Update on the CETP inhibitor Anacetrapib Douglas Johns, PhD, FAHA Basic Science Lead, CETP/Anacetrapib Merck Research Laboratories Rahway, NJ

Douglas G. Johns, PhD Stocks, Stock Options, other ownership interest: Merck and Company, Inc.

Outline Review/update of Anacetrapib clinical program DEFINE Hps3-TIMI55-REVEAL Effects of anacetrapib on HDL functionality Reverse cholesterol transport, cholesterol excretion HDL function: Cholesterol efflux and pre-beta HDL HDL function: Anti-inflammatory effects of HDL

Anacetrapib clinical program

Cannon CP et al. N Engl J Med 2010;363 (19) online 11/17/2010 Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months. Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitor The reversal phase of the DEFINE trial is being evaluated in long-term follow-up

Worldwide cardiovascular outcome study N=30,000, anacetrapib 100mg po or placebo on background of atorvastatin Sponsor: University of Oxford Clinical Trial Service Unit Population: Stable cardiovascular disease with high risk of recurrent events Primary outcomes: Coronary mortality, myocardial infarction, coronary revascularization Follow-up: minimum median follow up of at least 4 years Progress: First patient enrolled May 2011, first patient randomized August 2011, currently enrolling in North America, Europe and Asia, enrollment is on schedule Lipid studies have been initiated in parallel (familial hypercholesterolemia)

Effects of anacetrapib on HDL functionality

DEFINE: Effects on LDL-C and HDL-C Study Week Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 HDL-C (mg/dL) (SE) 20 40 60 80 100 120 Anacetrapib Placebo Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 +138.1% increase at week 24 (p<0.001) LDL-C Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 LDL-C (mg/dL) (SE) 20 40 60 80 100 Anacetrapib Placebo Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666 The point estimates are for wk 24 Study Week -39.8% reduction at week 24 (p<0.001) Cannon CP et al. N Engl J Med 2010;363 (19)

With large increases in HDL-c, how is HDL functionality affected? Cholesterol efflux and RCT Anti-oxidant Anti-inflammatory Endothelial function Improve β-cell function Anti-thrombotic Anti-apoptotic

How does CETP inhibition affect HDL function? Cholesterol efflux and RCT Anti-oxidant Anti-inflammatory Endothelial function Improve β-cell function Anti-thrombotic Anti-apoptotic

Anacetrapib increases macrophage to feces reverse cholesterol transport in hamsters Increase in macrophage-derived 3H-tracer in HDL, suggesting increased cholesterol efflux from macrophages Increase in macrophage-derived 3H-chol and 3H-bile acids in the feces indicates net increase in macrophage-to-feces RCT 3H content in HDL 2.0 Control *** Anacetrapib (60mg/kg) 1.5 % of injected dose in HDL 1.0 0.5 0.0 24 48 72 Time (hours) 3H content feces 0.8 72 hours collection * 0.6 * % injected dose in feces 0.4 0.2 0.0 Control Ana Control Ana J Lipid Res. 2011, 52:1965-73 Cholesterol Bile acids

Cholesterol excretion Anacetrapib increases cholesterol in large HDL and promotes excretion of bulk cholesterol (no tracers) Cholesterol in HDL subfractions Increase in cholesterol is greatest in large HDL (HDL2) Beyond macrophage-to-feces RCT, ANA treatment increase fecal cholesterol and bile acid concentration These results indicate that anacetrapib is promoting movement of cholesterol out of the system From periphery to feces (RCT) Bulk cholesterol excretion 150 150 *** Vehicle Vehicle ** ** Ana 100 100 Cholesterol (mg/dL) 50 50 HDL3 HDL2 Day 0 Day 14 Ana (60mg/kg) Fecal cholesterol Fecal cholic acid 50 100 150 200 * ­ 29.4% Cholesterol excretion rate (ug/day) 5 10 19.3% CA ( m g/g feces) J Lipid Res. 2011, 52:1965-73

HDL functionality: Cholesterol efflux In addition to aqueous passive diffusion, cholesterol effluxes to HDL via protein-facilitated pathways ABCG1 and SR-BI facilitate cholesterol efflux to large/alpha HDL ABCA1 transports cholesterol to pre-beta HDL Ex vivo methods Apply serum from treated animals/humans and assess functional properties Macrophage ABCG1 α cholesterol SR-BI α ABCA1 Lipid-poor apoA-I Pre-β-HDL

Plasma from Anacetrapib-treated hamsters displays improved cholesterol efflux 14 ABCA1 Both major pathways of cholesterol efflux (alpha-HDL, pre-beta HDL) are increased with anacetrapib treatment ↑ABCA1-mediated efflux suggests increased pre-beta HDL component ↑ABCG1, ↑SR-BI mediated efflux indicates increased efflux to αHDL Similar observations with HDL from ANA-treated humans * 12 (% efflux) 10 8 6 Veh Ana SR-B1 ABCG1 5 2.0 ** *** 4 1.5 3 1.0 (% efflux) (% efflux) 2 0.5 1 0.0 Veh Ana Veh Ana J Lipid Res. 2011, 52:1965-73

Plasma from Anacetrapib-treated humans displays improved cholesterol efflux Total Cholesterol Free Cholesterol Cholesterol Ester *P<0,05, significant difference vs control PEG-HDL Increase in efflux at the equivalent HDL-c concentrations suggests an improvement in HDL “quality” 1Arterioscl Thromb Vasc Biol. 2010 30(7):1430-8

Evidence for increase in prebeta HDL concentration in Anacetrapib-treated hamsters Total ApoAI n.s. Control human plasma (left) and hamster plasma (right) run on the same gel for size comparison Pre-beta HDL measurements courtesy, Bela Aztalos, Tufts University

HDL from anacetrapib-treated hamsters and humans shows no impairment in anti-inflammatory properties Dyslipidemic hamsters HDL suppresses TNF-induced adhesion molecule expression VCAM, ICAM, E-selectin mRNA and protein Monocyte adhesion to endothelial cells suppressed by HDL No reduction in this effect with ANA-treated hamster HDL vs vehicle (not shown) Whether anacetrapib improves HDL function in humans with CV disease remains to be determined Vehicle Ana (30mg/kg) Humans (healthy normal) PBO Ana (20mg) Ana (150mg) Han et al. Biochim Biophys Acta doi:pii: S1388-1981(12)00262-4, 2012

Summary Multiple lines of evidence suggest that despite large increases in HDL cholesterol, HDL functionality is improved or “maintained” with anacetrapib inhibition of CETP Enhanced macrophage-to-feces reverse cholesterol transport in hamsters Improved excretion of bulk cholesterol/bile acids in hamsters Improvement in plasma cholesterol efflux capacity via ABCA1 (pre-beta-dependent), and via SR-BI/ABCG1 Increase in plasma pre-beta HDL concentration in anacetrapib-treated hamsters Increase in cholesterol efflux to plasma/HDL in anacetrapib-treated human subjects No impairment in anti-inflammatory properties of HDL Maintained suppressive effects on adhesion molecule expression, monocyte adhesion, NF-kB signaling Observed in hamsters and humans