cholesteryl ester transfer protein inhibitors - what have we learnt?

Philip Barter

The Heart Research Institute

Sydney, Australia

Cholesteryl ester transfer protein

inhibitors - what have we learnt?

Philip Barter Disclosures

Received honorariums for lectures, consultancies or

membership of advisory boards from:

AstraZeneca, CSL, MSD, Novartis, Pfizer, Roche,

Sanofi Aventis

QUESTION

Why continue the development of

CETP inhibitors after the failures of

torcetrapib and dalcetrapib?

What do we know about the relationship

between CETP and atherosclerosis?

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

CETP and Atherosclerosis in Rabbits

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.

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.

CETP Polymorphisms and Cardiovascular

Risk in Humans

Thompson et al JAMA2008;299:2777-278

Voight et al Lancet, online ahead of publication, 17 May 2012

Ridker et al. Circ Cardiovasc Genet 2009; 2: 26

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

Torcetrapib

CF3

F3C

N O

O

N

O O

CF3

Dalcetrapib

S

O

O

H

N

Anacetrapib

O

F3C

O

N

O

F3C

F

CETP inhibitors

Evacetrapib

Cao et al. J Lipid Res 2011; 52:2169

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

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

But

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

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

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

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

Off-target effects of torcetrapib

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

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;154:1465-1473. Hu et al. Endocrinology 2009;150:2211-

2219. Capponi et al. Circulation 2008;118:S:452.

Connelly et al. J Cardiovasc Pharmacol 2010; 55:459.

Simic et al. Eur Heart J. 2012 (in press)

Off-target effects of torcetrapib

unrelated to CETP inhibition

So, off-target adverse effects of torcetrapib

(unrelated to CETP inhibition) MAY have

been responsible for the adverse outcome in

the ILLUMINATE trial

Dalcetrapib

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

Effects of dalcetrapib in humans

15,600 patients 4-12 weeks

after an index ACS event

dal-OUTCOMES Trial

Dalcetrapib 600 mg Statin therapy to optimal LDL-C level

Placebo

Primary End Point

CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest

2.5-year follow-up

Schwartz et al. Am Heart J. 2009;158:896-901.

It was announced in early May 2012 that the dal-OUTCOMES

trial had been terminated on the basis of futility.

dal-OUTCOMES Trial

http://www.roche.com/media_releases/med-cor-2012-05-07.htm

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.

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.

Why did dalcetrapib fail to reduce CV events?

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.

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;154:1465-1473. Hu et al. Endocrinology 2009;150:2211-2219

.

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;30:1430-1438

1620 patients with CHD or

CHD risk equivalents

DEFINE trial Determining the EFficacy and Tolerability of CETP

INhibition with AnacEtrapib

Anacetrapib 100 mg Statin therapy to achieve LDL-C <100 mg/dL

Placebo

Primary End Point

Lipid efficacy and the safety

76 week follow-up

Cannon et al. NEJM. 2010; 363:2406-2415 Forrest et al. Br J Pharmacol. 2008;154:1465-1473. Hu et al. Endocrinology 2009;150:2211-2219.

DEFINE trial

ApoA-I (mg/dL)

Study Week

O 24 76 0

40

80

120

160

200

240 Anacetrapib

Placebo

Cannon et al. NEJM. 2010; 363:2406

Study Week

O 24 76 0

20

40

60

80

100

120

Anacetrapib

Placebo

HDL-C (mg/dL)

DEFINE trial

LDL-C

Study Week

0 24 76 0

20

40

60

80

100

Anacetrapib

Placebo


mg

/dL

DEFINE trial

Study Week

O 24 76 0

20

40

60

80

100

120

Anacetrapib

Placebo


Non-HDL-C (mg/dL) ApoB (mg/ml)

Study Week

20

40

60

80

100

Anacetrapib

Placebo

O 24 76 0

DEFINE trial

Study Week

0 24 76 0

10

20

30

40

50

Anacetrapib

Placebo


Lp(a) n

mo

l/L

Anacetrapib had no effect on levels of aldosterone,

sodium, potassium or bicarbonate and did not raise

blood pressure

DEFINE trial


Anacetrapib had no effect on BP

SBP

DBP

mm

Hg

mm

Hg

Week

Anacetrapib

Placebo

200

160

120

80

40

0

120

80

40

0 0 6 12 18 24 30 38 46 54 62 70 76

0 6 12 18 24 30 38 46 54 62 70 76


The event distribution in DEFINE indicated a 94%

probability that treatment with anacetrapib does not

result in a torcetrapib type increase in CV events

DEFINE trial


ILLUMINATE Trial 2007 (torcetrapib)

DEFINE Trial 2010 (anacetrapib)

0.5 1.0 1.5

CVD/MI/S/UA

Revascularization

0.75 1.25

CETP-I Better CETP-I worse

DEFINE trial N = 1,623 - Anacetrapib

ILLUMINATE Trial N=15,067 - Torcetrapib

CVD/MI/S/UA

Revascularization

0.25

Cannon et al. NEJM. 2010; 363:2406-2415

Barter et al, NEJM 2007;357:2109-2122

30,000 patients aged > 50 with with occlusive

arterial disease

REVEAL trial Randomized Evaluation of the Effects of Anacetrapib through Lipid-

modification

Anacetrapib 100 mg Atovastatin to achieve LDL-C target

Placebo

Primary End Point

Coronary death, myocardial infarction or coronary revascularization

4 year follow-up

www.revealtrial.org

Sites in North America, Europe and Asia

Planned completion in 2017

Evacetrapib

120%

100%

80%

60%

40%

20%

0%

Percent Change in HDL-C: Evacetrapib Plus statin

7.3%

86.6%* 79.9%*

94.0%*

1.4% 5.5%

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

0%

20%

40%

60%

Percent Change in LDL-C: Evacetrapib Plus statin

-34.9%

-46.1%* -47.6%* -52.3%*

-33.6%

-38.8%

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

• 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.

cholesteryl ester transfer protein inhibitors - what have we learnt?

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