Jay H. Traverse, MD Principal Investigator, TIME Study Minneapolis Heart Institute at Abbott Northwestern Hospital University of Minnesota Medical School Cardiovascular Cell Therapy Research Network (CCTRN) 2013 Scientific Sessions of the AHA The TIME Randomized Trial: One-Year Follow-up on the Effect of Timing of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells on Left Ventricular Function Following STEMI

2 TIME Study Design Study Aim: Assess effects of autologous BMCs and timing of delivery (Day 3 vs. 7) post-STEMI on measures of LV function Target Population: 120 pts w/first ant MI, reperfused by PCI + stent, with residual LV dysfunction (EF≤45%) Treatment: 150 x 10 6 autologous BMCs or placebo by intracoronary infusion (Stop Flow) Primary Endpoints: change in global and regional LV function from baseline to 6 months by cMRI Secondary Endpoints: change in infarct size and LV volumes Subgroups of interest: age, LVEF

Baseline Characteristics 3 Day7 Day BMC N=43 Placebo N=24 BMC N=36 Placebo N=17 P- Value Age in years, mean (SD)55.6 (10.8)57.0 (12.4)58.2 (11.3)57.0 (8.0)0.766 Female (%) White (%) History of: (%) Diabetes High Blood Pressure Hyperlipidemia Smoking Preinfarction Angina (%) Drug Eluting Stent (%) LAD Infarct Artery Qualifying LVEF (echo), mean (SD)36.1 (6.1)37.8 (6.6)36.5 (6.3)36.6 (4.1)0.763 Peak CKMB, median* (IQR)180.9 ( ) ( ) ( ) ( ) *N=29 BMC 3 Day, N=19 Placebo 3 Day, N=31 BMC 7 Day, N=15 Placebo 7 Day

Cell Processing of BMCs Sepax System – Automated local cell processing No significant RBC Contamination Only minuscule amounts of heparin in final product (0.1 U/ml) Sepax vs. Manual Ficoll No difference in cell recovery, migration or CFU ability No difference in recovery of perfusion in murine hind-limb ischemia model No difference in recovery of LV fxn in murine infarct model BMC Ficoll Manual Sepax 4

5 Cell Characteristics

6-Mo Primary Endpoint: Global 6 No difference in the change in LVEF between BMC (n=75) and Placebo (n=37) groups from baseline to 6 months JAMA 2012; 308 (22):2380-9

TIME at 1-Year Follow-up imaging at 1 and 2-years prospectively declared. 112 of 120 patients had analyzable MRIs at 6- months. 95 of 112 patients had analyzable MRIs at 1- year. (ICD=3, death=1, LTF/refused=2, not performed=1, no-show=10). Day-3 MRI utilized as baseline for all patients. Worst-case imputation for incomplete data. 7

Change in LVEF over 1-Year Day 3 vs 1-year: BMC < 0.01; Placebo = NS

Changes in Regional LV Function Infarct ZoneBorder Zone 3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (NS) 3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (p=0.002)

Change in Infarct Size 3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (p<0.001)

Change in LV Volumes Over 1 Year 11 LVEDV (ml/m2)LVESV (ml/m2) Day 36-Month1-YearDay 36-Month1-Year BMC77 ± ± 25 * 89 ± 25 * 42 ±14 45 ± 20 * 46 ± 21 * PLACEBO70 ± ± 23 * 83 ± 22 * 38 ± ± 18 * 43 ± 18 * * P < 0.01 versus Day 3

12 Clinical/Safety Outcomes at 1 Year BMCPlacebo Patients with events18/79 (23%)9/41 (22%) Deaths10 Reinfarctions23 Repeat Revascularizations96 Target Vessel44 Non-Target Vessel52 Hospitalization Heart Failure41 ICD Placements45 Stroke22 Total2217

Conclusions The recovery of LV function following STEMI is not enhanced by BMCs at any time-point. The improvement in global and regional function is nearly complete by 6 months. Infarct size and LV Mass in both groups decreased by 30% over the first 6-months, with a smaller, ongoing decrease out to 1-year. There is a small, ongoing increase in LV volumes 13

Acknowledgements 14 We would like to acknowledge partial funding for this work through the following grants: NIH NHLBI Cardiovascular Cell Therapy Network (CCTRN) under grant# 5 UM 1HL Industry partners: Biosafe and Boston Scientific The Clinical Centers, and DCC (Cleveland Clinic, Minneapolis Heart Institute, Texas Heart Institute, University of Florida, and Vanderbilt University, University of Texas School of Public Health), their satellites (University Hospitals, United Heart & Vascular Clinic, Metropolitan Cardiology Consultants, University of Minnesota, Mayo Clinic, DeBakey VA, and Pepin Heart Institute) and their research teams Core labs (Center for Cell & Gene Therapy, Baylor College of Medicine, University of Florida cMRI and Cleveland Clinic Echo Core Labs, University of Minnesota and University of Florida Biorepositories)

Sonia I. Skarlatos