PROTECTION AMI Inhibition of d -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction

1. Heart and Vascular Institute A. Michael Lincoff, M.D. Director, C5Research (Cleveland Clinic Coordinating Center for Clinical Research) Vice Chairman for Clinical Research, Lerner Research Institute Vice Chairman of Cardiovascular Medicine Professor of Medicine Late Breaking Clinical Trials – ACC 2011 PROTECTION AMI Inhibition of d-Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction

2. Speaker Disclosure – A. Michael Lincoff, MD Relationships with Industry Research Sponsors Consultant • Schering-Plough • Bioline • BMS • Merck • Baxter • Aztra Zeneca • Roche • Anthera • AstraZeneca • Atherosys • Bristol-Myers Squibb (BMS) • Centocor • Cordis • Guidant • Heartscape • J&J • KAI Pharma • Lilly • Mannkind • Medicines Company • Medtronic • Novartis • Novo Nordisk • Pfizer • Resverlogix • Roche / Genentech • Sankyo • Sanofi-Aventis • Schering-Plough • Scios • Takeda • VasoGenix

3. dPKC in Ischemia-Reperfusion Injury dPKC Activation in Response to IR Injury • activated in a variety of human, rodent and pig cells exposed to ischemic conditions in vitro and in vivo • during reperfusion, activated dPKC translocates to the mitochondria and mediates necrosis and apoptosis • dPKC KO mice have reduced free radical production from endothelial cells and decreased damage following cardiac ischemia, and reduced infarct size after stroke.

4. Delcasertib Peptide Inhibitor of PKC Localization - Selective Inhibitor • disrupts binding of activated dPKC with its RACK (Receptor for Activated C-Kinase) • reaches steady state within 5 - 30 minutes after the start of infusion, terminal T1/2 of 2 to 5 minutes • well-tolerated across range of doses • Animal Models: • reduced infarct size, myocyte and endothelial cellular damage • enhanced recovery of myocardial metabolic activity and regional LV function • improved infarct zone microvascular flow Ikeno F et al. Cardiovasc Res 2007;73:699-709

5. CK-MB AUC ST Recovery AUC 0.05 mg 0.5 mg 1.25 mg 5.0 mg Concurrent Placebo DELTA MI Trial Intracoronary Delcasertib in 1o PCI for Anterior STEMI Dose Escalation Phase 1/2 Trial – 154 Evaluable Patients Roe MT et al. Circulation 2008 117: 857-859

6. international, multi-center Phase 2b trial • randomized, placebo-controlled, double-blind, parallel group • acute STEMI subjects undergoing primary PCI Delcasertib in STEMI Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarction (PROTECTION AMI) Study Hypothesis: intravenous administration of delcasertib will reduce infarct size in subjects with anterior ST elevation myocardial infarction (STEMI) undergoing primary PCI.

7. Trial Design Inclusion and Exclusion Criteria • Acute STEMI with planned primary PCI • Cardiac ischemia for at least 30 minutes, arriving at PCI facility within 6 hrs of symptom onset • Persistent ST elevation of: • ≥ 2 mm in at least two contiguous precordial leads (V1-V4) (anterior STEMI cohort) • ≥ 2 mm in two inferior leads (II, III, aVF) with ST depression in two other contiguous leads - total ≥ 8 mm (inferior STEMI cohort) • Prior CABG • LBBB or paced rhythm • Persistent SBP <90 mm Hg unresponsive to IV fluids • Vasopressors or inotropes • ESRD on dialysis • Severe hepatic dysfunction • Fibrinolysis within prior 72 h • Pregnancy or breastfeeding • Suspicion of non-thrombotic cause of ST elevation

8. Trial Design Endpoints • Primary • CK-MB area under the curve (AUC) • Secondary • ECG – continuous 24 hr AUC and ST recovery • CK-MB Peak; Troponin I and CK AUC and Peak • Clinical Events – death, heart failure (HF), or serious ventricular arrhythmia through 1 year • Serum NT-pro-B-type natriuretic peptide level at 3 months • LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior STEMI cohort only

9. Trial Design STEMI to Undergo Planned Primary PCI Anterior Cohort ~908 Patients (227 per group) Inferior Cohort ~150 Pts (75 per group) Randomize 1:1 Randomize 1:1:1:1 Placebo Delcasertib 50 mg/hr Delcasertib 150 mg/hr Delcasertib 450 mg/hr Placebo Delcasertib 450 mg/hr Study drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomization Cardiac catheterization and PCI per standard of care Serial cardiac enzymes x 72 h 12-lead ECG monitoring x 24 h Clinical Endpoints, NT-Pro BNP and MUGA* at 3 months

10. Statistics Sample Size Calculations • Primary analysis and sample size based upon anterior MI cohort • Inferior MI cohort exploratory – sample not statistically based • Randomization stratified by region and Killip Class I vs II/III Assumptions • CK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mL • 20% reduction in mean with delcasertib • a = 0.05 (2-sided); b = 0.80 • Target 227 patients per Rx group – total 908 in anterior cohort

11. A. Michael Lincoff (PI) Mitchell Krucoff (Co-PI) Matthew Roe, USA John Galla, USA Phil Aylward, Australia Andrezej Rynkiewcz, Poland Victor Guetta, Israel Micheal Zelizko, Czech Republic Neal Kleiman, USA Tamàs Forster, Hungary Antonio Fernández-Ortiz, Spain Harry Suryapranata, Netherlands David Erlinge, Sweden Svend Eggert Jensen, Denmark Harvey White, New Zealand Danny Schoors, Belgium Peter Radke, Germany Shamir Mehta, Canada Shaun Goodman, Canada Dan Atar, Norway Michael Laine, Finland Jorge Manuel dos Santos Ferreira, Portugal Guido Belli, Italy Academic Leadership Steering Committee / National Coordinators Operations Committee

12. Cleveland Clinic Coordinating Center for Clinical Research Ellen McErlean, RN – Project Mnger Trial Sponsors Gregory Bell, MD - KAI Fred Fiedorek, MD - BMS Data Safety Monitoring Committee Michel Bertrand, MD - Chair Christopher Cannon, MD David Holmes, MD Kerry Lee, PhD CRO Medpace, Inc Cincinnati, OH Trial Organization

13. Enrollment Dec 4, 2008 - June 21, 2010 18 Countries 114 Hospitals 1176 Patients Randomized Enrollment Country National Coordinator Patients Poland Prof. Andrezej Rynkiewcz 226 Israel Prof. Victor Guetta 222 Czech Republic Dr. Micheal Zelizko 133 Australia Prof. Phil Aylward 85 United States Dr. Neal Kleiman 77 Netherlands Dr. Harry Suryapranata 53 Hungary Prof. Tamàs Forster 52 Spain Dr. Antonio Fernández-Ortiz 50 Sweden Prof. David Erlinge 49 Denmark Dr. Svend Eggert Jensen 45 New Zealand Dr. Harvey White 45 Belgium Dr. Danny Schoors 39 Germany Dr. Peter Radke 28 Canada Drs. Shamir Mehta/Shaun Goodman 23 Norway Dr. Dan Atar 22 Finland Dr. Michael Laine 19 Portugal Dr. Jorge Manuel dos Santos Ferreira 12 Italy Dr. Guido Belli 1

14. Enrollment Top 10 Enrolling Sites

15. 1010 patients randomized 166 patients randomized 11 patients not treated 2 patients PCI only 5 patients not treated 2 patients PCI only 997 patients treated with study drug 159 patients treated with study drug 86 patients no PCI 4 patients no PCI 911 patients treated with study drug and PCI 155 patients treated with study drug and PCI Patient Flow Anterior STEMI Cohort Inferior STEMI Cohort Treated Population Treated Population Efficacy Population Efficacy Population

16. Demographics and Treatment Anterior MI Cohort, Treated Population

17. Treatment Times Anterior MI Cohort, Treated Population

18. Mean and SEM p = 0.337 Mean and SEM p = 0.715 N=228 N=229 N=227 N=227 N=228 N=229 N=227 N=227 1o Endpoint – Anterior MI CK-MB Enzymes – Efficacy Population

19. Mean and SEM p = 0.523 Mean and SEM p = 0.420 ECG – Anterior MI Continuous 24 hr ECG – Efficacy Population

20. Clinical Events – 3 Months Anterior MI Cohort, Treated Population

21. Mean and SD Mean and SEM % of Pts with EF <30% 8.6% 5.1% 7.3% 9.0% N=197 N=189 N=186 N=186 N=193 N=190 N=187 N=180 MUGA and NT-Pro BNP 3 Month Outcome Anterior MI Cohort, Efficacy Population

22. TIMI 0/1 TIMI 2/3 p = 0.145 p = 0.186 Outcome by Pre-PCI TIMI Flow Anterior MI Cohort

23. p = 0.845 p = 0.962 p = 0.248 Inferior MI Cohort ST Recovery AUC CK-MB AUC NT-Pro BNP

24. Delcasertib in STEMI PROTECTION AMI - Conclusions • Delcasertib, administered IV prior to and during primary PCI for acute anterior STEMI, did not reduce myocardial infarct size or improve clinical outcome. • No differences in biomarkers of: • enzymatic infarct size • ECG markers of reperfusion • LV function by 3 months • NT-Pro BNP Other potential applications to IR injury yet to be investigated

25. Heart and Vascular Institute