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Randomized Controlled Trial
. 2025 Jun;66(6):1919-1932.
doi: 10.1111/epi.18342. Epub 2025 Mar 12.

Long-term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome

Ingrid E Scheffer  1 , Rima Nabbout  2 , Lieven Lagae  3 , Orrin Devinsky  4 , Stéphane Auvin  5   6   7 , Elizabeth A Thiele  8 , Elaine C Wirrell  9 , Tilman Polster  10 , Nicola Specchio  11   12 , Milka Pringsheim  13   14   15 , Katsumi Imai  16 , Michael D Lock  17 , Mélanie Langlois  18 , Rebecca Zhang Roper  19 , Amélie Lothe  18 , Joseph Sullivan  20
Affiliations
Randomized Controlled Trial

Long-term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome

Ingrid E Scheffer et al. Epilepsia. 2025 Jun.

Abstract

Objective: We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults.

Methods: Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults.

Results: A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively.

Significance: Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

Keywords: anti‐seizure medication; epilepsy; seizure.

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Conflict of interest statement

Ingrid E. Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, LivaNova, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai; has served as an investigator for Anavex Life Sciences, Cerebral Therapeutics, Cereval Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc., Epygenyx, ES‐Therapeutics, GW Pharma (now Jazz Pharmaceuticals), Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceutical, Zogenix (now a part of UCB), and Zynerba; has consulted for Atheneum Partners, Care Beyond Diagnosis, Epilepsy Consortium, Ovid Therapeutics, UCB and Zynerba Pharmaceuticals, Stoke Therapeutics, Praxis; and is a Non‐Executive Director of Bellberry Ltd. and a Director of the Australian Academy of Health and Medical Sciences. Rima Nabbout has received research funding from Eisai, GW Pharma (now Jazz Pharmaceuticals), Novartis, Shire, UCB, and Zogenix Inc. (now a part of UCB); is a consultant/advisor for Eisai, Biogen, GW Pharma (now Jazz Pharmaceuticals), Takeda, Novartis, Shire, and Zogenix Inc. (now a part of UCB); and a speaker for Advicenne, Eisai, BioMarin, GW Pharma (now Jazz Pharmaceuticals), Novartis, Nutricia, Neuraxpharma, and Zogenix Inc. (now a part of UCB) and UCB. Lieven Lagae has received grants from and is a consultant and/or speaker for Zogenix (now a part of UCB), LivaNova, UCB, Shire, Eisai, Novartis, Takeda/Ovid, NEL, and Epihunter. Orrin Devinsky has received Grant support from National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), Multidisciplinary University Research Initiative (MURI), Centers for Disease Control and Prevention (CDC), and National Science Foundation (NSF); equity and/or compensation from Tilray, Receptor Life Sciences, Qstate Biosciences, Hitch Biosciences, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, SilverSpike, and California Cannabis Enterprises (CCE); consulting fees from Zogenix (now a part of UCB), Ultragenyx, BridgeBio, GeneMedicine, and Marinus; patents for the use of cannabidiol in treating neurological disorders (owned by GW Pharmaceuticals, now Jazz Pharmaceuticals) for which he has waived any financial interests; other patents in molecular biology; and is managing partner of the PhiFundVentures. Stéphane Auvin has received personal fees from: Arvelle, Biocodex, GW Pharma (now Jazz Pharmaceuticals), and Xenon; personal fees and nonfinancial support from Biomarin, GW Pharma (now Jazz Pharmaceuticals), and Nutricia; personal fees/grants from Eisai and UCB for work as an investigator; and research support from Zogenix (now a part of UCB). Elizabeth A. Thiele has been a paid consultant for Zogenix (now a part of UCB), GW Pharma (now Jazz Pharmaceuticals), Upsher Smith, Aquestive; Research funding, GW Pharma (now Jazz Pharmaceuticals); Clinical trial site PI, GW Pharma (now Jazz Pharmaceuticals), and Zogenix (now a part of UCB). Elaine C. Wirrell has received consulting fees from Acadia, Amicus, Neurocrine, and Encoded Therapeutics. She also receives income from Epilepsy.com for serving as Co‐Editor in Chief. Tilman Polster has received research funding from Zogenix (now a part of UCB); served as a consultant for Jazz Pharmaceuticals and Zogenix (now a part of UCB) and speaker for Jazz Pharmaceuticals, Desitin, Shire, Novartis, UCB, Zogenix (now a part of UCB); and clinical trial site PI for Zogenix (now a part of UCB) and Marinus. Nicola Specchio has served on scientific advisory boards for GW Pharma (now Jazz Pharmaceuticals), BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Eisai, Biomarin, LivaNova, and Sanofi; and has served as an investigator for Zogenix (now a part of UCB), Marinus, Biomarin, UCB, and Roche. Milka Pringsheim has been an investigator for Fintepla, a consultant/advisor/speaker for Zogenix (now a part of UCB); received travel support from Jazz Pharmaceuticals; served as an investigator and served on advisory board for Takeda; and received a research grant from Zogenix (now a part of UCB). Katsumi Imai is a FINTEPLA Investigator for UCB; and received funding from the MHLW Research program on rare and intractable diseases, Grant number JPMH23FC1013. Michael Lock is a consultant/advisor for Zogenix (now a part of UCB). Mélanie Langlois, Rebecca Zhang Roper, and Amélie Lothe are employees of UCB with stock ownership. Joseph Sullivan has received research grants from Stoke, Marinus, Zogenix (now a part of UCB), Biopharm; Consultant/Advisor, Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharma (now Jazz Pharmaceuticals), Asceneuron, Longboard Pharmaceuticals, Knopp Biosciences, Neurocrine; Stock options, Epygenix; Travel support, Zogenix (now a part of UCB); Reviewer, Epilepsy Study Consortium.

Figures

FIGURE 1
FIGURE 1
Design of open‐label extension study of fenfluramine in patients with Dravet syndrome. aStudy 1 and Study 3 were initially planned as separate studies based on geographic location: United States and Canada (NCT02682927) and Western Europe and Australia (NCT02826863). Due to slow enrollment, the datasets were combined; subsequently, based on dates of enrollment, they were again split into Study 1 and Study 3. Study 3 also includes patients from Japan who enrolled later. bAny patient who transitioned to commercial product or to a separate extension study was not required to have post‐dosing and cardiac safety follow‐up visits, but cardiac safety follow‐up visits should have been continued as recommended. cOLE protocol amendment (February 2018) allowed enrollment of adult patients “de novo.” ASM(s), anti‐seizure medication(s); DS, Dravet syndrome; ECG, electrocardiography; ECHO, echocardiography; FFA, fenfluramine; OLE, open‐label extension; RCTs, randomized‐controlled trials; STP, stiripentol.
FIGURE 2
FIGURE 2
Overview of open‐label extension (Study 1503) enrollment. DS, Dravet syndrome; FFA, fenfluramine; OLE, open‐label extension; STP, stiripentol.
FIGURE 3
FIGURE 3
Effectiveness outcomes. (A) Median percentage change in monthly convulsive seizure frequency over the OLE. (B) Percentage of patients to achieve ≥50%, ≥75%, ≥90%, and 100% reductions in MCSF. MCSF, monthly convulsive seizure frequency; mITT, modified intent‐to‐treat; OLE, open‐label extension.
FIGURE 4
FIGURE 4
Caregiver and investigator ratings on CGI‐I at last visit for mITT population. aCGI‐I solicits a response on a 7‐point Likert‐like scale, with 1 indicating “very much improved,” 4 indicating “no change,” and 7 indicating “very much worse.” CGI‐I, Clinical Global Impression‐Improvement; mITT, modified intent‐to‐treat.
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