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.

Mesoblast MPCs Improve Heart Function in Patients with Congestive Heart Failure


Mesoblast Limited is a biotechology company with a singular interest in developing cell-based, regenerative therapies to treat some rather common, but severe ailments. Mesoblast has a proprietary cell system based on specialized cells known as mesenchymal lineage adult stem cells. These mesenchymal lineage adult stem cells (MLASCs) are being designed to serve as ‘off-the-shelf’ cell products for treating heart conditions, orthopedic disorders, immunologic/inflammatory disorders and cancer.

Mesoblast has recently released the results of a Phase 2 clinical trial that utilized their therapeutic product MPC-150-IM and tested it in patients with chronic congestive heart failure. The results of this study were published in the journal Circulation Research, a high-impact journal of the American Heart Association.

Patients who suffer from advanced heart failure have a poor long-term prognosis and they also have few therapeutic options. The pumping power of their hearts is weaker than normal, and the blood moves through the heart and body at a slower than normal rate. Consequently, fluid pressure in the heart increases and the chambers of the heart respond by stretching to hold more blood to pump through the body or by thickening and becoming stiff. This helps to keep the blood moving, but the heart muscle walls may eventually weaken and become unable to pump as efficiently. The kidneys respond by causing the body to retain fluid (water) and salt, and if the fluid builds up in the arms, legs, ankles, feet, lungs, or other organs, the body becomes congested, and congestive heart failure is the term used to describe the condition.

Mesoblast decided to test their proprietary Mesenchymal Precursor Cells (MPCs) to potentially induce heart muscle repair, stimulate new blood vessel growth, decrease cell death and reduce scar formation. Earlier studies established that MPCs are safe to give to heart patients. This new study examined the ability of these cells to improve heart function in patients with congestive heart failure.

In this study, 60-patients were subjected to a blinded, placebo-controlled trial. MPCs were injected directly into the heart muscle. One of the Primary Endpoints of this study was safety.

Patients included those with ischemic or non-ischemic heart failure (due to left ventricular systolic dysfunction), and in both groups, MPC injections were feasible and safe. There was a similar incidence of adverse events across all control and treatment groups. The patients who were treated with MPCs did not show any clinically significant immune response again the injected MPCs.

When it came to the main Secondary Efficacy Endpoints, patients who were treated with the highest MPC dose showed the greatest improvement in left ventricular remodeling compared to controls as evidenced by significant reductions in Left Ventricular End Systolic Volume (LVESV; p=0.015), and Left Ventricular End Diastolic Volume (LVEDV; p=0.02), 6 months after the treatment. LVESV and LVEDV increase as the heart gets weaker, but in these patients, the LVESV and LVEDV decreased. There were also parallel improvements in ejection fraction, but these improvements were not statistically significant. Patients treated with the highest dose of MPCs also showed the greatest improvement in functional exercise capacity compared to controls (p=0.062) 12 months after receiving their treatments.

Finally, in a post-hoc analysis of all patients 36 months after treatment, patients treated with MPCs showed significantly lower incidence of major adverse cardiac events when compared to the control group (0% vs 33% HF-MACE by Kaplan-Meier, p=0.026 by log-rank).

In their article, entitled ‘A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Non-Ischemic Heart Failure’, the authors concluded that high-dose MPC treatment seems to reduce heart failure-related major adverse cardiovascular events and provide beneficial effects on adverse left ventricular remodeling.

Lead author and investigator Dr Emerson C. Perin, Director, Research in Cardiovascular Medicine and Medical Director of the Stem Cell Center at the Texas Heart Institute, said: “The findings from this trial are very encouraging and suggest that a high-dose of Mesoblast’s allogeneic cell-based therapy may decrease major clinical events associated with progressive heart failure for at least three years, including repeated hospitalizations or death.

“These effects appear to be due to the ability of these cells to positively impact on adverse cardiac remodeling associated with chronic heart failure. If these results are confirmed in the ongoing Phase 3 trial currently recruiting at our institution and elsewhere, this new therapy has the potential to change the paradigm for the management of patients with advanced heart failure and a high risk of hospitalization and death,” Dr Perin added.

A randomized, placebo-controlled Phase 3 trial using Mesoblast’s high-dose MPC 150M is being conducted by Mesoblast’s development and its commercial partner, Teva Pharmaceutical Industries Ltd. Presently, this study is actively enrolling patients across multiple clinical sites in North America.

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.

Mesoblast Clinical Trial Shows Stem Cell Treatments Improve Glycemic Control in Type 2 Diabetics


Mesoblast Ltd has announced the results of their clinical trial in type 2 diabetics at the annual meeting of the American Diabetes Association.

Mesoblast has developed a proprietary adult stem cell they call a mesenchymal precursor cell or MPC, which they are attempting show can be used as an “off the shelf” medical product. MPCs seem to act like immature mesenchymal stem cells that can modulate the immune response and have greater flexibility.

In this trial, Mesoblast was banking of the ability of administered MPCs to suppress inflammation. Type 2 diabetes results from an insensitivity of tissues to secreted insulin. Consequently, cells do not receive enough of the insulin signal to take up sugar and make protein, glycogen, and fat. Another prominent feature of type 2 diabetes is chronic, low-level inflammation, which is largely due to the chronically high blood glucose concentrations that damages cells, blood vessels, nerves, and connective tissue. By treating type 2 diabetics with MPCs, Mesoblast was hoping to ascertain the ability of MPCs to quell chronic inflammation.

The trial was conducted across 18 sites in the US. 61 patients with type 2 diabetes received either one intravenous infusion of 0.3, 1.0 or 2.0 millions MPCs per kilogram body weight over 12 weeks. One group of patients were given a placebo. Patients had suffered from diabetes an average of 10 years and had poor control with the drug metformin (Glucophage), which is one of the most widely-used drugs for type 2 diabetes.

The results were largely positive:
When it comes to safety, there were no safety issues observed during the 12-week study period. The MPC cell infusions were well tolerated (with a maximal dose of 246 million cells). With regard to efficacy, there were dose-dependent improvement in glycemic control as evidenced by a decrease at all time points after week 1 in hemoglobin A1c (HbA1c) in MPC- treated patients compared with an increase in HbA1c in placebo treated subjects. HbA1c is a blood test that determines how much damage the high sugar levels are doing to the body. The test uses the blood protein hemoglobin to assess the damage that high glucose levels are doing to the rest of the body. In this clinical trial, significant reductions in HbA1c were observed after 8 weeks in the 2 M/kg MPC group compared to placebo (p<0.05) which was sustained through 12 weeks. The reduction in HbA1c was most pronounced in subjects with baseline HbA1c ≥ 8% (i.e. those patients with relatively poorer glucose control).

Fasting insulin levels were reduced in the 1 million and 2 million/kg groups compared to placebo (P<0.05), and reduced levels of inflammatory cytokines TNF-alpha and IL-6 (which are made at high levels during inflammation) were observed at 12 weeks in MPC groups compared to placebo.

The scientists and physicians involved in this clinical trial concluded there was sufficient evidence to support further evaluation into the use of MPCs in the treatment of type 2 diabetes and its complications. They also thought that there were grounds for exploring other therapeutic venues in which MPCs might prove useful.

Mesoblast Chief Executive Silviu Itescu said: “We are very pleased with these results which are consistent with an immunomodulatory mechanism by which our MPCs may have glucose-lowering effects in patients with type 2 diabetes. We are evaluating whether similar effects may be seen with the use of MPCs in the treatment of kidney disease and other complications of type 2 diabetes.”

While it is improbable in the extreme that this one-time treatment will improve the long-term clinical outcomes of diabetics, it is possible that repeated treatments will provide better Glycemic control for poorly controlled diabetics, and that these repeated treatments will produce long-term improvements in the health of these patients.

Stem Cell Injections Reduce Lower Back Pain


W. Jeremy Beckworth and his co-workers at Emory Orthopaedics and Spine Center, in collaboration with several other orthopedic care groups, have participated in a clinical trial that demonstrated that a single injection of stem cells into degenerative intervertebral discs significantly reduced lower back pain for at least 12 months according. Beckworth’s clinical trial consisted of 100-patients and was a phase II, international clinical trial.

Beckworth, assistant professor of Orthopaedics and Rehab Medicine, gave patient injections of a subset of mesenchymal stem cells isolated from bone marrow stem cells called mesenchymal precursor cells (MPCs) in order to attenuate pain in patients with lower back pain. On average, Beckworth and his colleagues discovered that stem cell injections led to a reduction in pain levels greater than 50 percent at 12 months. Additionally, patients who received stem cell injections felt less of a need for pain medications, showed an improvement in function, and less need for further surgical and non-surgical spine interventions. These results were compiled from patients with moderate to severe disc-related lower back pain.

“These are very exciting findings,” explains Beckworth. “The results provide significant hope for a condition that has been very tough to treat. Discogenic low back pain, a painful degenerative disc, is the most common cause of chronic low back pain.”

This phase II clinical trial builds on a previously reported preclinical study showed that highly purified MPCs were able to repair and restore disc structure. All the data from this trial showed that there were statistically significant improvements in patients who received stem cell injections compared to those in control groups who received no such injections.

“Currently there is no adequate treatment for discogenic low back pain,” says Beckworth. “Both conservative and surgical treatments fall short. These positive results pave the way for a phase III study that may be starting later this year.”

Adult Stem Cells Used for Spinal Disc Repair


The Australian regenerative medicine company Mesoblast Limited announced the results of their 12-month clinical trial that examined the use of their “off-the-shelf” product to treat patients with disc-related low back pain.

This phase 2 clinical trial enrolled 100 patients with chronic moderate to severe “discogenic low back pain” and tested the ability of “mesenchymal precursor cells” to shore up degenerating intervertebral discs.

Intervertebral discs

Intervertebral discs sit between each vertebra and act as shock absorbers. Each disc consist of an outer layer called the “annulus fibrosus.” The annulus fibrosus consists of several layers of fibrocartilage. The annulus fibrosus surrounds an inner layer called the nucleus pulposus, which contains loose fibers suspended in a mucoprotein gel with the consistency of jelly. This jelly-like center distributes pressure evenly across the disc. These discs absorb the impact of the body’s daily activities and keep the two vertebrae separated. The development of a prolapsed disc results when the jelly in the nucleus pulposus is forced out of the doughnut/disc, which may put pressure on the nerve located near the disc.

Intervertebral structure

More than six million people in the United States alone deal with chronic back pain that has persisted for at least three months, and 3.5 million people are affected by moderate or severe degenerative intervertebral disc disease.

In this clinical trial, Mesoblast Limited injected their mesenchymal precursor cells (MPCs) into the degenerating intervertebral discs of patients suffering from moderate to severe back pain. When compared with a control group, patients who received the MPC injections used less pain killers, went through fewer surgeries and non-surgical interventions, and had greater disc stability as ascertained by X-rays. MPC injections also were well tolerated and produced few side effects.

This phase 2 clinical trial extends earlier observations by Mesoblast Limited on laboratory animals. In preclinical trials, purified MPCs increased the quality of the jelly content of the nucleus pulposus and improved disc structure in sheep.

This present study enrolled 100 patients at 13 different sites across Australia and the United States with early disc degeneration and randomly assigned the subjects to one of four groups: 1) those who received saline injections; 2) those who received hyaluronic acid injections; 3) those who received low-dose MPCs in hyaluronic acid; and 4) those who received high-dose injections of MPCs in hyaluronic acid.

All patients received their injections in an outpatient procedure, and are being evaluated for safety and efficacy to evaluate long-term treatment effects.

At 12 months, the key findings were improvement in chronic low back pain, function, and disc stability. Also, no safety concerns emerged as a result of the treatment.

As this trial proceeds, more data should be forthcoming.