C-Cure Shows Positive Trends in Phase 3 Trial but Fails to Meet Primary Endpoints

Celyad has pioneered a stem cell treatment for the heart called C-Cure. C-Cure consists of bone marrow stem cells that are isolated from a bone marrow aspiration that are then treated with a proprietary concoction that drives the cells to become cardiac progenitor cells, After this treatment, the cells are administered to the patient by means of a catheter where they will hopefully regenerate dead heart muscle tissue, make new blood vessels to replace clogged and dead blood vessels, and also smooth muscle cells to regulate the diameter of the newly-formed blood vessels.

The first clinical trial for C-Cure was announced in the Journal of the American College of Cardiology in June 2013. At this time, Celyad reported in their published data that all the mesenchymal stem cells (MSCs) had been successfully primed with their cocktails and successfully delivered to each patient. The desired cell dose was achieved in 75% of patients in cell delivery without complications occurred in 100% of cases. Fortunately, there were incidents of increased cardiac or systemic toxicity induced by the therapy.

Patients also showed some improvements. For example, left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p = 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p = 0.001). Patients was received MSC therapy also improved their 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p = 0.01) and had a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. The initial trial examined 13 control patients who received standard care and 20 patients who received their own MSCs and followed them for 2 years.

The strategy surrounding C-Cure is based on preclinical experiments in laboratory mice in which animals that had suffered heart attacks were treated with human MSCs that had been isolated from volunteers and pretreated with a cocktail that consisted of transforming growth factor-beta1, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6. This cocktail apparently drove the cells to form a heart-like fate. Then the cocktail-treated MSCs were implanted into the hearts of the mice and in the words of the paper’s abstract, the cells “achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity.”. must say that I did not see definitive proof in this paper that the implanted cells actually formed new myocardium as opposed to inducing native cardiac stem cell population to form new myocardial cells.

This present trial is a Phase 3 clinical trial and it examined changes in patient mortality, morbidity, quality of life, six-minute walk test, and left ventricular structure and function at nine months after the treatment was given, The trial recruited 271 evaluable patients with chronic advanced symptomatic heart failure in 12 different countries in Europe and Israel. Like the trial before it, it was double blinded, placebo controlled.

First the good news: the procedure was well tolerated with no safety concerns.

The bad news was that a statistically-significant difference between the control group and treatment group was not observed 39 weeks after treatment. There is a silver lining to all this though: a positive trend was seen across all treatment groups. More interestingly, the primary endpoint was met (p=0.015) for a subset of the patients treated with their own MSCs. This subset represents 60% of the population of the CHART-1 study (baseline End Diastolic Volume (EDV) segmentation), which is pretty significant subset of the subject group. These patients showed less mortality and worsening of heart failure, better quality of life, an improved 6-minute walk test, end systolic volume and an improved ejection fraction.

On the strength of these data, Celyad thinks that this 60^ might represent the patient population for whom C-Cure is a viable treatment. What remains is to determine exactly who those patients are, the nature of their disease, and how much patients might be identified.

Dr. Christian Homsy, CEO of Celyad, commented: “For the first time in a randomized, double-blind, controlled, Phase III cell therapy study, a positive effect, consistent across all parameters tested, was observed for a substantial, clearly definable, group of heart failure patients.

CHART-1 has allowed us to better define the patient population that would benefit from C-Cure®. We are excited by the prospects for C-Cure® as a new potential treatment option for a highly relevant heart failure population. We are confident that the results will generate interest from potential partners that could accelerate the development and commercialization of C-Cure®.”

Prof. Jozef Bartunek, CHART-1 principal co-investigator, said: “This pioneering study has contributed greatly to our understanding of heart failure disease and the place of regenerative medicine in its management. The results seen for a large clinically relevant number of the patients are ground breaking. We look forward to completing the full analysis and making the data available to the medical community at ESC.

On behalf of the CHART 1 steering committee we wish to thank the patients and families who were enrolled in the study as well as all the physicians and medical teams that made this study possible.”

Prof. Gerasimos Filippatos, Immediate Past-President of the Heart Failure Association of the European Society of Cardiology, member of the CHART-1 dissemination committee, said, “The CHART-1 results have identified a well-defined group of patients with symptomatic heart failure despite optimal therapy. Those patients are a large subset of the heart failure population and present specific therapeutic challenges. The outcome of CHART-1 indicate those patients could benefit from this therapy”.

The Company will use their CHART-1 results as the foundation of their CHART-2 US trial, which will test the target patient group with C-CURE. Celyad is also in the process of seeking partnerships to accelerate further development and commercialization of C-Cure®.

Do C-CURE cells make new heart muscle cells?  Count me skeptical.,  Just because cells form something that looks like cardiac cells in culture is no indication that they form tried and true heart muscle cells.  This is especially true, since bone marrow-based cells lack the calcium handling machinery of heart muscle cells and until someone definitely shows that bone marrow cells can be transdiferentiated into cells that possess the calcium handling proteins of heart muscle cells, I will remain skeptical,

Having said that, this is a very interesting clinical trial despite the fact that it failed to meet its primary endpoints.  Further work might even make more of it.  Here’s to hoping.

Mayo Clinic Uses Reprogrammed Stem Cells to Heal the Heart

A Serbian heart patient named Miroslav Dlacic suffered from a heart attack, and this event thoroughly changed his life. His heart was so damaged that he was too tired to work in his garden or work at his leather-accessories workshop in the city of Belgrade. Like other heart attack suffers, Dlacic, at the age of 71, was sure that the rest of his life would be short, and spent without energy.

However, after prompting from the Serbian hospital where he was treated, he participated in a clinical trial at the Mayo Clinic trial that used stem cells to repair his damaged heart tissue, and the results completely changed his life for the better. Two years after his experimental treatment, Dlacic can walk without it wearing him out. “I am more active, more peppy,” he says. “I feel quite well.”

“It’s a paradigm shift,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine and senior investigator of the stem cell trial. “We are moving from traditional medicine, which addresses the symptoms of disease, to being legitimately able to cure disease.”

The treatment of heart patients has usually involved a series of medications that try to manage the decline a of weak heart. However, a collaboration between European and Mayo Clinic researchers have discovered a new way to repair a damaged heart that actually fixes the damaged tissue.

The procedure pioneered by the Mayo Clinic harvests stem cells from the patient’s bone marrow, and then cultures these cells in the laboratory so that they can become cardiac cells. These cultured cells are then injected into the patient’s heart so that they can regenerate healthy heart tissue.

According to Terzic, this Mayo Clinic study is the first successful demonstration in people of the feasibility and safety of transforming adult stem cells into heart cells.

This study could provide new life for millions of heart patients. According to the World Health Organization, cardiovascular disease is the leading cause of death worldwide. About 5.8 million people in the US alone have heart failure, and this number is growing, according to the National Institutes of Health.

Leukemia and lymphoma (cancers of the blood) have been successfully treated with stem cell transplants. However, using stem cells from another organ to treat the heart is a sizeable challenge.

“In leukemia and lymphoma, the transplanted bone marrow is repairing bone marrow,” Dr. Terzic says. “Here, we are asking something unique of the stem cells — to repair another organ. It’s an anatomical mismatch.”

The inspiration for this experiment can from an observation made in the early 2000s. When stem cells from 11 patients undergoing heart bypass surgery were examined and analyzed, cells from two of the patients had an unusually high expression of particular transcription factors. Transcription factors are proteins that control the flow of genetic information between cells, and these cells expressed transcription factors that are important in the formation of heart muscle cells. From a clinical perspective, these two patients did not appear any different from other patients, but their stem cells seemed to show unique capacity for heart repair.

“That gave us the idea to convert nonreparative stem cells to become reparative,” Dr. Terzic says.

Converting nonreparative stem cells into reparative stem cells that can successfully repair the heart requires a deep understanding of how precisely the human heart develops. This detailed, painstaking work was led by Atta Behfar, M.D., Ph.D., a cardiovascular researcher at Mayo Clinic in Rochester, Minn.

In collaboration with other members of the Terzic research team, Dr. Behfar identified hundreds of proteins involved in the process of heart development (cardiogenesis). This team then identified the proteins that are essential in driving a stem cell to become a cardiac cell.

By using computer models, they simulated the effects of eliminating specific proteins one by one from the process of heart development. That method yielded about 25 proteins, but the team was able to reduce this number down to 8 proteins that their data indicated were essential for heart development.

The research team was able to use these proteins to reprogram stem cells to become heart cells. The treated stem cells were dubbed cardiopoietic, or heart creative cells.

This team then used their cardiopoietic cells in a proof-of-principle study that was published in the Journal of the American College of Cardiology in 2010 and demonstrated in laboratory animal models with heart disease that the injection of cardiopoietic cells had improved heart function compared with animals injected with untreated stem cells.  This work was proclaimed as a “landmark work,” by the journal’s editorial writer, since this study demonstrated that it was indeed possible to reprogram stem cells to become cardiac cells.

ransformation: The cardiopoietic cells on the left react to the cardiac environment, cluster together with like cells and form tissue.
Transformation: The cardiopoietic cells on the left react to the cardiac environment, cluster together with like cells and form tissue.

However, the step between laboratory tests and clinical trials is a huge one.  The first hurdle is expanding stem cells in the laboratory so that there are enough cells for patient treatments.  To solve this problem, the Mayo Clinch team needed collaborators with expertise in expanding stem cells in the laboratory for clinical purposes.  To this end, they contacted Cardio3 Biosciences, a bioscience company in Mont-Saint-Guibert, Belgium.  Dr. Behfar went to Belgium and spent several months working with scientists at Cardio3.

“The interaction with Cardio3 was crucial to driving Mayo Clinic’s technology forward,” he says.

With these record of laboratory successes, Mayo Clinic applied to European regulatory agencies to conduct a clinical trial to test their cardiopoietic cells in human heart patients.  Why did they choose Europe as the setting for their first clinical trials?  Practically speaking, it is easier to acquire approval for clinical studies in Europe compared with the United States.  However, clinical trials will be held in the U.S. eventually, but Terzic has many previous collaborators at European medical centers who are ready to collaborate with him in this study.  Additionally, Cardio3 has a long history of coordinating trials in multiple countries.

The clinical trials involved 45 patients from Belgium, Switzerland and Serbia. All of the patients, including Miroslav Dlacic, experienced heart failure as a result of heart attacks.

Each of these patients were randomly assigned to a group that received cardiopoietic cells or to a control group that received standard care for heart failure.  This study examined the safety and feasibility of their procedure, but it should also lead to larger, multiple-site trials.

The results from this initial trial were significant. Stem cells from each patient in the cardiopoiesis group were successfully guided to become cardiac cells. The treated cells were injected into the heart wall of each of those patients without apparent complications.

“It’s critical that this new process of cardiopoiesis was achieved in 100 percent of cases, with a very good safety profile,” Dr. Terzic says. “We have demonstrated the feasibility and safety of this procedure.”

This initial clinical trial wasn’t designed to assess the procedure’s effectiveness, but the early indications are hopeful.  If you consider that a failing heart pumps less blood and eventually enlarge, then improvements six months after the cardiopoietic treatment are potentially indicative of increased heart regeneration.

In this study, when examined six months after stem cell therapy, every patient in the cardiopoiesis group had increased blood flow from the heart to the rest of the body, and showed decreased heart volume, all indicators of improved heart health.  Patients from the cardiopoietic group were also able to walk longer distances than they could before treatment — on average. By comparison, the 10 patients in the control group showed no change or even deterioration in these measures.

“This preliminary study was not designed to be definitive. But already at six months, there was a significant benefit for patients,” Dr. Terzic says.

Although such data is far from definitive, anecdotal evidence of improvement over the study’s two-year follow-up period came from one patient who was unable to summon sufficient breath to play his trumpet before the experimental treatment but now can do so, and from another who has resumed riding a bicycle.

“We are enabling the heart to regain its initial structure and function,” Dr. Terzic says, “and we will not stop here.”

The clinical trial findings were published in the Journal of the American College of Cardiology in 2013.

Meanwhile, research to improve the injection process and cell effectiveness is underway.

“We are working on novel delivery tools that dramatically increase the cardiopoiresis cells retained by the heart,” Dr. Behfar says. “We have technology and know-how about these stem cells that we couldn’t even have dreamed of 10 years ago when this work began.”

Multicenter, phase III clinical trials are being planned for larger groups in European centers, which will hopefully be followed by trials in the U.S.  Unfortunately, much more information is needed before this technique can be validated and approved for regular clinical use.

Mayo Clinic is uniquely positioned to pursue this complex therapy. In addition to its global reach, its Center for Regenerative Medicine is at the forefront of efforts to develop reparative solutions for a range of conditions besides heart disease.

“With the cardiopoiesis research, we have shown that regenerative medicine can really work,” Dr. Terzic says. “We are now actively working on regenerative medicine in the areas of diabetes, liver and lung disease, neurologic disorders, and orthopedic surgery.”

The interdisciplinary collaboration that provides the foundation for the Center for Regenerative Medicine epitomizes Mayo Clinic’s approach to research and treatment. So, too, does a commitment to using talent and technology to enhance patient care.

“The Mayo history of being an unbelievable medical and scientific center is the reason I am here,” Dr. Terzic says. “We have extremely creative people here as well as the environment that allows them to develop definitive solutions to problems.”

New Tool for Stem Cell Transplantation into the Heart

Researchers from the famed Mayo Clinic, in collaboration with scientists at a biopharmaceutical biotechnology company in Belgium have invented a specialized catheter for transplanting stem cells into a beating heart.

This new device contains a curved needle with graded openings along the shaft of the needle. The cells are released into the needle and out through the openings in the side of the needle shaft. This results in maximum retention of implanted stem cells to repair the heart.

“Although biotherapies are increasingly more sophisticated, the tools for delivering regenerative therapies demonstrate a limited capacity in achieving high cell retention in the heart,” said Atta Behfar, the lead author of this study and a cardiologist. “Retention of cells is, of course, crucial to an effective, practical therapy.”

Researchers from the Mayo Clinic Center for Regenerative Medicine in Rochester, MN and Cardio3 Biosciences in Mont-Saint-Guibert, Belgium, collaborated to develop the device. Development of this technology began by modeling the dynamic motions of the heart in a computer model. Once the Belgium group had refined this computer model, the model was tested in North America for safety and retention efficiency.

These experiments showed that the new, curved design of the catheter eliminates backflow and minimizes cell loss. The graded holes that go from small to large diameters decrease the pressures in the heart and this helps properly target the cells. This new design works well in healthy and damaged hearts.

Clinical trials are already testing this new catheter. In Europe, the CHART-1 clinical trial is presently underway, and this is the first phase 3 trial to examine the regeneration of heart muscle in heart attack patients.

These particular studies are the culmination of years of basic science research at Mayo Clinic and earlier clinical studies with Cardio3 BioSciences and Cardiovascular Centre in Aalst, Belgium, which were conducted between 2009 and 2010.  This study, the C-CURE or Cardiopoietic stem Cell therapy in heart failURE study examined 47 patients, (15 control and 32 experimental) who received injections of bone marrow-derived mesenchymal stem cells from their own bone marrow into their heart muscle.  Control patients only received standard care.  After six months, those patients who received the stem cell treatment showed an increase in heart function and the distance they could walk in six minutes.   No adverse effects were observed in the stem cell recipients.

This study established the efficacy of mesenchymal stem cell treatments in heart attack patients.  However, other animal and computer studies established the efficacy of this new catheter for injecting heart muscle with stem cells.  Hopefully, the results of the CHART-1 study will be available soon.

Postscript:  The CHART-2 clinical trial is also starting.  See this video about it.