Effect of ZX008 (Fenfluramine HCl Oral Solution) on Total Seizures in Dravet Syndrome

Abstract

Objective: Assess ZX008 (fenfluramine) effect on total seizure frequency in patients with Dravet syndrome. Background: Dravet syndrome (DS) is a rare, severe, treatment-resistant, developmental epileptic encephalopathy. In a Phase 3, randomised, double-blind, placebo-controlled trial, ZX008 significantly reduced convulsive seizure (CS) frequency (defined as tonic-clonic, hemiclonic, tonic, atonic, clonic, and focal motor seizures). We present secondary analyses of total seizure (TS) frequency (defined as CS plus absence or atypical absence, myoclonic, atonic, and focal seizures without clear observable motor signs). Methods: Patients (2-18y) with DS, and CSs not controlled by current anti-epileptic drug regimen were enrolled. Following a 6-week baseline period, patients were randomised 1:1:1 to placebo, ZX008 0.2 mg/kg/day (ZX008/0.2), or ZX008 0.8 mg/kg/day (ZX008/0.8; maximum 30 mg/day), and treated for 14 weeks, including 2-week titration. Caregivers recorded seizure number and type daily via electronic diary. Results: A total 119 patients were randomised (10.1% UK, mean age 9 ± 4.7y). Baseline median monthly TS frequency ranged from 40.7–53.9 across groups. ZX008 significantly reduced TS frequency in a dose-related manner during 14 weeks’ treatment. Median TS frequency reductions were 13.1% with placebo, 34.3% with ZX008/0.2 (p = 0.031), and 70.1% with ZX008/0.8 (p < 0.001). Median non-CS seizure subtype reductions (combined) were 55.6% with placebo and 75.1% with ZX008/0.8 (p < 0.035), including a 54.8 and 78.6% reduction in absence and 34.8 and 64.0% reduction in myoclonic seizures, respectively. Seizure freedom was experienced by 3 (7.5%) subjects with ZX008/0.8, 3 (7.7%) with ZX008/0.2, and none with placebo. Median longest seizure-free interval was significantly longer in ZX008 groups vs placebo. ZX008 was generally well-tolerated, and no cases of FDA-defined cardiac valvulopathy were observed; neither were there echocardiographic findings or clinical symptoms suggesting pulmonary hypertension. Conclusions: In addition to significantly reducing convulsive seizures, ZX008/0.8 mg/kg/day also significantly reduced other seizure types and Total seizure burden. ZX008 may represent an effective new treatment option for Dravet syndrome.L20068192442020-06-25 <br />