Ataluren is an investigational therapy being developed by PTC Therapeutics for genetic disorders that may include Dravet syndrome. It is marketed under the brand name Translarna and approved in more than 30 countries to treat Duchenne muscular dystrophy.

How ataluren works

Dravet syndrome is a genetic disorder associated with seizures resistant to many common anti-epileptic treatments. Several mutations have been identified that cause Dravet syndrome, including nonsense mutations. A nonsense mutation is a change in a gene that adds a “stop” signal (stop codon) that gives the cell instructions to stop making a protein. This results in the production of a shorter and nonfunctional version of the protein, which the body later destroys.

Although Dravet is most commonly associated with mutations in the SCN1A gene, one type of mutation that can cause this syndrome is a nonsense mutation in the CDKL5 gene.

Ataluren is a read-through compound, meaning that it’s designed to make the cellular protein-making machinery ignore a premature stop codon — while still responding appropriately to normal stop codons.

Increasing protein levels should address the underlying cause of Dravet syndrome, not just its symptoms. This means that ataluren also may improve nonseizure complications associated with Dravet syndrome, including cognitive, behavioral, and motor problems.

Ataluren in trials for Dravet

A Phase 2 randomized, double-blind, and placebo-controlled clinical trial (NCT02758626) recruited seven children with Dravet syndrome and eight children with the related condition CDKL5 Deficiency Syndrome (CDD). 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.

During the trial, participants received either ataluren or a placebo for 12 weeks, followed by a four-week wash-out period and crossover to the opposite treatment for 12 more weeks. Patients who completed this double-blinded part of the trial were then enrolled in an extension study.

Participants were monitored for up to a year from the trial’s start to assess the treatment’s safety and potential effects. This included assessing changes in seizure frequency, cognitive behavior, and quality of life.

Researchers found that ataluren did not reduce the frequency of seizures in Dravet patients. Likewise, no significant improvements in other measurements of function and quality of life were found.

Out of the seven children with Dravet syndrome, six reported adverse events (such as increased number of seizures and influenza) during ataluren treatment in the double-blinded part of the trial. However, researchers considered these events were not related to the treatment.

Among the eight children with CDD, seven experienced adverse events, including decreased levels of valproic acid, which was also considered unrelated to the ataluren treatment.

Digestive issues (such as burping, flatulence, and vomiting) that were likely related to ataluren treatment led two children to drop out of the study.

This trial was limited by its comparatively small sample size and short duration. Larger and longer studies may be necessary to determine ataluren’s potential as a Dravet therapy.

According to researchers, another possible explanation for these negative results is that ataluren may need to enter the brain to exert its 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.

Last updated: Dec. 1, 2021


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