Jay H Traverse, MD Principal Investigator, LateTIME Study

1. The LateTIME Randomized Trial: Effect of Intracoronary Deliveryof Autologous Bone Marrow Mononuclear Cells 2-3 Weeks following AMI Jay H Traverse, MD Principal Investigator, LateTIME Study Minneapolis Heart Institute at Abbott Northwestern Hospital University of Minnesota Medical School Cardiovascular Cell Therapy Research Network 2011 Scientific Sessions of the AHA JAMA 2011; 306:2110-19

2. Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) NHLBI Skarlatos DSMB PRC Chair Simari PDC P & P Steering Committee Data Coordinating Center UTSPH Moyé Cell Processing QC Lab Biorepository, cMRI, Echo, MVO2, SPECT Core Labs Skills Development Core Skills Development Core Texas Heart Institute Willerson U FL Pepine Cleveland Clinic Ellis Minneapolis Heart Institute Henry Vanderbilt University Zhao Cell Processing Cell Processing Cell Processing Cell Processing Cell Processing Satellites: DeBakey VA Satellites: Pepin Heart Institute Satellites: University Hospitals Satellites: United Heart & Vascular Clinic Metro Cardiology Consultants U MN Mayo Clinic 2

3. Rationale for LateTIME • Optimal timing for cell delivery post-AMI is unknown • Almost all BMC Trials delivered cells ≤7 days post-AMI • Cell delivery 2-3 wks post-MI may be an important time period for for patients: • -initially too sick, or • -presenting to hospitals without these capabilities 3 3

4. LateTIME Study Design Infuse product via LAD Study Aim: assess safety and efficacy of autologous BMCs delivered 2-3 wks post-MI on LV function Target Population: 87 patients w/first large MI, reperfused by PCI + stent, with residual LV dysfunction (EF≤45%) Treatment: 150 x 106 autologous BMCs or placebo delivered by intracoronary infusion (Stop Flow) 1⁰ Endpoints: change in global and regional LV function from baseline to 6 months by cardiac MRI. Secondary Endpoints: change in infarct size and LV Volumes 4

5. LateTIME STUDY FLOW Primary Measures cMRI IC Treatment Baseline cMRI Index AMI Informed Consent Echo EF≤45% CELL PRODUCT R 14-21 Days Double Blind Phase 6 Months Follow Up CELL-FREE PLACEBO Meets Inclusion/ Exclusion Criteria PCI + Stent Bone Marrow Aspiration/ Cell Processing IC Treatment Primary Measures cMRI R= Randomization

6. Automated Cell Processing First BMC Trial to utilize local, automated cell processing Validated by extensive pre-clinical testing Sepax System Automated processing Includes cell washing Closed system Sterile disposable set MNC Ficoll Sepax Manual

7. Baseline Characteristics

8. Medians of MI and Treatment Related Times BMC (N=58) Placebo (N=29)

9. Cell Characteristics

10. Primary Endpoint: Global The change in LVEF difference was not significantly different between BMC and Placebo 10

11. Primary Endpoint: Regional Difference in changes of wall motion in the infarct and border zone were not significant between BMC and Placebo 11

12. Indexed MRI Volumes and Total Infarct Volume Across All Segments

14. Conclusions Intracoronary delivery of autologous BMCs 2-3 weeks following primary PCI + stenting after moderate to large acute MIs is safe. No benefit of BMC therapy on global and regional LV function is observed at 6 months by c MRI. 14

15. Acknowledgements • National Heart Lung & Blood Institute • Biosafe • Boston Scientific • The clinical centers (Cleveland Clinic, Minneapolis Heart Institute, Texas Heart Institute, University of Florida, and Vanderbilt University), their satellites (University Hospitals, St. Paul Heart Clinic, Metropolitan Cardiology Consultants, University of Minnesota, Mayo Clinic, DeBakey VA, and Pepin Heart Hospital) and their research teams • University of Texas School of Public Health • Center for Cell & Gene Therapy, Baylor College of Medicine • The University of Florida cMRI and Cleveland Clinic Echo core labs • The University of Minnesota and University of Florida Biorepositories