Disease Team Therapy Planning I
Stroke leaves hundreds of thousands of Americans disabled every year. Beyond drugs that dissolve the blood clots causing the stroke, there is no effective therapy. These "clot-busting" drugs can only be used within the first few hours of the onset of symptoms, leaving many patients without treatment options. New advances in regenerative medicine offer hope to those with otherwise untreatable stroke disabilities. Several cell therapy products have advanced to human clinical trials. Effective therapies may be only a few years away. One of these new therapies uses a cell type obtained from adult bone marrow, called mesenchymal stromal cells. These cells are obtained from healthy donors, grown in the laboratory and modified with a gene that improves their ability to promote regeneration of the patient's own cells. These cells have advanced to the initial stage of human testing. A small number of stroke patients are being implanted with cells to determine if the therapy is safe. They will also be monitored for improvement in their disabilities. If this trial is successful the product will move to the next phase of human testing, determining the appropriate dose and timing needed for the product to be effective and determining which patients are most likely to benefit. This next phase will require the assembly of a multidiciplinary team of scientists and physicians to move forward. The formation of the team and the planning required to carry out this next human clinical trial is the goal of this proposal. This 6-month project will involve the planning of the details of the clinical trial, the recruitment of physicians and scientists to the team and the identification of university hospitals where the trial will take place. Also, cells must be prepared under strict guidelines to be used in the trial. Finally, plans for additional research on how exactly these cells promote the brain's regeneration after stroke injury are required in order to better select which patients will benefit from therapy and to more effectively test and predict the cellular product's effects. After the successful conclusion of this planning stage, the next phase of human testing can begin. Armed with the information obtained from this clinical trial, it is hoped that a conclusive clinical trial showing safety and efficacy will move forward, ultimately resulting in FDA approval and the availability of this regenerative medicine product to the many patients who suffer a stroke.
Statement of Benefit to California:
Like the rest of the developed world, stroke is the number one cause of permanent disability in the state of California. Regenerative therapies that promote recovery from stroke disability would reduced the costs of long-term medical and supportive care, increase independence and improve productivity for thousands of Californians. Stroke costs the state over $6 billion per year. This project continues the development of a regenerative cell therapy product currently in the earliest stages of human clinical testing. These cells are derived from the bone marrow of healthy donors and have proven very effective at treating stroke disability in animal models. The clinical trial described in this proposal will take place at a number of university hospitals. Many of these will be in the State of California, providing direct health benefits to patients living nearby and resources to the pioneering scientists and clinicians devoting time to this project. This work will continue the trend establishing California as the wolrd's leading center for regenerative medicine. Importantly, this project has already advanced to human clinical testing, overcoming challenges in manufacturing and regulatory hurdles not yet addressed by earlier stage products.
EXECUTIVE SUMMARY Project Synopsis: This Planning Award proposal focuses on a gene-modified mesenchymal stromal cell therapy for stroke. This therapy is currently undergoing the initial stage of human testing under an IND. For the Research Award, the applicant proposes to complete this initial clinical trial, and if that is successful, move into and complete the next phase of human testing. This next phase will include evaluation of dose, timing, and efficacy of the cell therapy. Significance and Impact: - Stroke is a significant unmet medical need with few treatment options. If successful, the proposed cell therapy could have a major impact. - The field of cell therapy for stroke is competitive and the applicant does not address the advantages of the proposed approach versus similar ones also currently under clinical development. - The information put forth in the Target Product Profile is vague and does not provide sufficient detail to permit adequate critical review. Project Rationale and Feasibility: - The timeline of the development plan is unrealistic; in particular, reviewers found it extremely unlikely that the milestones proposed for Years 1 and 4 could be achieved. This was described as a fatal flaw. - Reviewers would have appreciated the inclusion of early data from the initial phase of human testing, or an explanation of why it is not available. - Reviewers would have appreciated more information about the design of the proposed clinical trial in the next phase of human testing. - Reviewers expressed mixed opinions about the choice of patient population. Some questioned its suitability, given the potential mechanism(s) of action, while others appreciated the benefits of a stable baseline to assess efficacy. - Reviewers expressed mixed opinions about the quality of the preclinical animal model data. Some were fairly impressed while others found it less compelling and questioned the suitability of the behavioral assessments. Principal Investigator (PI) and Planning Leader: - The PI has significant experience in drug discovery and translational research. However it is not clear that s/he has the necessary expertise to lead a multi-center clinical trial. - The Planning Leader is highly experienced in cell therapies and regulatory issues and appropriately qualified for this position. - Reviewers recommended the integration of a vascular neurologist or neurosurgeon into the leadership of the team.
- This application scored below the initial scientific merit funding line, no programmatic reason to fund the application was proposed, and the GWG voted to place the application in Tier 3, Not Recommended for Funding.