A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome.
Introduction: Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy. Most patients develop a drug-resistant epilepsy. Fenfluramine recently demonstrated to be a highly efficacious and safe treatment option for DS patients. Fenfluramine has been recently approved by the FDA and 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 however 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.
Keywords: SCN1A; 5-HT receptor; Dravet Syndrome; Epileptic encephalopathy; Fenfluramine; Pharmacokinetic interaction; SUDEP; Serotonin (5-HT); Sigma 1; Stiripentol.