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Mobilized CD34+ Cells for Refractory Angina:

Mobilized CD34+ Cells for Refractory Angina:. Design and Rationale for the RENEW Study. Thomas J. Povsic, MD, PhD. on behalf of the RENEW Investigators. Grant/Research Support Grant/Research Support. Baxter Healthcare Corporation Revalesio Inc. Disclosure Statement of Financial Interest.

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Mobilized CD34+ Cells for Refractory Angina:

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  1. Mobilized CD34+ Cells for Refractory Angina: Design and Rationale for the RENEW Study Thomas J. Povsic, MD, PhD on behalf of the RENEW Investigators

  2. Grant/Research Support Grant/Research Support Baxter Healthcare Corporation Revalesio Inc. Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company

  3. Scope Estimated that 600,000 – 1.8 million Americans suffer from refractory angina 50,000 – 100,000 new cases per year Increasing incidence Poor QOL Variable outcomes Poor success of novel therapeutics

  4. PROTECT-CAD Trial Treatment effect of bone marrow cells implantation on total exercise time on treadmill test. Tse H et al. Eur Heart J 2007;28:2998-3005

  5. PROTECT-CAD Trial Treatment effect of bone marrow cells implantation on left ventricular ejection fraction as determined by cardiac magnetic resonance imaging. Tse H et al. Eur Heart J 2007;28:2998-3005

  6. Double Blind Placebo Controlled Trial of Treatment of Refractory Angina with BM MNCs van Ramshorst, J. et al. JAMA 2009;301:1997-2004

  7. Double Blind Placebo Controlled Trial of Treatment of Refractory Angina with BM MNCs van Ramshorst, J. et al. JAMA 2009;301:1997-2004

  8. Original Description of Endothelial Progenitor Cells (EPC) in Adults • CD34+ cells isolated • Cultured on fibronectin • Grew into colonies resembling embryonic blood islands Asahara et al. Science 1997;275:964-7

  9. PreClinical Models Treatment Groups 1) PBS: 100 µl 2) Low 34: 5X103 cells/ rat kg 3) Mid 34: 5X105 cells/ rat kg 4) Mid MNC: 5X105 cells/ rat kg 5) High MNC: tMNCs containing Mid EPC dose n=8~10 in each group

  10. Fractional Shortening (%) Regional Wall Motion Score 50 * * 28 * * * 40 * * 30 24 20 10 0 High MNC Low 34 Mid 34 Mid MNC Low 34 Mid 34 Mid MNC 20 High MNC PBS PBS 16 Human CD34 Transplant Improves Left Ventricular Function Post-MI Less fibrosis, more endothelial markers with CD34+ cells Kawamoto et al, Circulation (2006) 114:2163

  11. Phase 1 Randomized, Double-Blind, Placebo Controlled Dose-Escalation Trial of Autologous CD34+ Cell Therapy for Refractory Myocardial Ischemia • Subject population (n=24) • CCS class III or IV Angina • Attempted “best” medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia on SPECT • 1-6 min. Bruce protocol with angina or anginal equivalent at baseline • AICD or LifeVest Screening and Baseline Visits Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day 5 Randomization Placebo 5 x 104CD34+ cells/kg 1 x 105CD34+ cells/kg 5 x 105CD34+ cells/kg Endomyocardial Mapping and Injection with NOGA Isolex selected CD34+ cells / Placebo Rx Follow-up Safety and Efficacy Assessments: 1,2, 4 weeks and 2, 3, 6, 9, and 12 months; ETT at 3, 6, 12 months MRI at 6 months, SPECT at 6 & 12 months

  12. Phase I: The Dose Range is Feasible Actual Auto-CD 34+ Cell Dose Delivered / kg (n = 6 / dose group) Auto-CD 34+ Cell Dose/kg x 104 ( log scale) Losordo D W et al. Circulation 2007;115:3165-3172 Group 1 5 X 104 cells Control No cells Group 2 1 x 105 cells Group 3 5 X 105 cells

  13. Phase I: Angina FrequencyEpisodes per Week +6.5 -4.5 -15.6 -11.6** -12.6 Months 12 month control data is not represented due to control patient cross-over after 6 months **p=0.053 ANOVA between treatment groups Losordo D W et al. Circulation 2007;115:3165-3172

  14. Randomized, Double-Blind, Placebo Controlled Trial of Autologous CD34+ Cell Therapy for Refractory Myocardial Ischemia Screening and Baseline Visits • Subject population (n=167) • 21-80 yrs • CCS class III or IV Angina • Attempted “best” medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia on SPECT • 3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day 5 Randomization 1 x 10^5 CD34+ cells/kg (n = 55) Placebo (n = 56) 5 x 10^5 CD34+ cells/kg (n = 56) Endomyocardial Mapping and Injection with NOGA Isolex selected CD34+ cells / Placebo Rx Follow-up Safety and Efficacy Assessments: 1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months MRI at 6 months, SPECT at 6 & 12 months

  15. Change in Angina Counts

  16. Change in Angina – 12 months

  17. Change in Exercise Capacity

  18. Major Adverse Cardiac Events (12 Months) Pts with MACE events from start of mobilization thru 12 mo in injected pts; *= Fisher’s Exact Test

  19. Major Adverse Cardiac Events (24 Months) Pts. with MACE events from start of mobilization thru 12 mo in injected pts.; *= Fisher’s Exact Test

  20. Efficacy Comparison: Change in ETT

  21. RENEW: • RENEW is the first trial of cell therapy for CV disease designed to fulfill requirements for US regulatory approval • Powered to demonstrate efficacy on clinical endpoints • Largest planned US trial in cell therapy • Largest currently enrolling cell therapy trial in CV disease • RENEW represents a landmark study in the field, setting benchmarks for development of other cell therapies for CV disease. A Prospective, Randomized, Double-Blinded, Active-controlled Study to Determine the Efficacy and Safety of Targeted Intramyocardial Delivery of G-CSF Mobilized Autologous CD34+ Cells For the Improvement In Total Exercise Time in Subjects with Refractory Angina and Chronic Myocardial Ischemia

  22. RENEW Efficacy and Safety Endpoints * MACE: all death, non-fatal MI, CVA, Cardiac rehosp • Primary Efficacy Endpoint • Change in total exercise duration using a standardized Modified Bruce Protocol ETT at 12 months • Secondary Efficacy Endpoints • Change in angina frequency at 12 months • Change in exercise duration and angina frequency at 6 months • Exploratory Endpoints • Incidence of MACE* and SAEs in all subjects

  23. RENEW Study Design Screening and Baseline Visits Randomization Inclusion Criteria: • 21-80 yrs • CCS class III or IV Angina • Attempted “best”medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia w/stress • 3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline • ETT reproducible <20% • 7 angina/wk Exclusion Criteria: • Recent hospitalization • Other angiogenic trials • Must be willing to forgo other angiogenic/experimental txt x 2 years Pre-Qual Committee Central Review 1 x 105 CD34+ cells/kg (n = 200) Active Control (n = 100) Unblinded Standard of Care (n = 100) Cell Mobilization (G-CSF 5 mg/kg/d x 4d) Apheresis on Day 5 Safety Assessments during 24 month follow-up: AEs, SAEs, MACE

  24. Auto-CD34+ Cell Product: Centralized Processing • <48 hrs • <48 hrs • Receive product, NOGA mapping and injection in catheter lab • ISOLEX CD34+ cell selection, syringe preparation, release testing, and shipment to clinical sites • Mobilization, apheresis, and shipment to centralized manufacturing facility • Cell Processing at Centralized Facility • Apheresis at Clinical Site • Injection at Clinical Site • Auto CD34+ Cell Product

  25. RENEW Study Design Screening and Baseline Visits Randomization Inclusion Criteria: • 21-80 yrs • CCS class III or IV Angina • Attempted “best”medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia w/stress • 3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline • ETT reproducible <20% • 7 angina/wk Exclusion Criteria: • Recent hospitalization • Other angiogenic trials • Must be willing to forgo other angiogenic/experimental txt x 2 years Pre-Qual Committee Central Review 1 x 105 CD34+ cells/kg (n = 200) Active Control (n = 100) Unblinded Standard of Care (n = 100) Cell Mobilization (G-CSF 5 mg/kg/d x 4d) Apheresis on Day 5 Intramyocardial Mapping and Injection with NOGA ISOLEX selected CD34+ cells / Placebo Efficacy Assessments during 12 month follow-up: ETT, angina frequency, and QoL (SF-36) Safety Assessments during 24 month follow-up: AEs, SAEs, MACE Safety Assessments during 24 month follow-up: AEs, SAEs, MACE

  26. Monitoring Committees • Steering Committee • Responsible for oversight of study, data interpretation, protocol and amendments, publications • Oversee country activities • Data Safety Monitoring Board • Will be un-blinded and will oversee safety and integrity of study • Recommend changes in study arms • Meetings after 10, 25, 50, 100, 200 and 300 patients • Clinical Events Committee • Blindly adjudicate clinical events • Pre-Qualification Committee

  27. Study Population: Main Inclusion Criteria • Male or female subjects who are 21 to 80 years of age • CCS class III or IV chronic refractory angina • On maximal tolerated doses of anti-anginal drugs • At least 2 of 4 classes recommended • Unsuitable for conventional revascularization as determined at site and confirmed by an independent pre-qualification committee • Objective evidence of inducible ischemia in the potential injection target zone, using clinically accepted assessment of ischemia within 1 year of screening provided the subject has remained clinically stable • LVEF ≥25% at screening. • Minimum average of 7 angina or angina-equivalent episodes per week • Able to complete a minimum of 3 minutes but no more than 10 minutes on a treadmill using the Modified Bruce Protocol during 2 ETTs performed during screening period with ≤ 20% variability • Subject must experience angina or angina-equivalent symptoms at each of the 2 ETTs

  28. Comparator Arms

  29. Statistical Plan • Sample Size • 400 completed subjects • 90% power to detect 60 second difference in mean change from baseline in total exercise time • Statistical Approach • Closed form testing procedure on primary and secondary efficacy endpoints • Allows for potential inclusion of secondary efficacy endpoints in product label

  30. Conclusions • RENEW is the first trial of cell therapy for CV disease designed to fulfill requirements for US regulatory approval • Powered to demonstrate efficacy on clinically important endpoints • Largest planned US trial in cell therapy • Largest currently enrolling cell therapy trial in CV disease • RENEW represents a landmark study in the field, setting benchmarks for development of other cell therapies for CV disease.

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