The proposed research will demonstrate both safety and efficacy of a heart-derived stem cell product in patients who have experienced a heart attack either recently or in the past by conducting a mid-stage clinical trial. A prior early-stage trial showed that the product can repair damaged portions of the heart after a heart attack in ways that no commercial therapy currently can. Damaged areas turn irreversibly into scar tissue after the initial event, which can predispose a person to future events and lead to an ongoing worsening of general and heart health. Data from the early-stage trial suggest that treatment with the heart-derived cell product under development can turn scar tissue back into healthy heart muscle. The planned mid-stage trial will hopefully confirm that finding in a larger patient group and provide additional data to support the safety profile of the product. The product is manufactured using heart tissue obtained from a healthy donor and can be used in most other individuals. Its effect is thought to be long-lasting (months-years) although it is expected to be cleared from the body relatively quickly (weeks-months). Treatment is administered during a single brief procedure, requiring a local anesthetic and insertion of a tube (or catheter) into the heart. The overriding goal for the product is to prevent patients who have had a heart attack from deteriorating over time and developing heart failure, a condition which is defined by the heart’s inability to pump blood efficiently and one which affects millions of Americans. Successful completion of the proposed mid-stage trial would lead next to a final, confirmatory trial and then to the application process by which permission to market the product is obtained from the Food and Drug Administration. The end result could be an affordable stem cell therapy effective as part of a treatment regimen after a heart attack.
The manufacturer of the heart-derived stem cell product under development is a California-based small company who currently employs 7 California residents. Five new local jobs will be created to support the proposed project. Three medical centers located in California will participate in the proposed mid-stage clinical trial. The trial will hopefully bring notoriety to both the company and the medical centers involved while at the same time provide a novel therapeutic option for the many citizens of California afflicted with heart disease. Recent statistics place California among the 50% of states with the highest death rates for heart disease. Therefore, a successfully developed cell product could have a meaningful impact on the home population. Furthermore, as manufacturing needs grow to accommodate the demands of early commercialization, the company anticipates generating 100+ new biotech jobs.
The proposed project is focused on the clinical development of an allogeneic cardiac-derived stem cell product intended for use in patients with residual left ventricular dysfunction following a myocardial infarction (MI). The applicant proposes to conduct a mid-stage clinical trial to demonstrate both safety and efficacy of the product candidate.
Significance and Impact
- Should the product candidate work as intended, it could have a significant impact on treatment of MI and heart disease.
- Because of the lack of improvements in heart function observed in the pre-clinical efficacy data, some reviewers found it hard to be enthusiastic about the clinical competitiveness of this product candidate.
- The TPP is focused on the results of a phase 2 trial rather than on the attributes of a final product.
- In general, reviewers agreed that this program is well supported by data from a previous clinical trial as well as supporting data from three animal models, each with different iterations of the product candidate.
- Reviewers agreed that the data warrant further testing.
-The preliminary data trends in animal models are interesting
Therapeutic Development Readiness
- The proposed clinical plan is a major potential risk given the lack of significant cardiac function improvement noted in the Phase 1 study with an earlier candidate and the fact that the applicant proposes starting with a Phase 2 trial with the current candidate, but is still awaiting the pivotal pre-clinical study data.
- The cGMP cell production methods and scale-up manufacturing are well thought out, and physically in place. The procedures are quite developed and are ready for clinical development.
Feasibility of the Project Plan
- Although the therapeutic approach is promising, the proposed trial attempts to accomplish too many steps at once; a new phase I study is warranted first; the proposed clinical plan needs to be re-thought and re-designed.
- The study is being designed around a surrogate marker that has not been shown to correlate with functional outcome measures in the preclinical models or in a Phase 1 trial. This seems to be a fundamentally serious design flaw in the study and will not help the project in terms of achieving regulatory approval or reimbursement.
- Reviewers agreed that based on the data provided in the application, the large trial proposed is not justified. They would have supported the idea of a smaller, better-designed study that could answer a specific question.
- The budget is unrealistic. It is inadequate to perform a multicenter international trial of such scope and complexity.
Principal Investigator (PI) and Development Team
- A major concern is that neither of the two primary leaders has run a trial of this size, making the investment risky in terms of experience.
- Reviewers strongly recommend that an experienced CRO be hired to conduct the trial
Collaborations, Resources and Environment
- The resources and environment are good.
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.)
- See comment under ‘Feasibility of the Project Plan’.
- Budget for manufacturing expenses to prepare for Phase 3 is outside scope.
- Darin Weber
- Joyce Frey-Vasconcells
- Randal Mills