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Objective: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. Methods: This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine.2 mg/kg/day, or fenfluramine.7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure‐free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. Significance: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate the long‐term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS). Methods: Eligible patients with LGS who completed a 14‐week phase 3 randomized clinical trial enrolled in an open‐label extension (OLE; NCT03355209). All patients were initially started on.2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3‐month intervals. The protocol‐specified treatment duration was 12 months, but COVID‐19‐related delays resulted in 142 patients completing their final visit after 12 months. Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142, p <.0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192, p =.0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p <.0001, n = 106) and 35.8% (p <.0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment‐emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long‐term. Fenfluramine may provide an important long‐term treatment option for LGS. [ABSTRACT FROM AUTHOR]

Objective: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. Methods: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time‐to‐nth seizure), using a post hoc time‐to‐event (TTE) analysis of data from two Phase 3 placebo‐controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2–19 years were randomized to placebo or adjunctive fenfluramine (Study 1:.7 mg/kg/day or.2 mg/kg/day; Study 2:.4 mg/kg/day with stiripentol). Data were analyzed by Kaplan–Meier TTE curves and waterfall plots. Results: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine.7 mg/kg/day, 60%; fenfluramine.2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine.4 mg/kg/day, 58%; placebo, 2%). Median time‐to‐nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine.7 mg/kg/day, 13 weeks;.2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine.4 mg/kg/day, 13 weeks; placebo, 5 weeks; p <.001). Longest duration of convulsive seizure‐free days was increased in active groups versus the placebo group (Study 1: fenfluramine.7 and.2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p =.0001; p =.0352]; Study 2: fenfluramine.4 mg/kg/day, 22.0 days; placebo, 13.0 days [p =.004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue. Significance: These data demonstrate that fenfluramine can significantly reduce day‐to‐day seizure burden in patients with DS, providing prolonged periods of convulsive seizure‐free days, which may help reduce the physical and emotional disease toll while improving health‐related QOL for patients and caregivers. [ABSTRACT FROM AUTHOR]