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 The LateTIME Randomized Trial: The LateTIME Randomized Trial: Effect of Intracoronary Delivery of Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Autologous Bone Marrow Mononuclear Cells 2-3 Weeks following AMI Cells 2-3 Weeks following AMI JAMA 2011; 306:

Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) Data Coordinating Center UTSPHMoyé NHLBISkarlatos Texas Heart InstituteWillerson InstituteWillerson U FL Pepine PepineClevelandClinicEllisClevelandClinicEllisMinneapolis Heart Institute HenryMinneapolis HenryVanderbiltUniversityZhaoVanderbiltUniversityZhao Cell Processing Steering Committee ChairSimariChairSimari Skills Development Core Skills Development Core Skills Development Core Skills Development Core Cell Processing QC Lab Core Labs Biorepository, cMRI, Echo, MVO 2, SPECT Core Labs DSMBDSMB PRCPRC 2 PDC P & P Satellites: DeBakey VA Satellites: DeBakey VA Satellites: United Heart & Vascular Clinic Metro Cardiology Consultants U MN Mayo Clinic Satellites: United Heart & Vascular Clinic Metro Cardiology Consultants U MN Mayo Clinic Satellites: Pepin Heart Institute Satellites: Pepin Heart Institute Satellites: University Hospitals Satellites: University Hospitals

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 33

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 10 6 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 LateTIME Study Design Infuse product via LAD

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

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 Manual Sepax 6

Baseline Characteristics 7

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

9 Cell Characteristics

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

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

Indexed MRI Volumes and Total Infarct Volume Across All Segments 12

13

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

Acknowledgements 15 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