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ILLUSTRATEILLUSTRATE

Presented at the American College of Presented at the American College of Cardiology Annual Scientific Session Cardiology Annual Scientific Session

March, 2007March, 2007

Presented by Dr. Steven E. NissenPresented by Dr. Steven E. Nissen

Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by

CETP Inhibition and HDL Elevation

Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by

CETP Inhibition and HDL Elevation

Clinical Trial Results . orgClinical Trial Results . org

ILLUSTRATE Trial: BackgroundILLUSTRATE Trial: Background

• The goal of the trial was to evaluate the The goal of the trial was to evaluate the effect of treatment with torcetrapib, a effect of treatment with torcetrapib, a cholesteryl ester transfer protein (CETP) cholesteryl ester transfer protein (CETP) inhibitor, in addition to atorvastatin as inhibitor, in addition to atorvastatin as compared with atorvastatin treatment alone compared with atorvastatin treatment alone on disease progression among patients with on disease progression among patients with coronary artery disease.coronary artery disease.

• The goal of the trial was to evaluate the The goal of the trial was to evaluate the effect of treatment with torcetrapib, a effect of treatment with torcetrapib, a cholesteryl ester transfer protein (CETP) cholesteryl ester transfer protein (CETP) inhibitor, in addition to atorvastatin as inhibitor, in addition to atorvastatin as compared with atorvastatin treatment alone compared with atorvastatin treatment alone on disease progression among patients with on disease progression among patients with coronary artery disease.coronary artery disease.

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ILLUSTRATE Trial: Study DesignILLUSTRATE Trial: Study Design

Primary Endpoint: Change in percent atheroma volumePrimary Endpoint: Change in percent atheroma volume Secondary Endpoint: Normalized total atheroma volume; change in Secondary Endpoint: Normalized total atheroma volume; change in

atheroma volume in the most diseased 10-mm segmentatheroma volume in the most diseased 10-mm segment

Primary Endpoint: Change in percent atheroma volumePrimary Endpoint: Change in percent atheroma volume Secondary Endpoint: Normalized total atheroma volume; change in Secondary Endpoint: Normalized total atheroma volume; change in

atheroma volume in the most diseased 10-mm segmentatheroma volume in the most diseased 10-mm segment

Atorvastatin + Torcetrapib60 mgn=591

Atorvastatin + Torcetrapib60 mgn=591

Atorvastatin + Placebo60 mgn=597

Atorvastatin + Placebo60 mgn=597

1188 patients, aged 18-75 years, with clinically indicated cardiac catheterization showing 1188 patients, aged 18-75 years, with clinically indicated cardiac catheterization showing >> 1 stenosis on angiography with 1 stenosis on angiography with >> 20% narrowing and if target vessel had less than 20% narrowing and if target vessel had less than

50% obstruction throughout a segment 50% obstruction throughout a segment >> 40mm. 40mm.Randomized. Double-blind.Randomized. Double-blind.

Mean age = 57 years. 30% FemaleMean age = 57 years. 30% Female

1188 patients, aged 18-75 years, with clinically indicated cardiac catheterization showing 1188 patients, aged 18-75 years, with clinically indicated cardiac catheterization showing >> 1 stenosis on angiography with 1 stenosis on angiography with >> 20% narrowing and if target vessel had less than 20% narrowing and if target vessel had less than

50% obstruction throughout a segment 50% obstruction throughout a segment >> 40mm. 40mm.Randomized. Double-blind.Randomized. Double-blind.

Mean age = 57 years. 30% FemaleMean age = 57 years. 30% Female

RR

24 mos. follow up24 mos. follow up

4-10 week run-in phase of atorvastatin treatment titrated to achieve LDL level of 85-115mg/dl

4-10 week run-in phase of atorvastatin treatment titrated to achieve LDL level of 85-115mg/dl

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0.12%

0.19%

0.0%

0.1%

0.2%

0.3%

Torcetrapib Placebo

0.12%

0.19%

0.0%

0.1%

0.2%

0.3%

Torcetrapib Placebo

• The percent The percent change in change in atheroma atheroma volume did not volume did not differ between differ between treatment treatment groups.groups.

Cha

nge

in a

ther

oma

volu

me

Cha

nge

in a

ther

oma

volu

me

form

bas

elin

e (

%)

form

bas

elin

e (

%)

ILLUSTRATE Trial: Primary EndpointILLUSTRATE Trial: Primary Endpoint

n = 591n = 591 n = 597n = 597

p = 0.72p = 0.72

Percent change in atheroma volume from baselinePercent change in atheroma volume from baseline

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ILLUSTRATE Trial: Secondary Endpoint ILLUSTRATE Trial: Secondary Endpoint

• The change in The change in atheroma volume atheroma volume of the most of the most disease 10mm disease 10mm segment did not segment did not differ between the differ between the two treatment two treatment groups.groups.

-4.1

-3.3

-5

-4

-3

-2

-1

0

-4.1

-3.3

-5

-4

-3

-2

-1

0

Change in atheroma volume of the most diseased Change in atheroma volume of the most diseased 10mm segment10mm segment

Cha

nge

in a

ther

oma

volu

me

(mm

3 )

p = 0.12p = 0.12

n = 591n = 591 n = 597n = 597

PlaceboPlaceboTorcetrapibTorcetrapib

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ILLUSTRATE Trial: Secondary Endpoint ILLUSTRATE Trial: Secondary Endpoint

• The reduction in The reduction in normalized total normalized total atheroma volume atheroma volume was greater in the was greater in the torcetrapib group torcetrapib group (-9.4 mm(-9.4 mm33) ) compared with compared with atrovastatin alone atrovastatin alone (-6.3 mm(-6.3 mm33) (p=0.02).) (p=0.02).

-9.4

-6.3

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

-9.4

-6.3

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Reduction in normalized total atheroma volumeReduction in normalized total atheroma volume

Red

uctio

n in

nor

mal

ized

tot

al

athe

rom

a vo

lum

e (m

m3 )

p = 0.02p = 0.02

n = 591n = 591 n = 597n = 597

PlaceboPlaceboTorcetrapibTorcetrapib

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ILLUSTRATE Trial: LimitationsILLUSTRATE Trial: Limitations

• Commercial development of torcetrapib was Commercial development of torcetrapib was recently stopped after a large trial showed an recently stopped after a large trial showed an increase in mortality with torcetrapib, along with increase in mortality with torcetrapib, along with an increase in blood pressure.an increase in blood pressure.

• The present trial, while much smaller than the The present trial, while much smaller than the other trial, did not show a difference in mortality other trial, did not show a difference in mortality with torcetrapib, but there were only 14 deaths.with torcetrapib, but there were only 14 deaths.

• Commercial development of torcetrapib was Commercial development of torcetrapib was recently stopped after a large trial showed an recently stopped after a large trial showed an increase in mortality with torcetrapib, along with increase in mortality with torcetrapib, along with an increase in blood pressure.an increase in blood pressure.

• The present trial, while much smaller than the The present trial, while much smaller than the other trial, did not show a difference in mortality other trial, did not show a difference in mortality with torcetrapib, but there were only 14 deaths.with torcetrapib, but there were only 14 deaths.

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ILLUSTRATE Trial: SummaryILLUSTRATE Trial: Summary

• Among patients with coronary disease, treatment Among patients with coronary disease, treatment with the CETP inhibitor torcetrapib in addition to with the CETP inhibitor torcetrapib in addition to atorvastatin therapy was not associated with a atorvastatin therapy was not associated with a difference in change in percent atheroma volume difference in change in percent atheroma volume compared with atorvastatin alone at 24 months compared with atorvastatin alone at 24 months follow-up.follow-up.

• Among patients with coronary disease, treatment Among patients with coronary disease, treatment with the CETP inhibitor torcetrapib in addition to with the CETP inhibitor torcetrapib in addition to atorvastatin therapy was not associated with a atorvastatin therapy was not associated with a difference in change in percent atheroma volume difference in change in percent atheroma volume compared with atorvastatin alone at 24 months compared with atorvastatin alone at 24 months follow-up.follow-up.

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ILLUSTRATE Trial: Summary Cont.ILLUSTRATE Trial: Summary Cont.

• Torcetrapib was effective in raising HDL in the Torcetrapib was effective in raising HDL in the present study.present study.

• However, there was no effect on atherosclerosis However, there was no effect on atherosclerosis progression, despite having the expected impact on progression, despite having the expected impact on increasing HDL and lowering HDL.increasing HDL and lowering HDL.

• Torcetrapib was effective in raising HDL in the Torcetrapib was effective in raising HDL in the present study.present study.

• However, there was no effect on atherosclerosis However, there was no effect on atherosclerosis progression, despite having the expected impact on progression, despite having the expected impact on increasing HDL and lowering HDL.increasing HDL and lowering HDL.

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