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. All Rights Reserved, Duke Medicine 2007 Disclosure Statement of Financial Interest Grant/Research Support Baxter Healthcare Corporation Revalesio Inc. 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 RelationshipCompany

3. All Rights Reserved, Duke Medicine 2007 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. All Rights Reserved, Duke Medicine 2007 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 PROTECT-CAD Trial

5. All Rights Reserved, Duke Medicine 2007 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 PROTECT-CAD Trial

6. All Rights Reserved, Duke Medicine 2007 van Ramshorst, J. et al. JAMA 2009;301:1997-2004 Double Blind Placebo Controlled Trial of Treatment of Refractory Angina with BM MNCs

7. All Rights Reserved, Duke Medicine 2007 van Ramshorst, J. et al. JAMA 2009;301:1997-2004 Double Blind Placebo Controlled Trial of Treatment of Refractory Angina with BM MNCs

8. All Rights Reserved, Duke Medicine 2007 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. All Rights Reserved, Duke Medicine 2007 Treatment Groups 1) PBS: 100 µl 2) Low 34: 5X10 3 cells/ rat kg 3) Mid 34: 5X10 5 cells/ rat kg 4) Mid MNC: 5X10 5 cells/ rat kg 5) High MNC: tMNCs containing Mid EPC dose n=8~10 in each group PreClinical Models

10. All Rights Reserved, Duke Medicine 2007 0 10 20 30 40 50 * * * PBS Low 34 Mid MNC Mid 34 High MNC Fractional Shortening (%) 16 20 24 28 PBS Low 34 Mid MNC Mid 34 * * Regional Wall Motion Score High MNC * * Human CD34 Transplant Improves Left Ventricular Function Post-MI Kawamoto et al, Circulation (2006) 114:2163 Less fibrosis, more endothelial markers with CD34 + cells

11. All Rights Reserved, Duke Medicine 2007 1 x 10 5 CD34 + cells/kg 5 x 10 5 CD34 + cells/kg Endomyocardial Mapping and Injection with NOGA Isolex selected CD34 + cells / Placebo Rx Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day 5 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 Screening and Baseline Visits Placebo Randomization 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 5 x 10 4 CD34 + cells/kg

12. All Rights Reserved, Duke Medicine 2007 Phase I: The Dose Range is Feasible Control No cells Group 1 5 X 10 4 cells Group 2 1 x 10 5 cells Group 3 5 X 10 5 cells Auto-CD 34+ Cell Dose/kg x 10 4 ( log scale) Actual Auto-CD 34+ Cell Dose Delivered / kg (n = 6 / dose group) Losordo D W et al. Circulation 2007;115:3165-3172

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

14. All Rights Reserved, Duke Medicine 2007 1 x 10^5 CD34+ cells/kg (n = 55) 5 x 10^5 CD34+ cells/kg (n = 56) Endomyocardial Mapping and Injection with NOGA Isolex selected CD34+ cells / Placebo Rx Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day 5 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 Screening and Baseline Visits Placebo (n = 56) Randomization Randomized, Double-Blind, Placebo Controlled Trial of Autologous CD34+ Cell Therapy for Refractory Myocardial Ischemia 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

15. All Rights Reserved, Duke Medicine 2007 Change in Angina Counts

16. All Rights Reserved, Duke Medicine 2007 Change in Angina – 12 months

17. All Rights Reserved, Duke Medicine 2007 Change in Exercise Capacity

18. All Rights Reserved, Duke Medicine 2007 Control 1x10 5 CD34 +cells /kg5x10 5 CD34 +cells /kg p-value* Death3(5.4%)0(%) 0.107 MI7 (12.5%)3(5.5%)3(5.4%)0.305 Death, MI10(17.9%) 3(5.5%)3(5.4%) 0.058 Death, MI, Urgent Revasc 11(19.6%) 5(9.1%)4(7.1%) 0.106 Death, MI, Urgent Revasc, Worse CHF, ACS 15(26.8%)7(12.7%)7(12.5%)0.093 Pts with MACE events from start of mobilization thru 12 mo in injected pts; *= Fisher’s Exact Test Major Adverse Cardiac Events (12 Months)

19. All Rights Reserved, Duke Medicine 2007 Control 1x10 5 CD34 +cells /kg5x10 5 CD34 +cells /kg p-value* Death7(12.5%)1(1.8%)2(3.6%)0.081 MI10 (17.9%)9(16.4%)6(10.7%)0.587 Death, MI15(26.8%) 10(18.2%)6(10.7%) 0.096 Death, MI, ACS Hospitalization 17(30.4%) 10(18.2%)8(14.3%) 0.101 Death, MI, ACS or Worse CHF Hospitalization 19(33.9%)12(21.8%)9(16.1%)0.078 Pts. with MACE events from start of mobilization thru 12 mo in injected pts.; *= Fisher’s Exact Test Major Adverse Cardiac Events (24 Months)

20. All Rights Reserved, Duke Medicine 2007 Efficacy Comparison: Change in ETT

21. All Rights Reserved, Duke Medicine 2007

22. RENEW: 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 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.

23. All Rights Reserved, Duke Medicine 2007 RENEW Efficacy and Safety Endpoints 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 * MACE: all death, non-fatal MI, CVA, Cardiac rehosp

24. All Rights Reserved, Duke Medicine 2007 1 x 10 5 CD34+ cells/kg (n = 200) Unblinded Standard of Care (n = 100) Cell Mobilization (G-CSF 5 mg/kg/d x 4d) Apheresis on Day 5 Screening and Baseline Visits Active Control (n = 100) Randomization Safety Assessments during 24 month follow-up: AEs, SAEs, MACE RENEW Study Design 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

25. All Rights Reserved, Duke Medicine 2007 Auto-CD34 + Cell Product: Centralized Processing Mobilization, apheresis, and shipment to centralized manufacturing facility Apheresis at Clinical Site ISOLEX CD34+ cell selection, syringe preparation, release testing, and shipment to clinical sites Cell Processing at Centralized Facility Receive product, NOGA mapping and injection in catheter lab Injection at Clinical Site Auto CD34+ Cell Product <48 hrs

26. All Rights Reserved, Duke Medicine 2007 1 x 10 5 CD34+ cells/kg (n = 200) Unblinded Standard of Care (n = 100) Intramyocardial Mapping and Injection with NOGA ISOLEX selected CD34+ cells / Placebo Cell Mobilization (G-CSF 5 mg/kg/d x 4d) Apheresis on Day 5 Efficacy Assessments during 12 month follow-up: ETT, angina frequency, and QoL (SF-36) Safety Assessments during 24 month follow-up: AEs, SAEs, MACE Screening and Baseline Visits Active Control (n = 100) Randomization Safety Assessments during 24 month follow-up: AEs, SAEs, MACE RENEW Study Design 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

27. All Rights Reserved, Duke Medicine 2007 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

28. All Rights Reserved, Duke Medicine 2007 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

29. All Rights Reserved, Duke Medicine 2007 Comparator Arms Blinded Active ControlUnblinded Standard of Care Advantages  Only true double-blind design  Blinding minimizes both subject and assessor bias  Impact of placebo effect on safety endpoints allows for more rigorous comparisons  Allows for assessment of efficacy of the cell product  Regulatory Considerations (combo product)  Safety of Auto-CD34+ cell therapy versus SOC may be assessed  Eliminates potential impact of intervention on cardiac outcomes  Subjects will reflect those of general refractory angina population  Regulatory Considerations Challenges  Potential periprocedural safety risks due to minimal apheresis & femoral artery access  Utility of clinical comparison  May negatively impact subject enrollment and retention (issues with differential retention)  No placebo effect: subjects may have a poorer perception of overall health.  Patients may seek out other options  No reasonable efficacy assessment

30. All Rights Reserved, Duke Medicine 2007 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

31. All Rights Reserved, Duke Medicine 2007 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.