Strategic Partnership III Track A
$9 800 000
Recommended if funds allow
Currently, there are no effective therapies for treating severe traumatic brain injury, and there are no stem cell based treatments for severe traumatic brain injury in the CIRM portfolio. This proposal seeks to use a bone marrow derived adult progenitor cell product to treat severe traumatic brain injury in adults within 48 hours after injury. The proposed clinical trial is a Phase 2 clinical trial, meaning it seeks not only to determine safety, but also to determine if there are meaningful clinical improvements following cell therapy treatment. Additionally, the proposed trial will examine whether the cell therapy infusion after traumatic brain injury preserves specific brain structures that typically atrophy/degenerate in the months after injury. The proposed cell therapy product has been used in humans in multiple other clinical trials, demonstrating an excellent safety profile. Substantial pre-clinical (animal) data suggest that the cell therapy product improves functional outcomes by down-regulating the inflammatory response to the initial traumatic brain injury. The inflammatory response, when uncontrolled, can exacerbate the initial injury-ultimately worsening functional outcomes. Positive findings from this trial would accelerate cellular therapies for traumatic brain injury, and offer patients/families more advanced treatment options than are currently available.
Statement of Benefit to California:
The development of a novel treatment using cell-based therapy for traumatic brain injury would benefit California and its citizens in four main ways: (1) Californians with acute, severe, traumatic brain injury would benefit from having access to the most advanced and novel treatment for an injury that presently has no reparative therapies; (2) Expertise gained by California sites will establish these trauma centers as leaders in cell based therapy for traumatic brain injury, forming a critical element of the emerging Alpha Stem Cell Clinic infrastructure for stem cell therapies within the state; (3) Establishing the critical, collaborative clinical trial consortium to execute this trial will attract follow-on studies to be performed in California; and (4) Industry expansion in California will occur to support the trial yielding direct and indirect economic benefit.
Executive Summary This application proposes a Phase 2 clinical trial of bone marrow derived progenitor cells for traumatic brain injury (TBI). TBI is relatively common, with outcomes ranging from complete recovery to permanent disability and death. The applicants propose to test their cell product in severely injured patients within 48 hours of the TBI. The clinical trial is designed to assess safety of the transplanted cells as well as efficacy, as measured by a number of clinical and imaging endpoints. The cell product has been tested in early phase clinical trials for other indications. Activities proposed in this application include cell manufacturing, submission of an Investigational New Drug (IND) application with the Food and Drug Administration (FDA), clinical site initiation and training, patient enrollment and completion of a Phase 2 clinical trial. Significance and Impact - TBI is a devastating condition with no effective treatment and represents a large unmet medical need. - The Target Product Profile is generally reasonable but reviewers questioned whether the minimally acceptable criteria would be sufficient for FDA approval. - The application is responsive to the RFA. Scientific Rationale and Risk/Benefit - Reviewers raised significant concerns about the preclinical data supporting efficacy of the cell product in an animal model of TBI. They questioned whether these data are robust enough to justify moving into clinical trial. - Some reviewers questioned the scientific rationale for the therapeutic approach as well as the proposed mechanism of action. Others suggested that the rationale is supported by preclinical data from the field of stroke. - The proposed patient population, adults who have suffered severe TBI, is appropriate. Therapeutic Development Readiness - The timing to initiate treatment is currently being evaluated in a preclinical animal model to determine the therapeutic window for effective treatment. Reviewers noted that these are critical experiments to complete before designing and embarking on a clinical trial. They felt that funding this application would be premature without the evaluation of data supporting an optimal treatment window. - The applicants have had appropriate regulatory interactions and demonstrated an acceptable safety profile of their cell product when administered to patients in other clinical trials. Design and Feasibility - The current proposed treatment time after injury presents significant logistical challenges and reviewers questioned its feasibility. While preclinical work to support an alternate treatment schedule is ongoing, reviewers noted that data from these studies are not yet available. - Reviewers were concerned that the primary efficacy endpoints proposed for the clinical trial are surrogates, with cognitive and functional measures included only as secondary endpoints. They noted that a positive result with surrogate endpoints may not enable a pivotal trial and recommended adding patients to power the trial for a primary cognitive or functional endpoint if possible. - Reviewers would have appreciated more detail about how blinding would be performed to assure that investigators remain unaware of a patient’s assigned intervention during product administration and patient evaluation. - One reviewer suggested some changes to the proposed clinical protocol to exclude patients with hypotension or hypoxia, lower the percent reduction in oxygen partial pressure that would constitute a serious adverse event, and screen for and exclude patients with a patent foramen ovale. Principal Investigator (PI), Development Team and Leadership Plan - The leadership team is strong and experienced in all aspects of clinical development. - The PI has relevant experience and a documented track record translating stem cell therapies into the clinic. Budget - The budget is generally appropriate. - Reviewers raised minor concerns regarding the budgets for investigators meetings, Institutional Review Board fees, and study site training. Collaborations, Assets, Resources and Environment - The clinical investigators have excellent track records in the field and are capable of conducting the proposed clinical trial. - The manufacturing activities are well established and will be conducted by a respected CMO.
- Andrew Balber
- Carol Danielson
- Stewart Abbot