Traumatic Brain Injury (TBI) results from a strong blow or concussive force to the head. The injury to the brain can render the patient permanently disabled. TBI is a common injury. Over 1.7 million people seek treatment for a TBI in the United States each year. A number of treatments are being developed to reduce the short-term brain damage caused by TBI, but no therapies, beyond physical rehabilitation, have proven effective in lessening the long term or chronic effects of TBI. These long-term effects can include movement disorders and cognitive impairment.
An adult stem cell product, derived from the bone marrow of healthy donors, has recently been shown to reverse neurological disorders in rodent models of TBI. This same product is currently being tested in a human clinical trial for stroke patients. The FDA required extensive safety and efficacy testing of this product before permitting the stroke trial to proceed.
This project intends to initiate a clinical trial of this cell therapy product for chronic TBI patients. Much of the work required to initiate an FDA-approved clinical trial has already been done in order to be able to initiate the stroke trial. The cells have been produced according to the FDA’s exacting standards. The cells have been extensively tested for toxicity or unforeseen side effects in animal models. None were found. Mechanism-of-action studies have been ongoing for several years. An additional benefit of the stroke trial is the generation of preliminary safety data in human subjects.
This recent progress means the TBI clinical trial can be initiated fairly quickly. The goal of this first trial will be to determine the feasibility and safety of administering this cell therapy product in chronic TBI patients (a Phase 1 study). Because actual patients will be tested, preliminary efficacy measurements will also be made.
Based on this first TBI study, a second more extensive study will be undertaken. This study will determine the effective dose and ideal target patient profile. Additional safety and efficacy data will also be collected (a Phase 2 study).
Together, these two studies will set the stage for a definitive test of this product’s safety and efficacy for the treatment of chronic TBI (a Phase 3 study). The Phase 3 clinica trial is outside of the scope of this specific proposal and at least several years in the future.
TBI is a complex and as yet unmet medical need. Its effective treatment will most likely require a therapy employing multiple mechanisms. Cell therapy offers a potential solution. The results seen in animal models of TBI are very encouraging. If these results can be translated into human TBI patients, then a true therapeutic option will finally be available.
Statement of Benefit to California:
This project will test the safety and effectiveness of gene-modified stem cells in patients suffering from Traumatic Brain Injury (TBI).
Californians are active people. Californians traverse more freeway miles than the citizens of any other state. Unfortunately, this means Californians suffer a larger number of TBIs. Subsequently, California taxpayers suffer a larger burden paying for the long-term care of permanently disabled TBI patients. No other State stands to benefit as much as California if an effective therapy can be developed for chronic TBI.
This stem cell therapy has been developed at a California-based biotechnology company. The manufacturing processes were developed at a California-based Contract Manufacturing Organization. Initial human safety testing has been led by a major California university. This is a California project supporting many well-paying California jobs and generating significant tax revenue. This trend will continue and grow.
The first part of this project will take place in California. Two major California universities will serve as clinical sites for the proposed Phase 1/2a clinical trial. As the project progresses, clinical sites outside California will be required, but the “center of gravity” will remain in State.
Finally, if an approved therapeutic results from this project it will be available at reasonable cost to Californians by virtue of the financial agreements established with CIRM.
This application proposes two clinical trials of gene-modified mesenchymal stromal cells (MSCs) for chronic, focal, traumatic brain injury (TBI). TBI is a relatively common injury caused by a blow to the head. The outcomes of TBI can range from complete recovery to permanent disability and death. The applicant proposes to test gene-modified MSCs that are currently in clinical trial for stroke in two clinical trials for TBI. The first trial would primarily test safety while the second, larger trial would also test for efficacy. The applicant also proposes scale-up manufacturing activities required to support larger clinical trials.
Significance and Impact
- TBI is a significant unmet medical need with no effective treatment other than physical therapy.
- The Target Product Profile (TPP) does not adequately describe biological activity and the proposed efficacy endpoints are not standard for TBI.
- There is inadequate preclinical data supporting a potential for benefit for the therapeutic candidate in the proposed indication. The one relevant preclinical study was performed in an acute model of TBI that does not reflect the proposed patient population. In addition, this small study did not include appropriate behavioral tests or controls.
- The risks associated with surgical injection into one of the proposed regions may be too great for a Phase I safety study.
- The rationale for gene-modification of the MSCs is not clearly presented or supported by preclinical data in an animal model of TBI.
Design and Feasibility
- Reviewers believed that the proposed patient enrollment is not feasible given the very specific subset of TBI patients targeted by the proposed trials.
- Reviewers noted that the proposed clinical outcome measures may not be the most appropriate for TBI. They recommended adding a trauma neuropsychologist to the team to help revise these measures.
- Reviewers were not convinced that the timeline to enroll and complete both clinical trials is feasible. They recommended inclusion of enrollment tables or registry data from the proposed clinical sites to justify enrollment expectations.
- Reviewers appreciated that the proposed therapy has been evaluated by regulatory bodies and is currently in clinical trial for stroke. However, they were not convinced of the feasibility of the proposed regulatory strategy to leverage the data from this stroke trial. They also cited other regulatory risks that could substantially affect the project timeline.
- The cell manufacturing plan is reasonable and clearly outlined.
Principal Investigator (PI), Development Team and Leadership Plan
- Reviewers noted the presence of an experienced clinical lead investigator but did not get the sense that this individual was involved in the design of the clinical study.
- The PI has clinical experience but reviewers were concerned that the proposed level of effort might be unrealistic given his/her position at the company.
Collaborations, Assets, Resources and Environment
- The clinical sites are appropriate and include a world-class institution for neurology and neurosurgery.
- The contract manufacturing organization is experienced and appropriate.
(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.)
- Large subcontracts to the clinical sites are not well justified.
- Aspects of the manufacturing budget were confusing and poorly justified.