Cardiac Safety Research Consortium Update

Stem cell therapy for CVDs: Advances persist, challenges remain

The first randomized controlled trials of regenerative medicine in CVD were conducted in the early 2000s, involving intracoronary infusion of autologous unselected bone marrow cells in patients with prior MI and left ventricular systolic dysfunction. These small trials showed an inconsistent but small improvement in LV ejection fraction. Since that time, advances in technology have encouraged cardiologists to undertake clinical trials in regenerative medicine in patients with refractory angina and chronic HF. These clinical trials of second- and third-generation stem cell therapies have encouraging results. To date, 31 trials enrolling 1,521 patients treated with multiple different stem cell products via intracoronary infusion or endomyocardial injection have consistently shown a trend toward benefit, with significant reductions in death and HF hospitalization when these trials are aggregated.

Despite these successes, stem cell therapy faces a number of challenges, and the pathway to regulatory approval is uncertain. Barriers to regulatory approval include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical endpoints required for regulatory decisions. The FDA has recognized these challenges and, thus, created the Regenerative Medicine Advanced Therapy designation to facilitate the expedited development and review of regenerative medicine therapies.

We convened the inaugural Cardiac Safety Research Consortium/Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine, including academic leaders, the pharmaceutical industry and the FDA, to summarize the state of CV regenerative medicine, identify barriers to regulatory approval and discuss strategies to overcome these barriers. The meeting, from which a manuscript will shortly be forthcoming, addressed the following:

  1. reviewed stem cell clinical trial data to date for patients with refractory angina and chronic HF;
  2. discussed major challenges facing industry, academia and regulators in achieving regulatory approval; and
  3. delineated key ways to move the field forward toward regulatory approval.

Although significant challenges remain, cell therapy appears promising for the treatment of refractory angina. Three double-blind, placebo-controlled trials all demonstrated evidence of efficacy and no safety concerns with the use of selected CD34+ cells for this indication. Notably, in the Netherlands, intramyocardial injection of bone marrow cells for refractory angina is now approved and reimbursed based on data demonstrating decreased resource utilization and trends toward improvements in major CV events.

With the aid of patient stakeholders, industry and academic leadership, the Cardiac Safety Research Consortium hopes in future meetings to establish uniform guidelines and definitions for stem cell purity and potency as well as trial endpoints and designs. Such guidelines and definitions may aid in accruing data across individual trials and cell types and, in combination with the Regenerative Medicine Advanced Therapy designation, accelerate therapies toward clinical approval and improvements in the lives of patients.

Editor’s note: The Cardiac Safety Research Consortium Update is a new feature in Cardiology Today that will be published throughout the year when updates from the CSRC are available. It is edited by Peter R. Kowey, MD, Arrhythmia Disorders Section Editor for Cardiology Today. Email the Editors at cardiology@healio.com for more information.

The first randomized controlled trials of regenerative medicine in CVD were conducted in the early 2000s, involving intracoronary infusion of autologous unselected bone marrow cells in patients with prior MI and left ventricular systolic dysfunction. These small trials showed an inconsistent but small improvement in LV ejection fraction. Since that time, advances in technology have encouraged cardiologists to undertake clinical trials in regenerative medicine in patients with refractory angina and chronic HF. These clinical trials of second- and third-generation stem cell therapies have encouraging results. To date, 31 trials enrolling 1,521 patients treated with multiple different stem cell products via intracoronary infusion or endomyocardial injection have consistently shown a trend toward benefit, with significant reductions in death and HF hospitalization when these trials are aggregated.

Despite these successes, stem cell therapy faces a number of challenges, and the pathway to regulatory approval is uncertain. Barriers to regulatory approval include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical endpoints required for regulatory decisions. The FDA has recognized these challenges and, thus, created the Regenerative Medicine Advanced Therapy designation to facilitate the expedited development and review of regenerative medicine therapies.

We convened the inaugural Cardiac Safety Research Consortium/Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine, including academic leaders, the pharmaceutical industry and the FDA, to summarize the state of CV regenerative medicine, identify barriers to regulatory approval and discuss strategies to overcome these barriers. The meeting, from which a manuscript will shortly be forthcoming, addressed the following:

  1. reviewed stem cell clinical trial data to date for patients with refractory angina and chronic HF;
  2. discussed major challenges facing industry, academia and regulators in achieving regulatory approval; and
  3. delineated key ways to move the field forward toward regulatory approval.

Although significant challenges remain, cell therapy appears promising for the treatment of refractory angina. Three double-blind, placebo-controlled trials all demonstrated evidence of efficacy and no safety concerns with the use of selected CD34+ cells for this indication. Notably, in the Netherlands, intramyocardial injection of bone marrow cells for refractory angina is now approved and reimbursed based on data demonstrating decreased resource utilization and trends toward improvements in major CV events.

With the aid of patient stakeholders, industry and academic leadership, the Cardiac Safety Research Consortium hopes in future meetings to establish uniform guidelines and definitions for stem cell purity and potency as well as trial endpoints and designs. Such guidelines and definitions may aid in accruing data across individual trials and cell types and, in combination with the Regenerative Medicine Advanced Therapy designation, accelerate therapies toward clinical approval and improvements in the lives of patients.

Editor’s note: The Cardiac Safety Research Consortium Update is a new feature in Cardiology Today that will be published throughout the year when updates from the CSRC are available. It is edited by Peter R. Kowey, MD, Arrhythmia Disorders Section Editor for Cardiology Today. Email the Editors at cardiology@healio.com for more information.