New US Phase IIa Trial and Phase III Trial in Kazakhstan Examine CardioCell’s itMSC Therapy to Treat Heart Attack Patients

The regenerative medicine company CardioCell LLC has announced two new clinical trials in two different countries that utilize its allogeneic stem-cell therapy to treat subjects with acute myocardial infarction (AMI), which is a problem that faces more than 1.26 million Americans annually. The United States-based trial is a Phase IIa AMI clinical trial that is designed to evaluate the clinical safety and efficacy of the CardioCell Ischemia-Tolerant Mesenchymal Stem Cells or itMSCs. The second clinical trial in collaboration with the Ministry of Health in Kazakhstan is a Phase III AMI clinical trial on the intravenous administration of CardioCell’s itMSCs. This clinical trial is proceeding on the strength of the efficacy and safety of itMSCs showed in previous Phase II clinical trials.

CardioCell’s itMSCs are exclusively licensed from CardioCell’s parent company Stemedica Cell Technologies Inc. Normally, when mesenchymal stem cells from fat, bone marrow, or some other tissue source are grown in the laboratory, the cells are provided with normal concentrations of oxygen. However, CardioCell itMSCs are grown under low oxygen or hypoxic conditions. Such growth conditions more closely mimic the environment in which these stem cells normally live in the body. By growing these MSCs under these low-oxygen conditions, the cells become tolerant to low-oxygen conditions (ischemia-tolerant), and if transplanted into other low-oxygen environments, they will flourish rather than die.

Another advantage of itMSCs for regenerative treatments over other types of MSCs is that itMSCs secrete higher levels of growth factors that induce the formation of new blood vessels and promote tissue healing. These clinical trials have been designed to help determine if CardioCell’s itMSC-based therapies stimulate a regenerative response in acute heart attack patients.

“CardioCell’s new Phase IIa AMI study is built on the excellent safety data reported in previous Phase I clinical trials using our unique, hypoxically grown stem cells,” says Dr. Sergey Sikora, Ph.D., CardioCell’s president and CEO. “We are also pleased to report that the Ministry of Health in Kazakhstan is proceeding with a Phase III CardioCell-therapy study following its Phase II study that was highly promising in terms of efficacy and safety. Our studies target AMI patients who have depressed left ventricular ejection fraction (LVEF), which makes them prone to developing extensive scarring and therefore to the development of chronic heart failure. CardioCell hopes our itMSC therapies will inhibit the development of extensive scarring and, thus, the occurrence of chronic heart failure in these patients.”

The United States-based Phase IIa clinical trial will take place at Emory University, Sanford Health and Mercy Gilbert Medical Center. The CardioCell Phase IIa AMI trial is a double-blinded, multicenter, randomized study designed to assess the safety, tolerability and preliminary clinical efficacy of a single, intravenous dose of allogeneic mesenchymal bone-marrow cells infused into subjects with ST segment-elevation myocardial infarction (STEMI).

“While stem-cell therapy for cardiovascular disease is nothing new, CardioCell is bringing to the field a new, unique type of stem-cell technology that has the possibility of being more effective than other AMI treatments,” says MedStar Heart Institute’s Director of Translational and Vascular Biology Research and CardioCell’s Scientific Advisory Board Chair Dr. Stephen Epstein. “Evidence exists demonstrating that MSCs grown under hypoxic conditions express higher levels of molecules associated with angiogenesis and healing processes. There is also evidence indicating they migrate with greater avidity to various cytokines and growth factors and, most importantly, home more robustly to ischemic tissue. Studies like those underway using CardioCell’s technology are designed to determine if we can evoke a more potent healing response that will reduce the extent of myocardial cell death occurring during AMI and thereby decrease the amount of scar tissue resulting from the infarct. A therapy that could achieve this would have a major beneficial impact in reducing the occurrence of chronic heart failure.”

Kazakhstan’s National Scientific Medical Center is conducting a Phase III AMI clinical trial using CardioCell’s itMSCs, which are sponsored by local licensee Altaco. This clinical trial is entitled, “Intravenous Administration of itMSCs for AMI Patients,” and is proceeding based on a completed Phase II efficacy and safety study. However, the results of this previous Phase II study are preliminary because the sample group was so small. Despite these limitations, the findings demonstrated statistically significant elevation (more than 12 percent over the control group) in the ejection fraction of the left ventricle of the heart in patients who had received itMSCs. Also, a significant reduction in inflammation was also observed, as ascertained by lower CRP (C-reactive protein) levels in the blood of treated patients in comparison to control groups. Thus, Dr. Daniyar Jumaniyazov, M.D., Ph.D., principal investigator in Kazakhstan clinical trials states: “In our clinical Phase II trial for patients with AMI, treatment using itMSCs improved global and local myocardial function and normalized systolic and diastolic left ventricular filling, as compared to the control group. We are encouraged by these results and look forward to confirming them in a Phase III study.”

CardioCell’s treatment is the first to apply itMSC therapies for cardiovascular indications like AMI, chronic heart failure and peripheral artery disease. Manufactured by CardioCell’s parent company Stemedica and approved for use in clinical trials, itMSCs are manufactured under Stemedica’s patented, continuous-low-oxygen conditions and proprietary media, which provide itMSCs’ unique benefits: increased potency, safety and scalability. itMSCs differ from competing MSCs in two key areas. itMSCs demonstrate increased migratory ability towards the place of injury, and they show increased secretion of growth and transcription factors (e.g., VEGF, FGF and HIF-1), as demonstrated in a peer-reviewed publication (Vertelov et al., 2013). This can potentially lead to improved regenerative abilities of itMSCs. In addition, itMSCs have significantly fewer HLA-DR receptors on the cell surface than normal MSCs, which might reduce the propensity to cause immune responses. As another benefit, itMSCs are highly scalable. A single donor specimen can currently yield about 1 million patient treatments, and this number is expected to grow to 10 million once full robotization of Stemedica’s facility is complete.

Treating the Heart with Mesenchymal Stem Cells: Timing and Dosage

Stephen Worthley from the Cardiovascular Investigation Unit at the Royal Adelaide Hospital in Adelaide, Australia and his colleagues have conducted a timely experiment with rodents that examines the effects of dosage and timing on stem cell treatments in the heart after a heart attack.

Mesenchymal stem cells from bone marrow and other sources have been used to treat the heart of laboratory animals and humans after a heart attack. The optimal timing for such a treatment remains uncertain despite a respectable amount of work on this topic. Early intervention (one week) seems offer the best hope for preserving cardiac function, but the heart at this stage is highly inflamed and cell survival is poor. If treatment is delayed (2-3 weeks after the heart attack), the prospects for cell survival are better, but the heart at this time is undergoing remodeling and scar formation. Therefore, stem cell therapy at this time seems unlikely to work. Human clinical trials seem to suggest that mesenchymal stem cell treatment 2-3 weeks after a heart attack does no good (see Traverse JH, et al JAMA 2011;306:2110-9). The efficacy of the delivering mesenchymal stem cells to the heart at these different times has also not been compared.

If that degree of uncertainty is not enough, dosage is also a mystery. Rodent studies have used doses of one million cells, but studies have not established a linear relationship between efficacy and dose, and higher dosages seem to plateau in effectiveness (see Dixon JA, et al Circulation 2009;120(11 Suppl):S220-9). High doses might even be deleterious.

So what is the best time to administer after a heart attack, and how much should be administered? These are not trivial questions. Therefore a systematic study is required and laboratory animals such as rodents are required.

In this study, five groups of rats were given heart attacks by ligation of the left anterior descending artery, and two groups of rats received bone marrow-derived mesenchymal stem cells immediately after the heart attack. The first group received a low dose (one million cells) and the second group received twice as many cells. The three other groups received their treatments one week after the heart attack. The third group received the low dose of stem cells received the low dose of cells (one million cells), and the fourth group received the higher dose (two million cells). The fifth group received no such cell treatment.

All mesenchymal stem cells were conditioned before injection by growing them under low oxygen conditions. Such pretreatments increase the viability of the stem cells in the heart.

The results were interesting to say the least. when assayed four weeks after the heart attacks, the hearts of the control animals showed a left ventricular function that tanked. The ejection fraction fell to 1/3rd the original ejection fraction (~60% to ~20%) and stayed there. The early high dose animals showed the lowest decrease in ejection fraction (-8%). The early low dose group showed a greater decrease in ejection fraction. Clearly dose made a difference in the early-treated animals with a higher dose working better than a lower dose.

In the later-treated animals, dose made little difference and the recovery was better than the early low dose animals. when ejection fraction alone was considered. However, when other measures were considered, the picture becomes much more complex. End diastolic and end systolic volumes were all least increased in the early high dose animals, but all four groups show significantly lower increases than the controls. The mass of the heart, however, was highest in the late high-dose animals as was ventricular wall thickness.

When the movement of the heart walls were considered, the early-treated animals showed the best repair of those territories of the heart near the site of injection, but the later-treated animals showed better repair at a distance from the site of injection. The same held for blood vessel density: higher density in the injected area in the early-treated animals, and higher blood vessel density in those areas further from the site of injection in the later-treated animals.

The size of the heart scar clearly favored the early injected animals, which the lower amount of scarring in the early high dose animals. Finally when migration of the mesenchymal stem cells throughout the heart was determined by using green fluorescent protein-labeled mesenchymal stem cells, the later injected mesenchymal stem cells were much more numerous at remote locations from the site of injection, and the early treated animals only had mesenchymal stem cells at the site of injection and close to it.

These results show that the later doses of mesenchymal stem cells improve the myocardium further from the site of the infarction and the early treatment improve the myocardium at the site of the infraction. Cell dosage is important in the early treatments favoring a higher dose, but not nearly as important in the later treatments, where, if anything, the data favors a lower dose of cells.

Mesenchymal stem cells affect the heart muscle by secreting growth factors and other molecules that aids and abets healing and decreases inflammation. However, research on these cells pretty clearly shows that they modulate their secretions under different environmental conditions (see for example, Thangarajah H et al Stem Cells 2009;27:266-74). Therefore, the cells almost certainly secrete different molecules under these conditions.

In order to confirm these results, similar experiments in larger animals are warranted, since the rodent heart is a relatively poor model for the human heart as it beats much faster than human hearts.

See James Richardson, et al Journal of Cardiac Failure 2013;19(5):342-53.