Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth

Antonio Gil-Nagel; Joseph Sullivan; Berten Ceulemans; Elaine Wirrell; Orrin Devinsky; Rima Nabbout; Kelly G. Knupp; M. Scott Perry; Tilman Polster; Ronald Davis; Michael Lock; Robert M. Cortes; Arnold R. Gammaiton; Gail Farfel; Bradley S. Galer; Anupam Agarwal

doi:10.1016/j.yebeh.2021.108212

Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth

Antonio Gil-Nagel, Joseph Sullivan, Berten Ceulemans, Elaine Wirrell, Orrin Devinsky, Rima Nabbout, Kelly G. Knupp, M. Scott Perry, Tilman Polster, Ronald Davis, Michael Lock, Robert M. Cortes, Arnold R. Gammaiton, Gail Farfel, Bradley S. Galer, Anupam Agarwal

Neurology

Research output: Contribution to journal › Article › peer-review

Abstract

Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117–22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2–18 y/o; fenfluramine dose: 0.2–0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2–<0.3 mg/kg/day, 0.3–<0.5 mg/kg/day, and 0.5–0.7 mg/kg/day), averaged over time. Results: At the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of −0.056 for height and −0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were −0.025 for height and −0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.

Original language	English (US)
Article number	108212
Journal	Epilepsy and Behavior
Volume	122
DOIs	https://doi.org/10.1016/j.yebeh.2021.108212
State	Published - Sep 2021

Keywords

Developmental and epileptic encephalopathy
Dravet syndrome
Fenfluramine
Height
Weight
Z-score analysis

ASJC Scopus subject areas

Neurology
Clinical Neurology
Behavioral Neuroscience

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10.1016/j.yebeh.2021.108212

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Gil-Nagel, A., Sullivan, J., Ceulemans, B., Wirrell, E., Devinsky, O., Nabbout, R., Knupp, K. G., Scott Perry, M., Polster, T., Davis, R., Lock, M., Cortes, R. M., Gammaiton, A. R., Farfel, G., Galer, B. S., & Agarwal, A. (2021). Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth. Epilepsy and Behavior, 122, Article 108212. https://doi.org/10.1016/j.yebeh.2021.108212

Gil-Nagel, A, Sullivan, J, Ceulemans, B, Wirrell, E, Devinsky, O, Nabbout, R, Knupp, KG, Scott Perry, M, Polster, T, Davis, R, Lock, M, Cortes, RM, Gammaiton, AR, Farfel, G, Galer, BS & Agarwal, A 2021, 'Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth', Epilepsy and Behavior, vol. 122, 108212. https://doi.org/10.1016/j.yebeh.2021.108212

@article{1dfafd2a90a848cfb62a294f00d3ba92,

title = "Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth",

abstract = "Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117–22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2–18 y/o; fenfluramine dose: 0.2–0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2–<0.3 mg/kg/day, 0.3–<0.5 mg/kg/day, and 0.5–0.7 mg/kg/day), averaged over time. Results: At the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of −0.056 for height and −0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were −0.025 for height and −0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.",

keywords = "Developmental and epileptic encephalopathy, Dravet syndrome, Fenfluramine, Height, Weight, Z-score analysis",

author = "Antonio Gil-Nagel and Joseph Sullivan and Berten Ceulemans and Elaine Wirrell and Orrin Devinsky and Rima Nabbout and Knupp, {Kelly G.} and {Scott Perry}, M. and Tilman Polster and Ronald Davis and Michael Lock and Cortes, {Robert M.} and Gammaiton, {Arnold R.} and Gail Farfel and Galer, {Bradley S.} and Anupam Agarwal",

note = "Funding Information: The authors thank the patients and their families who participated in phase 3 studies. Medical writing and medical editing were provided by Danielle Ippolito, PhD, CMPP, MWC, and Dolores Matthews, MEd, of PharmaWrite, Inc. (Princeton, NJ), and were funded by Zogenix, Inc. Funding Information: This study was sponsored by Zogenix, Inc. (Emeryville, CA). Antonio Gil-Nagel discloses personal fees or research grants from Bial, Biocodex, Eisai, Esteve, GW Pharma, PTC Therapeutics, Stoke, UCB, and Zogenix. Joseph Sullivan received research grants from Stoke, Marinus, Zogenix, and Biopharm. He served as a consultant/advisor for the Dravet Syndrome Foundation, Epygenix, Encoded, and Neurocrine. He has stock options in Epygenix, and he served as a reviewer for the Epilepsy Study Consortium. He also received travel support from Zogenix. Berten Ceulemans discloses grants from Zogenix during the conduct of the study. He has a patent for ZX008 for treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. BC and the KU Leuven University/Antwerp University Hospital might benefit financially from a royalty arrangement that is related to this research if Zogenix is successful in marketing its product, fenfluramine. The terms of this arrangement have been reviewed and approved by the KU Leuven University/Antwerp University Hospital. Elaine Wirrell has served as a consultant for Biomarin and Encoded Therapeutics. Her current employer has received research support from Zogenix and GW Pharma. She has served as an advisor for the Dravet Syndrome Foundation. Orrin Devinsky received research grants from Zogenix during the conduct of this study, as well as from Novartis and PTC Therapeutics. He has equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings outside the submitted work. Rima Nabbout discloses research support from Zogenix. Kelly Knupp discloses personal fees from GW Pharma, Stoke Therapeutics, and Biomarin. She received grants from West Therapeutics outside the submitted work. M. Scott Perry received research support from Stoke, Encoded, and Zogenix, and received honoraria for speakers{\textquoteright} bureaus and advisory/consulting roles for Greenwich Biosciences, Zogenix, Neurelis, Encoded, Taysha, and Stoke. Tilman Polster reports personal fees from Zogenix during the conduct of the study, as well as from Desitin, Shire, Novartis, and UCB outside the submitted work. Ronald Davis reports speaker fees from LivaNova, Eisai, and Lundbeck. He served as an investigator for LivaNova, Eisai, Global Pharmaceuticals, Lundbeck, Pfizer, UCB, and Zogenix. Michael Lock, Anupam Agarwal, Robert Cortes, Arnold Gammaitoni, Gail Farfel, and Bradley Galer report employment and stock ownership with Zogenix during the conduct of the current work. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = sep,

doi = "10.1016/j.yebeh.2021.108212",

language = "English (US)",

volume = "122",

journal = "Epilepsy and Behavior",

issn = "1525-5050",

publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth

AU - Gil-Nagel, Antonio

AU - Sullivan, Joseph

AU - Ceulemans, Berten

AU - Wirrell, Elaine

AU - Devinsky, Orrin

AU - Nabbout, Rima

AU - Knupp, Kelly G.

AU - Scott Perry, M.

AU - Polster, Tilman

AU - Davis, Ronald

AU - Lock, Michael

AU - Cortes, Robert M.

AU - Gammaiton, Arnold R.

AU - Farfel, Gail

AU - Galer, Bradley S.

AU - Agarwal, Anupam

N1 - Funding Information: The authors thank the patients and their families who participated in phase 3 studies. Medical writing and medical editing were provided by Danielle Ippolito, PhD, CMPP, MWC, and Dolores Matthews, MEd, of PharmaWrite, Inc. (Princeton, NJ), and were funded by Zogenix, Inc. Funding Information: This study was sponsored by Zogenix, Inc. (Emeryville, CA). Antonio Gil-Nagel discloses personal fees or research grants from Bial, Biocodex, Eisai, Esteve, GW Pharma, PTC Therapeutics, Stoke, UCB, and Zogenix. Joseph Sullivan received research grants from Stoke, Marinus, Zogenix, and Biopharm. He served as a consultant/advisor for the Dravet Syndrome Foundation, Epygenix, Encoded, and Neurocrine. He has stock options in Epygenix, and he served as a reviewer for the Epilepsy Study Consortium. He also received travel support from Zogenix. Berten Ceulemans discloses grants from Zogenix during the conduct of the study. He has a patent for ZX008 for treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. BC and the KU Leuven University/Antwerp University Hospital might benefit financially from a royalty arrangement that is related to this research if Zogenix is successful in marketing its product, fenfluramine. The terms of this arrangement have been reviewed and approved by the KU Leuven University/Antwerp University Hospital. Elaine Wirrell has served as a consultant for Biomarin and Encoded Therapeutics. Her current employer has received research support from Zogenix and GW Pharma. She has served as an advisor for the Dravet Syndrome Foundation. Orrin Devinsky received research grants from Zogenix during the conduct of this study, as well as from Novartis and PTC Therapeutics. He has equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings outside the submitted work. Rima Nabbout discloses research support from Zogenix. Kelly Knupp discloses personal fees from GW Pharma, Stoke Therapeutics, and Biomarin. She received grants from West Therapeutics outside the submitted work. M. Scott Perry received research support from Stoke, Encoded, and Zogenix, and received honoraria for speakers’ bureaus and advisory/consulting roles for Greenwich Biosciences, Zogenix, Neurelis, Encoded, Taysha, and Stoke. Tilman Polster reports personal fees from Zogenix during the conduct of the study, as well as from Desitin, Shire, Novartis, and UCB outside the submitted work. Ronald Davis reports speaker fees from LivaNova, Eisai, and Lundbeck. He served as an investigator for LivaNova, Eisai, Global Pharmaceuticals, Lundbeck, Pfizer, UCB, and Zogenix. Michael Lock, Anupam Agarwal, Robert Cortes, Arnold Gammaitoni, Gail Farfel, and Bradley Galer report employment and stock ownership with Zogenix during the conduct of the current work. Publisher Copyright: © 2021 The Author(s)

PY - 2021/9

Y1 - 2021/9

N2 - Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117–22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2–18 y/o; fenfluramine dose: 0.2–0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2–<0.3 mg/kg/day, 0.3–<0.5 mg/kg/day, and 0.5–0.7 mg/kg/day), averaged over time. Results: At the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of −0.056 for height and −0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were −0.025 for height and −0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.

AB - Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117–22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2–18 y/o; fenfluramine dose: 0.2–0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2–<0.3 mg/kg/day, 0.3–<0.5 mg/kg/day, and 0.5–0.7 mg/kg/day), averaged over time. Results: At the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of −0.056 for height and −0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were −0.025 for height and −0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.

KW - Developmental and epileptic encephalopathy

KW - Dravet syndrome

KW - Fenfluramine

KW - Height

KW - Weight

KW - Z-score analysis

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Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth

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Keywords

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