Cholesteryl ester transfer protein inhibitors - what have we learnt? Philip Barter The Heart Research Institute Sydney, Australia

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1 Cholesteryl ester transfer protein inhibitors - what have we learnt? Philip Barter The Heart Research Institute Sydney, Australia

2 Philip Barter Disclosures Received honorariums for lectures, consultancies or membership of advisory boards from: AstraZeneca, CSL, MSD, Novartis, Pfizer, Roche, Sanofi Aventis

3 QUESTION Why continue the development of CETP inhibitors after the failures of torcetrapib and dalcetrapib?

4 What do we know about the relationship between CETP and atherosclerosis?

5 CETP and Atherosclerosis in Rabbits Rabbits have high level of activity of CETP Rabbits naturally highly susceptible to the development of atherosclerosis Inhibition of CETP in rabbits decreases atherosclerosis in all models, including genetic manipulation to inhibit CETP, use of an anti- CETP vaccine or by administration of small molecule CETP inhibitors Sugano et al. J Biol Chem.1998;273:5033. Rittershaus et al. ATVB. 2000;20:2106. Okamoto et al. Nature. 2000;406:203. Morehouse et al. J Lipid Res. 2007;48:1263.

6 CETP Polymorphisms and Cardiovascular Risk in Humans Two very large meta-analyses and one large study of 18,245 initially healthy American women all concluded that CETP gene polymorphisms associated with lower CETP mass and/or lower CETP activity had higher levels of HDL-C, lower levels of LDL-C and a significantly reduced coronary risk. Thompson et al JAMA2008;299: Voight et al Lancet, online ahead of publication, 17 May 2012 Ridker et al. Circ Cardiovasc Genet 2009; 2: 26

7 So, given the evidence that: (i) Inhibiting CETP in rabbits inhibits atherosclerosis (ii) Genetic variants of CETP in humans are accompanied by higher HDL-C, lower LDL-C and reduced CV risk and (iii) Inhibition of CETP in humans increases HDL-C and, in some cases, decreases LDL-C There is a strong case for developing CETP inhibitors as agents to reduce cardiovascular risk

8 CETP inhibitors Torcetrapib Dalcetrapib Anacetrapib Evacetrapib O N N O O O S H N O F 3 C O O O N F O CF 3 F 3 C CF 3 F 3 C Cao et al. J Lipid Res 2011; 52:2169

9 Torcetrapib Torcetrapib increased HDL-C by more than 60% and reduced LDL-C by more than 20% over and above the changes achieved by using high doses of statins. Barter et al, NEJM 2007;357:2109

10 But Inhibiting CETP with torcetrapib in humans did not reduce atherosclerosis in three imaging trials and in a large-scale clinical end-point trial (ILLUMINATE) increased CV events and both CV and non-cv mortality

11 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had adverse off-target effects unrelated to CETP inhibition

12 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had adverse off-target effects unrelated to CETP inhibition

13 Effects of torcetrapib on HDL function HDLs isolated from patients treated with anacetrapib have an enhanced ability to promote the efflux of cholesterol from macrophages. Yvan-Charvet et al. ATVB 2007;27:1132

14 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had adverse off-target effects unrelated to CETP inhibition

15 Off-target effects of torcetrapib In patients receiving torcetrapib in the ILLUSTRATE, RADIANCE 1 & 2 and ILLUMINATE studies there was a significant: Increase in blood pressure Decrease in serum potassium Increase in serum bicarbonate Increase in serum sodium Increase in serum aldosterone Barter et al, NEJM 2007;357:2109. Nissen et al. NEJM. 2007;356:1304. Kastelein et al. NEJM, 2007; 356:16. Bots et al. Lancet. 2007; 370:153

16 Off-target effects of torcetrapib unrelated to CETP inhibition Torcetrapib induced synthesis and secretion of both aldosterone and cortisol from human adrenal cells in tissue culture. Torcetrapib reduced expression of endothelial nitric oxide synthase mrna and protein, reduces nitric oxide release, increases expression of endothelin-1 and induces endothelial dysfunction animals independent of CETP inhibition Other CETP inhibitors do not have these off-target effects Forrest et al. Br J Pharmacol. 2008;154: Hu et al. Endocrinology 2009;150: Capponi et al. Circulation 2008;118:S:452. Connelly et al. J Cardiovasc Pharmacol 2010; 55:459. Simic et al. Eur Heart J (in press)

17 So, off-target adverse effects of torcetrapib (unrelated to CETP inhibition) MAY have been responsible for the adverse outcome in the ILLUMINATE trial

18 Dalcetrapib

19 Effects of dalcetrapib in humans Inhibits CETP activity by about 50% Increases HDL-C by about 30% Minimal effect on LDL-C levels Luscher et al. European Heart J, 2012;33:857

20 dal-outcomes Trial 15,600 patients 4-12 weeks after an index ACS event Statin therapy to optimal LDL-C level Dalcetrapib 600 mg Placebo 2.5-year follow-up Primary End Point CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest Schwartz et al. Am Heart J. 2009;158:

21 dal-outcomes Trial It was announced in early May 2012 that the dal-outcomes trial had been terminated on the basis of futility.

22 Why did dalcetrapib fail to reduce CV events? Two possible explanations are: (i) The increase in HDL-C concentration induced by dalcetrapib was not accompanied by an enhancement of the protective functions of HDL or (ii) that the inverse relationship between HDL-C concentration and cardiovascular risk observed in population studies is an epiphenomenon rather than being reflective of an ability of HDL to protect against cardiovascular disease.

23 Why did dalcetrapib fail to reduce CV events? It is also possible that inhibiting CETP with a relatively weak inhibitor such as dalcetrapib is not sufficient to have an impact on CV events. In addition, it is possible that CETP inhibition is not effective in patients treated soon after an acute coronary event as was the case with dal- OUTCOMES.

24 In my view, there is a compelling case for conducting new cardiovascular clinical outcome trials with agents such as anacetrapib and evacetrapib that do not have the off-target adverse effects of torcetrapib and are much more effective than dalcetrapib as inhibitors of CETP and as HDL-raising and LDL-lowering agents.

25 Anacetrapib Anacetrapib is a potent CETP inhibitor that has none of the off-target effects observed with torcetrapib Forrest et al. Br J Pharmacol. 2008;154: Hu et al. Endocrinology 2009;150:

26 Effects of anacetrapib on HDL function HDLs isolated from patients treated with anacetrapib have an enhanced ability to promote the efflux of cholesterol from macrophages. Yvan-Charvet L et al ATVB 2010;30:

27 DEFINE trial Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib 1620 patients with CHD or CHD risk equivalents Statin therapy to achieve LDL-C <100 mg/dl Anacetrapib 100 mg Placebo 76 week follow-up Primary End Point Lipid efficacy and the safety Cannon et al. NEJM. 2010; 363: Forrest et al. Br J Pharmacol. 2008;154: Hu et al. Endocrinology 2009;150:

28 DEFINE trial HDL-C (mg/dl) ApoA-I (mg/dl) Anacetrapib Anacetrapib Placebo Placebo O O Study Week Study Week Cannon et al. NEJM. 2010; 363:2406

29 mg/dl DEFINE trial LDL-C Placebo Anacetrapib Study Week Cannon et al. NEJM. 2010; 363:2406

30 ApoB (mg/ml) DEFINE trial Non-HDL-C (mg/dl) 100 Placebo 120 Placebo Anacetrapib Anacetrapib O O Study Week Study Week Cannon et al. NEJM. 2010; 363:2406

31 nmol/l DEFINE trial Lp(a) Placebo Anacetrapib Study Week Cannon et al. NEJM. 2010; 363:2406

32 DEFINE trial Anacetrapib had no effect on levels of aldosterone, sodium, potassium or bicarbonate and did not raise blood pressure Cannon et al. NEJM. 2010; 363:2406

33 mmhg mmhg Anacetrapib had no effect on BP SBP Anacetrapib Placebo DBP Week Cannon et al. NEJM. 2010; 363:2406

34 DEFINE trial The event distribution in DEFINE indicated a 94% probability that treatment with anacetrapib does not result in a torcetrapib type increase in CV events Cannon et al. NEJM. 2010; 363:2406

35 ILLUMINATE Trial 2007 (torcetrapib) Barter et al, NEJM 2007;357: DEFINE Trial 2010 (anacetrapib) Cannon et al. NEJM. 2010; 363: ILLUMINATE Trial N=15,067 - Torcetrapib CVD/MI/S/UA Revascularization DEFINE trial N = 1,623 - Anacetrapib CVD/MI/S/UA Revascularization CETP-I Better CETP-I worse

36 REVEAL trial Randomized Evaluation of the Effects of Anacetrapib through Lipidmodification 30,000 patients aged > 50 with with occlusive arterial disease Atovastatin to achieve LDL-C target Anacetrapib 100 mg Placebo Sites in North America, Europe and Asia Primary End Point Coronary death, myocardial infarction or coronary revascularization 4 year follow-up Planned completion in

37 Evacetrapib

38 Percent Change in HDL-C: Evacetrapib Plus statin 120% 100% 80% 86.6%* 79.9%* 94.0%* 60% 40% 20% 0% 7.3% 5.5% 1.4% Simvastatin 40 mg Atorvavastatin 20 mg Rosavastatin 10 mg Statin plus placebo Statin plus evacetrapib 100 mg * P<0.001 compared with placebo Nicholls et al. JAMA. 2011;306:2099

39 Percent Change in LDL-C: Evacetrapib Plus statin 0% 20% 40% -34.9% -33.6% -38.8% 60% -46.1%* -47.6%* -52.3%* Simvastatin 40 mg Atorvavastatin 20 mg Rosavastatin 10 mg Statin plus placebo Statin plus evacetrapib 100 mg * P<0.001 compared with placebo Nicholls et al. JAMA. 2011;306:2099

40 There is still a compelling case for further testing the hypothesis that inhibiting CETP will be anti-atherogenic in humans when using inhibitors that have none of the torcetrapib-like adverse effects and which have substantially greater HDL-raising and LDL-lowering than was achieved by dalcetrapib. The hypothesis is currently being tested in large CV clinical endpoint trials.