Dravet syndrome—toward an optimal and disease-specific treatment

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 Na_v1.1 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.