Current Status of Anacetrapib: A Second Generation CETP Inhibitor to Raise HDL and Lower LDL Yale Mitchel, MD Cardiovascular Disease Department Merck Research Laboratories

DISCLOSURES Yale B. Mitchel, MD Salary Merck & Co., Inc.

Role of CETP in Lipoprotein Metabolism Macrophage CE FC HDL Bile ABCA1 ABCG1 ApoA1 BA CE CE TG LCAT Nascent-Preb HDL FC, PL ApoA1 FC CE SR-B1 Lipases TG LDLR CE TG CETP inhibition CETP CE TG CE ApoB VLDL/LDL

Torcetrapib: “Beneficial” Effects on Lipoproteins, but Increased Cardiovascular and Non- Cardiovascular Morbidity and Mortality 8 week study Data from 12/18/02 analysts meeting N Engl J Med 2007;357:2109-22 Is the toxicity of torcetrapib related to the mechanism or the molecule?

Scientific Case for Developing the CETP inhibitor Anacetrapib CHD remains a significant unmet medical need; substantial residual CV risk on statins Strong biologic plausibility of CETP inhibition mechanism Strong epidemiology supporting CV protective role of HDL Large LDL-C lowering and HDL-C raising with anacetrapib No evidence that HDL from anacetrapib-treated patients is dysfunctional Anacetrapib clearly distinguished from torcetrapib Data suggests off-target vascular effects of torcetrapib Anacetrapib is well tolerated: No increase in BP, no change in electrolytes or aldosterone Merck believes that CETP inhibition target is at equipoise and that anacetrapib is an appropriate molecule to test the mechanism

Protocol 03: Anacetrapib Monotherapy Dose Ranging Study: Effects of Monotherapy LDL-C and HDL-C Weeks on Treatment -20 20 40 60 80 100 120 140 160 2 4 8 Percent Change from Baseline in HDL-C HDL-C Weeks on Treatment 2 4 8 -80 -60 -40 -20 20 Percent Change from Baseline in LDL-C Placebo Anacetrapib 10 mg Anacetrapib 40 mg Anacetrapib 150 mg Anacetrapib 300 mg Bloomfield et al. Am Heart J 2009;157:352-60

HDL cholesterol concentration (g/mL) concentration (g/mL) Effect of HDL from Anacetrapib-treated Patients (300 mg) on Cholesterol Efflux from Human THP-1 Macrophages MǾ incubated with 50μg/mL acLDL for 24h,then incubated with increasing PEG-isolated HDL-C concs (12, 36, 72μg/mL) from pre- and post-anacetrapib rx’ed pts for 6h TC, FC, CE measured in media in triplicate experiments. Values are means±SEM. 5 10 15 20 12 36 72 HDL cholesterol concentration (g/mL) (g/mg cell protein) ∆TC in media Before treatment After treatment * HDL cholesterol concentration (g/mL) ∆FC in media ∆CE in media *P<0,05, significant difference vs control PEG-HDL Tall A, 2009 XV International Symposium on Atherosclerosis; June 2009

Effect of HDL from Anacetrapib-treated Patients (300 mg) on Suppression of Inflammation in Macrophages MǾ rxed with 50μg/mL acLDL for 16h, then incubated with increased volumes of control and anacetrapib-HDL-2 for 3h, then washed and incubated with LipidA for 3h. Inflammatory transcript levels (TNFα, IL-6, MIP1α and MIP2) measured in triplicate experiments; means ±SEM expressed as arbitrary units (a.u). 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Basal LPS 5l 10l 25l IL-6 mRNA (a.u) Volume of HDL (l) 50 100 150 200 250 MIP1 mRNA (a.u) MIP1 mRNA IL-6 mRNA control-HDL Anacetrapib-HDL Tall, A 2009 XV International Symposium on Atherosclerosis; June 2009

MK-0859 Anacetrapib (50 mg/kg) Effect of Torcetrapib and Anacetrapib on Blood Pressure in Conscious Rhesus Monkeys Torcetrapib (500 mg/kg) MK-0859 Anacetrapib (50 mg/kg) 14.0 µM at 3 hrs 23.7 µM at 6 hrs 13.3 µM at 24 hrs Forrest et al. British Journal of Pharmacology (2008) 154, 1465–1473

The Effect of Torcetrapib and Anacetrapib on Aldosterone Secretion from Primary Rat Adrenocortical Cells Anacetrapib Anacetrapib has no effect on aldosterone release up to 10 uM Torcetrapib Dose-dependent increase in aldosterone release with torcetrapib Forrest et al., British Journal Pharmacology 2008;154:1465-1473

Phase I Study: Effect of Anacetrapib on 24-H Ambulatory Systolic Blood Pressure Krishna et al., Lancet 2007; 370: 1907–14

LS Mean % Change from Baseline (±SE) Protocol 03: Anacetrapib Dose Ranging Study Change in Blood Pressure -10 -5 5 10 Systolic Diastolic LS Mean % Change from Baseline (±SE) Placebo Placebo Treatment Anacetrapib 10 mg Anacetrapib 40 mg Anacetrapib 150 mg Anacetrapib 300 mg Anacetrapib 10 mg Anacetrapib 40 mg Anacetrapib 150 mg Anacetrapib 300 mg Bloomfield et al. Am Heart J 2009;157:352-60

Development Strategy for MK-859 Large outcome study necessary to demonstrate benefit of mechanism Merck embarked on a step-wise approach to the outcome study Atherosclerosis imaging tools/biomarkers not sufficiently robust for decision making Conduct phase II/III study (protocol 019: DEFINE); N=1600 high risk individuals treated for 18 months Gain additional clinical experience in a high risk patient population Careful evaluation on key safety parameters (BP, electrolytes, aldosterone, CV events) Safety monitoring by external DSMB Continuing investigations into mechanism of action Outcome trial triggered after “sufficient” experience gained in PN019

Program Timelines 2007 2008 2009 2010 2011 2012 13-17 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q Phase II/III Study (PN019) (Data trigger) Carco Outcomes Planning Activities Clinical Outcomes (PN031) 6 m * 12 m * 18 m * * All pts complete

Stable dose-regimen of statin ± other lipid-modifying therapy Phase II/III: PN019 Study Design Endpoints Co-Primary: change in LDL-C 24 wks Co-primary: Tolerability: Tier 1 AE: CK, AST/ALT, electrolytes, blood pressure, adjudicated CV events Stopping rules based on distribution of CV events using Bayesian approach Inclusion Criteria Age: 18-80 years CHD, CHD risk equiv LDL-C: > 50 mg/dL <100 mg/dL HDL-C<60 Statin ± other lipid modifying therapy Randomization 1:1 Ratio Anacetrapib 100 mg n=800 R Placebo n=800 Stable dose-regimen of statin ± other lipid-modifying therapy Treatment Phase Week -2 0 24 54 88 Cannon et al, Am Heart J 2009;158:513-19.e3.

DEFINE (P019) Status Enrollment 2423 patients screened & 1623 randomized Exposure (as of 8-Feb-10) Safety Thus far drug well tolerated No evidence of an effect on blood pressure or electrolytes Small number of liver function and muscle abnormalities No unexpected adverse experiences Weeks 6 12 18 24 30 38 46 54 62 70 76 # patient exp 1569 1509 1461 1409 1365 1317 1295 1261 958 555 232 Cannon et al, Am Heart J 2009;158:513-19.e3.

CETP Inhibition and Anacetrapib CETP inhibition mechanism is at equipoise Anacetrapib is an appropriate molecule to assess CETP inhibition mechanism Proceeding in a step-wise fashion Interim data from ongoing phase II/III study will trigger outcome study Outcome study will assess effect of anacetrapib on top of statin therapy in patients at high risk of CV events