A new drug appeared to cut seizures by up to 90% in children with a rare and devastating form of epilepsy called Dravet syndrome by tackling the underlying genetic mutation that causes the condition.
The findings are in an early stage that has not been designed to show efficacy, so it is not yet clear whether the results will hold up in a larger study. But if they do, it will be the first drug with the potential to alter the course of the disease, which comes with neurodevelopmental delays and a high risk of sudden death.
The results of the clinical trial, published on March 4 in New England Journal of Medicineshowed that the drug, called zorevunersen, can be safely given to children with Dravet syndrome and that it reduces the number of seizures and improves their overall quality of life.
The main purpose of this study was to test the drug’s safety and find an optimal dose, but Cross’ team also investigated whether the treatment led to seizure reduction, neurodevelopmental improvements and quality of life.
“We saw improvements in all of these domains, especially at higher doses,” he told LiveScience.
Addressing the root cause
In addition to frequent seizures, people with Dravet syndrome also have developmental delays, coordination problems, behavioral problems and other symptoms. And around half of the people who have Dravets will die suddenly and prematurely from the disease. These symptoms are all caused by a problem with interneurons, a type of cell that relays messages in the central nervous system. Antiepileptic drugs and implants may reduce the number of seizures somewhat, but do not improve developmental delays.
A gene called SCN1A controls the formation of sodium channels necessary for interneuron signaling. Most people have two copies of this gene, but in many people with Dravet syndrome, a genetic change prevents one of these copies from working properly. Zorevunersen solves this problem by increasing the amount of protein that the second, working copy of the SCN1A gene produces. The drug is a type of molecule called an antisense oligonucleotide, and it works by increasing messenger RNA which provide instructions for the working version of the SCN1A proteins.
To make sure the zorevunersen reaches the brain, it was given as a lumbar puncture — an injection into the spine that puts the drug into the cerebrospinal fluid, which bathes the brain. Although the treatment required a visit to the clinic for each dose, the study showed that the effect lasts for a few months.
A total of 81 children aged 2 to 18 took part in this early study at hospitals in the UK and US Cross and her colleagues were particularly interested in finding out which dose of zorevunersen would produce the best results, so they tried a few different doses. Some received a single treatment, while others received a series of lumbar punctures every few months. After this, 75 of the study participants continued to receive zorevunersen treatment every four months. The participants were followed for a total of three years.
After 20 months of treatment, children who received the highest dose at the start of the study had between 59% and 91% fewer seizures.
Several children in the study had mild side effects, such as headaches or vomiting from the lumbar puncture procedure, or increased levels of protein in the cerebral spinal fluid. But overall, the trial showed that the drug was safe for children.
The study has some limitations. It only studied a small group of children, and there was no placebo group.
In a larger study already underway, researchers are studying an additional 170 children to determine whether those receiving the treatment actually show more improvement than a control group.
“We’re targeting the actual underlying cause of the problem,” Cross said, “and so we’re not only reducing seizures, but improving other aspects of the disease.”
The trial is expected to be completed in October 2028, so even if the results are positive, it will be a few years before this treatment is available to all children with Dravet syndrome.
