Title: Efficacy of Fenfluramine as First-Line Add-On Therapy for Seizure Control in Dravet Syndrome: A Systematic Review and Meta-Analysis
Authors: Ana Leticia Fornari Caprara, Jamir Pitton Rissardo, Evren Burakgazi-Dalkilic
Conference: 2025 AES Annual Meeting, Atlanta, GA
Introduction
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by treatment-resistant seizures and high morbidity. Despite the emergence of targeted therapies, first-line management remains challenging. Fenfluramine (FFA), a serotonergic agent with anti-seizure properties, has shown promise as an add-on therapy.
Objective
This systematic review and meta-analysis aimed to evaluate the efficacy of FFA compared to placebo as a first-line add-on treatment in reducing seizure burden among patients with DS.
Methods
A systematic review was conducted according to PRISMA guidelines. Databases were searched for randomized controlled trials (RCTs) assessing FFA versus placebo in DS patients. Studies were eligible if they assessed FFA as a first-line add-on therapy and reported seizure outcomes, including median convulsive seizure frequency (MCSF) and ≥50% and ≥75% responder rates. Risk differences (RD) with 95% confidence intervals (CIs) were extracted or calculated for seizure reduction endpoints. Random-effects meta-analyses were performed using inverse variance methods.
Results
Three treatment arms across two high-quality, double-blind RCTs (PMIDs: 31862249, 31790543) were included, involving a total of 247 patients. FFA doses ranged from 0.2 to 0.7 mg/kg/day. Compared to placebo, the pooled RD for ≥50% reduction in MCSF was –0.18 (95% CI: –0.278 to –0.082), indicating a statistically significant benefit. The RD for ≥75% seizure reduction was –0.14 (95% CI: –0.222 to –0.059), also favoring FFA. The RD for change in median convulsive seizure frequency showed consistent trends but with wider confidence intervals (e.g., RD for 0.7 mg/kg/day: –55.7; 95% CI: –105.6 to 217.0), likely due to heterogeneity in baseline seizure rates. Subgroup analysis by dose suggested greater efficacy at 0.4–0.7 mg/kg/day compared to 0.2 mg/kg/day.
Three treatment arms across two high-quality, double-blind RCTs (PMIDs: 31862249, 31790543) were included, involving a total of 247 patients. FFA doses ranged from 0.2 to 0.7 mg/kg/day. Compared to placebo, the pooled RD for ≥50% reduction in MCSF was –0.18 (95% CI: –0.278 to –0.082), indicating a statistically significant benefit. The RD for ≥75% seizure reduction was –0.14 (95% CI: –0.222 to –0.059), also favoring FFA. The RD for change in median convulsive seizure frequency showed consistent trends but with wider confidence intervals (e.g., RD for 0.7 mg/kg/day: –55.7; 95% CI: –105.6 to 217.0), likely due to heterogeneity in baseline seizure rates. Subgroup analysis by dose suggested greater efficacy at 0.4–0.7 mg/kg/day compared to 0.2 mg/kg/day.
Conclusions
This meta-analysis supports the efficacy of fenfluramine as a first-line add-on therapy in reducing seizure frequency in patients with DS. Clinically meaningful improvements were observed in both ≥50% and ≥75% responder rates. The benefit appeared dose-dependent, with higher doses yielding greater seizure control. These findings support consideration of FFA in early treatment algorithms for DS, although further studies are needed to confirm long-term effectiveness and safety in broader clinical practice.
This meta-analysis supports the efficacy of fenfluramine as a first-line add-on therapy in reducing seizure frequency in patients with DS. Clinically meaningful improvements were observed in both ≥50% and ≥75% responder rates. The benefit appeared dose-dependent, with higher doses yielding greater seizure control. These findings support consideration of FFA in early treatment algorithms for DS, although further studies are needed to confirm long-term effectiveness and safety in broader clinical practice.
Citation
Fornari Caprara AL, Pitton Rissardo J, Burakgazi-Dalkilic E. Efficacy of Fenfluramine as First-Line Add-On Therapy for Seizure Control in Dravet Syndrome: A Systematic Review and Meta-Analysis. AES Annual Meeting 2025;2025:####. ####
Figure 1. Risk Difference (RD) for Change in Median Convulsive Seizure Frequency (MCSF). Forest plot showing pooled RDs for change in MCSF with fenfluramine versus placebo across included randomized controlled trials. Higher doses (0.4–0.7 mg/kg/day) demonstrated greater efficacy compared to 0.2 mg/kg/day, though confidence intervals were wider due to baseline heterogeneity.
Figure 2. Forest plot of ≥50% responder rate. Meta-analysis of RDs for achieving ≥50% reduction in MCSF with fenfluramine versus placebo. Pooled RD = –0.18 (95% CI: –0.278 to –0.082), favoring fenfluramine.
Figure 3. Forest plot of ≥75% responder rate. Meta-analysis of RDs for achieving ≥75% reduction in MCSF with fenfluramine versus placebo. Pooled RD = –0.14 (95% CI: –0.222 to –0.059), indicating significant benefit of fenfluramine.