Ataluren Fails to Lower Seizure Frequency in Children in Small Trial

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Ataluren, in development by PTC Therapeutics as a possible treatment for Dravet syndrome, showed an acceptable safety profile in a small clinical trial.

That trial, conducted at a single site in New York City, involved 15 children with either Dravet syndrome due to mutations in the CDKL5 gene, or a related seizure disorder.

However, the investigational medication did not reduce the frequency of seizures among the Dravet patients nor significantly improve other measurements of function and quality of life.

The results were reported in the Annals of Clinical and Translational Neurology, in a study titled “Ataluren for drug‐resistant epilepsy in nonsense variant‐mediated Dravet syndrome and CDKL5 deficiency disorder.”

One type of mutation that can cause Dravet syndrome is a nonsense mutation in the CDKL5 gene. Normally, when a cell’s protein-making machinery “reads” a gene, there is a specific sequence — called a stop codon — that tells the machinery when it has reached the end of the gene. A nonsense mutation causes there to be a stop codon in the middle of the gene, resulting in the production of a truncated or shortened protein that doesn’t work correctly.

Ataluren is a read‐through compound, meaning that it’s designed to make the cellular protein-making machinery ignore the abnormal stop codon — while still responding appropriately to normal stop codons. The therapy, marketed as Translarna, is approved in more than 30 countries to treat Duchenne muscular dystrophy caused by nonsense mutations.

In the new study, researchers at NYU Langone Health, in New York, reported the results of a small clinical trial that tested ataluren in 15 children with treatment-resistant seizures caused by nonsense mutations in the CDKL5 gene.

“This is the first assessment of a read‐through compound in patients with primary brain disorders,” the researchers wrote.

The clinical trial (NCT02758626) was sponsored by NYU Langone Health in collaboration with PTC. It enrolled seven children with Dravet syndrome, and eight children with the related condition CDKL5 Deficiency Syndrome (CDD). All of the participants were between the ages of 2 and 12, and all had failed to achieve adequate control of seizures with at least two anti-seizure medications.

For the first 12 weeks (about three months) of the trial, participants were given either ataluren (10 mg/kg in morning and midday, and 20 mg/kg in the evening) or a placebo. Then, after a four-week washout period, participants originally given ataluren were given a placebo, and vice versa, for another 12 weeks. Participants who completed this double-blinded part of the trial were then invited to enroll in an ongoing extension study.

The trial’s main goal was to assess the safety of ataluren. Among the seven children with Dravet syndrome, six experienced adverse events while on the investigational treatment in the double-blinded part of the study. Three of the children experienced severe adverse events — such as increased seizure frequency and influenza — that were deemed unrelated to ataluren treatment.

Of the eight children with CDD, seven reported adverse events, including one SAE, specifically decreased levels of valproic acid, which was considered unrelated to the ataluren treatment. Two children withdrew from the study due to adverse events. One of the adverse events that led to study discontinuation — digestive issues that included burping, flatulence, vomiting — was deemed possibly related to ataluren treatment.

Reported safety findings from the open-label portion of the study were generally consistent with what was observed during the double-blind portion, and with the medication’s known safety profile.

“Ataluren had a good safety profile in these children with severe developmental delays and treatment‐resistant epilepsy,” the researchers wrote.

The team assessed the impact of treatment on seizure frequency, cognition, behavior, and quality of life. None of these assessments showed a significant effect from treatment.

“Ataluren did not reduce seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with DS [Dravet syndrome] and CDD due to nonsense variants,” the researchers concluded.

The trial was limited by its comparatively small sample size and short duration, according to the researchers, who speculated that larger, longer studies may be needed to detect a therapeutic effect.

Another potential explanation for the apparent lack of efficacy, the researchers said, is that ataluren would need to get into participants’ brains to have a therapeutic effect. While studies in mice and rats suggest that the medication can pass from the blood into the brain, it’s not clear that it can do so in people.

The researchers also speculated that other factors — ranging from the age at treatment initiation to the sensitivity of measurements use to assess outcomes — may have affected the results, highlighting a need to consider these factors carefully when planning future clinical trials.