Exondys 51 may help protect DMD heart function: Study
Treatment slows heart function decline, lowering cardiomyopathy risk
Duchenne muscular dystrophy (DMD) treatment Exondys 51 (eteplirsen) may help protect the heart as well as muscles used for movement, a study found.
The treatment slowed heart function decline, raising the possibility it could lower the risk of cardiomyopathy, a serious condition that can lead to heart failure.
“This study is the first to demonstrate significant change in measured cardiac function with an innovative therapy that aims to increase dystrophin expression, suggesting clinically meaningful multi-year delays in reaching cardiomyopathy milestones,” the researchers wrote.
The study, “Association between exon-skipping therapy with eteplirsen and cardiac outcomes in Duchenne muscular dystrophy,” was published in the Journal of Neuromuscular Diseases.
DMD is caused when mutations in the DMD gene interfere with the function of dystrophin, a protein that helps protect muscles from strain. The loss of functional dystrophin results in muscle weakness and atrophy.
Exon skipping lets the cell do its job
Exondys 51 is an exon-skipping therapy. Genes are made of sections called exons, which act like building blocks for proteins. In DMD, mutations can disrupt these blocks and stop the body from making a working dystrophin. Exondys 51 helps the body skip over exon 51, so the cell can piece the protein together in a shorter but still functional form. About 13% of people with DMD have mutations that make them good candidates for Exondys 51.
Earlier studies have shown that people with DMD treated with Exondys 51 could maintain walking ability longer and had slower lung function decline than people who did not receive the treatment. Less is known about the effect of Exondys 51 on the muscles that allow the heart to pump blood throughout the body. Characteristic DMD symptoms can affect these cardiac muscles, leading to heart problems such as cardiomyopathy and, ultimately, heart failure.
The research team analyzed markers of heart function in people with genetic mutations predicted to respond to Exondys 51. Participants came from five clinical trials of Exondys 51 and three observational studies of DMD. Clinical trial participants formed the treatment group, while observational study participants formed the control group. There were 122 participants in each group, with both groups having a mean age of about 9.
Available data from the studies included left ventricular ejection fraction (LVEF), which the team used to estimate heart function. LVEF measures the percentage of blood the heart’s main pumping chamber pumps out with each heartbeat. “Declining LVEF is associated with long-term severe cardiovascular events, including hospitalisation for heart failure and cardiovascular disease–related mortality,” the researchers wrote.
LVEF values between 55% and 70% typically correspond to normal heart function, while values below 50% suggest reduced function. The team examined the risk of reaching this 50% threshold and earlier thresholds of 55% and 60% — which aren’t standard in clinical practice but could be precursors to lower function. Participants in both groups began with mean LVEF values of about 67%.
No participants in the treatment group reached the 50% threshold, while 22.1% of the control group fell below it. Fewer treated participants reached the 55% threshold (3.3% vs. 27.1%) and 60% threshold (10.7% vs. 49.2%).
Heart function stayed stronger for treated patients longer than for those who didn’t receive the drug. Those on Exondys 51 reached moderate declines in heart function (LVEF below 55% or 60%) several years later than similar patients who did not get the therapy — about eight extra years for 55% LVEF and nearly six extra years for 60% LVEF. A similar analysis wasn’t possible for the 50% threshold, because no treated participants reached this milestone.
The treated group also saw slower annual declines in LVEF. Average LVEF decreased by approximately 1.38 percentage points per year in controls, compared with 0.66 points in treated patients.
“Delaying the onset of LVEF thresholds could be clinically meaningful and help improve long-term outcomes of patients with DMD,” the researchers wrote.
The study’s findings suggest increases in dystrophin function in cardiac muscles with Exondys 51 treatment. However, the researchers couldn’t confirm this hypothesis without heart muscle samples to confirm protein levels. Slower LVEF decline could also result from other treatment effects.
“We cannot rule out a secondary cardiac benefit of dystrophin expression in respiratory skeletal musculature,” they wrote.
The study suggests “a positive association between [Exondys 51] and significantly lower risk of cardiac function decline,” the researchers concluded.
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