Allogeneic Cord Blood with NANEX Expansion for Critical Limb Ischemia

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1 Allogeneic Cord Blood with NANEX Expansion for Critical Limb Ischemia Christopher J. Cooper 1, M.D. Vincent Pompili 2, M.D., Gerald Zelenock 1, M.D., Nancy Collins 1, Ph.D., and Sakthivel Ramasamy 3, Ph.D., for the CLI Expanded Cord Blood Trial Group 1. University of Toledo, 2. Ohio State University, 3. Arteriocyte Inc.

2 Conflicts of Interest Research grant funding from: Arteriocyte Pfizer Cordis GlaxoSmithKline Centocor NIH AstraZeneca

3 Critical Limb Ischemia (CLI): Approximately 150,000 Americans undergo amputation annually for CLI Surgical or endovascular revascularization is first-line treatment, but many patients are poor candidates or are not revascularizable Results with alternative therapies have been disappointing Ramsey SD, N.K., Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 22, (1999). Dormandy, J., Verstraete, M., Andreani, D., et al. Second European consensus document on chronic critical leg ischemia. Circulation 84, 1-26 (1991). Brem, H., et al. Wound-healing protocols for diabetic foot and pressure ulcers. Surg Technol Int 11, (2003).

4 Cellular Therapy for CLI Several studies have or are evaluating autologous bone marrow or peripheral blood-derived stem cell preparations to promote angiogenesis Whether in humans such cells participate directly in new vessel development, or exert direct vasculogenic paracrine effects, non-specific inflammatory, or have no biologic role in new vessel growth remains unclear

5 Limitations of Autologous Cell Therapy Cells derived from diabetics appear to have lower functional capacity Advanced age may also have a deleterious effect on the robustness of autologous stem cells Both advanced age and diabetes are prominent risk factors for CLI Fadini, G.P.,, et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 26,, (2006). Schatteman, G. Are circulating CD133+ cells biomarkers of vascular disease? Arterioscler Thromb Vasc Biol 25,, (2005). Schatteman, G.C., Hanlon, H.D., Jiao, C., Dodds, S.G. & Christy, B.A. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106,, (2000).

6 Cord Blood Stem Cells Easily banked product of normal delivery No ethical or religious concerns Commonly used for marrow replacement Compared with bone marrow-derived: Increased HLA mismatch tolerance Decreased GVHD Enhanced proliferative capacity Warwick, R. & Armitage, S. Cord blood banking. Best Pract Res Clin Obstet Gynaecol 18,, (2004) Cornetta, K.,, et al. Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT). Biol Blood Marrow Transplant 11,, (2005). Lubin, B.H.a.G., M.F. Collection and storage of umbilical cord blood for hematopoietic cell transplantation. (2007). Laughlin, M.J.,, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 344,, (2001).

7 Potential Cord Blood Limitations Cell number insufficient Allogeneic sourcing: HLA matching required Tolerance not known Potential for GVHD Not seen with whole cord treatment in immunocompetent hosts 1 Lower rates than with allogeneic marrow transplantation 2 1. N, B. Placental umbilical cord whole blood transfusion: a safe and genuine blood substitute for patients of the under- resourced world at emergency. J Am Coll Surg 200,, (2005). 1. Brown, J.A. & Boussiotis, V.A. Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clinical immunology (Orlando, Fla 127,, (2008).

8 Preliminary Data Cord-derived CD 133+ cells cultured on an aminated nanofiber matrix 225-fold expansion achieved 93% of expanded cells CD34+ and 24% of these cells also CD133+ Control Expanded

9 Pre-Clinical Effectiveness of Nanofiber Expanded Cells Display early endothelial markers: CD31, vwf, VCAM-1, ICAM-1 2x increase in migratory ability

10 Blood Flow in Hind Limb Ischemic Mouse Model Control Fresh CD133+ Expanded CD133+ Baseline After Ligation Day 0 Day 7 Day 14 Day 21 Day 28

11 Nanex Expanded CD133+ Cells Increase Limb Blood Flow and Capillary Density

12 CLI Cord Blood Trial Study Design and Plan

13 Study Population A total of 15 patients are expected Critical limb ischemia with rest pain, tissue loss or gangrene Ankle pressure 50 mmhg or toe pressure 30 mmhg TcPO 2 40 mmhg Independent assessment that no option is available for percutaneous or surgical revascularization.

14 Study Design Prospective Registry Two Phases Phase 1: superficial delivery to evaluate host response to allogeneic cells in absence of immunosuppression 5 patients Phase 2: Direct IM injection of approximately 5 million cells into affected limb in 8 sites 10 patients

15 Safety Plan Safety: Safety: Limb evaluation Skin survey and LFTs for GVHD Retinal exam for untoward proliferation Peripheral blood immunohistochemistry 1-year follow-up

16 Effectiveness Assessment TcPO2 is primary effectiveness surrogate Predicts wound healing, limb viability, and limb salvage 1 May be responsive to changes in limb perfusion 2 Study designed to detect a 10 mmhg difference with 80% power Secondary endpoints: ABI, toe pressure, limb pain, QOL, CTA, limb survival and patient survival 1. Ubbink, D.T., Spinc le, G.H., Reneman, R.S. & Jacobs, M.J. Prediction of imminent amputation in patients with non-reconstructible leg ischemia by means of microcirculatory investigations. J Vasc Surg 30, (1999). 2. Tateishi-Yuyama, E., et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360, (2002).

17 Summary and Conclusion CLI is an important cause of non-traumatic limb loss Nanofiber expanded CD133+, umbilical cord-derived stem cells demonstrate robust promise in the lab The current study will evaluate the safety of UCB-derived treatment of CLI and provide insights into potential for clinical effectiveness in limb preservation