This proposal encompasses three projects, each with the goal of developing a therapy for saving limbs from amputation due to injuries or disorders of the vasculature, skin or bones. The projects will be undertaken by three teams, each dedicated to furthering the development of an independent stem cell therapy that is derived from a patient’s own bone marrow. The first group will undertake the late-stage development and testing of a specific cell population for treating critical limb ischemia (CLI) alongside conventional revascularization options. The second group will focus on the development of a topical cell-based preparation for treating wounds or chronic skin ulcers in patients with diabetes. The third group will compare the potential for specific cell preparations combined with a biodegradable matrix for enhancing bone repair in non-union fractures or avascular necrosis. While the relevant timelines and tasks will vary amongst the projects, the overall culmination of this effort would be the filing an Investigational New Drug application (IND) for each of the three proposed indications.
While this proposal addresses an important medical need, the reviewers were doubtful of its potential for success. Reviewers found the application’s lack of focus to be a critical weakness. The combining of three diverse and tangentially- related projects, each with its own set of feasibility and regulatory challenges, was thought to dilute the significance of the application as a whole and limit the feasibility of the individual efforts. Numerous questions were raised about the rationale and experimental design, and the leadership plan was found to lack cohesion and synergy. Ultimately, the reviewers felt that the majority of the work was insufficiently mature to consider clinical translation under the terms of this award.
In general, reviewers appreciated the scientific rationale for using the proposed cell preparations for regenerative purposes, as it has been reasonably well established that certain marrow-derived populations contribute to healing either by paracrine/angiogenesis or regenerative mechanisms. In particular, one reviewer cited decades of precedent to suggest bone marrow enhances repair of non-union fractures. Another praised the logic of the planned ex vivo treatment of cells with a particular biological agent in order to potentially overcome inhibitory influences in the context of a wound. Despite these affirmations, however, the reviewers were concerned that the applicants omitted key details about the rationale and design for the therapeutic cell sources, leaving open questions as to how the various cell populations would be specifically concentrated, expanded, manufactured or treated prior to administration. Without this clarification, the reviewers could not confidently evaluate these approaches.
From a clinical perspective, the reviewers did not doubt that there is an urgent need for better methods to protect limbs that become damaged from a variety of common and significant disorders, several of which are becoming increasingly prevalent. They argued that any therapeutic that could lessen the risk of amputation would likely lead to substantial improvements in quality of life while decreasing the overall financial burden to society. Despite this promise, however, the reviewers expressed concern that the proposed therapeutics would be competing in a background of established, although not clearly efficacious interventions as well as a number of therapies in the developmental pipeline. Furthermore, while it is possible that success in any one of the proposed indications could be medically significant, there was little hope that this would inform or enhance development of the other two programs due to their differences in approach, cell preparation, disease target and delivery route. As a result, the reviewers questioned the extent to which the broader impact of this work would be felt.
The reviewers judged the overall feasibility of this effort to be limited due to numerous weaknesses in the experimental rationale, approach and design. Of great concern was a lack of preclinical proof of concept data for the combination products that were proposed for wound and bone repair indications. Although preliminary data supported efficacy for the cells alone, the reviewers were not confident that this was sufficient to justify the development studies on the proposed combinations, which consisted of treating cells ex vivo and a cell/matrix composition. While the proof of concept data supporting the CLI therapeutic in vascular repair was much stronger, the reviewers were disappointed at the lack of preclinical evidence to support efficacy in the context of conventional revascularization. Furthermore, they were puzzled that clinical data for a related indication were not included, even though the applicants reported that the results were encouraging. In addition to their criticism of the project’s maturity, the reviewers were concerned that the preclinical models for ischemia and wound repair were not clearly translatable to the targeted human conditions, as they reflect a one-time injury rather than the culmination of years of microvascular pathology. The utility of such models for extrapolating cell dosing data for humans was also a particular concern. Finally, as a logistical consideration, the reviewers questioned the rationale for transferring manufacturing technology from the commercial to an academic sector under the auspices of this award. Without convincing justification, the reviewers viewed this goal as a distraction.
From a development and regulatory perspective, the reviewers had grave concerns about the achievability of this project. First, many of the experiments necessary for IND approval were absent or not adequately addressed, such as the GLP safety studies for ex vivo treated cell preparations and safety/biocompatibility studies for the proposed matrix formulation. Second, the applicants failed to provide a number of pertinent details or alluded to them so vaguely that the reviewers were unable to assess their merit. For example, rather than precisely defining the matrix formulation and structure for the bone repair studies, the applicants provided a very general description, leaving the reviewers to conclude that it might become necessary to obtain even more than three INDs in order for these projects to move forward. Third, the reviewers questioned whether meaningful clinical efficacy data could be gathered in the context of the proposed patient populations. For example, the CLI clinical trial would be performed alongside alternative revascularization treatments, thereby making it difficult to ascribe efficacy to particular intervention. Moreover, the decision to obtain IND-supporting clinical data for the ex vivo cell treatment agent alone in diabetics was questioned, as the proposed route could potentially mask symptoms of acute hypoglycemia and may thereby pose a risk to this target population. As a result of these deficiencies and concerns, the reviewers were compelled to recommend that the applicants recruit a regulatory consultant or a team member with FDA CBER experience in order to help navigate the challenges that are unique to cell therapies.
The reviewers were unsatisfied with the broad and vague milestones that were outlined in the application. As no quantitative metrics of progress were defined, it was impossible to discern how the timeline would progress. The reviewers were also disappointed at the absence of go/no go decision points that would halt the progress of the project or at least spur alternative approaches should unanticipated difficulties or unsatisfactory outcomes arise.
The reviewers acknowledged the experience of the principal investigator (PI) and co-PIs in their respective disease areas, and all were considered to be academically well qualified. The team as a whole, however, was viewed as three independent groups running separate programs, and therefore lacked the focus and synergy that are required to propel this effort forward. The project manager was described as highly qualified with a valuable added expertise, but because of his/her other obligations, the project would likely need a dedicated manager for day-to-day operations and for coordinating all of the moving parts. The reviewers were dissatisfied with the plan for conflict resolution, which described the collegiality amongst the project leaders but did not discuss how hard decisions would be made nor how progress would be critically monitored. Finally, while the budget was not found to be excessive, the reviewers questioned whether the funds requested for GMP production would be sufficient. They also considered it unlikely that each person that was designated at 100% effort would actually be needed at that level for the entirety of this award.
The reviewers described the research environment, which is rapidly becoming a world-class center for regenerative medicine approaches, as a clear strength. Resources were excellent, and documents of support, compliance and collaboration were well secured. The only concerns raised were the location and moderate size of the institution, which could make it difficult to recruit sufficient patients for some of the program studies as outlined, and that the diffuse nature of this project might preclude the efficient, campus-wide collaboration that is usually necessary for the success of translational projects.
In summary, while this proposal addresses a critical unmet need, the reviewers were unconvinced of its merits due to lack of focus, limited feasibility, scientific immaturity and inadequate research and leadership plans.
