mRNA technology may have potential to repair, regenerate cardiac tissue
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Tissue regeneration has been achieved in certain parts of the body, but not the heart. That could change if a novel therapeutic derived from messenger RNA succeeds.
AstraZeneca and Moderna are developing AZD8601, a locally administered messenger RNA (mRNA) therapy that encodes for vascular endothelial growth factor A. In preclinical and phase 1 studies, it demonstrated the potential for regenerative angiogenesis. It is now being evaluated for its ability to generate new cardiomyocytes and improve parameters in patients with conditions such as CVD and HF.
The phase 2 EPICCURE randomized trial, presented in November at the American Heart Association Scientific Sessions, was designed to evaluate the safety and tolerability of AZD8601. It included 11 patients with HF undergoing CABG, seven of whom were assigned an AZD8601 injection during their procedure and four of whom were assigned a placebo injection.
At 6 months, the agent was safe and well tolerated, and all seven patients in the AZD8601 group had N-terminal pro-B-type natriuretic peptide levels below the threshold for HF, compared with one of the four patients in the placebo group, whereas left ventricular ejection fraction and quality of life metrics also favored the AZD8601 group.
The trial was led by Regina Fritsche Danielson, PhD, senior vice president and global head of research and early development, cardiovascular, renal and metabolic diseases at AstraZeneca, and Ruchira Glaser, MD, MS, senior vice president and therapeutic area head of rare disease, autoimmune and cardiovascular at Moderna.
Healio spoke to Danielson and Glaser about the effect of mRNA on cardiac tissues, how AZD8601 works, the implications of the EPICCURE trial, the next steps in development and the trial being the first female-led study of an mRNA therapy.
Healio: How can mRNA be used to repair or regenerate cardiac tissues?
Danielson: VEGF is a well-known angiogenic factor; its biological method of action is primarily to induce the formation of new blood vessels from existing vessels. The secondary role, which has been discovered more recently, is that VEGF can also activate epicardial stem cells located on the surface of the heart, and induce differentiation of those cells into cardiomyocytes and endothelial cells. Those endothelial cells can also contribute to new vascularization, but also, potentially new cardiomyocytes could contribute to cardiac contractility. That is a hypothesis that still needs to be truly proven, but there are some animal data supporting that differentiation of stem cells. Right now, the most validated function of VEGF is the formation of new vessels.
Healio: What is the potential for AZD8601 in the cardiology space?
Danielson: We see this as a unique molecule to repair a damaged heart; primarily a heart that is ischemic and does not have enough oxygen supply. This would typically be in patients after MI, when the heart loses function of vessels and gets scar tissue, which leads to poor contraction. In those patients, we see a great opportunity to modify the disease in terms of making small vessels. There is also perhaps a use in patients with HF or severe CAD requiring bypass surgery; that is not always sufficient because some of these patients have microvascular disease that cannot be cleared by a bypass. We believe VEGF is a treatment that can be added during CABG to support the formation of new vessels and reperfusion of the whole cardiac muscle to improve function.
Healio: Why is VEGF-A production important for certain patients with CV conditions?
Glaser: In addition to what Dr. Danielson just said, patients who have areas of the heart that are still alive but the blood flow is not good enough are the ones who could benefit from something which promotes blood vessel growth by giving the mRNA. The mRNA is just a message to the cell to produce the protein that it would normally produce under certain conditions. Patients who have MI or have CAD with lots of blockages and have heart muscle dysfunction as a result are the ones who could benefit.
Healio: Why did you undertake the EPICCURE study and what did you hope to learn from it?
Danielson: EPICCURE was primarily a safety and tolerability study. It was a feasibility study to help us understand how we could deliver mRNA into the heart in the best way. The study included patients who had open-chest CABG surgery so we could access the heart easily and administer the mRNA in a safe way. We also had a placebo group, because we wanted to understand the effect of injecting the drug itself vs. injecting a saline solution. We learned that this was safe and tolerable. We also learned we could easily administer the injections in a short time period, so we did not have to have the patient on the surgical table for much longer. We also explored the efficacy of the therapy. The results give us the excitement to continue the program forward with larger studies. This was a small study, with seven patients who were treated with the mRNA and four who received placebo in the form of saline solution.
Healio: What were the most important findings from EPICCURE?
Danielson: We demonstrated that the therapy is safe and tolerable. This is a procedure that is easy to carry out in any cardiology lab via direct injection into the heart. We are exploring other means of access, such as using percutaneous catheters, as a way to bring the therapy to more patients in the future if this is successful. We were also able to look at biomarker data, echocardiography data, etc to see that the therapy mimicked what we saw in preclinical studies. It is always exciting when that happens, because it shows this could potentially make a big difference for these patients.
Glaser: We have to be careful not to overinterpret the results, but it is exciting to see that all the traditional markers of HF trended in the right direction. The biomarker levels returned to normal in all treated patients and only one placebo patient. The echocardiogram looked like heart muscle function improved more in the treated patients. The quality of life questionnaire also indicated more improvement in the treated patients. While this is a small study, those positive signs that confirm that we might be seeing what we hypothesized we would see encourage us to go to the next step.
Healio: What are the next steps in the development of AZD8601?
Danielson: We want to move into a bigger study so we can assess the efficacy of the drug and continue to assess the safety and tolerability. And to move into patients with severe HF who are not responding enough to standard of care and may need CABG, or in the future may not be eligible for CABG and have no option and may need a transplant. We are going to start with those severe patients and are working on designing a larger trial with enough patients to make firm conclusions on efficacy in terms of cardiac function, using echocardiography and traditional biomarkers used in HF trials such as NT-proBNP, and also assessing the well-being of patients using Kansas City Cardiomyopathy Questionnaires, because we believe that based on increasing oxygen supply to the heart, making the heart pump better will make patients feel better, which is important for these patients who have poor quality of life without treatment.
Healio: Are there any other plans to apply mRNA technology to CV problems?
Danielson: We are working on many research activities using different modalities, one of which is the mRNA modality. We have a lot of hope for mRNA when it comes to cardiac disease. This is based on the finding that the uptake of mRNA in cardiac tissue can produce the NT-proBNP level that we would like it to produce. This is unique to the heart tissue. We are looking at other factors that can produce cardiomyocyte proliferation such as transdifferentiation of fibroblasts into cardiomyocytes. We at AstraZeneca are primarily focusing on cardiac repair and regeneration at the moment.
Glaser: At Moderna, we are also looking at more systemic applications for CVD and HF. We believe this is the beginning for regenerative therapeutics, including in CVD, which remains an area of extremely high unmet need globally. We are pursuing additional pathways where mRNA may have an advantage over traditional therapies.
Healio: Much has been written about the underrepresentation of women in the cardiology field. What does having a female-led CV mRNA study for the first time mean for the field?
Glaser: That is an interesting question. My background is in interventional cardiology, which has a small number of women in it. It is a fabulous additional theme that a diverse group of talent including women can bring amazing, innovative science to the field. It takes an entire team to do that. Hopefully, the leadership piece inspires other women, including younger students, to pursue a STEM career, so we can attract the best talent to treat diseases, a rewarding and important mission.
Danielson: If we can be role models and inspire younger women to give them confidence that they can become key players in their field, whether it is cardiology or anywhere in science, that is great.
Healio: Is there anything else you would like to mention?
Danielson: We are excited about these efforts, even though it is too early to promise anything yet. We are figuring out how we can regenerate tissue in the future, capitalizing on new technologies like mRNA, gene therapy, cell therapy and others to make this a reality. Our line of study could make a big difference to patients and translate into real benefits.
Glaser: We are happy we had the opportunity to collaborate with AstraZeneca because this is an area where people wanted to make progress for a long time, but we just did not have the right tools. The promise that mRNA could do something transformative for HF, which is so prevalent and devastating, is inspiring. We are anxious to do more studies to see if the promise holds true.
Reference:
- Danielson RF, et al. Poster Presentations. Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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