Abstract Objective Long‐term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS) treated with fenfluramine in an open‐label extension (OLE) study after participating in a previous open‐label feeder study. Methods Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open‐label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day 26 mg/day without stiripentol or .4 mg/kg/day 17 mg/day with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long‐term safety/tolerability. Global functioning using caregiver‐ and investigator‐reported Clinical Global Impression of Improvement (CGI–I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc. Results A total of 412 patients enrolled (DS: 265 64.3%, LGS: 147 35.7%); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8–1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171–2800). In this OLE, ≥1 treatment‐emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine‐related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as “improved or no change” on CGI–I versus this study baseline; subdomain ratings of “improved or no change” were largely consistent with global assessment. Significance In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long‐term fenfluramine use in pediatric and adult patients with DS or LGS.
Gil‐Nagel et al. (Sat,) studied this question.