Safety and Effectiveness of Fenfuramine for the Treatment of Seizures in Lennox-Gastaut Syndrome: Results from the Final Analysis of an Open-Label Extension Study

Abstract

Objective: To describe the fnal long-term safety and effectiveness data from a fenfuramine (FFA) open-label extension (OLE) study in participants with Lennox-Gastaut syndrome (LGS) (NCT03355209). Background: LGS is a developmental and epileptic encephalopathy characterized by tonic seizures and other seizure types, intellectual impairment and specifc electroencephalogram fndings. In a randomized controlled trial (RCT, Cohort A), FFA 0.7 mg/kg/day demonstrated a 26.5% median reduction in seizures associated with a drop vs 7.6% in the placebo group (P=0.001). In an interim analysis of this OLE study, FFA demonstrated a median reduction in frequency of seizures associated with a drop of 28.6% (P<0.0001) over the OLE (n=241). Design/Methods: Participants started on FFA 0.2 mg/kg/day, then fexibly titrated to effectiveness/tolerability after 1 month. Wilcoxon signed-rank test was used for median percent change from RCT baseline (from Month 1-end of study) in seizures associated with a drop. Additional methods have been described [Knupp 2023 Epilepsia]. Results: 247 participants (mean age 14.3±7.6 years) were enrolled in the OLE; disposition unknown in 3/247 participants, 158/244 completed the study, and 86/244 discontinued FFA (13/86 due to adverse event). Median treatment duration was 364 days (range, 19-537). 205 (83.0%) participants experienced ≥1 treatment-emergent adverse event (TEAE). Of 41 participants with ≥1 serious TEAE, 12 had ≥1 related to FFA. TEAEs reported in ≥10% of participants were: decreased appetite (16.2%), fatigue (13.4%), nasopharyngitis (12.6%), seizure (10.9%), pyrexia (10.1%). No cases of valvular heart disease or pulmonary arterial hypertension were observed. Median decrease in frequency of seizures resulting in drop over the OLE (n=241) was 29.5% (P<0.0001). Conclusions: In this fnal analysis of an OLE study in participants with LGS, FFA was generally well tolerated with no new safety signals. FFA was associated with a sustained reduction in seizures, confrming FFA as an important treatment option for patients with LGS.