Funding opportunities

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Principle Investigator: 
Funds requested: 
$19 999 899
Funding Recommendations: 
Grant approved: 
Public Abstract: 

Patients with end-stage heart failure have a 2-year survival rate of only 50% with conventional medical therapy. This dismal survival rate is actually significantly worse than patients with AIDS, liver cirrhosis, stroke, and other comparable debilitating diseases. Currently available therapies for end stage heart failure include drug and device therapies, as well as heart transplantation. While drug and device therapies have proven effective at reducing symptoms, hospitalizations and deaths due to heart failure, new approaches are clearly required to improve this low survival rate. Organ transplantation is highly effective at increasing patient survival, but is severely limited in its potential for broad-based application by the very low number of hearts that are available for transplantation each year. Stem cell therapy may be a promising strategy for improving heart failure patient outcomes by transplanting cells rather than a whole heart. Several studies have convincingly shown that human embryonic stem cells can be differentiated into heart muscle cells (cardiomyocytes) and that these cells can be used to improve cardiac function following a heart attack. The key objective of this CIRM Disease Team Therapy proposal is to perform the series of activities necessary to obtain FDA approval to initiate clinical testing of human embryonic stem cell-derived cardiomyocytes in end stage heart failure patients.

Statement of Benefit to California: 

Coronary artery disease (CAD) is the number one cause of mortality and morbidity in the US. The American Heart Association has estimated that 5.7 million Americans currently suffer from heart failure, and that another 670,000 patients develop this disease annually. Cardiovascular disease has been estimated to result in an estimated $286 billion in direct and indirect costs in the US annually (NHLBI, 2010). As the most populous state in the nation, California bears a substantial fraction of the social and economic costs of this devastating disease. In recent years, stem cell therapy has emerged as a promising candidate for treating ischemic heart disease. Research by our group and others has demonstrated that human embryonic stem cells (hESCs) can be differentiated to cardiomyocytes using robust, scalable, and cGMP-compliant manufacturing processes, and that hESC-derived cardiomyocytes (hESC-CMs) can improve cardiac function in relevant preclinical animal models. In this proposal, we seek to perform the series of manufacturing, product characterization, nonclinical testing, clinical protocol development, and regulatory activities necessary to enable filing of an IND for hESC-CMs within four years. These IND development activities will be in support of a Phase 1 clinical trial to test hESC-CMs in heart failure patients for the first time. If successful, this program will both pave the way for a promising new therapy to treat Californians with heart failure numbering in the hundreds of thousands, and will further enhance California’s continuing prominence as a leader in the promising field of stem cell research and therapeutics.

Review Summary: 

This proposal is focused on the preclinical development of allogeneic human embryonic stem cell-derived cardiomyocytes (hESC-CMs) for the treatment of end-stage heart failure (ESHF). The key objective of this proposal is to complete the preclinical, manufacturing, regulatory and clinical activities required to submit an Investigational New Drug (IND) application to the FDA within the four-year timeframe. The Phase 1 clinical study, which is beyond the scope of this proposal, will assess the safety of transplantation of hESC-CMs in ESHF patients undergoing left ventricular assist device (LVAD) implantation as a bridge toward heart transplantation.

Significance and Impact
- Regenerative treatment for heart failure is an unmet medical need. Potentially millions of individuals could benefit if this therapeutic approach were found to be safe and efficacious.

- Reviewers noted that this would be one of the few hESC-derived therapeutics in this highly competitive field.

- The Target Product Profile (TPP) adequately describes the product, dosing considerations, endpoints and potential safety concerns. The clinical objective should be clarified to reflect the team’s minimal and optimal goals for a meaningful clinical and quality-of-life benefit.

- Head-to-head comparisons in preclinical models would be useful to assess competitiveness of the proposed product versus others in early clinical development.

Project Rationale
- The clinical rationale for the project is based on the unmet need for regenerative therapeutics for patients with ESHF.

- This program lays the scientific and regulatory groundwork for a unique first-in-human study which has the potential to answer key questions about cell fate and safety in diseased human hearts.

- The panel understood that the target population for the Phase 1 study is not an intended patient population for treatment, but is rather an important first step to demonstrate safety of the therapeutic candidate.

- One reviewer stated that it was not clear that the preclinical model is representative of ESHF. Others noted it may be the best available model.

Therapeutic Development Readiness

- The therapeutic approach is based on the applicant’s (and other’s) supporting data in multiple preclinical models of experimental cardiac infarction. These preliminary data show that cells engraft and positively impact function by multiple endpoints.

- Early data show no evidence of teratoma formation or other critical safety concerns in two studies in one preclinical model.

- The intended therapeutic candidate may not yet be fully characterized. The panel noted the importance of batch-to-batch reproducibility of proportions of both cardiomyocytes and other bystander cell types.

- It was not clear from the application whether the team considered the current achievable purity adequate to begin development. Reviewers recommended setting a concrete goal for the first year’s process optimization efforts.

Feasibility of the Project Plan
- The project plan is a strength of this application, judged to be conservative and methodical, it addresses all potential roadblocks.

- Reviewers noted sound characterization methods, tools, assays, expertise and a well-considered plan to address the characterization and manufacturing hurdles.

- Transplant rejection and its potential untoward effects should be further addressed in the relevant preclinical model.

- Some milestones did not have clear success criteria; for example success criteria for biologic activity/efficacy should specify a desired functional outcome.

- One reviewer felt that the preclinical studies should include additional study groups; one group with a similar implanted cardiac device, and a second treated with immunosuppression only.

Principal Investigator (PI) and Development Team
- This international collection of experts in cardiac stem cell biology, clinical innovation, imaging, and hESC manufacturing was noted as a major strength of the application.

- Many of the California leaders in cardiac stem cell biology and cardiac therapeutic development are participating in this proposed project.

- The team has a strong track record in cardiac therapeutic innovation.

- The degree of regulatory experience among the scientific team for this type of therapeutic approach was unclear in the application.

- The leadership plan did not address a process for making Go / No Go decisions.

Collaborations, Resources and Environment
- The team will need to negotiate key licenses in order to commercialize the potential therapeutic. This was not judged to be a barrier to completing the project, but should be addressed immediately.

- An extensive network of collaborators, both existing and new, was judged to be a strength of the application.

- The resources available to the team across non-clinical, clinical, and early stage manufacturing are considered among the best-in-class.

Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.)
- One reviewer judged the budget to be high overall to take the cell-based therapy to IND filing (with no clinical costs included).

- One reviewer noted the large number of post docs on the award, suggestive of a large amount of research activities.

Programmatic review: 
  • A motion was made to move this application into Tier 1, Recommended for Funding. The project seeks to develop an hESC-derived therapeutic. The application represents a unique opportunity to address cell fate and safety in an optimal first clinical setting, and will move the field significantly beyond information that can be gained in a xenotransplantation setting. The motion carried.
  • David Pepperl