DMD is caused by a lack of the muscle protein dystrophin due to mutations in the DMD gene. Some people with DMD have a specific mutation called a nonsense mutation. Simply put, this type of mutation causes the cellular protein-making machinery to stop too early when the gene is “read” to produce dystrophin.
Translarna allows cells to ignore this abnormal stop signal, thereby enabling the production of a full-length, functional dystrophin protein.
PTC sponsored a Phase 2 clinical trial (NCT03648827) to evaluate whether the investigational medication can increase dystrophin levels in muscle tissue of individuals with DMD caused by a nonsense mutation (nmDMD).
The study enrolled 20 boys, ages 2 to 7. They were given Translarna in an oral suspension — 10 mg/kg in the morning, the same dose at midday, and 20 mg/kg in the evening. Muscle biopsies were collected at the start and end of the study.
Two participants were not evaluable at the end of the study; one did not take the medications as directed, and another had biopsy samples of insufficient quality for analysis. As such, the study ultimately evaluated 18 participants.
In the study’s original design, muscle biopsies were to be taken at treatment start and after 40 weeks. Ten of the evaluable boys followed this schedule. However, due to delays associated with the COVID-19 pandemic, the remaining eight participants had their second biopsies collected between 62 and 70 weeks of treatment. Patient characteristics, including age and steroid use, were similar across both groups.
Dystrophin levels were measured using two validated methods: electrochemiluminescence (ECL) and immunohistochemistry (IHC).
“These methods were selected to ensure that we can reliably measure full-length dystrophin in a quantifiable way … Both assays went through extensive validation and [U.S. Food and Drug Administration, FDA] review, and both are sensitive at low levels of dystrophin” Peltz said.
In the evaluable participants, mean dystrophin levels measured with IHC increased significantly, by 7% relative to the start of the trial. Dystrophin levels as measured by ECL also increased, but the difference was not statistically significant.
“Also, over 80% of evaluable subjects demonstrated increase in dystrophin expression, signifying a consistent effect,” Peltz said.
Notably, the increase in dystrophin levels was generally higher among individuals who had been treated longer (for 62-70 weeks instead of 40).
“These results suggest that longer duration of treatment resulted in greater biological effect,” said Peltz, adding that this is consistent with data from other studies.
Also notably, there were no differences in dystrophin level increases based on dystrophin levels at the start of the study, or among individuals with different specific mutations.
Treatment with Translarna also reduced levels of creatine kinase, a marker of muscle damage. Measurements of physical function — such as time to run/walk 10 meters (about 11 yards) and ability to climb up and down stairs — also generally improved.
Peltz said the findings from this study add to a body of research from other clinical trials, as well as real-world data, that demonstrates the effectiveness of Translarna.
He also highlighted findings from STRIDE (NCT02369731), an ongoing observational study that is recruiting across multiple care centers in Europe and Israel. This registry aims to follow more than 250 patients for a minimum of five years.
Findings from STRIDE indicated that Translarna could delay loss of ambulation significantly — by about 3.5 years — in people with nmDMD. Results also showed that the treatment could prevent the loss of lung function.
Overall, the findings from the new study add “to the totality of Translarna data which includes demonstration of increased full-length dystrophin production, clinical benefit across multiple endpoints [goals] in several placebo-controlled trials, and real-world evidence of long-term clinical benefit on key aspects of disease progression,” Peltz wrote in a letter to the Duchenne community.
PTC is currently running a Phase 3 clinical trial (NCT03179631) to evaluate the long-term effects of Translarna in DMD patients, ages 5 and older, who are able to walk. Results of this trial are anticipated in July to September 2022.
According to Peltz, PTC is planning to discuss the whole Translarna program results with the FDA to determine whether an accelerated path toward approval is possible.
The FDA rejected an application seeking approval of Translarna in 2017, pointing out that more research was needed.
In the European Union, Translarna is approved for some nmDMD patients ages 2 and up who can walk. A label extension has been recommended to expand the approval to individuals who cannot walk.
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