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

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

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

Initial CETP Inhibitors Torcetrapib Dalcetrapib

Current CETP Inhibitors Under Development Anacetrapib

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):2406-2415. Copyright © 2010 Massachusetts Medical Society.

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

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 11111. 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. 2014 Elsevier Inc. All rights reserved. (Am Gotto A et al, JACC 2014; 113:76–83.

Current CETP Inhibitors Under Development Anacetrapib Evacetrapib

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

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

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

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

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

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%

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.