Positive Results From Phase 2 Trial Of Mesoblast’s Adult Stem Cell Therapy

Mesoblast announced positive Phase 2 heart failure trial results of its off-the-shelf, adult stem cell product Revascor after all patients had completed a minimum follow-up of 12 months, and a mean follow-up of 22 months. The Phase 2 trial results were presented at the American Heart Association annual meeting in Orlando, Florida, by independent principal investigator Dr Emerson C. Perin, Director of Research in Cardiovascular Medicine and Medical Director, Stem Cell Center, Texas Heart Institute in Houston.

Mesenchymal Precursor Cells or MPCs are bone marrow stem cells that have none of the markers expressed by mature mesenchymal stem cells (MSCs), but they are the stem cells population that gives rise to mesenchymal stem cells. Therefore, they have the advantages of MSCs – such as they are not recognized by the immune system, but because they are not mature MSCs, they can differentiate into a far wider variety of cell types than mature MSCs.

MPC treatment in this trial pooled data from patients that received all different doses and these pooled data showed that patients who had received MPC treatments had a significant reduction in cardiac mortality. Furthermore, at the highest dose, the MPCs completely prevented heart failure hospitalization events. Mesoblast expects that these outcomes will be central to the primary endpoint of a Revascor Phase 3 trial for product regulatory approval by the United States Food and Drug Administration (FDA).

This phase II trial used a randomized, placebo-controlled 60-patient Phase 2 trial that compared the safety and efficacy of three doses of Revascor in addition to maximal approved therapies versus maximal therapies alone in patients with moderate-to-severe congestive heart failure (CHF) defined by New York Heart Association (NYHA) class II or III status and ejection fraction below 40%. The trial enrolled both ischemic and non-ischemic heart failure patients. Heart failure patients with this degree of severity are known to have a high cardiac mortality over a 12-24 month period despite being on maximal approved drug and device therapies.

Treatment with MPCs was well-tolerated. Over a 22-month mean follow-up period, only 1/45 (2%) patients who received a single injection of Revascor died of cardiac causes compared with 3/15 (20%) of the control group (p=0.02). In addition, MPC treatment significantly delayed the time to a first Major Adverse Cardiac Event, MACE, a composite of cardiac death, heart attack or revascularization procedures (p=0.036), and reduced the overall risk for MACE by 78% (p=0.011). Over a mean follow-up of 18 months, 0/15 patients who received the highest dose of MPC (150M) had been hospitalized for heart failure or had died. In contrast, 3/15 (20%) controls and 6/30 (20%) patients who received low (25M) or mid (75M) doses of MPC had either been hospitalized with heart failure or had died. This clinical improvement associated with the 150M dose was accompanied by evidence of cardiac remodeling (reduction in left ventricular end systolic volumes compared with controls at 6 months, p=0.015) and improved functional heart capacity (gain of 52.6 meters over 6 minutes’ walk compared with controls at 12 months, p=0.06).

After 12 months, 40% of all treated patients had reverted to class I NYHA status compared with 14% of all controls, and this effect remained when patients were matched for the presence of class II status at baseline. The group who received the 25M MPC dose showed a significant 8.9 point improvement in ejection fraction over controls at 3 months (p=0.008), with a sustained but less pronounced effect over 12 months. In contrast, the group who received 150M MPC did not show improved ejection fraction, suggesting that the positive effects of this dose on clinical outcomes, remodeling, and functional capacity may be due to other mechanisms such as anti-fibrosis.

Dr. Perin stated: “These clinical findings are the first using any cell therapy in heart failure patients to show a concordant positive effect on clinical outcomes, cardiac remodeling, and functional capacity, the three key parameters in congestive heart failure. Together, they indicate that a single 150 million dose of Revascor may significantly reduce both heart failure hospitalizations and death in these very sick patients who have such a poor prognosis despite maximal existing therapies. Based on their defined product characterization, batch to batch consistency, immediate availability, and lack of clinically relevant immunogenicity, MPCs appear to be an ideal cell type to provide a new level of patient care in congestive heart failure. We look forward to progressing the Revascor clinical program into Phase 3.”

Revascor is being jointly developed by Mesoblast and its strategic alliance partner, Teva Pharmaceutical Industries Ltd. Teva’s Corporate Vice President Global Branded Products, Kevin Buchi, said: “These independently-reviewed results serve to reinforce Teva’s commitment to its strategic investment in Mesoblast’s adult stem cell technology and to our continued support for the clinical development of Revascor.”

Mesoblast Chief Executive, Professor Silviu Itescu, said, “Together with our partners at Teva, we are deeply committed to bringing to market an effective cell therapy product to reduce recurrent hospitalization episodes and risk of death in patients with progressive heart failure. The exciting results presented at the American Heart Association meeting reinforce the strength of our technology and emphasize the need to maintain a rapid development path in order to make this product available for the many patients suffering with heart failure.”

New Heart Cells Increase By 30 Percent After Stem Cell Infusion

Chronic ischemic heart disease results from the partial blockage of blood flow to the heart. It can result in damage to the heart, and symptoms that consist of shooting pain in the chest called “angina.” Fortunately, there are good, animal models of chronic ischemic heart disease and better ways to treat this disease are being investigated. A presentation at the American Heart Association annual meeting has shown that new heart cells can be produced in animals that have been given infusions of stem cells derived from cardiac biopsies or “cardiospheres.”

Research conducted at the University at Buffalo School of Medicine and Biomedical Sciences has demonstrated that the hearts of animals with chronic ischemic heart disease experience a 30 percent increase in healthy heart muscle cells within one month after receiving cardiosphere-derived cells (or CDCs). This finding is contradicts conventional medical wisdom which avers that heart cells are terminally differentiated and thus, are unable to divide.

Ischemic heart disease results from narrowing of coronary arteries and prior heart attacks are the most common cause of heart failure. Other investigators have largely focused on regenerating muscle in scarred tissue, but this UB group has shown that cardiac repair can be achieved by infusing CDCs slowly into coronary arteries of the diseased as well as normal areas of the heart. Study co-author John M. Canty Jr., MD, the Albert and Elizabeth Rekate Professor of Medicine in the UB medical school and UB’s chief of cardiovascular medicine explains: “Whereas most research has focused upon irreversible damage and scarring following a heart attack, we have shown that a single CDC infusion is capable of improving heart function in areas of the heart that are viable but not functioning normally.” Particular areas of heart dysfunction even their there is no fibrotic scarring are common in patients with heart failure from coronary artery disease. Heart failure results from “remodeling” in response to a heart attack, in which the heart enlarges to adjust to the loss of heart muscle. Another consequence of a heart attack and periods of inadequate blood flow to the heart muscle is so-called hibernating myocardium, in which segments of heart muscle exhibit abnormalities of contractile function. Canty commented further: “The rationale for our approach is somewhat analogous to planting seeds in fertile soil versus trying to grow plants in sand.

Gen Suzuki, MD, research assistant professor of medicine in the UB medical school and lead author on the research, noted: “We have shown that cells derived from heart biopsies can be expanded outside of the body and slowly infused back into the coronary arteries of animals with chronic dysfunction from restricted blood flow or hibernating myocardium. The new cardiac muscle cells are small and function more normally than diseased large, hypertrophied myocytes.”

Canty also noted that infusing stem cell formulations directly into coronary arteries also delivers the cells throughout the heart and is much simpler than injecting cells directly into heart muscle which requires equipment that is not widely available.

The research currently is in a preclinical phase but the UB researchers expect that translation to determine effectiveness in patients could take place within two to three years or possibly even sooner.