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.
A) Pre-clinical: The remainder of the IND-enabling studies for the development candidate MSC/VEGF were designed in consultation with Biologics Consulting Group (BCG). The project will begin with the IND-enabling phase and transition through regulatory approvals and through the Phase I clinical trial. The project has a Preclinical unit under the leadership of co-PI Dr. Jan Nolta, and a Clinical unit under the leadership of PI Dr. John Laird. The two units are well integrated, since the team has been meeting frequently since 2008 to plan the testing of the current and prior development candidates. The team is currently performing a Phase I stem cell therapy to test a medical device, as the result of those interactions. During the planning phase we met weekly, and worked continually on the MSC/VEGF project.
Co-PI Jan Nolta, Ph.D. is Scientific Director of the UC Davis/CIRM GMP Facility. Dr. Nolta’s team is expert in translational applications of gene-modified MSC at the level of GLP. The Pre-Clinical team is performing all IND-enabling studies for MSC/VEGF, and will manufacture and qualify the MSC and MSC/VEGF products in the GMP facility at UC Davis that is directed by Dr. Bauer (CMC lead). These studies are ongoing and we have been advised by BCG consulting lead Andra Miller, who was formerly Gene Therapy Group Leader at the FDA, CBER, Division of Cell and Gene Therapies. BCG is assisting with preIND preparation, through the planning grant period funding for this project.
B) Clinical: The Clinical team is led by PI John Laird MD, Medical Director of the UCD Vascular Center, who is an internationally recognized leader in the field of peripheral vascular interventions. He is the PI for multicenter and multinational trials to evaluate novel treatments for peripheral arterial disease. He has led clinical trials investigating the use of FGF-1, Hif, and VEGF to treat claudication and CLI. Christy Pifer is the experienced Project Manager who will guide the entire process. She is the Vascular Center’s clinical trials manager and orchestrates accrual of patients to all trials, including one ongoing Phase I stem cell clinical trial and another pending, as well as a Phase III gene transfer clinical trial. Ms. Pifer has coordinated over 100 Phase I, II and III clinical trials over the past 12 years. The planning grant allowed Ms. Pifer to contribute significant amounts of time to conducting meetings and designing the clinical study with Dr. Laird and other Vascular Center faculty. We had weekly meetings with the clinical and translational team members to finalize the CIRM Disease Team Grant Application.
C) Consultant meetings conducted through the Planning Grant Mechanism:
- Paragon was chosen as our CRO for the proposed trial. We had on-site meetings and conference calls with Paragon during the planning phase.
- Our consultant Dr. Andy Balber, was a Founder, and for ten years served as the CSO of Aldagen, Inc. At Aldagen since 2000, he helped the Company establish and maintain a clinical program during which patients were treated with stem cell products under seven cleared INDs. Dr. Balber has assisted our team with preparation of the preIND application, and will assist with further dialog with the FDA. We met frequently through conference call and email, and he edited our Disease Teams Grant proposal.
- Andra Miller, Director, Cell and Gene Therapy, Biologics Consulting Group, Inc, is a consultant for the development of regulatory strategies to facilitate rapid development of our cell and gene based therap. She and her team are providing support for CMC submission, pre-IND, RAC and IND preparation, Phase I product development strategies and assessment of cGLP compliance. Dr. Miller was Gene Therapy Group Leader for the Division of Cellular and Gene Therapies, Office of Therapeutics of FDA's Center for Biologics Evaluation and Research, for ten years. We met through conference call and email during the Planning Grant period and she edited our Disease Teams grant application.
Partner PI group: Dr. Herrera from the Reina Sofia Hospital, Cordoba University, Andalucia, is our partner, identified through the planning grant phase. Her team is currently performing clinical trials of MSC injections for CLI using intra-arterial administration. Now, using the strong development candidate MSC/VEGF, the two teams will each embark upon parallel clinical trials in their respective countries, each capitalizing on their own team’s stem cell delivery strengths to patients at the same stage of no option CLI. The two teams will use similar inclusion and exclusion criteria and will work closely together, if funded, to develop Phase I trials that are highly similar except for the route of injection. We had Skype and conference call meetings with interpreters, and frequent email contact during the Planning Grant phase. This partnership would not have been possible without the CIRM Planning Award.