Senior Medical Director, Cardiovascular Evacetrapib: Lipoprotein Profile and Clinical Trial of a Novel CETP Inhibitor Jeffrey S. Riesmeyer, MD Senior Medical Director, Cardiovascular Eli Lilly and Company

Employee of Eli Lilly and Company Jeffrey S. Riesmeyer, MD Employee of Eli Lilly and Company

Proposed mechanism for cholesteryl ester transfer by CETP Zhang L et al. Nat Chem Biol. 2012; 8(4):342-349

Cholesteryl ester transfer protein Liu S et al. J Biol Chem. 2012;287(44):37321-37329

Chemical structure Liu S et al. J Biol Chem. 2012;287(44):37321-37329

Evacetrapib is a potent CETP inhibitor Human CETP/ApoAI Double Transgenic Mouse Model Cao G et al. J Lipid Res. 2011;52(12):2169-2176

Evacetrapib is a potent CETP inhibitor Human CETP/ApoAI Double Transgenic Mouse Model Cao G et al. J Lipid Res. 2011;52(12):2169-2176

Evacetrapib does not induce aldosterone or cortisol synthase mRNA in human cortical carcinoma H295R cells Cao G et al. J Lipid Res. 2011;52(12):2169-2176

Preclinical: BP not increased with evacetrapib Cynomolgus Monkeys Eli Lilly and Company, Data on file

Evacetrapib – pharmacokinetic profile summary Peak plasma concentrations 1-6 hours after oral dose Steady-state achieved by 10 days with daily dosing Half-life (t1/2) 30-50 hours, independent of dose For either low or high fat meal: Fed AUC(0-∞) ≈1.5X Fasted AUC(0-∞) No prolonged exposure after drug discontinuation

Evacetrapib – metabolism summary Primarily hepatic metabolism (CYP3A > CYP2C8) No significant renal excretion in human 14C study Weak inhibitor of CYP3A , not an inhibitor of CYP2C9 No clinically relevant induction of CYP1A2, CYP2B6, CYP3A Multiple metabolic pathways (CYP3A and CYP2C8) minimize potential for drug-drug interactions In Phase 3, no exclusion of CYP3A inhibitors unless in combination with CYP2C8 inhibitor, such as gemfibrozil

Phase 2: percent changes in HDL-C and LDL-C Nicholls SJ et al. JAMA. 2011;306(19):2099-109

Phase 2: percent changes in HDL-C: evacetrapib 100 mg combined with statin therapy Nicholls SJ et al. JAMA. 2011;306(19):2099-109

Phase 2: percent changes in LDL-C: evacetrapib 100 mg combined with statin therapy Nicholls SJ et al. JAMA. 2011;306(19):2099-109

Phase 2: blood pressure Nicholls SJ et al. JAMA. 2011;306(19):2099-109

Phase 2: safety evaluation Parameter Placebo (n=38) Eva 30 mg (n=40) Eva 100 mg (n=38) Eva 500 mg (n=40) Statin (n=121) Statin + Eva 100 mg (n=116) Drug-related AE 18.4% 20.0% 13.2% 25.0% 18.2% 26.7% AE leading to discontinuation 2.6% 5.0% 12.5% 2.5% 7.8% SAE 0.0% 0.8% 1.7% Creatinine >ULN 5.2% 10.0% 7.6% CK > 5 X ULN ALT > 3 X ULN 0.9% Aldosterone (ng/dL)* -1.00 -0.45 0.96 -0.30 -1.12 Salivary Cortisol (μg/dL)* -0.003 -0.03 0.002 0.004 0.03 0.01 *Absolute change Nicholls SJ et al. JAMA. 2011;306(19):2099-109

Phase 2: drug exposure on treatment and after 4 week washout 8 12 16-18 After Washout 2 31 30 33 32 127 122 120 117 133 35

Phase 2: percent changes in HDL-C on treatment and after 4 week washout

Phase 2: percent changes in LDL-C on treatment and after 4 week washout

11,000 patients with High-risk Vascular Disease Evacetrapib 130 mg ACCELERATE: Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-risk for Vascular Outcomes 11,000 patients with High-risk Vascular Disease Evacetrapib 130 mg LDL-C at target or on maximal tolerated statin Placebo Primary End Point Cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for unstable angina (UA), or coronary revascularization 3 year follow-up (anticipated) www.clinicaltrials.gov Sites in North America, Europe, South America, Africa, and Asia/Pacific Planned completion in 2015

Conclusions: Evacetrapib Potent CETP inhibitor Increase in HDL-C and decrease in LDL-C as monotherapy, or in combination with atorvastatin, simvastatin, or rosuvastatin Well tolerated, with no evidence of adverse blood pressure or mineralocorticoid effects No delayed washout after drug discontinuation Impact of evacetrapib on cardiovascular events is being tested in ongoing Phase 3 ACCELERATE Study