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ABSTRACT
Introduction: Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy. Fenfluramine recently demonstrated to be a highly efficacious and safe treatment option for DS patients. Fenfluramine has been recently approved by the FDA and EMA and is marketed as Fintepla®.
Areas covered: DS and the need for additional anticonvulsive treatment options is discussed. The results of three placebo-controlled phase III studies (1 with and 2 without stiripentol) and 2 open label (extension) studies are reviewed. All studies demonstrate a consistent and impressive seizure reduction, confirming the results of two smaller investigator-initiated trials. The mechanism of action of fenfluramine is discussed. Finally, the place of fenfluramine in the future treatment of DS is outlined.
Expert opinion: Fenfluramine has a potent anticonvulsive effect in DS. Although not yet fully elucidated, the anticonvulsive mechanism of fenfluramine seems to be mainly serotonergic. Fenfluramine is generally well tolerated. A dose reduction is necessary in combination with stiripentol. Considering new competitors, efficacy seems lower for cannabidiol and is comparable with stiripentol. Preclinical studies indicate a disease specific action and possible disease modification in DS. The latter would support the use of fenfluramine above its anticonvulsive effect and needs to be further elaborated.
Article highlights
Fenfluramine significantly reduced seizure frequency in DS in three international randomized, placebo-controlled phase 3 studies (responder rate of 54% - 72.9%)
Fenfluramine was generally well tolerated without cardiovascular side effects
Combination with stiripentol requires a dose reduction and does not seem to be more effective
Mechanism of action is mainly serotonergic, with a 5-HT release and more specific stimulation of 5-HT1D and 5-HT2C receptors by fenfluramine and its active metabolite norfenfluramine.
DS mice models show an increased sensibility of serotonergic receptors (5-HT1A and 5-HT2A/2C) after seizure onset
Fenfluramine restores the arborization of GABAergic interneurons in DS zebrafish models which might suggest a disease modification, independent from its anticonvulsive effect.
Declaration of interest
B Ceulemans reports grants from Zogenix, and B Ceulemans and Antwerp University Hospital may benefit from a royalty arrangement that if Zogenix, Inc is successful in marketing ZX008. AS Schoonjans has received research support for Zogenix. The authors also declare participation in the international placebo-controlled trial with fenfluramine and the open label extension study, both of which were sponsored by Zogenix. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.