Lipoprotein- associated Phospholipase A 2 (Lp-PLA 2 ) activity: Background

1. STABILITYStabilization of Atherosclerotic plaque By Initiation of darapLadIbTherapYHarvey D White on behalf of The STABILITY Investigators

2. Lipoprotein- associated Phospholipase A2(Lp-PLA2) activity: Background native LDL carrier of Lp-PLA2 Lp-PLA2 Leukocyte Lumen Atheroma Sustained Inflammation Lp-PLA2 Intima Necrotic Core Expansion Oxidized LDL substrate for Lp-PLA2 Macphee, Biochem J 1999; Zalewski and Macphee, ATVB 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006

3. Characteristics of Stable versus Ruptured Plaques Thick Fibrous Cap Thin Fibrous Cap Modest Lipid Pool Large Lipid Pool Lumen Lumen Lp-PLA2 Lp-PLA2 Stable Plaque • Low Lp-PLA2 content (dark staining) • May have significant stenosis • Thick fibrous cap / high collagen content • Modest lipid pool • Few inflammatory cells Ruptured Plaque • High Lp-PLA2 content (dark staining) • May have minimal stenosis • Thin fibrous cap / low collagen • content • Large lipid pool • Many inflammatory cells Corson et al. Am J Card 2008;101(Suppl):41F-50F

4. Rationale for STABILITY Darapladib is a selective oral inhibitor that decreases Lp-PLA2 by ~60% Association studies Intervention with darapladib EPIDEMIOLOGY Higher Lp-PLA2 levels predict CV events PRECLINICAL Reduces Lp-PLA2 in plaque and necrotic core area (pig) GENETICS Deficiency in Lp-PLA2 due to null allele results in decreased CHD HUMAN ATHEROMA Reduces carotid plaque Lp-PLA2 activity CORONARY IMAGING IBIS-2 Halts progression of coronary artery necrotic plaque core volume PATHOLOGY Up-regulation of Lp-PLA2 in vulnerable plaques

5. STABILITY Trial Study Design Patients with chronic CHD (prior MI >1 mth, prior coronary revascularization, multivessel CAD) Enrichment criteria: ≥60 years of age, diabetes mellitus, low HDL, current smoking, significant renal dysfunction, polyvascular disease 15,828 patients randomized Darapladib 160mg daily Placebo Optimized guideline-recommended treatment Median follow-up 3.7 years, 1588 events Primary endpoint: composite of CV death, MI, stroke Secondary endpoints: major coronary events, total coronary events Design paper reference: White H, et al. Am Heart J 2010;160:655-61.

6. Global Recruitment (N=15,828) North America (25%) Western Europe (22%) Eastern Europe (22%) USA 3102 Canada 780 Mexico 141 Belgium 202 Denmark 102 France 250 Greece 187 Germany 1089 Italy 256 Netherlands 444 Norway 113 Spain 474 Sweden 299 UK 184 Bulgaria 222 CzRepublic 774 Estonia 77 Hungary 410 Poland 510 Romania 411 Russia 654 Slovakia 120 Ukraine 353 E & SE Asia China 369 Korea 503 HongKong 117 Taiwan 200 Japan 318 India 398 Pakistan 250 Thailand 207 Philippines 219 Australia 306 NewZealand 202 South America Argentina 542 Brazil 384 Chile 195 Peru 78 SouthAfrica 386 Asia-Pacific/Latina (31%)

7. Demographics

8. Chronic Coronary Heart Disease Qualifying Diagnosis

9. Enrichment Criteria

10. High Standard of Care

11. Patient Follow-up

12. Primary Endpoint: Time to First Occurrence of CV Death, MI, Stroke Placebo events = 819 (10.4%)Darapladib events = 769 (9.7%) HR = 0.94 (95% CI, 0.85 - 1.03) P-value = 0.199 Percentage of Patients

13. Subgroup Analyses for CV Death, MI, Stroke

14. Subgroup Analyses for CV Death, MI, Stroke

15. Cardiovascular and Mortality Endpoints P Placebo Darapladib HR CV Death, MI, Stroke CV Death, MI, Stroke CV Death Myocardial Infarction Stroke All-Cause Mortality, MI, Stroke All-Cause Mortality Favors Placebo Favors Darapladib

16. Time to First Occurrence Major Coronary Events(CHD Death, MI, Urgent Coronary Revascularization) Placebo events = 814 (10.3%)Darapladib events = 737 (9.3%) HR = 0.90 (95% CI, 0.82- 1.00) P-value = 0.045 Percentage of Patients

17. Time to First Occurrence Total Coronary Events(CHD Death, MI, Any Coronary Revascularization, Hospitalization for Unstable Angina) Placebo events = 1269 (16.1%)Darapladib events = 1159 (14.6%) HR = 0.91 (95% CI, 0.84- 0.98) P-value = 0.019 Percentage of Patients

18. Coronary-Specific Endpoints P HR Placebo Darapladib Major Coronary Events CHD Death1 Myocardial Infarction Urgent Coronary Revasc2 Total Coronary Events Any Coronary Revasc2 Hosp for Unstable Angina1 Favors Placebo Favors Darapladib 1 - Component of pre-specified composite, but not a pre-specified endpoint 2 - Component of pre-specified composite, pre-specified as an endpoint of interest

19. Coronary-Specific Endpoints These findings should be considered exploratory and of uncertain significance in light of the lack of effect on the primary endpoint

20. Adverse Events

21. Darapladib Side Effects Leading to Study Drug Discontinuation

22. Conclusions Darapladib in patients with stable CHD followed for 3.7 years on a background of optimal medical therapy resulted in • No significant reduction in the incidence of the primary composite endpoint of CV death, MI or stroke • A signal of efficacy on the pre-specified coronary-specific secondary endpoints of major coronary events and total coronary events with nominal significance (p<0.05) • A safety profile that was well characterized

23. Implications The STABILITY trial is the first large scale randomized global trial to test a novel mechanism of inhibition of inflammation in the atherosclerotic plaque Further analyses of the trial results based on biomarkers and genetics will explore if darapladib might be useful in specific patient subsets