1. 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

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

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

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

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

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

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

8. 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):

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

10. 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) 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

11. 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

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

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

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

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

16. 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):

17. Phase 2: drug exposure on treatment and after 4 week washout8 12
16-18
After
Washout 2 31 30 33 32
127
122
120
117
133 35

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

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

20. 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)
Sites in North America, Europe, South America, Africa, and Asia/Pacific
Planned completion in 2015

21. 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