–18 years old) with Dravet syndrome. Fenfluramine, previously marketed for weight loss, was withdrawn from the market in 1997 following reports of cardiac valvular heart disease (VHD) and pulmonary hypertension in obese adults treated with ≥ 60 mg/day. Here we report the cardiovascular safety findings from an interim analysis of the long-term safety extension study (NCT02823145) of low-dose fenfluramine for the treatment of Dravet syndrome in children and young adults.

Methods: Patients with Dravet syndrome who successfully completed one of the Phase 3 trials were eligible to enroll in this open-label extension (OLE) study. Patients with current cardiac VHD, pulmonary arterial hypertension, or any degree of aortic or mitral valve regurgitation were excluded from entering any of the Phase 3 trials. All patients in the OLE were started on fenfluramine at 0.2 mg/kg/day, and after 4 weeks the dose could be titrated in 0.2 mg/kg/day increments every 2 weeks based on effectiveness and tolerability up to a maximum of 0.8 mg/kg/day but not to exceed 30 mg/day (0.5 mg/kg/day and 20 mg/day if they were taking concurrent stiripentol). Echocardiography was performed at extension study baseline, Week 6, and every 3 months thereafter to assess cardiac valve function and pulmonary artery pressure. Cardiac VHD was defined as the presence of ≥ moderate mitral regurgitation and/or ≥ mild aortic regurgitation. Pulmonary hypertension was considered to be present when pulmonary artery systolic pressure exceeded 35 mmHg.

Results: A total of 232 patients enrolled in the study as of the interim cut-off date of March 13, 2018 and received at least one dose of fenfluramine. Twenty-two (9.5%) patients have discontinued treatment due to: lack of efficacy (16), subject withdrawal (2), adverse event (1), death (1, SUDEP), physician decision (1), or withdrawal by caregiver (1). Demographics include 128 (55.2%) male patients and a mean±SD age of 9.1±4.7 years. The median duration of treatment with fenfluramine was 256 days (58–634 days). No patient demonstrated cardiac VHD or pulmonary arterial hypertension at any time during the study. The most common finding was intermittent and transient physiologic/trace valve regurgitation, a finding seen in normal healthy children and young adults.

Conclusions: The results of this long-term safety study demonstrate no development of cardiac VHD or pulmonary hypertension after daily treatment with fenfluramine for up to 21 months in patients with Dravet syndrome. Together with the efficacy data from the Phase 3 trials, fenfluramine appears to have a positive benefit-risk profile in this patient population.

No conflict of interest has been declared by the author(s).