Mesoblast Limited Scales Down Phase 3 Trial


Mesoblast Limited announced that the number of subjects treated in their ongoing Phase 3 clinical trial in chronic heart failure (CHF) that is testing their proprietary cell-based medicine MPC-150-IM will be substantially reduced.

CHF is characterized by an enlarged heart, coupled with insufficient blood supply to the organs and extremities of the body. Unfortunately, this is a progressing condition that tends to get worse with time. CHF is caused by many different factors such as chronic high blood pressure, faulty heart valves, infections, or congenital heart problems.

Mesoblast centers their company around the isolation and expansion of so-called mesenchymal precursor cells (MPCs) from bone marrow.  Mesenchymal stem cells are found in many different tissues and organs throughout our bodies.  They play vital roles in maintaining tissue health.  However, relatively speaking, mesenchymal stem cells are rare cells.  They are found around blood vessels and respond to signals associated with tissue damage.  They secrete mediators and growth factors that promote tissue repair and control the immune response to prevent it from going out of control.

Mesoblast uses an array of monoclonal antibodies to isolate primitive mesenchymal stem cells that are actually precursors to mesenchymal stem cells or mesenchymal precursor cells (MPCs).  These cells are then expanded in culture without being differentiated into any other cell type.

Mesoblasts, MPC-150-IM product consists of 150 million MPCs that are injected straight into the heart muscle (hence the moniker, “IM” for intramuscular).  Once in the heart muscle, the MPCs induce the formation of new blood vessels to feed the heart muscle, stimulate resident stem cell populations in the heart to repair the heart muscle, and quell inflammation that can cause scarring and decrease heart function (see Yanping Cheng, et al., Cell Transplantation 22(12): 2299-2309; Jaco H. Houtgraaf, Circulation Research. 2013; 113: 153-166). 

Initially, Mesoblast planned to test their product on 1,165 subjects, but have scaled that number back to approximately 600 patients.

Mesoblast’s development and commercial partner, Teva Pharmacueticals has communicated this reduction in the number of subjects to the US Food and Drug Administration (USFDA). “The reduction in the size of the Phase 3 trial may significantly shorten the time to trial completion,” said Mesoblast CEO Silviu Itescu.

The reduction in the number of patients was due to a proposed change in the primary endpoint of the trial. The revised primary endpoint is now a comparison of recurrent heart failure-related major adverse cardiovascular events (HF-MACE) between patients treated with Mesoblast’s MPC-150-IM cells and the control patients who were not treated with these cells.

Why the change in the primary endpoint? The reason lies in the success that MPC-150-IM cells had their Phase 2 clinical trial. In this trial, a single injection of MPC-150-IM cells successfully prevented HF-MACE over three years. This second, confirmatory study will be conducted in parallel with a patient population that has an identical clinical profile; approximately 600 of them using the same primary endpoint.

In the completed Phase 2 trial, patients treated with MPC-150-IM had no HF-MACE over 36 months of follow-up, compared with 11 HF-MACE in the control group. From this same clinical trial, of those patients who suffered from advanced heart failure (defined by baseline Left Ventricular Systolic Volume being greater than 100 milliliters), 71 percent of the controls (who received no cells) had at least on HF-MACE versus none of those who received a single injection of MPC-150-IM cells. As it turns out, this Phase 2 patient population closely resemble the patients being recruited in the Phase 3 trial.

“Patients with advanced heart failure continue to represent among the largest unmet medical needs, where existing therapies are inadequate and the economic burden is the greatest. The current Phase 3 trial targets this patient population, continues to recruit well across North America, and is now expanding to Europe,” said Itescu.

NIH and Mesoblast Partner for Clinical Trial in End-Stage Heart Failure


Mesoblast Limited has partnered with the National Heart, Lung, and Blood Institute (a branch of the National Institutes of Health or NIH) to conduct a large clinical trial that uses Mesoblast’s proprietary adult stem cell treatment in patients with advanced heart failure that requires an implantable Left Ventricular Assist Device (LVAD) to maintain proper circulatory support. The Canadian Institutes for Health Research and the National Institute of Neurological Disease and Stroke are also supporters of this trial.

Mesoblast is an Australian company whose Mesenchymal Precursor Cells (MPCs) have shown some promise in several pre-clinical studies and a few small clinical trials. The main objective in this study is to use the MPCs in heart failure patients and to examine the ability of MPCs to reduce the need for LVADs. Also, the study will ascertain is MPCs reduce long-term complications of LVAD transplantation, the most common of which is repeated hospitalizations.

This 120-patient study, to be conducted by the NIH-funded Cardiovascular Surgical Trials Network, will evaluate the effects of MPC transplantation into the hearts of patients with advanced heart failure. 150 million MPCs will be injected into the hearts of each patient and this product is being tested as an “off-the-shelf” medical product.

This new clinical trial builds upon previous successful but small trials in which 30 heart patients were treated with either 25 million MPCs or MPC culture medium during LVAD implantation. This was a double-blind, placebo-controlled study, and it showed that the MPC-treated patients tended to show higher rates of not needing their LVADs anymore 90 days after implantation and 12 months after implantation. This study was complicated by the fact that several patients died during the trial, which is not surprising because patients who received LVADs tend to be very sick. Nevertheless, these results were suggestive that the MPCs were effective. This study was published in the journal Circulation, which is an American Heart Association publication.

This second study will examine 150 patients who will receive a higher dose of the MPCs and a phase three study is on the board in collaboration with Teva Pharmaceutical Industries Ltd, which is Mesoblast’s development and commercial partner, which will examine 1,700 patients.

One of the first measurements examined in this study is how long after the treatment until the patient experiences their first adverse heart event. These are called HF-MACEs or heart failure-related major adverse cardiac events. If MPCs delay the onset of the patient’s first HF-MACE, then the cells might be making the heart healthier and stronger.

Congestive heart failure is a chronic condition characterized by an enlarger heart and insufficient blood flow to the organs and extremities of the body. According to the American Heart Association, congestive heart failure affected ~5.1 million people 20 years of age or older in the US in 2010, and there are 825,000 new cases diagnosed annually. 50% of heart failure patients die within five years of diagnosis.

30%-40% of heart failure patients suffer from moderate/severe class II/III heart failure with low ejection fractions and 10% have advanced heart failure (NYHA class IV heart failure). the only treatment options for end-stage or class IV heart failure are a heart transplant or mechanical support with a LVAD. Heart transplants cannot meet the large need due to donor availability, and permanent LVAD support is currently limited by clinical complications.

Taiwanese Group Identifies Stem Cell-Based Drug to Rejuvenate Aged Hearts


A southern Taiwan-based National Cheng Kung University research team led by Patrick Ching-Ho Hsieh has discovered that a molecule called prostaglandin E2 can regenerate aged hearts in rodents.

This discovery provides a useful new perspective on heart regeneration and presents an effective option for heart disease patients other than heart transplant.

According to Hsieh, congestive heart disease and other cardiovascular diseases are a leading cause of morbidity and mortality throughout the world. There are some six million patients with congestive heart failure in the US alone and some 400,000 in Taiwan. Despite intensive drug, surgical and other medical interventions, 80 percent of all heart patients die within 8 years of diagnosis.

Even though several experiments and clinical trials have established that heart regeneration can take place, the means by which the heart regenerates is still not completely clear, and there are also no drugs to stimulate heart regeneration by the resident stem cell population in the heart.

Now, after seven years of hard work, Hsieh’s team has identified the critical time period and the essential player that directs heart repair.

Hsieh and his colleagues used genetically engineered mice that Hsieh had developed as a postdoctoral research fellow at Harvard Medical School. By using this transgenic mouse strain, Hsieh and others showed that the self-repair process of the heart begins 7 days after injury and peaks at 10 days after injury.

The “director” of this self-repair process is the molecule PGE2. PGE2 regulates heart-specific stem cell activities.

PGE2

“More importantly, both young and old mice have significant improvements for cardiac remodeling if you treat both of them [with] PGE2,” said Hsieh.

Hsieh’s team also established that PGE2 decreases expression of a gene associated with aging, TGF-beta1. PGE2 also rejuvenates the micro-environment of the aged cells, according to Hsieh.

Stem Cell Homing Factor Used to Treat Heart Patients


In a clinical trial that is probably one of the first of its kind, researchers from the laboratory of Marc Penn at the Summa Cardiovascular Institute in Akron, Ohio, activated the stem cells of heart failure patients by means of gene therapy.

Penn and his colleagues delivered a gene that encodes stromal-cell derived factor-1 or SDF-1. SDF-1 is a member of the chemokine family of signaling proteins, and chemokines are proteins that direct cells to get up and move somewhere. Thus, for stem cells, SDF-1 acts as a kind of “homing” signal.

Stromal-cell derived factor
Stromal-cell derived factor

In this unique study, Penn and his collaborators introduced SDF-1 into the heart in order to summon stem cells to the site of injury and enhance the body’s stem cell-based repair process. In a typical stem cell-based study, researchers extract and expand the number of cells, then deliver them back to the subject, but in this study, no stem cells were extracted. Instead they were summoned to the site of injury by SDF-1.

Marc Penn, professor of medicine at Northeast Ohio Medical University in Rootstown, Ohio and the director of research at Summa Cardiovascular Institute said of his clinical trial: “We believe stem cells are always trying to repair tissue, but they don’t do it well — not because we lack stem cells but, rather, the signals that regulate our stem cells are impaired.”

Previous research by Penn and colleagues has shown SDF-1 activates and recruits the body’s stem cells to sites of injury and this increases healing. Under normal conditions, SDF-1 is made after an injury but its effects are short-lived. For example, SDF-1 is naturally expressed after a heart attack but this augmented expression of SDF-1 only lasts only a week.

In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients’ stem cells. The trial enrolled 17 NYHA Class III heart failure patients, with left ventricular ejection fractions less than 40% and an average time from heart attack of 7.3 years. Three escalating JVS-100 doses were evaluated: 5 mg (cohort 1), 15 mg (cohort 2) and 30 mg (cohort 3). The average age of the participants was 66 years old.

Researchers injected one of three doses of the SDF-1 gene (5mg, 15mg or 30mg) into the hearts of these patients, and monitored them for up to a year. Four months after treatment, they found:
1. Patients improved their average distance by 40 meters during a six-minute walking test.
2. Patients reported improved quality of life.
3. The heart’s pumping ability improved, particularly for those receiving the two highest doses of SDF-1 compared to the lowest dose.
4. No apparent side effects occurred with treatment.
According to Penn, “We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level,” Penn said. “They still had evidence of damage, but they functioned better and were feeling better.”

Penn’s study suggests that our stem cells have the potential to induce healing without having to be taken out of the body. Penn said, “Our study also shows gene therapy has the potential to help people heal their own hearts.”

At the start of the study, participants didn’t have significant reversible heart damage, but lacked blood flow in the areas bordering their damaged heart tissue. The study’s results — consistent with other animal and laboratory studies of SDF-1 — suggest that SDF-1 gene injections can increase blood flow around an area of damaged tissue, which has been deemed irreversible by other testing.

In further research, Penn and his team are comparing results from heart failure patients receiving SDF-1 with patients who are not receiving SDF-1. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years, Penn said.

Umbilical Cord Stem Cells Outperform Bone Marrow Stem Cell in Heart Repair


A study from the laboratory of Armand Keating at the University of Toronto and Princess Margaret Hospital has compared the ability of umbilical cord stem cells and bone marrow stem cells to repair the hearts of laboratory animals after a heart attack. The umbilical cord stem cells showed a clear superiority to bone marrow stem cells when it came to repairing heart muscle.

Keating used human umbilical cord perivascular cells (HUCPVCs) for his experiment, and these cells are widely regarded as a form of umbilical cord mesenchymal stem cell that surround the umbilical cord blood vessels.

Transplantation of cells from either bone marrow or umbilical cord into the heart soon after a heart attack improved the function and structure of the heart. However, functional measurements showed that the HUCPVCs were twice as effective as bone marrow stem cells at repairing the heart muscle.

Keating added: “We are hoping that this translates into fewer people developing complications of heart failure because their muscle function after a heart attack is better.”

In addition to further pre-clinical tests, Keating and his research team hope to initiate clinical trials with human patients within 12-18 months. Keating is also interested in testing the ability of umbilical cord stem cells to heal the hearts of those cancer patients who have experienced heart damage as a result of chemotherapy. In such patients, chemotherapy rids their bodies of cancer, but the cure is worse than the cancer, since the drugs also leave the patients with a severely damaged heart. Such stem cell transplantations could potentially strengthen the hearts of these patients, and give them a new lease on life. My own mother died from congestive heart failure as a result of an experimental arsenic treatment that killed her heart muscle. My mother suffered from chronic myelogenous disease and the arsenic was meant to kill off all the rogue cells in her bone marrow, but instead it killed her heart. If such a stem treatment were available then, my mother might still be with me.

There are over 250 clinical trials with mesenchymal stem cells to date to treat conditions ranging from Crohn’s disease to neurological conditions.  Also, a recent meta-analysis has established the safety of mesenchymal stem cell treatments for several different conditions (see Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, et al. (2012) Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials. PLoS ONE 7(10): e47559. doi:10.1371/journal.pone.0047559).