Critical limb ischemia (CLI) represents a significant unmet medical need without any approved medical therapies for patients who fail surgical or angioplasty procedures to restore blood flow to the lower leg. CLI affects 2 million people in the U.S. and is associated with an increased risk of leg amputation and death. Amputation rates in patients not suitable for surgery or angioplasty are reported to be up to 30-50% after 1 year. Patients who are not eligible for revascularization procedures are managed with palliative care, but would be candidates for the proposed phase I clinical trial.
In an effort to combat CLI, prior and ongoing clinical trials that our group and others have conducted have evaluated direct injection of purified growth factors into the limb that has low blood flow. Some trials have tested plasmids that would produce the blood vessel growth factors for a short period of time. These therapies did show benefit in early stage clinical trials but were not significantly better than controls in Phase III (late stage) trials, probably due to the short duration of presence of the growth factors and their inability to spread to the areas most needed. Other clinical trials ongoing in our vascular center and others are testing the patient’s own stem cells, moved from the bone marrow to the damaged limb, and those studies are showing some benefit, although the final assessments are not yet completed. Stem cells can have benefit in limb ischemia because they can actively seek out areas of low oxygen and will produce some growth factors to try to encourage blood vessel growth. But in cases where the circulation needs very high levels of rescue, this strategy might not be enough.
As an improved strategy we are combining the stem cell and growth factor approaches to make a more potent therapy. We have engineered human Mesenchymal Stem Cells (MSCs) to produce high levels of the strong angiogenic agent VEGF for this novel approach (MSC/VEGF). We and others have documented over the past 20+ years that MSC are capable of sustained expression of growth factors, migrate into the areas of lowest oxygen in the tissues after injection, and wrap around the damaged or tiny blood vessels to secrete their factors where they are needed most.
These MSC/VEGF cells are highly potent, safe and effective in our preclinical studies. These human stem cells designed to produce VEGF as “paramedic delivery vehicles armed with growth factor to administer” rapidly restored blood flow to the limbs of rodents who had zero circulation in one leg. With funding that could be potentially obtained through the proposed application we will follow the detailed steps to move this candidate therapy into clinical trials, and will initiate and complete an early phase clinical trial to test safety and potential efficacy of this product that is designed to save limbs from amputation.
Critical Limb Ischemia (CLI) represents a significant unmet medical need without any curative therapies in its end stages, after even the best revascularization attempts using sophisticated catheters, stents, and bypass surgeries have failed. CLI affects over 2 million people in the US and the prevalence is increasing due to the aging of our population and the diabetes epidemic. In 2007, the treatment of diabetes and its complications in the USA generated $116 billion in direct costs; at least 33% of these costs were linked to the treatment of ischemic foot ulcers, associated with CLI. Once a patient develops CLI in a limb, the risk of needing amputation of the other limb is 50% after 6 years, with devastating consequences. Treatment costs are immense and lives are significantly shortened by this morbid disease.
The symptoms associated with this very severe form of lower extremity peripheral artery disease (PAD) are pain in the foot at rest, non- healing ulcers, limb/digital gangrene and delayed wound healing. The quality of life for those with CLI is extremely poor and reported to be similar to that of patients with end stage malignancy. Most patients with CLI will undergo repeat hospitalizations and surgical/endovascular procedures in an effort to preserve the limb, progress to immobility and need constant care. Unfortunately, the limb salvage efforts are often not effective enough, and despite multiple attempts at revascularization, the wounds still fail to heal. The final stage in 25% of cases is limb amputation, which is associated with a high mortality rate within 6 months. Amputation rates in patients not suitable for revascularization are reported to be up to 30-50% after 1 year. Fewer than half of all CLI patients achieve full mobility after an amputation and only one in four above-the-knee amputees will ever wear a prosthesis.
Between 199– 1999, over 28,000 first time lower extremity bypass procedures were performed in California for CLI, and 29% of patients were admitted to the hospital for at least one subsequent bypass operation or revision procedure. The 5-year amputation free survival rate for this group of CLI patients from California was only 51.1%. The direct costs to California for the treatment of CLI and diabetic ischemic ulcers are substantial.
The lost ability of no-option CLI patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. The goal of the proposed study is to develop and apply a safe and effective stem cell therapy to save limbs from amputation due to disorders of the vasculature that currently cannot be cured. The successful implementation of our planned therapies will significantly reduce the cost of healthcare in California and could bring people currently unable to work due to immobility back to the workforce and active lifestyles, with a significantly improved quality of life.
The applicant’s goal is to submit an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and complete a phase 1 clinical trial for the use of banked allogeneic mesenchymal stem cells (MSCs) engineered to secrete vascular endothelial growth factor (VEGF) for the treatment of critical limb ischemia (CLI). CLI occurs when blood flow to the feet or legs is restricted and can result in limb amputation or death in patients where surgical and angioplasty treatment options have been exhausted. While systemic VEGF treatment did not prove sufficiently efficacious in Phase III trials, the applicant proposes that sustained expression of VEGF and localized delivery to areas of hypoxic injury using MSC-based delivery system will lead to improvements in these patients for whom existing treatment options have been exhausted. The primary endpoint of the proposed Phase I trial will be the demonstration of safety in no-option CLI patients, however, secondary endpoints will include the measurement of angiogenesis and limb salvage.
Significance and Impact
- The unmet medical need for no-option CLI patients is immense, and the proposed product, if successful, would provide benefit to patients with little alternative other than amputation.
- Clinical trials are ongoing using MSC to treat CLI and the success of those trials could decrease the impact of developing this MSC delivered VEGF approach unless VEGF inclusion offers significant additional benefit.
- The target product profile (TPP) is a protocol synopsis for the Phase 1 trial rather than a true TPP. Reviewers recommended that the applicants utilize the FDA guidance document (Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool for instructions on how to prepare a TPP) in preparing the TPP should a full application be submitted.
- The application is fully responsive, as a single development candidate has been proposed that meets the criteria set forth in the RFA.
Project Rationale and Feasibility
- The proposed project is sufficiently mature and completion of the IND-enabling and the Phase I studies is realistic.
- The high quality preclinical data is compelling, supportive of the hypothesis that MSC-mediated delivery of VEGF will lead to production of therapeutic levels of VEGF at the site of injury in CLI patients, and is relevant to the proposed Phase I study.
- The applicant provides a clear rationale, which is justified by the available evidence.
- The therapeutic approach, though not particularly innovative given the completed and ongoing trials with VEGF and MSCs, is feasible.
- The proposed Phase I trial is appropriate for the stage of development, and its design supports advancement of this technology and addresses the major question of whether MSC-mediated delivery of VEGF provides additional efficacy as compared to VEGF or MSCs alone.
- The reviewers noted several areas of poor grantsmanship where additional information or clarity is necessary should a full application be submitted (outlined in the remaining bullet points).
- The application does not clearly state which IND-enabling studies are completed and which still need to be performed nor does it clearly describe the planned safety-toxicology studies. Further, safety issues regarding unwanted angiogenesis and tumorigenesis need attention in the full application, if submitted.
- The regulatory timeline needs clarification. It is not clear when the pre-IND meeting will occur as compared to submission of the IND. The timing of this meeting is critical as FDA feedback can result in additional studies and impact the planned IND submission date.
- Though experience from other trials may provide sufficient evidence for the feasibility and sustained activity of allogeneic cell grafts in the absence of immunosuppression, the applicants should address this issue.
- The CMC section indicates that the transduced MSC bank will be used for all proposed patients for the phase 1 trial, but the trial design calls for a subset of patients to receive control MSCs. This discrepancy should be clarified.
- Several CMC items that were marked as completed in the checklist are briefly described in the proposal overview and included in the milestones so it is not clear what has actually been completed and what needs to be completed.
- It is unclear whether the applicant intends to start or complete the Phase I study as one section of the application indicates that accrual for the Phase I study will be completed at the end of 4 years and another section suggests that the 6-month follow-up will be completed on all patients.
Principal Investigator (PI) and Planning Leader
- The PI has outstanding qualifications and is an internationally renowned physician-scientist in translational vascular research. S/he has significant and appropriate experience in vascular clinical trials, though his/her specific contributions to translational research involving the development candidate are not clearly stated.
- The planning leader is sufficiently qualified with a professional history in managing and coordinating clinical research. However, his/her pivotal role in regulatory issues involving the FDA is not clear in the application.
- Andrew Balber