Stiripentol for the treatment of seizures associated with Dravet syndrome

ABSTRACT

Introduction: Stiripentol is an orphan drug approved for the treatment of seizures associated with Dravet syndrome (since 2007 in Europe). Therapeutic options recently grew in this rare and severe early-onset epilepsy with the approval of stiripentol and cannabidiol in 2018 in the US and the positive trials just completed with fenfluramine.

Areas covered: First, the short-term efficacy of stiripentol as adjunctive therapy to clobazam and valproate, which was discovered by serendipity thanks to a basket study and then confirmed in 1998 despite the small number of samples in phase III trials. Second, the further observational series worldwide, which showed sustained efficacy and satisfactory tolerability for up to 20 year exposure. Third, why it took more than 20 years for stiripentol be approved in a number of countries despite these extensive data: drug-drug interactions between stiripentol and comedication will be addressed, as well as the experimental and pharmacogenetic data which support the anticonvulsant effect of stiripentol per se.

Expert opinion: Considering current and future competitors (cannabidiol and fenfluramine), efficacy seems lower for cannabidiol and seizure freedom seems occasionally be obtained with fenfluramine. Additionally, stiripentol could be especially useful in two critical conditions of the disease, very young age (<2 years) and convulsive status epilepticus.

KEYWORDS:

• Cannabidiol
• childhood epilepsy
• clobazam
• CYP2C19
• Dravet syndrome
• epileptic encephalopathy
• fenfluramine
• pharmacokinetic interactions
• SCN1A
• stiripentol

Article highlights

• Stiripentol (in comedication with clobazam and valproate) proved to be efficient on the generalized (tonic)-clonic seizures associated with Dravet syndrome in children, with a high superiority to placebo.

• A dose adjustment of clobazam is required when it is used as comedication with stiripentol.

• Stiripentol is to be recommended for Dravet patients with refractory seizures as soon as the first year of life, when diagnosis is reasonably suspected.

• It is beneficial for epilepsy outcome to pursue stiripentol treatment from childhood though adulthood for as long as efficacy is observed.

• Safety is acceptable as compared with the only competitor today (cannabidiol), with the on-going competitor (fenfluramine) and with drugs/therapies competitively used despite their lack of approval for DS (topiramate, ketogenic diet, bromide).

This box summarizes key points contained in the article.

Declaration of interest

C Chiron has received honoraria as a consultant and/or speaker for Biocodex, Zogenix, UCB Pharma, Advicenne Pharma, BIAL and Orphelia. 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.

Additional information

Funding

This paper was not funded.