Cell Therapy

While stem cell therapy development programs for heart disease elsewhere have used cells from embryonic or non-cardiac tissue, Capricor’s unique approach begins and ends with the heart.

Capricor’s hypothesis, which is supported by a large and growing preclinical database as well as clinical trial results, is that cardiac cells are best equipped to harness the heart’s own restorative capabilities. For this reason, Capricor uses the heart as the source of cells for its cardiosphere-derived cell (CDC) products. Capricor’s lead product candidate, CAP-1002, is an “off the shelf” product that contains CDCs made from donor hearts (allogeneic), and can be stored for later use.

What are CDCs?

Capricor’s core technology is based on cardiospheres (CSps), which are clusters of cells obtained from heart muscle. Cardiosphere-derived cells (CDCs) are CSp cells that have been formatted into a single layer, and Capricor is developing CDCs as the potential therapeutic product CAP-1002. CDCs possess regenerative properties, meaning these cells are able to promote the growth of new heart cells. They accomplish this not by becoming part of the recipient’s heart, but by acting at a distance to cause cells in the recipient heart to divide and/or differentiate. CDCs can be injected into the coronary arteries without damaging the heart muscle, in doses sufficient for activity. Because CDCs originate in the myocardial cell lineage, Capricor believes that they are particularly well-suited to stimulate the heart’s innate restorative capabilities. The CDCs in CAP-1002 originate from tissue taken from donor hearts.

While the heart muscle appears capable of healing from daily “wear and tear”, its repair systems are insufficient to address extensive damage such as that which results either from an acute event, such as a heart attack, or from chronic injury, which may be associated with a variety of conditions. Capricor believes that, following their infusion, CDCs track to the area of injury and release growth factors and cytokines (molecules that stimulate specific cell responses) that signal the heart to repair itself. Although the infused CDCs are eventually cleared from the body, their salutary effects are believed to be long-lasting.

Since the discovery of the cardiosphere over a decade ago, basic research on CSPs and CDCs has generated a large and growing body of peer-reviewed literature. It has been shown that CDCs exert several effects that can mitigate damage and promote repair and regeneration at sites of injury, including anti-scarring, anti-programmed cell death and blood vessel growth functions. The cumulative clinical experience with CDCs has provided initial validation of their potential benefits, and is characterized by favorable safety and tolerability.

CDC’s Unique Mechanism of Action

Capricor’s CDCs secrete factors that promote the following effects:

  • Reduction of host cell apoptosis (programmed cell death)
  • Recruitment of existing stem cells
  • Heart cell growth
  • Reduction in scar formation
  • Increase in blood vessel density

The CDCs are eventually cleared from the body, essentially serving as a temporary local drug delivery system.

Capricor believes its cells are better equipped to embody the heart’s innate restorative capabilities than those derived from non-cardiac tissue, such as bone marrow. This was demonstrated in a preclinical study conducted by Cedars-Sinai which compared CDCs with other stem cell types (from either bone marrow or fat tissue). In this study, only the CDC group led to statistically significant improvement in ejection fraction (a measure of heart function). As compared to the other cell types, CDCs led to:

  • The highest cell engraftment and cardiac differentiation rates
  • The least degree of adverse remodeling
  • The lowest rate of cell apoptosis (programmed cell death)

CAP-1002 Attributes

Within cardiac cell therapy, Capricor’s cells have several differentiating characteristics that we believe make them more efficacious and easier to deliver than other cell types.

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  • ALLOGENEIC: Allogeneic cells, which are derived from donor tissue, offer several advantages over autologous alternatives (derived from patient’s own tissue). First, as numerous doses can be created from one donor heart, the therapy can be available “off-the-shelf,” meaning the therapy could be available when needed. Additionally, there is no need for the patient to undergo an invasive tissue harvesting procedure. Finally, the cost of production is significantly less than with an autologous product.

  • INTRACORONARY DELIVERY: The majority of cardiac cell therapies utilize an intramyocardial injection catheter system for delivery. This entails electronic mapping of the heart followed by direct injection of the cells into the heart muscle via a catheter. Capricor delivers its cells intracoronary (IC), meaning the cells are infused into an artery, rather than injected into the heart. IC has numerous advantages over intramyocardial injection, including 1) no damage to the heart muscle, 2) faster treatment with greater ability to treat acute cases, and 3) lower cost of treatment, as additional clinician training is minimal, and no additional capital equipment or software is required. Importantly, IC infusion is a routine procedure in catheter laboratories.

  • CARDIAC DERIVED: The prevailing scientific dogma has long held that the heart is a terminally differentiated organ, meaning heart cells are incapable of self-renewal. Discoveries within the last few years have proven that the heart indeed contains its own stem cells. On their own, these cells are believed to compensate for normal every day wear-and-tear, but do not suffice to offset devastating injuries such as heart attacks. Capricor’s CDCs in general do not retain expression of the purported cardiac stem cell marker known as c-kit, but are uniformly identifiable by numerous other markers, and are believed to be a highly regenerative population.

Capricor believes its cells are better equipped to embody the heart’s innate restorative capabilities than those derived from non-cardiac tissue, such as bone marrow. This was demonstrated in a 2012 Cedars-Sinai preclinical study comparing CDCs head-to-head with other stem cell types (from either bone marrow or fat tissue). At three weeks, CDCs showed the following results:

  • CDCs were the only group in which ejection fraction (a measure of heart function) improvement reached statistical significance
  • The highest cell engraftment and cardiac differentiation rates
  • The least degree of adverse remodeling
  • The lowest rate of cell apoptosis (programmed cell death)

The same study also compared CDCs to purified c-kit cells, a cell population purified on the basis of a single marker called c-kit, and CDCs once again demonstrated improved performance, specifically:

  • CDCs showed greater improvement in ejection fraction (a measure of heart function)
  • CDCs released higher VEGF, SDF, IGF-1, and HGF (growth factors)

Manufacturing

The manufacturing process for Capricor’s first generation autologous CDC product, CAP-1001 – which was evaluated in the CADUCEUS trial – began with a biopsy of cardiac tissue from the patient. This tissue was put into culture and CDCs were generated through a series of proprietary unit operations. CAP-1001 was then administered back to the same individual.

The manufacturing process for CAP-1002, Capricor’s allogeneic CDC product candidate, starts with tissue taken from donor hearts. Following expansion, processing, release testing, and quality review, CAP-1002 is cryopreserved (stored at a low temperature), allowing an inventory of “off the shelf” product to be available for administration to many patients. Under these conditions, CAP-1002 has a useful life of at least three years.

Capricor’s current manufacturing process is adequate to meet current clinical trial demands. In collaboration with Janssen Biotech, Inc., Capricor has been working toward the establishment of a commercial-scale process.