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Fenfluramine for the Treatment of Dravet Syndrome and Lennox–Gastaut Syndrome

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Abstract

The last 50 years has seen the introduction of a great number of antiepileptic drugs, relieving the burden of seizures for many patients. However, some conditions remain a challenge for epileptologists, especially Dravet syndrome and Lennox–Gastaut syndrome, which are severe epileptic and developmental encephalopathies characterized by multiple seizure types and electroencephalographic abnormalities that are often unresponsive to combinations of antiepileptic drugs. The re-purposing of an old drug such as fenfluramine could provide an indispensable tool for clinicians, especially because only a few drugs have been tested in relatively homogeneous populations, like Dravet syndrome. It could also provide insights into precision medicine approaches to the treatment of epileptic syndromes. We searched for relevant papers within MEDLINE, EMBASE, and the Clinical Trial Database, considering publications through July 2020. Pre-clinical studies show a mechanism of action for fenfluramine that goes beyond its pro-serotoninergic activity and that is at the intersection of several pathways involved in excitation/inhibition balance. From the ongoing clinical trial data, it is evident that fenfluramine is proving to be a promising antiepileptic drug with very favorable pharmacokinetics and with a good overall safety profile when used at a lower dosage (0.2–0.7 mg/kg/day), despite its previously link to major cardiac adverse events that prompted its withdrawal from the market in 1997. Here, we review the experimental and clinical evidence of the efficacy of fenfluramine, including the latest results from ongoing clinical trials, and critically discuss the future potential of fenfluramine in terms of safety and precision medicine. Available data from the literature suggest a very good efficacy for both epileptic syndromes with a reduction in seizure burden and a longer seizure-free interval. We note the higher prevalence of evidence in patients with Dravet syndrome. Fenfluramine has been used in association with both first- and second-line medications, while its use in monotherapy still needs to be assessed.

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Authors and Affiliations

  1. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy

    Ganna Balagura & Pasquale Striano

  2. Pediatric Neurology and Muscular Diseases Unit, IRCCS ‘G. Gaslini’ Institute, Genoa, Italy

    Ganna Balagura & Pasquale Striano

  3. Department of Pediatrics, University of L’Aquila, Via Vetoio 1, 67100, Coppito, L’Aquila, Italy

    Marta Cacciatore, Eleonora A. Grasso & Alberto Verrotti

  4. Department of Pediatrics, University of Chieti, Chieti, Italy

    Marta Cacciatore & Eleonora A. Grasso

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  1. Ganna Balagura
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  2. Marta Cacciatore
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  3. Eleonora A. Grasso
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  4. Pasquale Striano
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  5. Alberto Verrotti
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Correspondence to Alberto Verrotti.

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No funding was used to assist in the preparation of this article.

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Ganna Balagura, Marta Cacciatore, Eleonora A. Grasso, Pasquale Striano, and Alberto Verrotti have no conflicts of interest that are directly relevant to the content of this article.

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All authors have collected the data from the literature, discussed these data, and have written this article. All authors listed equally contributed to this work.

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Balagura, G., Cacciatore, M., Grasso, E.A. et al. Fenfluramine for the Treatment of Dravet Syndrome and Lennox–Gastaut Syndrome. CNS Drugs 34, 1001–1007 (2020). https://doi.org/10.1007/s40263-020-00755-z

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  • DOI: https://doi.org/10.1007/s40263-020-00755-z

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