New CETP inhibitors and modulators

Jean-Claude Tardif MD, FRCPC, FACC, FCAHS Director, MHI Research Center

Professor of Medicine UdeM Endowed Research Chair in Atherosclerosis

Montreal Heart Institute Université de Montréal

Biological plausibility for benefit of raising HDL-C in CAD patients

♦  Cholesterol efflux, reverse cholesterol transport

♦ “Pleiotropic” effects of HDL

♦  Improves endothelial function and repair

♦  Anti-oxidant properties

♦  Anti-inflammatory properties

♦  Anti-thrombotic properties

Comparison of CETP inhibitors

Dalcetrapib Torcetrapib Anacetrapib

CETP binding site Cys 13 residue1 Helices at the end

ofthe C and N

barrels2

? (Similar to torcetrapib)3

IC50 9 µM1 0.05 µM2 0.057 µM3

CETP inhibition 37.2%4 ≥80%5 90%3

HDL-C increase 33.9%4 91%5 129%6

Blood pressure increase No7 Yes8 No3

Increases aldosteroneproduction (in vitro)

No7 Yes7 No9

1Okamoto et al. Nature 2000;406:203–7; 2Clark et al. J Lipid Res 2006;47:537–52; 3Masson D. Curr Opin Invest Drugs 2009;10:980-7; 4de Grooth et al. Circulation 2002;105:2159–65; 5Clark et al. Arterioscler Thromb Vasc Biol 2004;24:490–7; 6Krishna et al. Lancet 2007;370: 1907–14; 7Stein et al. Am J Cardiol 2009;104:82–91; 8Barter et al. N Engl J Med 2007;357:2109–22; 9Forrest et al. Br J Pharmacol 2008; 154:1465–73

NOTE: The clinical relevance of these differences is not known; these compounds have not been studied in head to head clinical trials, therefore no conclusion should be drawn based on these comparisons. Clinical development of torcetrapib was halted due to off-target adverse effects

Dalcetrapib and torcetrapib differ in mechanism by which they decrease CETP

activity

dalcetrapib

HDL

CETP

HDL

●  Dalcetrapib binds to CETP, inducing a conformational change to CETP that inhibitslipid transfer from HDL to LDL and VLDL1

●  Dalcetrapib does not inhibit lipid transfer between HDL sub-particles in vitro2

●  Torcetrapib binding to CETP results in a highaffinity complex of torcetrapib, HDL, and CETP that blocks lipid transfer3,4

1Okamoto et al. Nature. 2000;406:203-207; 2Dernick et al. Poster presented at 6th IAS-Sponsored Workshop on HDL. May 17-20, 2010; Whistler, BC, Canada; 3Niesor et al. Atheroslerosis. 2008;199:231; 4Clark et al. J. Lipid Res. 2006;47:537–552

torcetrapib

The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through CETP modulation treats the underlying disease of atherosclerosis and will attenuate CV risk

dal-OUTCOMES1

15,600 patients recently hospitalized for ACS To evaluate the effect of dalcetrapib on CVoutcomes RECRUITMENT COMPLETE

dal-VESSEL2

450 patients withCHD or CHD risk equivalent To evaluate the effect of dalcetrapib onendothelial function and blood pressure, measured by FMD and ABPM RECRUITMENT COMPLETE

dal-PLAQUE3

130 patients withCHD To evaluate the effect of dalcetrapib oninflammation, plaque size and burden, measured by PET/CT and MRI RECRUITMENT COMPLETE

The dal-HEART Programdalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport

1Schwartz et al. Am Heart J 2009;158:896-901; 2http://clinicaltrials.gov/ct2/show/NCT00655538 Accessed April 1st 2010; 3http://clinicaltrials.gov/ct2/show/NCT00655473 Accessed April 1st 2010; 4http://clinicaltrials.gov/ct2/show/NCT01059682 Accessed April 1st 2010 .

dal-PLAQUE-24

900 patients withCAD To evaluate the effect of dalcetrapib onatherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasound RECRUITING

DAL-OUTCOMES Study DesignA double-blind, randomized, placebo-controlled, parallel group, multi-centre study in 15,600 patients recently hospitalized for ACS

Visit 1 Visit 2

Visit 3 randomizatio

n1 : 1

Double-blind

Single-blind Placebo Run-in

4-12 Weeks

Until 1600 events

occur but at least a minimum

of2 years

Follow up 1st year: every 3 months

Following years: every 4 months

Dalcetrapib 600 mg

Placebo

dal-PLAQUE-2: Study Design •  Objective: to assess the effect of dalcetrapib versus placebo

on atherosclerotic disease progression in patients with CAD

•  A double-blind, randomized, placebo-controlled, parallel-group multicenter study in 900 patients with CAD

dalcetrapib 600 mg

placebo

Randomization 24 months

Primary endpoints: IVUS and CIMT at 24 months Other assessments: CIMT at 6+12 months; QCA at 24 months

Pre-rando phase Screening phase up to 8 weeksBaseline IVUS, QCA and CIMT

Double-blind

Background of contemporary evidence-basedtherapy for CAD and CV risk factors

Effects on LDL-C and HDL-C

HDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(mg/

dL) (

SE)

0

20

40

60

80

100

120

Anacetrapib Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (m

g/dL

) (SE

)

0

20

40

60

80

100

Anacetrapib Placebo

Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Anacetrapib had no effect on BP

SBP

DBP

Syst

olic

blo

od p

ress

ure

(mm

Hg)

Dia

stol

ic b

lood

pre

ssur

e (m

mH

g) Baseline 6 1 2 1 8 2 4 3 0 3 8 4 6 5 4 6 2 7 0 7 6 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0

A = A n a c e t r a p i b B = P l a c e b o

0 2 0 4 0 6 0 8 0

1 0 0 1 2 0 1 4 0

A = A n a c e t r a p i b B = P l a c e b o

Week

Baseline 6 1 2 1 8 2 4 3 0 3 8 4 6 5 4 6 2 7 0 7 6 Week

L

L

10

Conclusions •  Despite current optimal care, substantial residual CV risk remains •  HDL-C is a promising target to reduce the burden of CV diseases

–  Studies using coronary IVUS suggest that raising HDL-C can slow progression of atherosclerosis

•  Clinical trials with dalcetrapib and anacetrapib have demonstrated

–  Effective raising of HDL-C (> 30% after 12 weeks) –  Excellent tolerability profile

•  The dal-HEART program (dalcetrapib) and REVEAL trial (anacetrapib) will: –  Evaluate the effects of the CETP modulator dalcetrapib on

atherosclerosis progression and clinical outcomes –  Evaluate the effects of the CETPi anacetrapib on clinical

outcomes