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Dravet syndrome—toward an optimal and disease-specific treatment

Dravet-Syndrom – auf dem Weg zu einer optimalen und krankheitsspezifischen Behandlung

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Abstract

Dravet syndrome is a severe developmental and epileptic encephalopathy associated with SCN1A mutations. Drug-resistant epilepsy is common despite polypharmacy, but new therapeutic options will soon be available. Cannabidiol was added to the therapeutic armamentarium in 2019 after demonstrating a significant reduction in seizure frequency in two phase III studies. Results appear somewhat less convincing compared with stiripentol or fenfluramine, and there does not seem to be a disease-specific action (yet). In 2020, fenfluramine, previously used for the treatment of obesity, achieved FDA (Food and Drug Administration) and EMA (European Medicines Agency) approval for the treatment of convulsions in Dravet syndrome. Fenfluramine was found to be highly efficacious in two randomized, placebo-controlled phase III studies (one without stiripentol, one with stiripentol). It was generally well tolerated with a mild decrease in appetite as the most common side effect. To date, no cardiovascular side effects have been seen. Although not yet fully elucidated, the anticonvulsive mechanism seems to be mainly serotonergic. Preclinical studies indicate a disease-specific action and possible modification of the disease in Dravet syndrome. The latter would support the use of fenfluramine over and above its anticonvulsive effect and needs to be further elaborated. Clinical trials with other serotonergic products (clemizole and lorcaserin) have started. Current therapies unfortunately do not address the underlying genetic cause of Dravet syndrome and therefore do not have a major impact on patient cognition and other comorbidities. Therapies focusing on amplification of the Nav1.1 channel, based on the TANGO (targeted augmentation of nuclear gene output) technology (antisense oligonucleotides), will start soon (phase I and II studies). This technology seems promising and will probably be the start of an exciting period in the management of patients with a Dravet syndrome.

Zusammenfassung

Das Dravet-Syndrom stellt eine schwere entwicklungsbezogene und epileptische Enzephalopathie dar, die mit SCN1A-Mutationen einhergeht. Therapieresistente Epilepsie ist trotz Polypharmazie häufig, aber bald werden neue Therapieoptionen verfügbar sein. Im Jahr 2019 wurde das therapeutische Spektrum durch Cannabidiol erweitert, nachdem dafür in 2 Phase-III-Studien eine signifikant verminderte Anfallshäufigkeit nachgewiesen wurde. Die Ergebnisse sind jedoch etwas weniger überzeugend als für Stiripentol oder Fenfluramin, und bisher scheint es (noch) keine krankheitsspezifische Wirkung zu geben. Fenfluramin, das vorher für die Therapie der Adipositas eingesetzt worden war, erlangte 2020 die Zulassung durch die US-amerikanische Food and Drug Administration (FDA) für die Therapie von Krampfanfällen beim Dravet-Syndrom. In 2 randomisierten placebokontrollierten Phase-III-Studien (eine ohne Stiripentol, eine mit Stiripentol) erwies sich Fenfluramin als hochwirksam. Es wurde i. Allg. gut vertragen – mit geringer Appetitminderung als häufigster Nebenwirkung. Bisher wurden keine kardiovaskulären Nebenwirkungen beobachtet. Zwar ist der antikonvulsive Mechanismus noch nicht vollständig geklärt, aber er scheint hauptsächlich serotonerg zu sein. Präklinische Studien ergaben Hinweise auf eine krankheitsspezifische und eine mögliche krankheitsmodifizierende Wirkung beim Dravet-Syndrom. Letzteres würde die Anwendung von Fenfluramin über seine antikonvulsive Wirkung hinaus unterstützen und muss weiter untersucht werden. Klinische Studien mit anderen serotonergen Präparaten (Clemizol und Lorcaserin) haben begonnen. Die derzeitigen Therapien zielen leider nicht auf die zugrunde liegende genetische Ursache des Dravet-Syndroms ab und haben daher keinen wesentlichen Einfluss auf die Kognition der Patienten und auf andere Komorbiditäten. Therapien mit Fokus auf der Amplifikation des Nav1.1-Kanals auf Basis der TANGO-Technologie (Antisense-Oligonukleotide; „targeted augmentation of nuclear gene output“) werden bald starten (Phase-I- und -II-Studien). Diese Technologie erscheint vielversprechend und kennzeichnet wahrscheinlich den Beginn einer spannenden Phase der Therapie von Patienten mit einem Dravet-Syndrom.

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Authors and Affiliations

  1. Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, 2650, Edegem, Belgium

    A.-S. Schoonjans & B. Ceulemans

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  1. A.-S. Schoonjans
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  2. B. Ceulemans
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Correspondence to A.-S. Schoonjans.

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Conflict of interest

A.-S. Schoonjans received research support from Zogenix. B. Ceulemans reports grants from Zogenix, and BC and Antwerp University Hospital may benefit from a royalty arrangement that if Zogenix, Inc is successful in marketing ZX008.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

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Schoonjans, AS., Ceulemans, B. Dravet syndrome—toward an optimal and disease-specific treatment. Z. Epileptol. 34, 146–153 (2021). https://doi.org/10.1007/s10309-021-00399-z

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