Abstracts

Rationale: Fenfluramine (FFA) has been shown in 2 randomized, placebo-controlled clinical trials to substantially reduce the frequency of convulsive seizures in children and young adults with Dravet syndrome (DS, median % reduction compared with placebo, 54% and 65%). FFA had been previously marketed as a weight loss drug for obese adults but was withdrawn following reports of valvular heart disease (VHD). Here we report an update on the cardiovascular safety of patients with DS treated for up to 3 years.

Methods: Patients who successfully completed one of the three phase 3 trials were eligible to enroll in this open-label extension (OLE) study (NCT02823145). Upon entry into the OLE, all patients started FFA at 0.2 mg/kg/day. After 4 weeks, the dose could be titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) for patients concomitantly receiving stiripentol. During the OLE, all patients were assessed with transthoracic echocardiography (TTE) using a priori standardized methods and blinded readings in accordance with American Society of Echocardiography standards for echocardiography core laboratories (Douglas, 2009). TTEs were performed at OLE entry, then after 4-6 weeks, and every 3 months thereafter. VHD was defined as ≥ moderate mitral regurgitation (MR) and/or ≥ mild aortic regurgitation (AR) and physical signs or symptoms attributable to valve disease (eg, structural lesion/restriction of valve movement of the aortic or mitral valve, abnormal left ventricular systolic function with depressed left ventricle ejection fraction, left ventricle dilatation, left atrial enlargement). Systolic pulmonary artery pressure >35 mmHg (measured by tricuspid regurgitant jet velocity) was considered evidence of pulmonary artery hypertension (PAH).

Results: As of 11/30/2021, 327 patients had enrolled in the OLE and received at least 1 dose of FFA (mean age at enrollment [±SD], 9.2±4.7 years; 46.5% female). A total of 262, 191, and 100 patients had echocardiograms after 12, 24, and 36 months of treatment in the OLE, respectively. A total of 3308 TTEs have been conducted (mean±SD per patient, 10.1±3.2) during the study. A single patient (0.3%) had a finding of mild MR (considered physiologic) during the study, and no patients demonstrated moderate or greater MR during the OLE. A single patient (0.3%) demonstrated mild (considered pathologic) AR at Month 15—a finding that triggered additional investigation. A transesophageal echocardiogram (TEE) performed 6 weeks later found absent AR with trace MR. No abnormalities of valve morphology were found on TEE or on TTE. No VHD or PAH was observed in any patient during the OLE.

Conclusions: This study is the largest, longest, and most rigorous prospective examination of the cardiovascular safety of FFA, and its results continue to demonstrate absence of clinically significant VHD or PAH. These data support a positive benefit-risk profile for FFA in the treatment of patients with DS.

Funding: Please list any funding that was received in support of this abstract.: Zogenix, Inc.