1. Robert K Huff PharmD. Candidate May 2012

2. Objectives The study was designed to examine 3 main aspects Biochemical effects Safety Tolerability Evacetrapib was used as monotherapy and in combination with statins Used in patients with dylipidemia

3. Design The study was a randomized controlled trial conducted among 398 patients with elevated LDL or elevated low HDL (HDL-c) levels Multicenter, randomized, double-blind, placebo controlled trial Conducted from April 2010 to January 2011 Studies conducted in The United States and Europe

4. Patients Patients had to be at least 18 years old and must have had low HDL-C or high LDL-C in the presence of Tg levels >400mg/dl. This after a dietary lead in period HDL Low HDL-c critera had an HDL-c level of <45mg/dL for men and <50mg/dL for women Needed an LDL-C level that met NCEP ATP III panel goals.

5. Patients LDL-c criteria LDL-c level b/w 100-190mg/dl in the presence of (0 or 1 risk factors) b/w 100-160mg/dl in the presence of (at least 2 risk factors) and a 10-year coronary risk of < 10% b/w 100-130mg/dl with at least 2 risk factors and a 10 – year coronary risk of 10 to 20%.

6. Patients Exclusion Criteria Clinical manifestation of atherosclerotic disease Hypertension (systolic > 140 mm Hg or diastolic >90 mm HG ) Documented hyperaldosteronism Uncontrolled diabetes (A1C >8%) Liver, kidney, cardiac or neuromuscular disease

7. Design Cont Patients entered a 2 to 8 week washout period Used to evaluate the effect of NCEP Therapeutic Lifestyle Changes Also used as a washout for any previous lipid therapy Study evaluated the effects of 12 weeks of tx with evacetrapib as monotherapy and in combination with statins.

8. Dosing Monotherapy evaluation Patients received Evacetrapib 30mg/d, 100mg/d, 500mg/d Combination treatment Patients received Evacetrapib 100 mg/d in combination with the 3 most prescribed statins used in clinical practice simvastatin 40mg/d rosuvastatin 10mg/d atorvastatin 20mg/d

9. Randomization Randomization to statin groups Performed by an interactive voice response system and was stratified according to geographic region and baseline levels of HDL-C and Tg’s. Clinic Visits Examine during scheduled visits at 2, 4, 8 and 12 weeks during the treatment phase Follow-up visit of 4 to 6 weeks after cessation of the study drug

10. Lipid Measurements A central laboratory (Covance) performed all biochemical determinations. Enzymatic assay was performed for LDL-c HDL-c Triglycerides Immunonephelometry was performed for High Sensitivity C-Reactive Protein Enzyme linked immunosorbent assay used to measure CETP All reported CV events and rashes were evaluated and adjudicated by a blinded clinical end-point committee

11. Statistics Samples of 35 patients per group was calculated to provide 87% power to simultaneously detect a 40% increase in HDL-C and a 10% decrease in LDL-C compared with statin alone for each or in combined therapy groups. Gives (0.1 type 1 error rate for a 2 sided-test) Reflects an increase in HDL-c greater than observed in Niacin therapy Incremental reduction in LDL-c of at least 10% in addition to statin therapy

12. Results Participants April 15 2010 through January 14 2011 – 1154 patients were screened in the study at 70 sites Baseline characterisitics Similar for all treatment groups Mean age 58.3 56% of patients were women Baseline lipid profiles LDL-c mean 144.3 HDL-c mean 55.1 TG – median 121.3

13. P-value Used to measure level of significance Usually <.05 or <.1 When the p-value is less than the significance level we can reject the null hypothesis (no difference) In this study a p value <.05 is statistically significant

14. Results – lipoprotein effects Evacetrapib monotherapy Dose dependent increases in HDL-c ranging from 30.0 t 66.0 mg/dl (53.6% to 128.8%; P<.001 vs placebo) Decrease in LDL-c 0f -20.5 to -51.4 mg/dl (-13.6% to - 35.9%; P<.001 vs. placebo) Triglyceride levels decreased by 26.7 mg/dl (10.8%) with 500mg/d dosage (P <0.006) Dose-dependent reductions in non HDL-c by -23.2 to -45.8 mg/dl (-12.9 to -26.4% ; P<.001 vs. placebo) Dose-dependent reductions in Apolipoprotein B by -13.8 to - 29.7 mg/dl (-12.4 to -26.6%; P<.001 vs. placebo)

15. Results evacetrapib in combination with statin 100mg/d increased HDL-c levels by 42.1 to 50.5 mg/dl (78.5% to 88.5%; P<.001 vs. statin alone) Resulted in greater reductions in LDL-c (P<.001) and non-HDL-c (P<.05) * for atorvastatin and rosuvastatin When compared with effects observed with statin mono. Evacetrapib in combo with statins resulted in greater reductions in LDL-c but showed no greater increase in HDL-c

16. Results Increase in HDL-c with evacetrapib produced dose dependent increases in apolipoprotein A1 ranging from 35.7 to 72.6 mg/dl (22.7 to 49.6% ; P<.001 vs. placebo) Apolipoprotein A-2 by 4.8 to 7.4 mg/dl (12.7 to 19.7%; P<.001 vs. placebo ) Apolipoprotein E by 5.7 to 9.2mg/dl (15.8 to 83.7% ; P<.001 for the 2 highest doses compared to placebo)

17. Results Dose dependent decrease in CETP activity From -11.5 to -20.8 pmol/mL per minute (-49.5 to 89.1%; P<.001 vs. placebo in evacetrapib monotherapy C-reactive protein levels remained unchanged through the 12 week administration period. There were no changes in as monotherapy or in combination with statins.

18. Notes Differences b/w evacetrapib monotherapy and placebo Greater percentage increases in HDL-c among patients who were younger, had lower baseline HDL-c and had higher baseline triglycerides Also greater percentage decreases in LDL-c among patients who were younger and had lower baseline LDL- c levels.

19. Safety Evacetrapib as monotherapy was not associated with an increase in blood pressure compared with placebo Increases in blood pressure were observed when evacetrapib 100mg/d was administered in combination with simvastatin 40mg/d vs. simvastatin monotherapy. P<.02 No other differences were observed in diastolic or systolic blood pressure changes. 2 significant rashes were observed and one patient developed angioedema One patient also had a morbilliform reaction post cessation

20. Safety Evacetrapib administered as monotherapy or in combination with statin therapy was not associated with significant laboratory abnormalities related to liver, kidney or muscle toxicity. No adjudicated cardiovascular events were observed during the study.

21. Comments No new classes of antiatherosclerotic therapies with clinically proven benefits have emerged since the introduction of statins in the 1980’s. Drugs that inhibit CETP produce the largest increases in HDL-c This study demonstrated that evacetrapib produced marked alterations in important lipoproteins, including large increases in HDL-c level and decreases in LDL-c levels. HDL changes were significantly greater in patients with lower levels of HDL and higher TG’s at baseline

22. Study Underpowerd to rule out uncommon adverse effects Evacetrapib use in combo with statins showed potentially useful effects as HDL increased and LDL decreased at percentages to be considered clinically significant. Previous CETP inhibitor Torcetrapib Increase in HDL Did not slow disease progression and lead to increased mortality Some researches think this showed the detrimental effect of CETP inhibition on HDL functionality. Additional studies found that torcetrapib had off target effects that more than likely contributed to the observed adverse cardiovascular outcomes.

23. evacetrapib Low rate of treatment related adverse effects No increase in blood pressure No mineralocorticoird or glucocorticoid activity were observed Some rashes occurred *full safety assessment of evacetrapib will require exposure to a much larger group of patients Inability of torcetrapib to slow disease progression in humans raised concerns and questions about HDL functionality.

24. conclusion No studies have yet demonstrated that any CETP inhibitor reduces disease progression or promotes plaque regression. There is a need for prospective, randomized, clinical outcome trials. This study provides the foundation needed for a larger phase 3 clinical trial to further assess the safety and efficacy of evacetrapib. Funded by Eli Lilly

25. Level of Evidence