Terje R. Pedersen, M.D. Presented by Oslo, Norway MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Presented by Terje R. Pedersen, M.D. Oslo, Norway Clinical Trials Slide Set 1

Patients Randomized by Country MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Patients Randomized by Country Source: EZT 2005-W-166238-SS 187 330 292 Denmark n=330 Sweden n=401 Norway n=425 UK n=187 Germany n=292 Ireland n=17 Finland n=221 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 2

SEAS Steering Committee MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM SEAS Steering Committee Source: EZT 2005-W-166238-SS Terje R. Pedersen (Chairman) Anne B. Rossebø (Coordinator) Kurt Boman John Chambers Kenneth Egstrup Eva Gerdts Christa Gohlke-Bärwolf Ingar Holme (Statistician) Antero Y. Kesäniemi Christoph Nienaber Simon Ray Terje Skjærpe Kristian Wachtell Ronnie Willenheimer Nonvoting members: Philippe Brudi (MSP) William Malbecq (MSD statistician) Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 3

SEAS Study Design Randomized Double-blind Placebo-controlled MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM SEAS Study Design Source: EZT 2005-W-166238-SS Randomized Double-blind Placebo-controlled Multicentre 4 weeks placebo/diet run-in Simvastatin 40 mg + ezetimibe 10 mg or placebo Median duration: 4.5 years (minimum follow-up 4 years) Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 4

SEAS: Primary End Point Source: EZT 2005-W-166238-SS Major Cardiovascular (CV) Events: CV death Aortic valve replacement surgery (AVR) CHF as a result of progression of AS Non-fatal myocardial infarction CABG PCI Hospitalized unstable angina Non-hemorrhagic stroke Ref 1, C1, Table 2 Ref 1, Table 1, C1 Ref 1, C3, ¶1,3 Ref 1, Table 2 PCI = percutaneous coronary intervention CHF= congestive heart failure CABG = coronary-artery bypass grafting Rossebø et al. NEJM 2008;359 (Epub ahead of print). Reference Rossebø A, Pedersen T, Skjaerpe T, et al, for the SEAS Steering Committee. Design of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Presented at: XIII International Symposium on Atherosclerosis; September 28–October 2, 2003; Kyoto, Japan. Poster 3P-0870.

SEAS: Secondary End Points Aortic Valve Events Aortic valve replacement CHF as a result of progression of AS CV death Ischemic CV Events Nonfatal MI CABG PCI Hospitalized unstable angina Nonhemorrhagic stroke Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Echocardiography Safety Other Objectives Source: EZT 2005-W-166238-SS Ref 1, C1, Table 2 Ref 1, Table 1, C1 Ref 1, C3, ¶1,3 Ref 1, Table 2 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Reference Rossebø A, Pedersen T, Skjaerpe T, et al, for the SEAS Steering Committee. Design of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Presented at: XIII International Symposium on Atherosclerosis; September 28–October 2, 2003; Kyoto, Japan. Poster 3P-0870.

Patient Definition Men and women Age 45 - 85 years Asymptomatic Source: EZT 2005-W-166238-SS Men and women Age 45 - 85 years Asymptomatic Valvular AS: Aortic valve thickening on echocardiographic evaluation Doppler jet velocity ≥2.5 - ≤4.0 m/sec Normal LV systolic function Ref 1, C1, Table 2 Ref 1, Table 1, C1 Ref 1, C3, ¶1,3 Ref 1, Table 2 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Reference Rossebø A, Pedersen T, Skjaerpe T, et al, for the SEAS Steering Committee. Design of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Presented at: XIII International Symposium on Atherosclerosis; September 28–October 2, 2003; Kyoto, Japan. Poster 3P-0870.

Exclusion Criteria Statin therapy or indication for statins MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Exclusion Criteria Statin therapy or indication for statins Coronary heart disease Other important valvular disease: Significant mitral valve stenosis or regurgitation Severe or predominant aortic regurgitation Rheumatic valvular disease or AV prosthesis or subvalvular (hypertrophic, obstructive cardiomyopathy) or supravalvular AS Diabetes mellitus Other conditions precluding participation Rossebø AB, Pedersen TR, Allen C, Boman K, Chambers J, Egstrup K, Gerdts E, Gohlke-Bärwolf C, Holme I, Kesäniemi VA, Malbecq W, Nienaber C, Ray S, Skjaerpe T, Wachtell K, Willenheimer R. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol. 2007;99(7):970-3. Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 9

Baseline Characteristics MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Baseline Characteristics Placebo Simvastatin + Ezetimibe n= 929 n= 944 Age (years) 67.4 67.7 Women (%) 38.8 38.5 SBP (mm Hg) 144 146 DBP (mm Hg) 82 Smoker (%) 18 20 Ex-smoker (%) 37 35 Never smoker (%) 45 BMI (kg/m2) 26.8 26.9 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 10

Simvastatin + Ezetimibe MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Baseline Medications Placebo Simvastatin + Ezetimibe n= 929 n= 944 ACE inhibitors 16.0 14.7 A-II blockers 10.5 10.1 Ca antagonists 17.2 16.6 Beta-blockers 28.8 25.6 ASA 28.0 25.0 Diuretics 24.7 22.1 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 11

Baseline Lipids and Lipoproteins MK-0653A PN043 NOT APPROVED FOR USE Baseline Lipids and Lipoproteins 5/10/2018 7:41 AM Fasting serum lipid and lipoprotein levels at baseline (n=1,873) Concentration (mmol/L) Concentration (mg/dL) Total cholesterol 5.74 222 LDL cholesterol 3.60 139 HDL cholesterol 1.49 58 Triglycerides 1.42 126 Apolipoprotein B - 1.31 (g/L) Values given as mean ± SD (Table 2, p972) Rossebø AB, Pedersen TR, Allen C, Boman K, Chambers J, Egstrup K, Gerdts E, Gohlke-Bärwolf C, Holme I, Kesäniemi VA, Malbecq W, Nienaber C, Ray S, Skjaerpe T, Wachtell K, Willenheimer R.Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol. 2007;99(7):970-973. Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 12 12

Baseline Echocardiography MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Baseline Echocardiography Mean Values Placebo Simvastatin + Ezetimibe n= 929 n= 944 Transaortic Peak velocity (m/sec) 3.10 3.09 Peak gradient (mm Hg) 39.6 39.3 Mean gradient (mm Hg) 23.0 22.7 Aortic valve area (cm2) 1.27 1.29 Bicuspid valve (%) 6.3 5.0 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 13

LDL-Cholesterol Mean (mg/dL) ±SE Year 150 Placebo 125 100 75 50 MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM LDL-Cholesterol Intention-to-Treat Population 150 Placebo 125 100 75 Mean (mg/dL) ±SE 50 Ezetimibe/Simvastatin 10/40 mg 25 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Year Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 14

Patients with first event (%) MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Primary End Point MCE 50 Intention-to-Treat Population Placebo 40 Hazard ratio: 0.96, P=0.591 30 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg 20 10 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 906 817 713 618 53 Placebo 884 791 696 586 56 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 15

Second End Point: Aortic Valve Events MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Second End Point: Aortic Valve Events Years in study Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk 914 836 732 635 55 895 814 725 611 58 Intention-to-Treat Population 1 2 3 4 5 10 20 30 40 50 Hazard ratio: 0.97, P=0.732 Patients with first event (%) Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 16

Aortic Valve Replacement MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Aortic Valve Replacement 50 Intention-to-Treat Population 40 Placebo Hazard ratio: 1.00, P=0.968 30 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg 20 From Terje Pedersen 10 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 915 837 734 640 55 Placebo 896 816 728 618 61 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 17

Peak Aortic - Jet Velocity MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Peak Aortic - Jet Velocity Intention-to-Treat Population 0.75 0.60 Ezetimibe/Simvastatin 10/40 mg 0.45 Change from baseline (m/sec) mean (±SE) 0.30 0.15 Placebo 0.00 Year 1 Year 2 Last follow-up Time Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 18

Second End Point: Ischemic CV Events MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Second End Point: Ischemic CV Events 30 Intention-to-Treat Population Hazard ratio: 0.78, P=0.024 Placebo 20 Patients with first event (%) 10 Ezetimibe/Simvastatin 10/40 mg 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 917 867 823 769 76 Placebo 898 838 788 729 76 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 19

Coronary Artery Bypass Grafting MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Coronary Artery Bypass Grafting 30 Intention-to-Treat Population 20 Hazard ratio: 0.68, P=0.015 Patients with first event (%) Placebo 10 Ezetimibe/Simvastatin 10/40 mg 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 925 887 848 797 80 Placebo 909 862 819 761 80 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 20

Clinical Adverse Events (AE) All Patients as Treated Population Placebo Ezetimibe/ Simvastatin N=929 N=943* n P= Any serious AE (SAE) 463 468 Drug discontinuation due to SAE 79 77 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Clinical Adverse Events All Patients as Treated Population Placebo Ezetimibe/ Simvastatin N=929 N=943 n P= Any SAE 463 468 Drug disconuation due to SAE 79 77 Musculoskeletal AE 181 165 0.28 Myopathy / rhabdomyolysis Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Clinical Adverse Events All Patients as Treated Population Placebo Ezetimibe/ Simvastatin N=929 N=943 n P= Any SAE 463 468 Drug disconuation due to SAE 79 77 Musculoskeletal AE 181 165 0.28 Myopathy / rhabdomyolysis New cancer 65 102 0.01 Recurrent cancer, same site 5 3 Cancer (total ) 70 105 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Cumulative percentage Fatal Cancer 20 Intention-to-Treat Population 15 Hazard ratio: 1.67 P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Cumulative percentage 10 Ezetimibe/Simvastatin 10/40 mg n=39 (4.1%) 5 n=23 (2.5%) Placebo 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Ezetimibe/simvastatin (N=943) Incident Cancer All Patients as Treated Population Site Placebo (N=929) Ezetimibe/simvastatin (N=943) n Lip, oral pharynx, oesophagus 1 Stomach 5 Large bowel / intestine 8 9 Pancreas 4 Liver, gallbladder, bile ducts 3 2 Lung 10 7 Other respiratory Skin (any) 18 Breast Prostate 13 21 Kidney Bladder Genital Hematological Other/unspecified 12 Rossebø et al. NEJM 2008;359 (Epub ahead of print). All differences are non-significant

Cumulative percentage MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM All-cause Mortality 30 Intention-to-Treat Population Hazard ratio: 1.04, P=0.799 20 Ezetimibe/Simvastatin 10/40 mg Cumulative percentage 10 Placebo 1 2 3 4 5 Years in study No. risk Ezetimibe/Simvastatin 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94 Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 26

Major CV Events - Components MK-0653A PN043 NOT APPROVED FOR USE 5/10/2018 7:41 AM Major CV Events - Components ITT Population # of Events Placebo Ezetimibe/Simvastatin 355 56 278 23 26 100 17 8 29 333 47 267 25 69* 5 33 End Points Hazard ratio (95% CI) Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Nonhematological stroke *P=0.02 vs. placebo 0.1 1.0 10.0 Favours Ezetimibe/Simvastatin 10/40 mg Favours Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print). Clinical Trials Slide Set 27