Allogenic Cardiac Stem Cells Show Some Promise for LV Remodeling Post-MI

By Marilynn Larkin

August 12, 2020

NEW YORK (Reuters Health) - Infusion of allogenic cardiosphere-derived cells (CDCs) in patients with left ventricular (LV) dysfunction after acute myocardial infarction (MI) did not reduce LV scarring but did have a favorable impact on LV remodeling and a heart failure biomarker at six months, new data show.

The ALLSTAR study was stopped prematurely for failing to show benefit in a six-month interim analysis based on the primary efficacy endpoint of reducing infarct size.

The study protocol, designed in 2011, "used single, low cell doses and cumbersome intracoronary delivery," Dr. Eduardo Marban of the Smidt Heart Institute at Cedars-Sinai in Los Angeles told Reuters Health. "We have learned a lot in the intervening nine years; we would next administer multiple, higher doses via the simple IV route."

"Cell therapy for heart disease, which has been marked by cycles of hype and dashed hopes, may finally be settling into a mature phase of development with realistic expectations," he said by email. "Whether or not it's going to be a game-changer remains to be seen, but we are certainly encouraged by our collective findings of safety and efficacy in multiple patient populations, including ischemic heart disease, dilated cardiomyopathy, and muscular dystrophy."

As reported in the European Heart Journal, the researchers randomized 90 patients to receive CDCs and 44 to receive placebo in the infarct-related artery by stop-flow technique. Inclusion criteria included a post-MI interval of 4 weeks to 12 months, MI, with LV ejection fraction (LVEF) no more than 45% and LV scar size at least 15% of LV mass by magnetic resonance imaging (MRI).

The primary safety endpoint, during the month after intracoronary infusion, was the occurrence of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event, i.e., death or hospitalization for heart failure or non-fatal MI or need for LVAD or heart transplant.

The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion.

Participants' mean age was about 54 and about 85% were men. The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass.

No primary safety endpoint events occurred, and there was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at six months.

However, the current analysis shows that compared with placebo, there were significant reductions in LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and N-terminal pro b-type natriuretic peptide (NT-proBNP) at six months in CDC-treated patients.

The authors state, "Despite the lack of an effect on scar size, infusion of allogeneic CDCs was associated with the attenuation of post-infarct cardiac remodeling. Both LVEDV and LVESV remained relatively unchanged at six-month follow-up in CDC-treated patients, in contrast to the increases in LV volumes observed in the placebo group. The reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs."

The authors further note that the ALLSTAR results "represent the lower limit estimates" of CDCs' potential efficacy, as treatment was delivered only once and only into a single coronary artery.

"The potential for augmenting the benefits of CDC therapy on cardiac remodeling and NT-proBNP levels with repeat administration of allogeneic CDCs, in one or multiple coronary arteries; or alternate cell delivery methods, remains to be determined," they conclude.

Dr. Marban said, "CDCs are furthest along in clinical development for Duchenne muscular dystrophy, a genetic disease with both a skeletal myopathy and a cardiomyopathy. If the US Food and Drug Administration grants licensing approval for Duchenne, which it might do as early as 2021, then development for other indications, such as ischemic cardiomyopathy, would be markedly accelerated."

Dr. Shunji Sano of the Division of Pediatric Cardiothoracic Surgery at the University of California San Francisco called the findings "promising." That said, he told Reuters Health by email, this is only the beginning for the new treatment. "No one knows the benefit beyond six months."

By contrast, he noted, "CDCs (stem cell) therapy in neonates and small children with hypoplastic left heart syndrome and single ventricle brings significant improvement of cardiac function, quality of life and weight (gain)," as demonstrated in his group's clinical trials, such as PERSEUS, in Japan. (https://bit.ly/2XQwfX3)

The differences in results between children and adults could be due to several factors, he said. For example, "there are four to five times more CDCs in neonates and infants compared to adults. Also, our aim is not to turn fibrous tissue into healthy myocardium; it is to increase contractility or power up cardiac function."

"While the ALLSTAR result is promising," he added, "there are more hurdles to overcome."

The trial was funded in part by Capricor, Inc. A number of the coauthors are employed by or receive fees from the company.

SOURCE: https://bit.ly/2XQWb4U European Heart Journal, online August 4, 2020.

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