Efficacy and safety of fenfluramine in Dravet syndrome: The impact of patient clinical characteristics

Rima Nabbout; Joseph Sullivan; Stéphane Auvin; J Helen Cross; Orrin Devinsky; Antonio Gil‐Nagel; Renzo Guerrini; Kelly G Knupp; M Scott Perry; Rocío Sánchez‐Carpintero; An‐Sofie Schoonjans; Ingrid E Scheffer; Nicola Specchio; Adam Strzelczyk; James Wheless; Elaine C Wirrell; Diego Morita; Patrick Healy; Mélanie Langlois; Amélie Lothe; Lieven Lagae

doi:10.1002/epi4.70340

. 2026 Aug 22;11(5):1692–1705. doi: 10.1002/epi4.70340

Efficacy and safety of fenfluramine in Dravet syndrome: The impact of patient clinical characteristics

Rima Nabbout ^1,², Joseph Sullivan ³, Stéphane Auvin ^4,^5,^6,⁷, J Helen Cross ^8,⁹, Orrin Devinsky ¹⁰, Antonio Gil‐Nagel ¹¹, Renzo Guerrini ¹², Kelly G Knupp ¹³, M Scott Perry ¹⁴, Rocío Sánchez‐Carpintero ¹⁵, An‐Sofie Schoonjans ¹⁶, Ingrid E Scheffer ^17,^18,^19,²⁰, Nicola Specchio ^21,²², Adam Strzelczyk ²³, James Wheless ^24,²⁵, Elaine C Wirrell ²⁶, Diego Morita ²⁷, Patrick Healy ²⁸, Mélanie Langlois ²⁹, Amélie Lothe ^29,^✉, Lieven Lagae ^30,³¹

^¹Reference Centre for Rare Epilepsies, Hôpital Universitaire Necker‐Enfants Malades, AP‐HP, Member of the European Reference Network (ERN) EpiCARE, Paris, France

^²Institut Imagine, INSERM 1163, Université Paris Cité, Paris, France

^³University of California San Francisco Weill Institute for Neurosciences, Benioff Children's Hospital, San Francisco, California, USA

^⁴AP‐HP, Reference Center for Rare Epilepsies, Member of ERN EpiCARE, Hôpital Universitaire Robert Debré, Paris, France

^⁵Institut Hospitalo‐Universitaire Robert‐Debré du Cerveau de l'Enfant, Paris, France

^⁶INSERM NeuroDiderot, Université Paris‐Cité, Paris, France

^⁷Institut Universitaire de France (IUF), Paris, France

^⁸UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK

^⁹Great Ormond Street Hospital, London, UK

^¹⁰Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, New York, USA

^¹¹Hospital Ruber Internacional, Madrid, Spain

^¹²Meyer Children's Hospital IRCCS & University of Florence, Florence, Italy

^¹³University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

^¹⁴Jane and John Justin Institute for Mind Health, Cook Children's Medical Center, Fort Worth, Texas, USA

^¹⁵Pediatric Neurology Unit, Clinica Universidad de Navarra, Pamplona, Spain

^¹⁶Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium

^¹⁷Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

^¹⁸The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

^¹⁹Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia

^²⁰Murdoch Children's Research Institute, Parkville, Vicotria, Australia

^²¹Bambino Gesú Children's Hospital, IRCCS, Member of the ERN, EpiCARE, Rome, Italy

^²²University Hospitals KU Leuven, Leuven, Belgium

^²³Goethe University Frankfurt, Epilepsy Center Frankfurt Rhine‐Main, University Medicine Frankfurt, Frankfurt am Main, Germany

^²⁴University of Tennessee Health Science Center, Memphis, Tennessee, USA

^²⁵Le Bonheur Children's Hospital, Memphis, Tennessee, USA

^²⁶Mayo Clinic, Rochester, Minnesota, USA

^²⁷UCB, Morrisville, North Carolina, USA

^²⁸UCB, Smyrna, Georgia, USA

^²⁹UCB Pharma S.A. Courbevoie, France

^³⁰University of Leuven, Leuven, Belgium

^³¹Leuven Childhood Epilepsy Center, Leuven Brain Institute, UZ Leuven, Member of the European Reference Network EpiCARE, Leuven, Belgium

Correspondence , Amélie Lothe, UCB Pharma S.A., 7 allée de l'Arche, Courbevoie 92400, France. Email: amelie.lothe@ucb.com

^✉

Corresponding author.

PMCID: PMC13499604 PMID: 42632015

Abstract

Objective

To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status.

Methods

In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2–18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1–3; 4–6; ≥7), and SCN1A pathogenic variant status (SCN1A+; SCN1A−). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure‐free interval, and Clinical Global Impression–Improvement [CGI–I] scale scores rated by parents/caregivers and investigators), and safety (treatment‐emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved).

Results

Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure‐free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement (“Much Improved”, “Very Much Improved”) on CGI–I scores across all stratified groups. CGI–I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator‐rated CGI–I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end‐of‐study.

Significance

Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well‐tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted.

Plain Language Summary

Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2–18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A. They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

Keywords: convulsive seizure frequency, developmental and epileptic encephalopathy, global functioning, pediatrics, safety and efficacy studies, SCN1A

This graphical abstract provides an overview of the content from this post hoc analysis evaluating the efficacy and safety of fenfluramine in patients with Dravet syndrome stratified by age, number of previously attempted antiseizure medications, and SCN1A pathogenic variant status using data pooled from the three pivotal randomized controlled trials.

graphic file with name EPI4-11-1692-g003.webp

Key points.

Patients (N = 348) with Dravet syndrome from three RCTs were stratified by age, total previous antiseizure medications, and SCN1A status.
Fenfluramine was superior to placebo in seizure and global functioning outcomes for all studied clinical characteristic groups.
A greater proportion of patients had improved ratings on the Clinical Global Impression–Improvement Scale with fenfluramine versus placebo.
Most (142/172; 83%) treatment‐emergent adverse events with fenfluramine resolved by end‐of‐study.
Of 216 patients treated with fenfluramine, 10 (5%) discontinued treatment due to an adverse event.

1. INTRODUCTION

Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy (DEE) characterized by a high seizure burden including multiple types of seizures; motor, behavioral, and cognitive impairments; and a high risk of premature mortality. ¹ , ² More than 90% of patients with DS have pathogenic variants in SCN1A encoding the voltage‐gated sodium channel Na_V1.1 α‐subunit. ² , ³ , ⁴ , ⁵ , ⁶ Adequate seizure control is not attained in most patients with DS despite regimens of multiple antiseizure medications (ASMs). ² , ⁷ , ⁸ The epileptic component of DS severity can be assessed in multiple ways, including the number of previously attempted ASMs. ⁹

Fenfluramine modulates serotonin release and signaling at multiple serotonin receptors; it also modulates sigma‐1 receptors. ¹⁰ Fenfluramine is approved for treatment of seizures associated with DS in many countries in patients aged 2 years or older. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Treatment with the highest approved doses of fenfluramine (0.7 mg/kg/day, maximum 26 mg/day; 0.4 mg/kg/day, maximum 17 mg/day with stiripentol) reduced monthly convulsive seizure frequency (MCSF) by 54.0%–68.8% across three DS randomized controlled trials (RCTs; ZX008‐1501/EP0208, NCT02682927 ¹⁷ ; ZX008‐1502/EP0209, NCT02826863 ¹⁸ ; ZX008‐1504/EP0210, NCT02926898 ¹⁹ ). Fenfluramine treatment also improved global functioning according to ratings from parents/caregivers and investigators on the Clinical Global Impression–Improvement (CGI–I) scale. ¹⁷ , ¹⁸ , ¹⁹ Fenfluramine was well tolerated in all three RCTs. The open‐label extension study demonstrated long‐term maintenance of seizure control and clinical improvements in CGI–I in pediatric and adult patients. ²⁰

Revised international consensus treatment statement from both physicians and caregivers supports initiating valproate after DS diagnosis and adding fenfluramine as either first‐ or second‐line treatment for the management of seizures associated with DS. ² Subanalyses of pooled data from multiple RCTs provide a means of addressing specific clinical characteristics that can further inform data‐driven clinical decision‐making, such as treatment efficacy in different age groups, number of previously attempted ASMs, and genotype.

2. AIM/OBJECTIVE

To investigate the potential impact of patient clinical characteristics on the efficacy and safety of fenfluramine in DS, data from three pivotal phase 3 RCTs were pooled and stratified by age at RCT entry, number of previously attempted ASMs, and presence of SCN1A pathogenic variant.

3. MATERIALS AND METHODS

3.1. Data

Patient data from three RCTs (NCT02682927 and NCT02826863 [Study 1 and 3], ¹⁷ , ¹⁸ and NCT02926898 [Study 2] ¹⁹ ) were pooled by dose group and stratified by baseline characteristics of age (<4 years; ≥4 years), number of ASMs attempted prior to enrollment (1–3; 4–6; ≥7), and SCN1A pathogenic variant status (positive [SCN1A+]; negative [SCN1A−] determined by genetic testing for the presence of a likely pathogenic variant of SCN1A).

3.2. Study design, ethics, and oversight

Trial design and oversight were described previously in each respective study publication. ¹⁷ , ¹⁸ , ¹⁹ The RCTs complied with the current International Council for Harmonisation Good Clinical Practice guidelines. The study protocols were approved by applicable regulatory authorities and independent ethics committees or institutional review boards at each participating institution. Prior to enrollment, written informed consent was provided by parents or legal guardians for all patients.

Complete descriptions of the RCT methods have been reported previously. ¹⁷ , ¹⁸ , ¹⁹ Study 1 and Study 3 compared fenfluramine treatment without stiripentol (0.7 and 0.2 mg/kg/day; maximum daily dose, 26 mg/day) with placebo. ¹⁷ , ¹⁸ Study 2 compared fenfluramine combined with stiripentol (0.4 mg/kg/day; maximum daily dose, 17 mg/day) versus placebo. ¹⁹ The primary endpoints included comparison of median change in MCSF during the treatment period (titration and maintenance, Studies 1 and 3: 14 weeks; Study 2: 15 weeks) versus pretreatment baseline for each fenfluramine dose group with placebo. Secondary endpoints included comparisons of fenfluramine dose groups with placebo on the longest interval of convulsive seizure‐free days and of patient CGI–I scores as assessed by parents/caregivers and investigators.

3.3. Post hoc analyses endpoints

Pooled data were assessed by treatment group stratified by age at RCT entry, number of previously attempted ASMs, and SCN1A pathogenic variant status. Treatment groups analyzed were placebo, fenfluramine 0.7 and 0.2 mg/kg/day (without stiripentol), fenfluramine 0.4 mg/kg/day (with stiripentol), and all combined fenfluramine doses (pooled) stratified by stiripentol use. A cutoff of 4 years of age was selected to assess the effect of treatment early in the disease course due to poor cognitive outcomes associated with poor seizure control in patients younger than 5 years. ²¹ , ²² Cutoff values for previously attempted ASMs (1–3, 4–6, ≥7) were selected based on population data on concomitant medications and seizure burden in patients with DS. ² , ⁷ , ⁸ , ⁹

For this analysis, efficacy endpoints included the median percentage change in MCSF (per 28 days) between the treatment period and pretreatment baseline period, the median longest interval of convulsive seizure‐free days during the treatment period, and the proportion of patients with clinically meaningful improvement (“Much Improved” or “Very Much Improved”) on patient CGI–I scores as rated by parent/caregivers and investigators during the final week of the treatment period. Data were analyzed in each stratified group by fenfluramine dose versus placebo or by pooled fenfluramine doses versus placebo.

Safety was assessed by dose group and pooled fenfluramine, with the following outcomes: treatment‐emergent adverse events (TEAEs; occurring in ≥10% of any pooled fenfluramine treatment group), ≥1 serious TEAE, any TEAE resulting in treatment discontinuation, any TEAE resulting in death, days to onset of the earliest occurrence of common TEAEs (mean ± SD), and the proportion of resolved TEAEs.

3.4. Statistics

Continuous variables were summarized using descriptive statistics (mean ± SD; estimate of percentage difference; estimate of median treatment difference). Categorical variables were summarized with frequencies and percentages. The summary of concomitant ASMs did not include previously attempted ASMs.

Change in MCSF was analyzed using an analysis of covariance (ANCOVA) model with treatment group and age group (<6 years, ≥6 years) as factors for the analyses by stratification (excluding models stratified by age: <4 and ≥4 years), study as an additional factor for the pooled group, log baseline convulsive seizure frequency as a covariate, and log convulsive seizure frequency in the combined treatment period as the response. The estimate of percentage difference (and 95% CI) in MCSF from placebo was obtained from the least squares means on the log scale as follows: 100 × [1 – exp. (LS‐mean active – LS‐mean placebo)].

For interval between seizure‐free days, the estimate of median (and 95% CI) treatment difference between baseline and the treatment period was based on the Hodges‐Lehman estimator of treatment difference. Pooled fenfluramine was assessed versus placebo using the Wilcoxon rank sum test.

Clinically meaningful change in CGI–I assessing fenfluramine versus placebo was based on the Mantel–Haenszel odds ratio, adjusting for age group in the number of previously attempted ASMs, and SCN1A status subanalyses.

To identify predictors of MCSF following fenfluramine treatment, an ANCOVA model was used with age, number of previously attempted ASMs, and SCN1A pathogenic variant status as factors adjusted for log‐transformed baseline MCSF and weight at baseline and log (convulsive seizure frequency) + 1 as response, followed by backward selection. Similarly, a logistic model with the same covariates was used to identify predictors of 50% responder status among patients who received fenfluramine.

All p‐values are considered nominal due to the post hoc nature of the analysis.

4. RESULTS

4.1. Baseline characteristics

Across three RCTs, 348 patients with DS aged 2–18 years were included in the analysis (Table 1).

TABLE 1.

Patient demographic and clinical characteristics (N = 348).

	FFA 0.7 mg/kg/day without STP (n = 88)	FFA 0.4 mg/kg/day with STP (n = 43)	FFA 0.2 mg/kg/day without STP (n = 85)	Placebo (n = 132)	Pooled FFA (n = 216)
Female sex, n (%)	45 (51.1)	20 (46.5)	39 (45.9)	57 (43.2)	104 (48.2)
Age group, n (%)
2 to <4 years	13 (14.8)	7 (16.3)	9 (10.6)	15 (11.4)	29 (13.4)
≥4 years	75 (85.2)	36 (83.7)	76 (89.4)	117 (88.6)	187 (86.6)
Race, n (%)
White	67 (76.1)	23 (53.5)	70 (82.4)	96 (72.7)	160 (74.1)
Asian	9 (10.2)	2 (4.7)	7 (8.2)	12 (9.1)	18 (8.3)
Other or unknown	7 (8.0)	5 (11.6)	6 (7.1)	10 (7.6)	18 (8.3)
Not reported ^a	5 (5.7)	13 (30.2)	2 (2.4)	14 (10.6)	20 (9.3)
SCN1A+, n (%)	77 (87.5)	37 (86.0)	72 (84.7)	113 (85.6)	186 (86.1)
Number of previously attempted ASMs, n (%) ^b
1–3	13 (14.8)	22 (51.2)	7 (8.2)	32 (24.2)	42 (19.4)
4–6	28 (31.8)	21 (48.8)	29 (34.1)	54 (40.9)	78 (36.1)
≥7	47 (53.4)	0	49 (57.6)	46 (34.8)	96 (44.4)
Number of concomitant ASMs, n (%)
1–3	78 (88.6)	20 (46.5)	69 (81.2)	101 (76.5)	167 (77.3)
4–6	10 (11.4)	23 (53.5)	15 (17.6)	31 (23.5)	48 (22.2)
Concomitant ASMs in ≥20% of any group, n (%)
Valproate, all forms ^c	59 (67.0)	32 (74.4)	58 (68.2)	90 (68.2)	149 (68.1)
Clobazam	53 (60.2)	40 (93.0)	43 (50.6)	96 (72.7)	136 (63.0)
Levetiracetam	17 (19.3)	6 (14.0)	25 (29.4)	29 (22.0)	48 (22.2)
Stiripentol	0	43 (100)	0	44 (33.3)	43 (19.9)
Topiramate	26 (29.5)	14 (32.6)	20 (23.5)	29 (22.0)	60 (27.8)
Other concomitant treatments, n (%)
Ketogenic diet	11 (12.5)	3 (7)	6 (7.1)	N/A	20 (9.3)
VNS implant	9 (10.2)	2 (4.7)	18 (21.2)	N/A	29 (13.4)
Baseline MCSF
Mean ± SD	67.5 ± 288.1	27.9 ± 36.9	58.3 ± 175.5	30.1 ± 36.2	56.0 ± 214.7
Median (range)	16.9 (2.7–2700.7)	14.0 (2.7–213.3)	17.5 (4–1464)	14.8 (2.7–229.3)	16.3 (2.7–2700.7)

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Note: Maximum FFA daily dose with STP was 17 mg/day; without STP, 26 mg/day.

Abbreviations: ASM, antiseizure medication; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency; N/A, not available; STP, stiripentol; VNS, vagal nerve stimulation.

^{^a}

Not reported or missing; privacy laws in some regions and countries preclude disclosure of certain personal information.

^{^b}

Previously attempted ASMs do not include concomitant ASMs.

^{^c}

Includes valproic acid, valproate semisodium, valproate sodium.

The pooled fenfluramine group (n = 216) included 29 (13.4%) patients aged 2 to <4 years and 187 (86.6%) patients ≥4 years. Patients had previous exposure to 1–3 (42/216, 19.4%), 4–6 (78/216, 36.1%), and ≥7 (96/216, 44.4%) ASMs. Most patients (186/216, 86.1%) were positive for an SCN1A pathogenic variant. The pooled placebo group (n = 132) included 15 (11.4%) patients aged 2 to <4 years and 117 (88.6%) patients ≥4 years. Patients had previous exposure to 1–3 (32/132, 24.2%), 4–6 (54/132, 40.9%), and ≥7 (46/132, 34.8%) ASMs. A total of 113/132 (85.6%) patients were SCN1A+.

Within each group (fenfluramine 0.7, 0.4, and 0.2 mg/kg/day and placebo), most patients were ≥4 years (36/43 [83.7%]–76/85 [89.4%]), had pathogenic SCN1A variants (72/85 [84.7%]–77/88 [87.5%]), and a history of exposure to 4–6 (28/88 [31.8%]–21/43 [48.8%]) or ≥7 (46/132 [34.8%]–49/85 [57.6%]) ASMs. No patients treated with fenfluramine 0.4 mg/kg/day had exposure to ≥7 prior ASMs.

Most patients received regimens of 1–3 concomitant ASMs (101/132; 76.5% [placebo] to 78/88; 88.6% [fenfluramine 0.7 mg/kg/day]), with the exception of patients in the fenfluramine 0.4 mg/kg/day group, where 23/43 (53.5%) were taking 4–6 concomitant ASMs. The most common concomitant ASMs were valproate (pooled fenfluramine, 149/216 [68.1%]; placebo, 90/132 [68.2%]) and clobazam (pooled fenfluramine, 136/216 [63.0%]; placebo, 96/132 [72.7%]). Study 2 was the only study to include stiripentol, resulting in 43/216 (19.9%) of the pooled fenfluramine group and 44/132 (33.3%) of the placebo group taking stiripentol.

Median baseline MCSF was lower in the fenfluramine 0.4 mg/kg/day group (14.0) and placebo (14.8) than in the fenfluramine 0.7 (16.9) and 0.2 mg/kg/day (17.5) dose groups.

4.2. Efficacy

For each of the three RCTs, the MCSF change from baseline in each fenfluramine dose group was significantly greater than that in the placebo group (Table S1). ¹⁷ , ¹⁸ , ¹⁹ The estimate of the median treatment difference of MCSF percentage change was significantly greater in the pooled fenfluramine group compared with placebo in most stratified groups: age (<4 years: −42.1%, p = 0.0562 [NS]; ≥4 years: −57.1%, p < 0.0001; Figure 1A), previously attempted ASMs (1–3 ASMs: −46.5%, p = 0.0006; 4–6 ASMs: −58.8%, p < 0.0001; ≥7 ASMs: −55.7%, p = 0.0002; Figure 2A), and SCN1A status (SCN1A+: −53.8%, p < 0.0001; SCN1A−: −63.5%, p < 0.0001; Figure 3A). The MCSF percentage change was significantly greater than placebo groups in all fenfluramine dose groups in patients aged ≥4 years, with 4–6, and ≥7 previously attempted ASMs, and regardless of SCN1A status (Figures S1A, S2A, and S3A). In patients with DS who were SCN1A+ and in patients ≥4 years, increasing doses of fenfluramine resulted in a progressively greater MCSF change.

Efficacy of fenfluramine treatment stratified by age (<4 years; ≥4 years), measured by (A) MCSF percentage change, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348). ***p < 0.0001; **p < 0.001; *p < 0.05. All p‐values are only presented in an exploratory manner, and differences are nominal. p‐values and estimates of percentage treatment difference in median MCSF percentage change are obtained by an ANCOVA model predicting log convulsive seizure frequency. p‐values and estimates of percentage treatment difference in longest interval of convulsive seizure‐free days are obtained by the Wilcoxon rank‐sum test. Clinically meaningful improvement is defined as ratings of “Much Improved” or “Very Much Improved” and is assessed by odds ratios: Mantel–Haenszel. The number of patients in each stratified group is included at the bottom of each bar. ANCOVA, analysis of covariance; CGI–I, Clinical Global Impression–Improvement; CI, confidence interval; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency.

Efficacy of fenfluramine treatment stratified by number of previously attempted ASMs measured by (A) percent change in MCSF, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348). ***p < 0.0001; **p < 0.001; *p < 0.05. All p‐values are only presented in an exploratory manner, and differences are nominal. p‐values and estimates of percentage treatment difference in median MCSF percentage change are obtained by an ANCOVA model predicting log convulsive seizure frequency. p‐values and estimates of percentage treatment difference in longest interval of convulsive seizure‐free days are obtained by the Wilcoxon rank‐sum test. Clinically meaningful improvement is defined as ratings of “Much Improved” or “Very Much Improved” and is assessed by odds ratios: Mantel–Haenszel. The number of patients in each stratified group is included at the bottom of each bar. ANCOVA, analysis of covariance; ASM, antiseizure medication; CGI–I, Clinical Global Impression‐Improvement; CI, confidence interval; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency.

Efficacy of fenfluramine treatment stratified by *SCN1A* status, measured by (A) percent change in MCSF, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348). ***p < 0.0001; **p < 0.001; *p < 0.05. All p‐values are only presented in an exploratory manner, and differences are nominal. p‐values and estimates of percentage treatment difference in median MCSF percentage change are obtained by an ANCOVA model predicting log convulsive seizure frequency. p‐values and estimates of percentage treatment difference in longest interval of convulsive seizure‐free days are obtained by the Wilcoxon rank‐sum test. Clinically meaningful improvement is defined as ratings of “Much Improved” or “Very Much Improved” and is assessed by odds ratios: Mantel–Haenszel. The number of patients in each stratified group is included at the bottom of each bar. ANCOVA, analysis of covariance; CGI–I, Clinical Global Impression–Improvement; CI, confidence interval; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency.

The estimate of the median treatment difference of longest convulsive seizure‐free interval (days) between pooled fenfluramine and placebo was significantly greater for patients ≥4 years (10; p < 0.0001), for patients within each prior ASM exposure group (1–3 ASMs: 6.0, p = 0.036; 4–6 ASMs: 12.5, p < 0.0001; ≥7 ASMs: 9.0, p < 0.0001), and patients who were SCN1A+ (9.0; p < 0.0001; Figures 1B, 2B, and 3B). The estimate of the median treatment difference of longest convulsive seizure‐free interval between pooled fenfluramine and placebo was not significantly different within the <4 years (2.5; Figure 1B) and SCN1A− groups (7.5; Figure 3B). The increase in longest convulsive seizure‐free interval was significantly higher in the highest fenfluramine dose groups (0.7 and 0.4 mg/kg/day) compared with placebo in patients aged ≥4 years and patients who had previously attempted 4–6 or ≥7 ASMs (Figures S1B and S2B). Patients with SCN1A+ status treated with any dose of fenfluramine had significantly greater increases in convulsive seizure‐free intervals than patients who received placebo; patients with SCN1A− status had nominally greater increases (Figure S3B).

Proportions of patients demonstrating clinically meaningful improvement on parent/caregiver‐ and investigator‐reported CGI–I were significantly higher across all stratified groups in fenfluramine‐treated cohorts relative to placebo (p < 0.05), except for the <4 years group (Figures 1C, 2C, and 3C). Within the small sample size of patients <4 years old, a greater proportion of patients receiving placebo had clinically meaningful improvement as rated by parents/caregivers and investigators than patients aged ≥4 years. In patients ≥4 years and across all three levels of prior ASM exposure, a significantly greater proportion of patients treated with fenfluramine 0.7 mg/kg/day had clinically meaningful improvement (Figures S1C and S2C) compared with placebo. Patients treated with fenfluramine 0.4 or 0.2 mg/kg/day who had previously attempted 1–3 ASMs were more frequently rated as having clinically meaningful improvement compared with patients who had previously attempted 4–6 or ≥7 ASMs treated at those doses. Proportions of clinically meaningful improvement ratings in the fenfluramine 0.7 mg/kg/day group were consistent regardless of prior ASM exposure. The proportion of patients rated with clinically meaningful improvement on CGI–I was significantly greater at all fenfluramine doses in patients with SCN1A+ status compared with placebo (Figure S3C); in patients with SCN1A− status, a nominally greater proportion of patients treated with fenfluramine 0.2 and 0.4 mg/kg/day were rated with clinically meaningful improvement in comparison to the placebo group.

Model estimates for age, number of previously attempted ASMs, and SCN1A pathogenic variant status were not significant.

4.3. Safety

At least one TEAE (pooled fenfluramine: 203/216, 94.0%; placebo: 108/132, 81.8%) was reported for most patients in all dose groups (Table S2). Pooled results in this analysis were consistent with results from original analyses of the pivotal trials. ¹⁷ , ¹⁸ , ¹⁹ Incidence of TEAEs was similar in patients treated with fenfluramine regardless of age, number of previously attempted ASMs, and SCN1A variant status (Table 2) and were consistent with those seen in the pooled dose groups. In total, ten patients (2.9%) withdrew from a study due to a TEAE. As previously reported, no cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were reported for any patient. ¹⁷ , ¹⁸ , ¹⁹

TABLE 2.

TEAEs ^a in patients treated with fenfluramine (pooled) by age, number of previously attempted ASMs, and presence of SCN1A variant (n = 216).

	Age, years		Previously attempted ASMs, n			SCN1A variant status
	<4 (n = 29)	≥4 (n = 187)	1–3 (n = 42)	4–6 (n = 78)	≥7 (n = 96)	SCN1A+ (n = 186)	SCN1A− (n = 30)
Patients with ≥1 TEAE, ^a n (%)	27 (93.1)	176 (94.1)	41 (97.6)	74 (94.9)	88 (91.7)	176 (94.6)	27 (90.0)
Decreased appetite	8 (27.6)	64 (34.2)	15 (35.7)	24 (30.8)	33 (34.4)	58 (31.2)	14 (46.7)
Diarrhea	12 (41.4)	31 (16.6)	15 (35.7)	12 (15.4)	16 (16.7)	38 (20.4)	5 (16.7)
Pyrexia	6 (20.7)	28 (15.0)	9 (21.4)	17 (21.8)	8 (8.3)	30 (16.1)	4 (13.3)
Somnolence	5 (17.2)	23 (12.3)	4 (9.5)	9 (11.5)	15 (15.6)	26 (14.0)	2 (6.7)
Fatigue	1 (3.4)	26 (13.9)	6 (14.3)	15 (19.2)	6 (6.3)	25 (13.4)	2 (6.7)
Blood glucose decreased	2 (6.9)	23 (12.3)	4 (9.5)	8 (10.3)	13 (13.5)	22 (11.8)	3 (10.0)
Nasopharyngitis	5 (17.2)	18 (9.6)	7 (16.7)	11 (14.1)	5 (5.2)	21 (11.3)	2 (6.7)
Upper respiratory tract infection	4 (13.8)	15 (8.0)	5 (11.9)	6 (7.7)	8 (8.3)	18 (9.7)	1 (3.3)
Tremor	1 (3.4)	13 (7.0)	6 (14.3)	4 (5.1)	4 (4.2)	11 (5.9)	3 (10.0)
Bronchitis	–	6 (3.2)	2 (4.8)	3 (3.8)	1 (1.0)	4 (2.2)	2 (6.7)

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Note: Maximum FFA daily dose with STP was 17 mg/day; without STP, 26 mg/day. FFA was titrated to the full dose by Day 14.

Abbreviations: ASM, antiseizure medication; FFA, fenfluramine; RCT, randomized clinical trial; TEAE, treatment‐emergent adverse event.

^{^a}

Listed TEAEs occurred in ≥10% of any treatment group pooled across all three RCTs.

Mean days to onset and proportion of resolution of the most common TEAEs were not analyzed in the original studies. The mean days to onset of the earliest occurrence of common TEAEs (≥5% reported across all participants) were between 24.1 ± 29.9 and 30.1 ± 31.2 in fenfluramine‐treated patients compared with 41.0 ± 38.4 in the placebo group (Table S2). The mean days to onset were similar regardless of age (21.9 ± 26.0 to 27.8 ± 30.4), number of previously attempted ASMs (23.0 ± 25.2 to 29.8 ± 34.0), and SCN1A variant status (24.7 ± 28.7 to 27.3 ± 30.1). By the end of the treatment period, 82.6% of common TEAEs reported in the pooled fenfluramine group and 72.7% of common TEAEs reported in the placebo group were reportedly resolved. The proportion of common TEAEs at earliest occurrence that resolved in patients treated with fenfluramine was similar regardless of age (62.4%–75.0%), number of previously attempted ASMs (61.5%–66.2%), and SCN1A variant status (52.2%–66.0%). The number of patients with one or more serious TEAEs was between 9.1% and 14.0% across all treatment groups. A TEAE that resulted in treatment discontinuation was reported in a greater proportion of patients in the fenfluramine 0.7 mg/kg/day (8.0%) and 0.4 mg/kg/day (4.7%) than the fenfluramine 0.2 mg/kg/day (1.2%) or placebo (1.5%) groups.

5. DISCUSSION

In this pooled analysis of three RCTs assessing the efficacy and safety of fenfluramine in the treatment of patients with DS aged 2–18 years, fenfluramine treatment improved seizure burden as well as global functioning (as assessed by the CGI–I, reflecting both overall clinical status and the impact of symptoms [not limited to seizures]) regardless of age, number of previously attempted ASMs, or SCN1A status, supported by multivariate modeling. The highest treatment dose of fenfluramine (0.7 mg/kg/day) was associated with greater seizure reduction and seizure‐free interval than its lower doses (0.4 mg/kg/day with stiripentol; 0.2 mg/kg/day) or placebo. However, differences in PK interaction may account for the numerically lower seizure reduction and seizure‐free interval in patients treated with fenfluramine 0.4 mg/kg/day with stiripentol than 0.7 mg/kg/day. ¹⁹ , ²³ No new safety signals were identified for fenfluramine regimens, with or without stiripentol.

Fenfluramine was generally well tolerated. The most commonly reported TEAEs (decreased appetite, diarrhea, and pyrexia) were clinically managed with dose adjustment and/or routine nutritional and supportive therapies. ²⁴ Most of these TEAEs resolved by the end of the RCT, with few patients across the three pivotal fenfluramine RCTs discontinuing treatment due to adverse events. Decreased appetite was reported for a greater percentage of patients ≥4 years old in comparison to patients <4 years old, consistent with a previous real‐world report in which loss of appetite was reported for a greater percentage of patients ≥6 years in comparison to patients <6 years old. ²⁵ Compared with the RCTs, decreased appetite was observed in a smaller proportion of patients treated long‐term with fenfluramine for DS, with 35/100 patients with ongoing decreased appetite at the end of the open‐label extension. These results are consistent with previous reports that decreased appetite resolves over time in many patients ²⁶ and that fenfluramine has no observed long‐term effects on weight and growth in children and young adults. ²⁴ , ²⁵ , ²⁷ When previously used as a weight loss drug, cases of VHD and PAH were reported with higher doses of fenfluramine (median fenfluramine 60 mg/day and phentermine 30 mg/day) ²⁸ ; thus, patients were carefully monitored in the RCTs. No cases of VHD or PAH were reported in the RCTs (exposure up to 7.5 years). ²⁹ Yet, it should be noted that infrequent cases of PAH and VHD have been reported through post‐marketing surveillance, often involving confounding factors, in pediatric and adult patients with DS or Lennox‐Gastaut syndrome treated with fenfluramine within the approved dose range. ³⁰ No treatment‐related deaths occurred in the fenfluramine treatment groups over the 14‐ to 15‐week study duration of the RCTs. One death (probable sudden unexpected death in epilepsy [SUDEP] as assessed by the investigator) occurred in the placebo group ¹⁸ ; the DS population in general is known to have a high SUDEP rate. ³¹ , ³²

The preschool years are foundational for neurodevelopment ³³ ; neuronal impairments in patients with DS, caused by both the underlying disease and resulting seizures, can affect later quality of life, cognition, and behavior. ³⁴ Poor seizure control in children <5 years old tends to correspond with worse cognitive outcome. ²¹ , ²² Previous studies in this age group (preschool‐aged children with DS) showed that fenfluramine improved executive function—the ability to self‐regulate behavior, emotions, and cognition in everyday life. ³⁵ Prior reports also showed improved executive functioning in patients with DS >4 to 18 years of age. ³⁶ The results of this pooled analysis are consistent with prior and recent evaluations of seizure outcomes and CGI–I of fenfluramine for the treatment of DS stratified by patient age. ²⁵ , ³⁷ , ³⁸ Earlier effective and well‐tolerated treatment could potentially lead to better long‐term seizure outcomes in patients with DS.

DS is a highly treatment‐resistant DEE, as evidenced by the number of ASMs that had been previously attempted in all three studies and the high median baseline MCSF. Interestingly, patients taking stiripentol had lower baseline MCSF than patients without stiripentol – this may point to potential clinical characteristic differences between these patient populations and may warrant further investigation. Fenfluramine was effective in ameliorating seizure frequency and global functioning even in the most drug‐resistant cases (4–6 or ≥7 previously attempted ASMs), consistent with a retrospective and observational Danish study that found that fenfluramine was effective regardless of baseline GTCS frequency, another measure of severity. ³⁷

Fenfluramine treatment in patients with DS has previously been associated with clinically meaningful improvement on CGI–I scores as evaluated by caregivers and investigators, ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ as well as improved executive functioning as measured by Behavior Rating Inventory of Executive Function®—Preschool (BRIEF®‐P), BRIEF® parent form, and BRIEF®2. ³⁵ Overall, global functioning as assessed by CGI–I was more frequently rated as Much or Very Much Improved (clinically meaningful) in patients who had previously attempted 1–3 ASMs versus those with a higher number of previously attempted ASMs. This result aligns with the hypothesis that earlier effective treatment is associated with better outcomes in patients with DEEs. ³² However, the placebo effect tended to be greatest in the 1–3 ASM group. This observation was not entirely attributable to younger age: the 1–3 and 4–6 ASM groups had comparable median ages (7.0 and 7.5 years, respectively). Younger patients typically have attempted fewer ASMs than older patients. Although the number of previously attempted ASMs is an important factor in patient characteristics, analysis of fenfluramine efficacy as a function of seizure burden (number of convulsive seizures at baseline), developmental and cognitive delays, and/or behavior would be needed to test this hypothesis. ⁸ , ⁹ , ²¹ , ²² , ³⁹ Fenfluramine efficacy on seizures and other relevant symptoms associated with DS, including executive function, behavior, and sleep, in drug‐resistant DS may be attributable to the modulation of serotonin release and signaling at multiple serotonin receptors, including 5‐HT_1D, 5‐HT_2A, 5‐HT_2C, and 5‐HT₄ receptors, and sigma‐1 receptors. ¹⁰ , ⁴⁰ , ⁴¹

Because more than 90% of patients with DS in the population present with pathogenic SCN1A variants, ² , ⁵ few studies have examined responsiveness of patients who did not test positive for the SCN1A pathogenic variant. A 2016 study evaluating the efficacy of ASMs in DS with different genotypes showed no significant differences in efficacy between SCN1A+ and SCN1A− groups among the eight ASMs evaluated, with the exception of bromide (significantly more effective in patients with SCN1A− than SCN1A+ disease). ⁴² However, this post hoc analysis is the first to compare the efficacy of fenfluramine in SCN1A+ and SCN1A− disease. Fenfluramine treatment was effective relative to placebo regardless of fenfluramine dose, with comparable efficacy for patients with SCN1A+ and SCN1A− status. Our data are consistent with reports of fenfluramine effectiveness in severe DEEs not associated with SCN1A pathogenic variants (e.g., Lennox–Gastaut syndrome or CDKL5 deficiency disorder), ⁴³ , ⁴⁴ , ⁴⁵ and other DEEs associated with other SCN pathologies (e.g., SCN8A‐developmental and epileptic encephalopathy and SCN1B‐related disorder). ⁴⁶ , ⁴⁷ As only a minority of patients with DS do not have SCN1A pathogenic variants, studies with larger patient populations are needed to confirm our results.

Our results support consideration of fenfluramine as an early‐line treatment in DS ² across diverse patient subgroups over a spectrum of ages, severities, and SCN1A pathogenic variant status. While the sample size of patients aged 2 to <4 years was small in our study, the efficacy of fenfluramine in this age group across nearly all measures in our study supports the most recent international consensus for early, first‐line treatment with fenfluramine. ² The improvements in both seizure and global functioning support the benefit of early use of fenfluramine in DS across a range of subpopulations of patients. Non‐seizure outcomes, such as those assessed by CGI–I, are important factors in treatment choice for parents/caregivers of patients with DS and play a crucial role in assessment of quality of life. ⁴⁸ The frequency, severity, and unpredictability of seizures create psychological and emotional stress for patients and their caregivers. ⁴⁸ , ⁴⁹ , ⁵⁰ Decreasing seizure burden is one of the important factors in improving patient quality of life by increasing the number of seizure‐free days. ⁵¹ , ⁵²

5.1. Limitations

The limitations of this study include those inherent to post hoc analyses, as well as variable sample sizes within strata and short treatment duration (2–3 weeks of titration plus 12 weeks of maintenance), requiring cautious interpretation and additional long‐term studies. Due to the relatively low sample size, the study did not evaluate the effect of fenfluramine dose on other DS characteristics or synergies with concomitant medications. Analyses of larger populations may provide a better understanding of the effect of fenfluramine on different DS populations; however, due to small populations living with any single rare disease, such as DS, such studies may not be feasible. Patient age and number of previously attempted ASMs have the potential to be confounding factors; patients who had previously attempted ≥7 ASMs were on average older than patients who had previously attempted 1–3 or 4–6 ASMs. The number of attempted ASMs may be affected by the length of time patients had to attempt other ASMs prior to the trial. However, without further assessment, the effect of age and/or number of attempted ASMs on one another cannot be determined.

5.2. Future studies and analyses

Further analyses of the pivotal fenfluramine RCTs may provide additional guidance for clinical decision‐making in the use of adjunctive fenfluramine for patients with DS. The efficacy of fenfluramine could be further analyzed by stratifying patients by seizure frequency at baseline, which is a measure of seizure burden and other relevant comorbidities associated with DS. In the combined RCTs, most patients were prescribed 1–3 ASMs. Stratifying efficacy data by concomitant ASMs may increase benefit with adjunctive fenfluramine treatment. Finally, analyzing the RCT data by length of time before achieving optimal seizure control and improved global functioning could provide guidance for the duration to administer fenfluramine to determine whether the drug will be effective for a particular patient. Further, adults >18 years of age were not included in the fenfluramine DS RCTs. A previous analysis of patients with DS treated with fenfluramine in both the open‐label extension and a real‐world setting showed comparable responder rates of profound MCSF reduction (≥75% reduction) and of clinically meaningful improvement on the CGI–I in patients <6, 6–17, and ≥18 years old (maximum age, 46 years), suggesting that efficacy is retained at higher patient age. ²⁰ , ²⁵

6. CONCLUSIONS

Fenfluramine offers an effective, well‐tolerated treatment option in DS. This pooled analysis of patients with DS from RCT data confirms that many of the most common TEAEs associated with fenfluramine treatment resolved by the end of the study. Fenfluramine treatment was superior to placebo in reducing seizure frequency and improving global functioning regardless of patient age, number of previously attempted ASMs, and SCN1A pathogenic variant status, with greater efficacy seen in patients treated with the highest fenfluramine dose compared with lower doses. Overall, this pooled analysis further confirms the positive benefit/risk balance for fenfluramine in patients with DS. Larger sample sizes with additional (i.e., non‐post hoc) analyses are needed to support these findings.

AUTHOR CONTRIBUTIONS

All authors contributed to the conceptualization of the manuscript, were involved in the methodology of this analysis, critically revised the drafts, and approved the final version for publication. RN, JS, SA, HC, OD, AGN, RG, KGK, MSP, RSC, A‐SS, IES, NS, AS, JW, ECW, and LL contributed to the acquisition of data. PH analyzed the data.

FUNDING INFORMATION

This work was supported by UCB.

CONFLICT OF INTEREST STATEMENT

RN reports research funding from Biocodex, GW Pharma (now Jazz Pharmaceuticals), Neuraxpharma, and UCB. She received consultancy and/or lecture fees from Advicenne, Biogen, BioMarin, Eisai, GW Pharma (now Jazz Pharmaceuticals), Longboard, Novartis, Nutricia, Orion, Servier, Stoke, Takeda, and Zogenix (now a part of UCB). She served as investigator (last 5 years) for Eisai, Jazz Pharmaceuticals, Nutricia, Takeda, and UCB. JS reports research grants with Biopharm, Marinus, Stoke, and Zogenix (now a part of UCB); consultant/advisor for Asceneuron, Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharma (now Jazz Pharmaceuticals), Knopp Biosciences, Longboard Pharmaceuticals, and Neurocrine; stock options: Epygenix; travel support: Zogenix (now a part of UCB); and reviewer for the Epilepsy Study Consortium. SA is Deputy Editor for Epilepsia. He has received personal fees for lectures or advice from Angelini, Biocodex, Eisai, Encoded, GRIN Therapeutics, Jazz Pharmaceuticals, Longboard, Neuraxpharm, Nutricia, Orion, Proveca, Servier, Stoke, UCB, and Xenon. He has been an investigator for Eisai, Marinus, Proveca, Takeda, and UCB. HC reports research grants received from EPSRC, ERUK, the Great Ormond Street Hospital (GOSH) NIHR Biomedical Research Centre, GOSH Charity, GW Pharma (now Jazz Pharmaceuticals), Marinus, National Institute of Health Research (NIHR), Stoke Therapeutics, Ultragenyx, Vitaflo, the Waterloo Foundation, and Zogenix (now a part of UCB); served as consultant/advisor for Biocodex for which remuneration was made to the department outside of the submitted work, GW Pharma (now Jazz Pharmaceuticals), Longboard, and Zogenix (now a part of UCB); served as the Chair of the Medical Board for Dravet UK, Hope for Hypothalamic Hamartoma, and Matthews Friends; and served as the endowed chair at UCL Great Ormond Street Institute of Child Health. OD reports research funding from Eisai, Jazz Pharmaceuticals, and UCB; holds equity interest in Actio Biosciences, Ajna Biosciences, Blackrock Neurotech, California Cannabis Enterprises (CCE), Diatiro Health, Empatica, Regel Biosciences, Script Biosciences, Somnum Pharma, and Tevard Biosciences; and received consulting fees or equity options from Emotiv, Praxis, Spine Care, Tennex, UCB, and Ultragenyx. AGN served on speaker's bureaus, advisory boards, or committees for Angelini Pharma, Bial, Biocodex, Eisai, Esteve, GW Pharma (now Jazz Pharmaceuticals), Oils 4 Cure, Pharvaris, PTC Therapeutics, Rapport Therapeutics, Stoke, UCB, and Zogenix (now a part of UCB); and received research support from Biogen, Jazz Pharmaceuticals, PTC Therapeutics, and UCB. RG reports research grants from Zogenix (now a part of UCB) during conduct of the study; served as speaker/consultant for Zogenix (now a part of UCB) outside the submitted work; served as an investigator for studies with Angelini, Biocodex, Eisai, and UCB; and served as speaker and/or on advisory boards for Biocodex, BioMarin, GW Pharma (now a part of Jazz Pharmaceuticals), and Novartis, outside the submitted work. KGK reports disclosed research grants from Encoded Therapeutics, Stoke, and Zogenix (now a part of UCB); received consulting fees from Biocodex, BioMarin, and Epygenix; and received other support as a Data and Safety Monitoring Board member from Epygenix and Greenwich Pharmaceuticals. MSP reports research support from Encoded, Marinus, Stoke, Takeda, and Zogenix (now a part of UCB); and received honoraria (speakers' bureaus, advisory/consulting roles) from Biocodex, Jazz Pharmaceuticals, Neurelis, Stoke, and UCB. RSC reports honoraria and/or research funds from Biocodex, Jazz Pharmaceuticals, and Zogenix (now a part of UCB). A‐SS reports research support from Zogenix (now a part of UCB); and a consultant role with Brabant and Zogenix (now a part of UCB). IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Longboard Pharmaceuticals, Nutricia, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from Akumentis, Biocodex, BioMarin, Chiesi, Eisai, GlaxoSmithKline, Liva Nova, Nutricia, Praxis, Stoke Therapeutics, UCB, and Zuellig Pharma; has received funding for travel from Biocodex, BioMarin, Eisai, Encoded Therapeutics, GlaxoSmithKline, Longboard Pharmaceuticals, Stoke Therapeutics, and UCB; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, Epiminder Inc., Epygenix, ES‐Therapeutics, GW Pharma (now Jazz Pharmaceuticals), Longboard Pharmaceuticals, Marinus, Neurocrine Biosciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix (now a part of UCB), and Zynerba Pharmaceuticals; has consulted for Atheneum Partners, BioMarin, Biohaven Pharmaceuticals, Care Beyond Diagnosis, Encoded Therapeutics, Epilepsy Consortium, Ovid Therapeutics, Praxis, Stoke Therapeutics, UCB, and Zynerba Pharmaceuticals; is a Non‐Executive Director of Bellberry Ltd., and a Director of the Australian Academy of Health and Medical Sciences. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc. and licensed to various diagnostic companies; and has a patent molecular diagnostic/theragnostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012‐009). NS served on scientific advisory boards for Arvelle, BioMarin, GW Pharma (now Jazz Pharmaceuticals), Marinus, and Takeda; received speaker honoraria from Eisai, BioMarin, Livanova, and Sanofi; and served as an investigator for BioMarin, Marinus, Roche, and UCB. AS reports personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, Jazz Pharmaceuticals, Longboard, Neuraxpharm, Takeda, UCB, and UNEEG. JW served as a speaker or a member of a speakers bureau for Biocodex, LivaNova, Neurelis, SK Life Science Inc., and UCB; received grants for clinical research from Biohaven, GW Pharma (now Jazz Pharmaceuticals), LivaNova, Longboard, Neurelis, NeuroPace, NIH, Praxis, SK Life Science Inc., Stoke, UCB, and Zogenix (now a part of UCB). ECW reports consulting fees from Acadia, Amicus, Encoded Therapeutics, and Neurocrine, and receives income from Epilepsy.com for serving as Co‐Editor‐in‐Chief. LL received grants and is a consultant and/or speaker for Grin Therapeutics, GW Pharma, Lundbeck, and UCB. DM, PH, ML, and AL report employment and/or stock ownership in UCB. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

PATIENT CONSENT STATEMENT

All patients or their parents or legal representatives provided written informed consent before enrolling in the study.

CLINICAL TRIAL IDENTIFIERS

NCT02682927, NCT02826863, NCT02926898.

Supporting information

Figure S1. Efficacy of fenfluramine treatment at 0.7 and 0.2 mg/kg/day without concomitant STP and 0.4 mg/kg/day with concomitant STP in patients with DS stratified by age (<4 years; ≥4 years), measured by (A) percent change in MCSF, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348).

Figure S2. Efficacy of fenfluramine treatment at 0.7 and 0.2 mg/kg/day without concomitant STP and 0.4 mg/kg/day with concomitant STP in patients with DS stratified by number of previously attempted ASMs, measured by (A) percent change in MCSF, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348).

Figure S3. Efficacy of fenfluramine treatment 0.7 and 0.2 mg/kg/day without concomitant STP and 0.4 mg/kg/day with concomitant STP in patients with DS stratified by SCN1A status, measured by (A) percent change in MCSF, (B) longest convulsive seizure‐free interval, and (C) clinically meaningful improvement in global functioning as assessed by the CGI–I (N = 348).

Table S1. Estimated difference in MCSF change from baseline in patients with DS treated with fenfluramine versus placebo (N = 216).

Table S2. Safety and tolerability in patients treated with fenfluramine and placebo (N = 348).

EPI4-11-1692-s001.docx^{(255.7KB, docx)}

ACKNOWLEDGMENTS

This study was sponsored by UCB. The authors acknowledge Katerina Kumpan, PhD (UCB), for managing the development of the manuscript, and Mari Willeman, PhD, Danielle Ippolito, PhD, CMPP, MWC, Courtney Breuel, ELS, and Scott Bergfeld, PhD, of the Sensified Division of Woven Health Collective, LLC, for writing and editorial assistance, which was funded by UCB.

DATA AVAILABILITY STATEMENT

Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the United States and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient‐level data and redacted trial documents, which may include: analysis‐ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org, and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre‐specified time, typically 12 months, on a password–protected portal.

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23. Boyd B, Smith S, Gammaitoni A, Galer BS, Farfel GM. A phase I, randomized, open‐label, single‐dose, 3‐period crossover study to evaluate the drug‐drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects. Int J Clin Pharmacol Ther. 2019;57(1):11–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Gil‐Nagel A, Sullivan J, Ceulemans B, Wirrell E, Devinsky O, Nabbout R, et al. Treatment with fenfluramine in patients with Dravet syndrome has no long‐term effects on weight and growth. Epilepsy Behav. 2021;122:108212. [DOI] [PubMed] [Google Scholar]
25. Guerrini R, Specchio N, Aledo‐Serrano Á, Pringsheim M, Darra F, Mayer T, et al. An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real‐world practice setting: a report from the fenfluramine European early access program. Epilepsia Open. 2022;7(4):578–587. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, et al. Fenfluramine HCl (Fintepla). Epilepsia. 2020;61(11):2396–2404. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Guerrini R, Specchio N, Aledo‐Serrano A, Strzelczyk A, Pringsheim M, Mayer T, et al. Fenfluramine provides clinical benefit in adults and children with Dravet syndrome: real‐ world experience from the European early access program. Epilepsia. 2021;62(S3):291–292. [Google Scholar]
28. Li R, Serdula MK, Williamson DF, Bowman BA, Graham DJ, Green L. Dose‐effect of fenfluramine use on the severity of valvular heart disease among fen‐phen patients with valvulopathy. Int J Obes Relat Metab Disord. 1999;23(9):926–928. [DOI] [PubMed] [Google Scholar]
29. Knupp KG, Scheffer IE, Schoonjans AS, Sullivan J, Lagae L, Auvin S, et al. Final analysis from an open‐label extension study of fenfluramine for the treatment of seizures in Lennox‐Gastaut syndrome: long‐term impact on patients and caregivers. Epilepsy Behav. 2025;173:110753. [DOI] [PubMed] [Google Scholar]
30. Bass A, Morita D, Shepherd‐Smith J, Zhang‐Roper R, Gitelson A, Tselenti E, et al. Interim results of the US fenfluramine oral solution cardiovascular safety registry study [poster]. Presented at American Academy of Neurology (AAN) 2025 Annual Meeting, April 5–9, 2025, San Diego, CA (encore presentation from AES 2024). [Google Scholar]
31. Sullivan J, Benítez A, Roth J, Andrews JS, Shah D, Butcher E, et al. A systematic literature review on the global epidemiology of Dravet syndrome and Lennox‐Gastaut syndrome: prevalence, incidence, diagnosis, and mortality. Epilepsia. 2024;65(5):1240–1263. [DOI] [PubMed] [Google Scholar]
32. Donnan AM, Schneider AL, Russ‐Hall S, Churilov L, Scheffer IE. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology. 2023;100(16):e1712–e1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Brown TT, Jernigan TL. Brain development during the preschool years. Neuropsychol Rev. 2012;22(4):313–333. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Nabbout R, Chemaly N, Chipaux M, Barcia G, Bouis C, Dubouch C, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis. 2013;8:176. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Bishop KI, Isquith PK, Gioia GA, Knupp KG, Scheffer IE, Nabbout R, et al. Fenfluramine treatment is associated with improvement in everyday executive function in preschool‐aged children (<5 years) with Dravet syndrome. Epilepsy Behav. 2023;138:108994. [DOI] [PubMed] [Google Scholar]
36. Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long‐term extension study in children/young adults with Dravet syndrome. Epilepsy Behav. 2021;121(Pt A):108024. [DOI] [PubMed] [Google Scholar]
37. Gjerulfsen CE, Nikanorova M, Olofsson K, Johannessen Landmark C, Rubboli G, Møller RS. Fenfluramine treatment in pediatric patients with Dravet syndrome reduces seizure burden and overall healthcare costs: a retrospective and observational real‐world study. Epilepsia Open. 2024;9:1891–1900. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Villanueva V, González‐Alguacil E, Smeyers P, Hernández S, Soto‐Insuga V, Fernández‐Cabrera A, et al. Effectiveness and tolerability of fenfluramine in pediatric and adult patients with developmental and epileptic encephalopathies: a multicenter, retrospective, real‐world clinical‐practice study. Epilepsia. 2026;1–15. 10.1002/epi.70342. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Lagae L. Dravet syndrome. Curr Opin Neurol. 2021;34(2):213–218. [DOI] [PubMed] [Google Scholar]
40. Sourbron J, Smolders I, de Witte P, Lagae L. Pharmacological analysis of the anti‐epileptic mechanisms of fenfluramine in scn1a mutant zebrafish. Front Pharmacol. 2017;8:191. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B. Fenfluramine acts as a positive modulator of sigma‐1 receptors. Epilepsy Behav. 2020;105:106989. [DOI] [PubMed] [Google Scholar]
42. Shi X‐Y, Tomonoh Y, Wang W‐Z, Ishii A, Higurashi N, Kurahashi H, et al. Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes. Brain Dev. 2016;38(1):40–46. [DOI] [PubMed] [Google Scholar]
43. Knupp K, Scheffer I, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox‐Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–564. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Devinsky O, King L, Schwartz D, Conway E, Price D. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia. 2021;62(7):e98–e102. [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Specchio N, Marsh E, Devinsky O, Aledo‐Serrano Á, Battaglia DI, Rajaraman R, et al. Fenfluramine in CDKL5 deficiency disorder: primary efficacy and safety results from a phase 3, randomized, double‐blind, placebo‐controlled study; 2025. [cited 2025 Nov 24]. Available from: https://aesnet.org/abstractslisting/fenfluramine‐in‐cdkl5‐deficiency‐disorder‐primary‐efficacy‐and‐safety‐results‐from‐a‐phase‐3‐randomized‐double‐blind‐placebo‐controlled‐study [Google Scholar]
46. Aledo‐Serrano Á, Cabal‐Paz B, Gardella E, Gómez‐Porro P, Martínez‐Múgica O, Beltrán‐Corbellini A, et al. Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: a case series. Epilepsia Open. 2022;7(3):525–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Zhu Z, Bolt E, Newmaster K, Osei‐Bonsu W, Cohen S, Cuddapah VA, et al. SCN1B genetic variants: a review of the spectrum of clinical phenotypes and a report of early myoclonic encephalopathy. Children. 2022;9(10):1507. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Nabbout R, Auvin S, Chiron C, Thiele E, Cross H, Scheffer IE, et al. Perception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures. Dev Med Child Neurol. 2019;61(10):1229–1236. [DOI] [PubMed] [Google Scholar]
49. Jensen MP, Gammaitoni AR, Galer BS, Salem R, Wilkie D, Amtmann D. Fenfluramine treatment for Dravet syndrome: real‐world benefits on quality of life from the caregiver perspective. Epilepsy Res. 2022;185:106976. [DOI] [PubMed] [Google Scholar]
50. Berg AT, Kaiser K, Dixon‐Salazar T, Elliot A, McNamara N, Meskis MA, et al. Seizure burden in severe early‐life epilepsy: perspectives from parents. Epilepsia Open. 2019;4(2):293–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
51. Auvin S, Nortvedt C, Fuller DS, Sahebkar F. Seizure‐free days as a novel outcome in patients with Lennox‐Gastaut syndrome: post hoc analysis of patients receiving cannabidiol in two randomized controlled trials. Epilepsia. 2023;64(7):1812–1820. [DOI] [PubMed] [Google Scholar]
52. Sullivan J, Specchio N, Devinsky O, Auvin S, Perry MS, Strzelczyk A, et al. Fenfluramine significantly reduces day‐to‐day seizure burden by increasing number of seizure‐free days and time between seizures in patients with Dravet syndrome: a time‐to‐event analysis. Epilepsia. 2022;63(1):130–138. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Estimated difference in MCSF change from baseline in patients with DS treated with fenfluramine versus placebo (N = 216).

Table S2. Safety and tolerability in patients treated with fenfluramine and placebo (N = 348).

EPI4-11-1692-s001.docx^{(255.7KB, docx)}

Data Availability Statement

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[epi470340-bib-0036] 36. Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long‐term extension study in children/young adults with Dravet syndrome. Epilepsy Behav. 2021;121(Pt A):108024. [DOI] [PubMed] [Google Scholar]

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[epi470340-bib-0038] 38. Villanueva V, González‐Alguacil E, Smeyers P, Hernández S, Soto‐Insuga V, Fernández‐Cabrera A, et al. Effectiveness and tolerability of fenfluramine in pediatric and adult patients with developmental and epileptic encephalopathies: a multicenter, retrospective, real‐world clinical‐practice study. Epilepsia. 2026;1–15. 10.1002/epi.70342. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[epi470340-bib-0042] 42. Shi X‐Y, Tomonoh Y, Wang W‐Z, Ishii A, Higurashi N, Kurahashi H, et al. Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes. Brain Dev. 2016;38(1):40–46. [DOI] [PubMed] [Google Scholar]

[epi470340-bib-0043] 43. Knupp K, Scheffer I, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox‐Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–564. [DOI] [PMC free article] [PubMed] [Google Scholar]

[epi470340-bib-0044] 44. Devinsky O, King L, Schwartz D, Conway E, Price D. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia. 2021;62(7):e98–e102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[epi470340-bib-0045] 45. Specchio N, Marsh E, Devinsky O, Aledo‐Serrano Á, Battaglia DI, Rajaraman R, et al. Fenfluramine in CDKL5 deficiency disorder: primary efficacy and safety results from a phase 3, randomized, double‐blind, placebo‐controlled study; 2025. [cited 2025 Nov 24]. Available from: https://aesnet.org/abstractslisting/fenfluramine‐in‐cdkl5‐deficiency‐disorder‐primary‐efficacy‐and‐safety‐results‐from‐a‐phase‐3‐randomized‐double‐blind‐placebo‐controlled‐study [Google Scholar]

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[epi470340-bib-0049] 49. Jensen MP, Gammaitoni AR, Galer BS, Salem R, Wilkie D, Amtmann D. Fenfluramine treatment for Dravet syndrome: real‐world benefits on quality of life from the caregiver perspective. Epilepsy Res. 2022;185:106976. [DOI] [PubMed] [Google Scholar]

[epi470340-bib-0050] 50. Berg AT, Kaiser K, Dixon‐Salazar T, Elliot A, McNamara N, Meskis MA, et al. Seizure burden in severe early‐life epilepsy: perspectives from parents. Epilepsia Open. 2019;4(2):293–301. [DOI] [PMC free article] [PubMed] [Google Scholar]

[epi470340-bib-0051] 51. Auvin S, Nortvedt C, Fuller DS, Sahebkar F. Seizure‐free days as a novel outcome in patients with Lennox‐Gastaut syndrome: post hoc analysis of patients receiving cannabidiol in two randomized controlled trials. Epilepsia. 2023;64(7):1812–1820. [DOI] [PubMed] [Google Scholar]

[epi470340-bib-0052] 52. Sullivan J, Specchio N, Devinsky O, Auvin S, Perry MS, Strzelczyk A, et al. Fenfluramine significantly reduces day‐to‐day seizure burden by increasing number of seizure‐free days and time between seizures in patients with Dravet syndrome: a time‐to‐event analysis. Epilepsia. 2022;63(1):130–138. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Efficacy and safety of fenfluramine in Dravet syndrome: The impact of patient clinical characteristics

Rima Nabbout

Joseph Sullivan

Stéphane Auvin

J Helen Cross

Orrin Devinsky

Antonio Gil‐Nagel

Renzo Guerrini

Kelly G Knupp

M Scott Perry

Rocío Sánchez‐Carpintero

An‐Sofie Schoonjans

Ingrid E Scheffer

Nicola Specchio

Adam Strzelczyk

James Wheless

Elaine C Wirrell

Diego Morita

Patrick Healy

Mélanie Langlois

Amélie Lothe

Lieven Lagae

Abstract

Objective

Methods

Results

Significance

Plain Language Summary

Key points.

1. INTRODUCTION

2. AIM/OBJECTIVE

3. MATERIALS AND METHODS

3.1. Data

3.2. Study design, ethics, and oversight

3.3. Post hoc analyses endpoints

3.4. Statistics

4. RESULTS

4.1. Baseline characteristics

TABLE 1.

4.2. Efficacy

FIGURE 1.

FIGURE 2.

FIGURE 3.

4.3. Safety

TABLE 2.

5. DISCUSSION

5.1. Limitations

5.2. Future studies and analyses

6. CONCLUSIONS

AUTHOR CONTRIBUTIONS

FUNDING INFORMATION

CONFLICT OF INTEREST STATEMENT

PATIENT CONSENT STATEMENT

CLINICAL TRIAL IDENTIFIERS

Supporting information

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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