1. Update on Clinical Trials with Novel CETP Inhibitors to Raise HDL: Where are We Today?
H. Bryan Brewer, Jr. Washington Cardiovascular Associates Washington Hospital Center Medstar Heart and Vascular Institute
Washington, DC

2. Disclosure
Consulting Agreements: Merck & Co.; Pfizer Inc; Sanofi; AstraZeneca; Roche; Genentech; InfraReDx
Speakers’ Bureau/Honorarium Agreements: Merck & Co.; Roche; Genentech; Pfizer Inc; Sanofi; AstraZeneca; InfraReDx; HDL Therapeutics
Financial Interests/Stock Ownership: Medicines Company; InfraReDx, HDL Therapeutics

3. Plasma Lipoproteins Following CETP Inhibition
Triglycerides
B-100
C-III E
Triglycerides
B-100
C-III
LDLR
Modification CE
CETP TG
SR-BI
VLDL
LDL
LRP
ABCG1
LCAT
HDL-VL, (α1)
A-I
ABCA1
LCAT
HDL-L, (α2)
LCAT
HDL-M, (α3)
A-I
Macrophage
Arterial Wall
A-I
HDL-S, (α4)
HDL-VS Preβ-HDL
Potential Reduction in CVD Due to both Increased HDL and Decreased LDL

4. Initial CETP Inhibitors
Torcetrapib
Dalcetrapib

5. Current CETP Inhibitors Under Development
Anacetrapib

6. Define Trial: Effect of Anacetrapib on Plasma HDL and LDL
110
100 90 80 70 60 50 40 30 20 10
LDL (mg/dL) 6 12 18 24 46 62 76
Week
Baseline
Anacetrapib Placebo
HDL (mg/dL)
Decrease LDL-C = 40%
Increase HDL-C = 138%
Cannon CP, et al. N Engl J Med. 2010;363(25): Copyright © 2010 Massachusetts Medical Society.

7. 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

8. Long-Half Life of Anacetrapib: Analysis of the Follow up of the DEFINE Trial
The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for cholesterol (73.0%) and apolipoprotein A-1 (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing Elsevier Inc. All rights reserved. (Am
Gotto A et al, JACC 2014; 113:76–83.

9. Current CETP Inhibitors Under Development
Anacetrapib
Evacetrapib

10. Percent Change in HDL-C and LDL-C
Evacetrapib:
Percent Change in HDL-C and LDL-C
HDL-C
LDL-C
150%
120%
90%
60%
30% 0%
10%
-10%
-20%
-30%
-3.0%
53.6%*
94.6%*
128.8%*
3.9%
-13.6%*
-22.3%*
-35.9%*
-30%
-40%
Placebo
30 mg
100 mg
500 mg
* P<0.001 compared with placebo
Nicholls S, et al. JAMA. 2011;306:2099

11. Evacetrapib Clinical Program
ACCELERATE
Evacetrapib Clinical Program
High Risk Vascular Disease (HRVD) – defined by the following groups:
History of ACS ≥ 30 days through 365 days after discharge from ACS
Cerebrovascular Atherosclerosis Disease
Peripheral Arterial Disease (PAD)
Diabetes Mellitus w/ documented Coronary Artery Disease
Evacetrapib 130 mg
Follow up every 3 months
with an initial 1 month visit
Safety follow up 1 month after end of treatment
Randomization 1:1
Placebo
Study continues until all the following occurred:
1136 patients with 1o endpoint : CVD/MI/stroke/hospitalization for UA/coronary revascularization
2) 500 patients with CVD/MI/stroke
3) 1.5 years after last patient entered treatment

12. Current CETP Inhibitors Under Development
Anacetrapib
Evacetrapib
Dezima Dez-001 (TA-8995)

13. Cholesterol Ester Inhibitor DEZ-001 (TA-8995)
Licensed from Mitsubishi Tanabe Pharma Corporation
Phase 1 SAD and MAD studies show:
Clean safety profile, even at very high dosing
Highest potency with regards to lipid normalizing properties
Extensive preclinical and clinical safety profile
Short half life – no storage in fat

14. TA – 8995 (DEZ-001): Multiple Ascending Dose phase 1 Efficacy
1mg*
N=10
2.5mg
5mg
10mg
25mg
CETP activity
-67%
-90%
-92%
-98%
-99%
HDL-C
+38%
+95%
+118%
+140%
+136%
LDL-C
-30%
-39%
-42%
-44%
-53%
Efficacy relative to baseline after 21days
Significant reduction in Lp(a) seen in all dose groups

15. Comparison of the Changes in the Plasma Lipoproteins with the Current CETP Inhibitors Underdevelopment
Compound
Company
Study
Dosing
LDL-C
HDL-C
LP(a)
Trigs
Anacetrapib*
Merck
Phase 2
100 mg
- 40%
+ 138%
- 36%
- 7%
Evacetrapib
Lilly
- 22%
+ 95%
- 28%
500 mg
+ 129%
- 37%
- 17%
TA-8995
Dezima
Phase 1
5 mg
- 42%
+ 118%
- 70%
Minimal
10 mg
- 44%
+ 140%
25 mg
- 53%
+ 136%

16. Take Home Messages √ √ √ √
Novel HDL therapies are under development including CETP Inhibitors as well as HDL infusions to reduce cardiovascular events. √
CETP Inhibitors produces both marked increases in HDL-C and significant reduction in LDL-C. √
CETP Inhibitors also significantly reduce Lp(a). √
Clinical trials are currently underway to definitive established if CETP Inhibition will be associated with decreased clinical cardiovascular events.