Enrollment Completed in Phase 2 ALLSTAR Cardiac Clinical Trial

Capricor Therapeutics Inc. has announced the completion of patient enrollment in their Phase 2 ALLSTAR clinical trial.  ALLSTAR stands for ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration, and this trial will test Capricor’s CAP-1002 product in patients suffering from cardiac dysfunction following a heart attack.

CAP-1002 cells are cardiosphere derived cells (CDCs) that were isolated from donors.  This investigational therapy is an off-the-shelf “ready to use” cardiac cell therapy that comes from donor heart tissue.  CAP-1002 cells are made to be directly infused into a patient’s coronary artery during a catheterization procedure.

These CDCs were tested in the CADUCEUS clinical trial, in which they were shown to decrease scar size and increase viable heart tissue when implanted into the hearts of heart attack patients.  One-year follow-up examinations of these confirmed the earlier results.

ALLSTAR will study a population similar to the one in the CADUCEUS study (patients who had experienced a heart attack 30-90 days earlier), except that ALLSTAR will treat patients 91-365 days after suffering a heart attack.  The extension of the patient pool was to see if the indication window for CAD-1002 could be extended.

The Capricor CEO Linda Marbàn said, “With the last patient in ALLSTAR having been dosed on September 30, we expect to report top-line 12-month primary efficacy outcome results in the fourth quarter of 2017.”

ALLSTAR is being sponsored by Capricor and is led by Drs. Timothy Henry and Rajendra Makkar of the Cedars-Sinai Heart Institute.  The trial is being conducted at approximately 25-40 sites across the U.S.

The Phase I portion of the trial was funded in part by the National Institutes of Health and completed enrollment in December 2013, and the Phase II portion of the trial is supported in large part by the California Institute for Regenerative Medicine (CIRM).

Cardiosphere-Derived Injections Improve Heart Function in Children with Hypoplastic Left Heart Syndrome

Hypoplastic Left Heart Syndrome or HLHS accounts for 2 to 3 percent of all congenital heart disease. It shows a prevalence rate of two to three cases per 10,000 live births in the United States. HLHS is the most common form of functional single ventricle heart disease. The National Inpatient Sample database has estimated that there were an estimated 16,781 cases of HLHS among neonates born between 1988 and 2005 in the United States. More males have HLHS than females with the male to female ratio being about 1.5:1. Despite its low incidence relative to other congenital cardiac disorders, HLHS, if left untreated, is responsible for 25 to 40 percent of all neonatal cardiac deaths.

In HLHS patients, the left ventricle (the main pumping chamber of the heart), aorta, and related components are underdeveloped.

Children born with HLHS typically require surgery within a few days of birth and additional long-term treatment is required to address issues associated with right ventricular-dependent circulation.

Results from a clinical trial conducted by researchers at Okayama University and Okayama University Hospital show that children who suffer from HLHS seem to benefit from injections of cardiosphere-derived cells (CDCs).

Apparently in children, cardiac progenitor cells that can differentiate into several different heart-specific cell types are more abundant and self-renewing in children than adults.

The research group, led by Hidemasa Oh, monitored the heart function of seven patients who had received injections of cells and a control group of seven patient who had not received any such injections. They concluded that, “Our prospective controlled study, the first pediatric phase I clinical trial of stem cell therapy for heart disease to our knowledge, suggests that intracoronary infusion of autologous cardiac progenitor cells is a feasible and safe approach to treat children with HLHS.”

The cardiac progenitor cells used in this study came directly from the hearts of the patients. When these heart-specific progenitor cells are isolated and grown in cell culture, they form tiny balls of cells called “cardiospheres.” These patient-derived cardiosphere-derived cells (CDCs) were administered to the experimental subjects in this study after they were confirmed to contain a normal number of chromosomes and express a host of heart-specific genes. The transcoronary administration of the CDCs did not produce any adverse effects.

The heart functions monitored by the research group included the right ventricular ejection fraction or RVEF, end-systolic volume (ESV), which is the volume of blood within the ventricle at the maximum point of contraction, and the end-diastolic volume or EDV, which is the volume of blood at the maximum filling point, stroke volume, and cardiac output. Additionally, the levels of brain natriuretic peptide or BNP (a direct measure of heart failure) were also monitored. BNP is made by the ventricles of the heart in response to excessive stretching of the heart muscle.

Because of the rarity of this disease, this study was necessarily small. This study was also a non-randomized study. Therefore, this study is more of an evaluation of the safety of this procedure rather than its efficacy. However, the improvement in the RVEP in the stem cell-treated patients compared to the non-treated group 18 months after CDC administration provides possible evidence of the efficacy of this treatment.

Clearly more work is needed, but we will know more as the data rolls in.

Doubts About Cardiac Stem Cells

Within the heart resides a cell population called “c-kit cells,” which have the ability to proliferate when the heart is damaged. Several experiments and clinical trials from several labs have provided some evidence that these cells are the resident stem cell population in the heart that can repair the heart after an episode of cardiac injury.

Unfortunately, a few new studies, and in particular, one that was recently published in the journal Nature, seem to cast doubt on these results. Jeff Molkentin of Cincinnati Children’s Hospital Medical Center and his co-workers have used rather precise cell lineage tracing studies in mice to follow c-kit cells and their behavior after a heart attack. His results strongly suggest that c-kit cells rarely produce heart muscle cells, but they do readily differentiate into cardiac endothelium, which lines blood vessels.

“The conclusion I am led to from this is that the c-kit cell is not a cardiac stem cell, at least in term of its normal, in vivo role,” said Charles Murry, a heart regeneration researcher at the University of Washington who was not involved in this study.

Molkentin’s study is what some stem cells researchers are calling the nail in the coffin for c-kit cells. In fact the Molkentin paper is simply the latest in a series of papers that were unable to reproduce the results of others when it comes to c-kit cells. Worse still, one of the leading laboratories in the c-kit work, Piero Anversa at Harvard Medical School, has had to retract on of this papers and there is also some concern about his publication regarding the SCIPIO trial. Eduardo Marbán, an author of the new study and a cardiologist at the Cedars-Sinai Heart Institute in Los Angeles, said, “There’s been a tidal wave in the last few weeks of rising skepticism,” Nevertheless, the present dispute is not yet settled, and many scientists still regard the regenerative powers of c-kit cells as a firmly established fact.

In his laboratory, Piero Anversa and his colleagues and collaborators have shown that c-kit cells—cardiac progenitor cells expressing the cell surface protein c-kit—can produce new heart muscle cells (cardiomyocytes). Anversa and others also helped usher these cells, which are also known as CPCs or cardiac progenitor cells, into clinical trials to test whether they might help repair damaged cardiac tissue. This culminated in the SCIPIO trial, which showed that patients treated with their own CPCs showed long-lasting and remarkable improves in heart function.

Follow-up work by other research teams, however, has not been able to confirm these studies, and their work has raised doubts about the potential of c-kit cells to actually build new heart muscle. In his contribution to the c-kit controversy, Molkentin and his colleagues genetically engineered mouse strains in which any c-kit-expressing cells and their progeny would glow green. To do this, they inserted a green fluorescent protein gene next to the c-Kit locus. Therefore any c-kit-expressing cells in the heart would not only glow green, but whatever cell type they differentiated into would also glow green. After inducing heart attacks in these mice, Molkentin and others discovered that only 0.027 percent of the heart muscle cells in the mouse heart originated from c-kit cells. “C-kit cells in the heart don’t like to make myocytes,” Molkentin told The Scientist. “We’re not saying anything that’s different” from groups that have not had success with c-kit cells in the past,” Molkentin continued, “we’re just saying we did it in a way that’s unequivocal.”

Molkentin’s study did not address why there’s a discrepancy between his results and those of Anversa and another leader in the c-kit field, Bernardo Nadal-Ginard, an honorary professor at King’s College London. Last year in a paper published in the journal Cell, Nadal-Ginard and his colleagues showed that heart regeneration in rodents relies on c-kit positive cells and that depleting these cells abolishes the regenerative capacity of the heart.

In an email to a popular science news publication known as The Scientist, Nadal-Ginard suggested that technical issues with Molkentin’s mouse model could have affected his results, causing too few c-kit cells to be labeled. Additionally, “the work presented by Molkentin used none of our experimental approaches; therefore, it is not possible to compare the results,” Nadal-Ginard said in an e-mail.

Anversa said his lab is working with the same mouse model Molkentin used, “but our data are too preliminary to make any specific comment. Time will tell.”

Molkentin’s paper seems point to further problems with Aversa’s work with c-kit cells.  Last month, one of the papers Anvera and his group had published in the journal Circulation had to be retracted because the data used the write that paper were “sufficiently compromised.”  Then a few days later, the paper describing the results of the SCIPIO study that appeared the journal The Lancet expressed concern about supplemental data that was included with the published results.  These data came from the human clinical trial that treated heart patients with their own c-kit cells.  Harvard Medical School and Brigham and Women’s Hospital are investigating what went wrong with this study and the publication itself.

Regardless of Anversa’s present tribulations, Marbán is advancing another type of heart-specific stem cell, called cardiosphere-derived cells or CDCs.  Marbán and his colleagues have already used CDCs in a human clinical trial known as the CADUCEUS trial.  In this trial, heart attack patients treated with CDCs saw their heart scars shrink.  Marbán said he had been a true believer in c-kit cells, until the data started mounting against them. “The totality of the evidence now says the c-kit cell is no longer a cardiomyocyte progenitor,” he said.

Now even if c-kit cells do not make new heart muscle, it is possible that they heal the heart through other means.  The patients in the SCIPIO trial saw real, genuine improvements in their heart function and these results cannot be so cavalierly dismissed.  In fact, Murry said that just because the mechanistic basis for the human study remains in doubt, promising clinical results should not be dismissed. “Those results can be considered independent,” he said.  Molkentin also added that it’s possible that c-kit cells work in unknown ways to repair heart tissue.  Since clinical treatments involves high levels of c-kit cells that have been immersed in culture conditions, “Perhaps these cells act a little different,” Molkentin said.

Nadal-Ginard also noted that discrepancies do exist between his data and those of others, and that these discrepancies should not be papered over, but should be robustly debated and addressed.  He said he’d be willing to work with Molkentin to get to the bottom of it. “The concept under dispute is too important for the field of regenerative medicine—and regenerative cardiology, in particular—to turn into a philosophical/dogmatic argument instead of settling it in a proper scientific manner.”  Here here.

Phase 2 Clinical Trial that Tests Stem Cell Treatment for Heart Attack Patients to be Funded by California Institute for Regenerative Medicine

A new stem cell therapy that treats heart attack patients with cells from a donor has been approved to begin a Phase 2 clinical trial.

Capricor Therapeutics Inc. a regenerative medicine company, has developed this treatment, which extracts donor stem cells from the heart called “cardiosphere-derived cells,” and then infuses them into the heart of the heart attack patient by means of a heart catheter procedure, which is quite safe. These stem cells are introduced into the heart to reduce scarring in the heart and potentially replace dead heart muscle cells. One clinical trial called the CADUCEUS trial has already shown that cardiosphere-derived cells can reduce the size of the heart scar.

In a previous phase I study (phase I studies typically only ascertain the safety of a treatment), cardiosphere-derived cells were infused into the hearts of 14 heart attack patients. No major safety issues were observed with these treatments, and therefore, phase 2 studies were warranted.

Alan Trounson, Ph.D., president of the California Institute for Regenerative Medicine (CIRM), which is funding the trial, said this about the phase 2 trial approval: “This is really encouraging news and marks a potential milestone for the use of stem cells to treat heart disease. Funding this type of work is precisely what our Disease Team Awards were designed to do, to give promising treatments up to $20 million dollars to develop new treatments for some of the deadliest diseases in America.”

Capricor was given approval by the National Heart Lung and Blood Institute (NHLBI) Gene and Cell Therapy (GST) to move into the next phase of clinical trials after these regulatory bodies had thoroughly reviewed the safety data from the phase 1 study. After NHLBI and GST determined that the phase 1 study met all the required goals, CIRM also independently reviewed the safety data from the Phase 1 and other aspects of the Phase 2 clinical trial design and operations. Upon successful completion of the independent review, Capricor was given approval to move forward into the CIRM-funded Phase 2 component of the study

Capricor CEO Linda Marbán, Ph.D., said, “Meeting the safety endpoints in the Phase 1 portion of the trial is a giant leap forward for the field and for Capricor Therapeutics. By moving into the Phase 2 portion of this trial, we can now attempt to replicate the results in a larger population.”

For the next phase, an estimated 300 patients who have had heart attacks will be evaluated in a double-blind, randomized, placebo-controlled trial. One group of heart-attack patients will include people 30 to 90 days following the heart attack, and a second group will follow patients 91 days to one year after the incident. Other patients will receive placebos and neither the patients nor the treating physicians know who will receive what.  This clinical trial should definitely determine if an “off-the-shelf” stem cell product can improve the function of a heart attack patient’s heart.

The California Institute for Regenerative Medicine (CIRM) is funding this clinical trial, and for this CIRM should be lauded.  However, when CIRM was brought into existence through the passage of proposition 71, it sold itself as a state-funded entity that would deliver embryonic stem cell-based cures.  Now I know that director Alan Trounson has denied that, but Wesley Smith at the National Review “Human Exceptionalism” blog and the LA times blogger Michael Hiltzik have both documented that Trounson and others said exactly that.  Isn’t ironic that one of the promises intimated by means of embryo-destroying research is now being fulfilled by means of non-embryo-destroying procedures?  If taxpayer money is going to fund research like this, then I’m all for it, but CIRM has to first clean up its administrative act before they deserve a another penny of taxpayer money.