Diacomit (stiripentol) add-on therapy is more effective in children with Dravet syndrome who have pathogenic (disease-causing) SCN1A mutations than in those with variants of unknown significance and benign SCN1A mutations, a study has found.
The study, “Efficacy of Stiripentol in Dravet Syndrome with or without SCN1A Mutations,” were published in the Journal of Clinical Neurology.
Approximately 70 percent of all Dravet patients carry genetic mutations in the sodium channel alpha-1 subunit (SCN1A). Sodium channels are found mostly in the brain and their main function is to control the transport of sodium ions into cells, participating in the generation and transmission of electric signals between nerve cells.
When these channels malfunction in inhibitory neurons (those that prevent neuronal activity, also known as GABAergic neurons), brain activity becomes excessive, causing epilepsy.
Diacomit, developed by Biocodex, is an anticonvulsant medication that is able to bind and control the activity of GABAA receptors by mimicking GABA, the neurotransmitter that normally binds to these receptors.
In 2001, Diacomit was approved for the treatment of Dravet syndrome as an orphan drug by the European Medicines Agency (EMA). In 2018, the U.S. Food and Drug Administration (FDA) approved Diacomit as an add-on therapy for seizures associated with Dravet syndrome in patients 2 and older who are undergoing treatment with Onfi (clobazam), an anticonvulsant therapy marketed by Lundbeck.
Although most patients with Dravet syndrome carry mutations in the SCN1A gene, in approximately 20 percent of patients this is not the case, indicating that other genes, such as the GABAA receptor gamma 2 sububit (GABRG2) and the sodium channel beta subunit 1 (SCN1B), also may play a role in the disease.
Researchers investigated the effectiveness of Diacomit add-on therapy to Depacon (valproate) and Onfi in Dravet syndrome patients carrying known pathogenic (disease-causing) mutations in the SCN1A gene.
The study enrolled 32 children with a confirmed diagnosis of Dravet syndrome. All children were genetically sequenced and divided into two groups, based on the guidelines defined by the American College of Medical Genetics and Genomics (ACMG): a mutation group, which included 15 children with known or likely pathogenic mutations in SCN1A; and a non-mutation group, which included 17 children with benign or unknown mutations.
Diacomit treatment was introduced at a daily dose of 25 mg/kg and gradually increased over the course of four weeks to a target daily dose of 100 mg/kg. Treatment effectiveness, reflected by a significant reduction in the frequency of seizures, was compared between the mutation and non-mutation groups.
In children from the mutation group, Diacomit add-on therapy led to a reduction in seizure frequency of 72.53% compared to baseline, while in the non-mutation group there was a 50.58% reduction in seizure frequency compared to baseline.
Among children with pathogenic SCN1A mutations, Diacomit treatment was more effective in those carrying missense (single nucleotide mutation that alters protein composition) mutations (reduction of 87.50% in seizure frequency), compared to those carrying truncation (mutation that makes proteins shorter) mutations (reduction of 70.50% in seizure frequency).
However, Diacomit treatment was not favorable in children carrying mutations in regions between different domains, or between segments of the same domain of the SCN1A gene, or at splicing sites (regions of the gene that are prone to be removed or shifted to generate different proteins).
Despite “the relative smallness of the sample and it being designed as a retrospective review of clinical data, we were able to demonstrate that STP [stiripentol] has better efficacy in DS [Dravet syndrome] patients with definite SCN1A mutations than in DS patients with VOUS [variants of unknown significance] and benign SCN1A mutations,” researchers wrote.