Strategic Partnership I
Stroke is the leading cause of disability and the third leading cause of death in the United States. Recent estimates by the American Heart Association suggest that in 2011, ~800,000 people in the US suffered a stroke, with 80-90% of those strokes being ischemic strokes involving blockage of a blood vessel in the brain, resulting in a lack of oxygen and nutrients to the tissue and subsequent cell death. Calculated costs of stroke on our health care system point to total combined direct and indirect costs of $73.7 Billion dollars annually, with lifetime costs associated with caring for stroke victims approaching $200,000 per survivor. Despite these statistics, there are few treatment options for people suffering strokes. Drug development efforts have largely focused on stroke prevention, "clot-buster" drugs, or neuroprotectants and have been almost universal failures. Only tPA, a thrombolytic or clot-buster, has received FDA approval for treatment of ischemic stroke, and unfortunately, must be administered within 4.5 hours of the onset of the stroke. As such, only 3-8% of all Americans suffering an acute ischemic stroke who could benefit receive tPA due to the delayed recognition of the symptoms associated with stroke, coupled with the limited window for receiving tPA treatment. This equates to ~650,000 Americans in 2011 who could have benefited from an alternative effective stroke therapy. Other than tPA, the primary standard of care and treatment for stroke victims is hospitalization and rehabilitation, which are clearly not intended to target the primary tissue injury and the associated lasting neurological deficits. The numbers of affected individuals, and costs to facilitate their care and rehabilitation, combined with the lack of current therapies reiterates stroke represents a current unmet medical need of significance. Our company has been developing an adult stem cell product for treatment of stroke. We have completed extensive preclinical safety and efficacy studies with our stem cell product and have developed an FDA reviewed manufacturing plan for producing the cells for intravenous administration following stroke. We have received FDA authorization of an IND for using the stem cell product to treat patients suffering from an acute stroke in the first 1-2 days after onset, increasing the window of therapeutic intervention for stroke patients. We are currently enrolling patients in a Phase I clinical study evaluating the safety of the cells in ischemic stroke patients. We are submitting this application requesting funds to do process development to improve the formulation of the cell product to allow for administration of the product at all hospitals, as well as funding to test the stem cell product in a larger Phase II study, evaluating both the efficacy and safety of the cells. Funding this study could accelerate a novel cell based therapy for treating stroke patients who would otherwise have no therapeutic options.
Statement of Benefit to California:
The proposed project could benefit the citizens of California in at least four important ways, including: improving clinical outcomes and enhancing patient quality of life for patients that have suffered a stroke; reducing overall healthcare costs, especially those covered by the taxpayers of California; reducing the loss of economic productivity for working age individuals that suffer long term disability after a stroke, and; by creating high quality jobs in the state. Stroke is a leading cause of death and serious long term disability, and represents a major area of healthcare costs. In 2011 the American Heart Association estimated that approximately 800,000 people suffered a stroke in the U.S. (85 – 90% are ischemic strokes). Roughly half of stroke survivors are disabled or experience permanent weakness on one side of their body. Approximately three-quarters of all stroke victims are over the age of 65, and of these, ~26% require full time institutional care following the stroke, while many others require home care or assistance from family members. According to U.S. Census data, California represents approximately 12% of the national population, which suggests more than 82,000 victims of ischemic stroke annually in California alone (although a 2006 study by the Milken Institute estimated the number of California residents suffering a stroke was more than 240,000 annually). Given the aging demographic profile, and that the risk of stroke increases substantially with age, the number of Californians affected by stroke is expected to increase significantly in the years ahead. The economic burden of stroke is enormous. The national impact of stroke was recently estimated at more than $73 billion annually. Although there have been few efforts to precisely measure the economic impact within the state of California alone, the national data suggests that this exceeds $8.7 billion annually. This includes the cost of hospitalization, extended physical therapy and rehabilitation for patients with permanent weakness on one side of their body or more serious disability, long term institutional care or home care, and the loss in economic productivity. By improving clinical outcomes, and achieving a better quality of life for stroke patients, much of the downstream costs that are currently incurred could be minimized or avoided entirely. Given that most strokes occur in the elderly population, much of this economic impact occurs through the Medicare and Medicaid systems, and is born by the taxpayers of California. Over time, the economic benefits of reducing direct costs and improving productivity could be many billions of dollars for the state. Finally, if CIRM makes the award, it would enable our company to establish a more meaningful commercial presence in the state of California, which could lead to the creation of many high quality jobs over time, such as in research and development, bio-manufacturing, and commercialization.
EXECUTIVE SUMMARY The applicant proposes to use an adult stem cell product to treat stroke. There is currently only one FDA-approved treatment for stroke which must be administered within 4.5 hours of stroke onset, leaving a significant clinical need for other persons experiencing a stroke. This project proposes to use cell therapy to treat patients 24-36 hours after stroke onset. The applicant is currently enrolling a Phase 1 trial to test safety for ischemic stroke patients. The proposal considered here requested funds to conduct process development activities to change the cell therapy formulation and to conduct a Phase 2 clinical trial. Significance and Impact - Stroke represents a significant unmet clinical need, since the only approved treatment, tissue plasminogen activator (TPA), can only be used within a limited time window of stroke onset. - Reviewers did not see convincing data that this cell therapy approach, with a proposed mechanism of action of immune modulation, would have an impact on stroke. Risk/Benefit - Few significant adverse events (SAEs) have been attributed to the cell product in other on-going clinical studies, providing preliminary assurance that the risk may be low; but, potential benefit of this therapeutic candidate for stroke is unclear. - Potential benefit is suggested by data from just one preclinical study report that was published in a journal of modest impact. Other data cited supporting benefit are unpublished. The lack of quantitative histopathology, considered the gold-standard method of outcomes assessment in this indication, was noted as an important gap. - Reviewers discussed whether the target treatment benefit in the proposed trial is an acceptable and clinically meaningful outcome. Design and Feasibility - IND has already been approved, but there was concern about feasibility of the timeline especially with respect to coordinating key manufacturing activities with the clinical program. - Changing the formulation, as is proposed within this study, is not trivial and may affect project feasibility. Specific concern was expressed about the timeline to complete the necessary stability testing. - Insufficient detail was provided to demonstrate the ability to scale production of the therapeutic to the capacity required and show comparability within the proposed timeline. - The trial is a conventional design and feasible with a more homogeneous patient population than has been used in other stroke trials. It was suggested, though, that including patients who have already received other treatment may introduce an additional variable to the study that should be considered in the trial design, perhaps as a stratifying criterion. - Endpoints were judged to be appropriate. The primary endpoint was not as stringent as has been used in other trials. Secondary endpoints were judged to be more stringent. - Additional Phase 1 data with stroke patients is strongly advised before moving into the proposed larger Phase 2 study. Additional clinical studies may further illuminate clinical dose since the preclinical data may not have sufficiently narrowed the possible dose range. - Go/No Go decision points were not clearly identified in the research plan. Principal Investigator (PI), Development Team and Leadership Plan - The PI does not have development experience beyond Phase 2 so there was concern about reliance on the contractor for product development expertise. - Clinical sites indicated are satisfactory with appropriate expertise to conduct the proposed study. Collaborations, Assets. Resources and Environment - The Contract Manufacturing Organization (CMO) identified is a recognized leader but reviewers were unclear whether they have the resources and capacity immediately to scale up this product within the proposed timeline. - Some considered the plan to have a CMO address the process changes a risk. 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. - Reviewers deferred to CIRM to ascertain how much of the proposed budget would actually be spent in California.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. Discussion reiterated concerns related to limited preclinical data, lack of evidence that this therapeutic approach will benefit stroke, and concerns regarding manufacturing within the proposed timeline. Since other trials are ongoing for stroke, reviewers were not convinced of a programmatic reason for CIRM to fund the proposed study as submitted. The motion carried.
- Charles S. Cox