1. Safety of Anacetrapib in Patients with or at Risk for Coronary Heart Disease Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD, Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD, DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons, MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip Barter, MD, PhD, for the DEFINE Investigators

2. Disclosures C.P. Cannon has received research grants/support from the following companies: Accumetrics, AstraZeneca, Glaxo Smith Kline, Intekrin, Merck, and Takeda. He has served on advisory boards, (but donates funds to charity) for Alnylam, Bristol-Myers Squibb/Sanofi Partnership, and Novartis. He has received honoraria for educational symposia from AstraZeneca and Pfizer. He also serves as a clinical advisor and holds equity in Automedics Medical Systems. P. Barter has served on advisory boards for AstraZeneca, Merck, Pfizer, Roche and Sanofi-Aventis; has received honoraria from Abbott, AstraZeneca, BMS, Merck, Pfizer, Roche and Sanofi-Aventis. Other co-authors disclosures are listed in the published paper. The trial was supported by Merck Research Laboratories, Rahway, NJ.

3. Background - HDL l While statin therapy has reduced morbidity and mortality from coronary heart disease by more than 25%, CV disease remains the #1 cause of death worldwide l Epidemiologic studies: high HDL associated with ↓ risk l Current therapies raise HDL by 5-30%, but none has yet been proven to reduce CV risk in current statin era l l Cholesteryl ester transfer protein (CETP) inhibitors substantially raise HDL l l But, the first agent, torcetrapib, was found to have “off target” effects in adrenal gland, and lead to increased BP, mortality and CV events.

4. Background: CETP inhibition HDL LDL / VLDL Liver Bile CE LDL-R FC FC LCAT CETP CE SR-B1 X inhibition Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig. Free Cholesterol (FC) in Extrahepatic tissues

5. Anacetrapib l Orally active, potent, selective CETP inhibitor l Robust lipid efficacy in Phase I-II studies l No effects on blood pressure, electrolytes, and aldosterone in preclinical and Phase I-II clinical studies l In vitro HDL functional assays: HDL particles isolated from anacetrapib-treated patients demonstrate preserved (and possibly enhanced) cholesterol efflux properties l Dose of 100 mg selected based on PK/PD modeling: minimal dose to achieve maximal effects on HDL and LDL

6. Study Objectives and Endpoints l Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalent disease l The primary objective of this study was to evaluate safety to allow decision making for large outcomes study l Pre-specified safety parameters: BP, potassium, chloride, sodium and bicarbonate, liver function tests, CPK, myalgia, adjudicated major CV-events (CV death, non-fatal MI, non- fatal stroke, unstable angina) and death l Efficacy endpoints: Primary: LDL-C at Wk 24 Key Secondary: HDL-C, Apo B, Apo A-1, non-HDL-C, TG at week 24 & 76, and LDL-C at week 76

7. Patient Population Men and women, ≥18 and ≤80 years of age, with CHD or CHD risk- equivalent disease (Framingham Risk score > 20%) on background statin therapy +/- other lipid-modifying medications. l LDL-C ≥50 and ≤100 mg/dL l HDL-C <60mg/dL l Triglycerides ≤400 mg/dL Major Exclusion Criteria Major Exclusion Criteria l Chronic heart failure l Uncontrolled hypertension l Hepatic disease l Severe renal impairment l Treatment with warfarin, digoxin or potent inhibitors/inducers of CYP3A4

8. Study Design Age: 18-80 years LDL-C @ NCEP ATPIII goal < 100 mg/dL Statin ± other lipid modifying therapy Week -2 0 6 12 18 24 30 38 46 54 62 70 76 80 84 88 Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 Screening Placebo Run-in Treatment Phase Stable dose-regimen of lipid-modifying therapy R 12 week follow-up Anacetrapib 100 mg n=750 Placebo n=750 Randomization 1:1 Ratio Reversibility Phase Study drug stopped if LDL-C<25mg/dL during treatment

9. Safety Monitoring and Bayesian Analyses l Periodic review of unblinded safety throughout trial by external, independent safety monitoring committee (SMC) l Statistical analyses performed by external, independent statistical group l All CV serious adverse events and deaths adjudicated by an external, independent adjudication committee. l A Bayesian approach was applied to determine the predictive probability (confidence) to dismiss a torcetrapib-like 25%↑ in CV events as observed in ILLUMINATE.

10. Baseline Characteristics Characteristic Anacetrapib (N=811) Placebo (N=812) Age, mean years ± SD62.5 ± 8.762.9 ± 9.0 Male gender, n (%)77.6%76.1% CHD, n (%)55.1%54.3% CHD risk equivalent, n (%)44.9%45.7% Hypertension, n (%)69.1%66.6% Diabetes, n (%)53.1%53.2% Prior MI, n (%)22.5%22.8% Statin therapy, n (%)99.5%99.1% BMI, mean kg/m2 ± SD30.4 ± 5.530.1 ± 5.2 LDL-C, mean mg/dL ± SD81.4 ± 21.382.2 ± 20.7 HDL-C, mean mg/dL ± SD40.5 ± 9.340.4 ± 9.1

11. Effects on LDL-C and HDL-C LDL-C Study Week BaselineWk 6Wk 12Wk 18Wk 24Wk 30Wk 46Wk 62Wk 76 LDL-C (mg/dL) (SE) 0 20 40 60 80 100 Anacetrapib Placebo Anacetrapib n =804771716687646604568540 Placebo n =803759741743735711691666 -39.8% (p<0.001) +138.1% (p<0.001)

12. Lipid Parameters Parameter LS Mean Percent (95% CI) Placebo-Adjusted Change from Baseline Week 24Week 76 Non-HDL-C -31.7* (-33.6, -29.8) -29.4* (-31.6, -27.3) Apo B -21.0* (-22.7, -19.3 )-18.3* (-20.2, -16.4) Apo A-1 44.7* (42.8, 46.5) 42.3* (40.5, 44.1) TC 13.7* (12.0, 15.3) 15.6* (13.8, 17.3) TG -6.8 (-9.9, -3.9) -5.3 (-8.9, -1.7) Lp(a) -36.4 (-40.7, -32.3) -38.8 (-44.5, -33.9) ApoE 29.2* (24.7, 33.7) 35.3* (30.6, 40.1) *p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown

13. Anacetrapib had no effect on BP

14. Anacetrapib had no effect on key safety parameters Safety Parameters Anacetrapib n (%) Placebo n (%) Absolute Difference (%) 95% CI n/N (%) p-value Sodium >ULN86/800 (10.7)84/797 (10.5)0.2 (-2.8, 3.2)0.89 Chloride>ULN23/800 (2.9)27/797 (3.4)-0.5 (-2.3, 1.2)0.56 Bicarbonate > ULN11/800 (1.3)17/797 (2.1)-0.8 (-2.2, 0.6)0.25 Potassium < LLN38/800 (4.8)38/797 (4.8)-0.0 (-2.2, 2.1)0.99 Consecutive elevations of ALT /or AST ≥ 3x ULN1/800 (0.1)8/797 (1.0)-0.9 (-1.9, -0.2)0.019 CK ≥ 10*ULN0/8002/797(0.3)-0.3 (-0.9, 0.2)0.16 Any muscle symptom32 (4.0)28 (3.5)0.5(-1.4, 2.4)0.61 Aldosterone change from baseline (median +/-SD) 15.0 ± 46.5 13.5 ± 48.4 2.0 (-3.0, 7.0)0.27

15. Adjudicated CV Events and Death Anacetrapib N=808 n (%) Placebo N=804 n (%) Hazard ratio (95% CI) P value Pre-specified adjudicated CV Safety endpoint 16 (2.0)21 (2.6)0.76 (0.39, 1.45)0.40 Cardiovascular Death 4 (0.5)1 (0.1) Non-fatal MI 6 (0.7)9 (1.1) Unstable Angina 1 (0.1)6 (0.7) Non-fatal Stroke 5 (0.6) Death from any Cause 11 (1.4)8 (1.0) Revascularization8 (1.0)28 (3.5)0.29 (0.13, 0.64) 0.001 Death or major CV event (Death/MI/UA/S/Revasc)** 27 (3.3)43 (5.3)0.62 (0.38, 1.01)0.048 **Post hoc analysis Primary Bayesian Analysis: Event Distribution indicates a 94% predictive probability of dismissing a 25% increase (Torcetrapib-Type) in CV Events

16. l Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months. l Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. l Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitor l The long term safety and efficacy of anacetrapib will now be tested in a large clinical outcomes trial. Conclusion Cannon CP et al. N Engl J Med 2010;363 (19) online 11/17/2010

17. 30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Scheduled follow-up: 4 years Primary outcome: Coronary death, myocardial infarction or coronary revascularization www.revealtrial.org