November 15, 2021
Ruchira Glaser, SVP and Therapeutic Area Head of Rare Diseases, Cardiovascular Disease and Autoimmune Diseases
Paul Burton, Chief Medical Officer
What if mRNA could treat life-threatening cardiovascular diseases such as heart failure?
Moderna and AstraZeneca are collaborating on a locally administered mRNA therapeutic (AZD8601) that encodes for vascular endothelial growth factor-A (VEGF-A) to promote recovery of cardiac function through tissue regeneration. Importantly, it is directly delivered into the myocardium—the muscular middle layer of the wall of the heart—to produce the VEGF-A protein in a specific place.
We’ve recently shared exciting new data from our Phase 2a study—known as EPICCURE—of this approach. Presented at the American Heart Association’s Scientific Session 2021 annual meeting, this Phase 2 study met the primary endpoint of safety and tolerability. This was a small study, but exploratory endpoints in the heart failure domain trended in favor of AZD8601, consistent with the hypothesis that local administered mRNA encoding VEGF may improve heart failure. These results support further investigation of AZD8601 in future larger cardiovascular studies.
It’s an important study for us at Moderna as well because it shows you can administer a mRNA therapeutic directly into the heart, and it forms a compelling bridge between preclinical and early stage human studies now to the clinical setting. This is another big step in the evolution of care of people with cardiovascular disease, using a remarkable new therapeutic platform.
The VEGF-A protein is a potent promoter of the growth of blood vessels, and this is the basis for the VEGF program. Coronary heart disease is caused by insufficient blood flow because of blockages in these main coronary arteries. In patients with myocardium infarction, combining therapeutic angiogenesis, the formation of new blood vessels, with revascularization could improve outcomes by promoting the growth of new blood vessels and regeneration of injured myocardium.
Moderna believes mRNA medicines have the potential to address cardiovascular disease related to ischemia, or restrictions of blood flow. Coronary disease is the primary cause of ischemic heart failure and affects the arteries that provide blood supply to the heart muscle. It's the most common type of heart disease, which is the leading cause of death in the United States, and millions of people around the world are living restricted lives due to heart failure.
Patients whose myocardium is active but have insufficient blood flow can have chronic impairment in their left ventricular function. So those who can't get complete revascularization through coronary artery bypass surgery could potentially improve their heart function if that new blood flow could be restored.
The current study builds on a stepwise approach to researching mRNA VEGF. First, animal studies demonstrated improvement in heart function and infarct size with treatment. Next, our Phase 1 safety study for this therapy was very promising. It primarily looked at safety, but also suggested blood vessel growth potential. This study was performed in men with type 2 diabetes, and they received injections of AZD8601 or placebo at randomized sites on their forearm. From a perspective of safety, the only treatment-related adverse events were mild injection site reactions.
Meanwhile, it showed average VEGF-A protein levels in mRNA-treated sites were significantly elevated after administration. That suggested that mRNA VEGF-A has the potential for regenerative blood vessel growth, and we can stimulate vessel regeneration to improve cardiovascular outcome.
This led to the Phase 2a study, which delivered the further encouraging positive data. We look forward to learning more about whether mRNA can offer a therapeutic approach to improving cardiac function for patients over time.
We believe that AZD8601 may provide a unique regenerative treatment option for patients with heart failure, diabetic wound healing, and other ischemic vascular diseases, for example people living with peripheral arterial disease. We are encouraged about the great progress so far and looking forward to the larger trials, aimed at demonstrating the potential for our mRNA technology in heart disease, an important disease afflicting millions of people worldwide.
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