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The ERASE Trial: Effect of rHDL on Atherosclerosis-Safety and EfficacyThe ERASE Trial: Effect of rHDL on Atherosclerosis-Safety and Efficacy

Presented at American College of Cardiology Presented at American College of Cardiology Annual Scientific Session 2007Annual Scientific Session 2007

Presented by Dr. Jean-Claude Tardif, M.D. Presented by Dr. Jean-Claude Tardif, M.D.

ERASE TrialERASE Trial

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ERASE Trial: BackgroundERASE Trial: Background

• CSL-111 is an apolipoprotein A-I isolated from CSL-111 is an apolipoprotein A-I isolated from human plasma and phosphatidylcholine derived human plasma and phosphatidylcholine derived from soybean.from soybean.

• Commercial development of the cholesteryl ester Commercial development of the cholesteryl ester transfer protein inhibitor torcetrapib was recently transfer protein inhibitor torcetrapib was recently stopped after a trial showed an increase in stopped after a trial showed an increase in mortality with torcetrapib.mortality with torcetrapib.

• CSL-111 is an apolipoprotein A-I isolated from CSL-111 is an apolipoprotein A-I isolated from human plasma and phosphatidylcholine derived human plasma and phosphatidylcholine derived from soybean.from soybean.

• Commercial development of the cholesteryl ester Commercial development of the cholesteryl ester transfer protein inhibitor torcetrapib was recently transfer protein inhibitor torcetrapib was recently stopped after a trial showed an increase in stopped after a trial showed an increase in mortality with torcetrapib.mortality with torcetrapib.

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ERASE Trial: BackgroundERASE Trial: Background

• CSL-111 is a different class of agents targeting CSL-111 is a different class of agents targeting increasing HDL and is not a CETP inhibitor but is increasing HDL and is not a CETP inhibitor but is derived from human plasma.derived from human plasma.

• The goal of this trial was to evaluate the effect of The goal of this trial was to evaluate the effect of plaque burden of reconstituted HDL compared with plaque burden of reconstituted HDL compared with placebo among patients with recent acute placebo among patients with recent acute coronary syndromes. coronary syndromes.

• CSL-111 is a different class of agents targeting CSL-111 is a different class of agents targeting increasing HDL and is not a CETP inhibitor but is increasing HDL and is not a CETP inhibitor but is derived from human plasma.derived from human plasma.

• The goal of this trial was to evaluate the effect of The goal of this trial was to evaluate the effect of plaque burden of reconstituted HDL compared with plaque burden of reconstituted HDL compared with placebo among patients with recent acute placebo among patients with recent acute coronary syndromes. coronary syndromes.

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CSL-111

40 mg/kg

n=111

ERASE Trial: Study Design

CSL-111

80 mg/kg

n=12

Placebo

Matching Dose

n=60

183 patients aged 30-75 years with clinical need for coronary angiography, defined as ≥ 1 narrowing ≥20% coronary angiography at baseline; within 2 weeks of having an acute

coronary syndrome defined as unstable angina or non-ST-segment or ST-segment elevation MIPlacebo-controlled. Randomized. Double-blinded. Mean follow-up: 6 weeks. 17% female.

183 patients aged 30-75 years with clinical need for coronary angiography, defined as ≥ 1 narrowing ≥20% coronary angiography at baseline; within 2 weeks of having an acute

coronary syndrome defined as unstable angina or non-ST-segment or ST-segment elevation MIPlacebo-controlled. Randomized. Double-blinded. Mean follow-up: 6 weeks. 17% female.

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Primary Endpoint: Percentage change in atheroma volume from Primary Endpoint: Percentage change in atheroma volume from baseline to 6 weeksbaseline to 6 weeks

Secondary Endpoint: Absolute change in plaque volume, change in Secondary Endpoint: Absolute change in plaque volume, change in plaque characterization indexes on IVUS, and change in coronary plaque characterization indexes on IVUS, and change in coronary score on quantitative coronary angiography.score on quantitative coronary angiography.

Primary Endpoint: Percentage change in atheroma volume from Primary Endpoint: Percentage change in atheroma volume from baseline to 6 weeksbaseline to 6 weeks

Secondary Endpoint: Absolute change in plaque volume, change in Secondary Endpoint: Absolute change in plaque volume, change in plaque characterization indexes on IVUS, and change in coronary plaque characterization indexes on IVUS, and change in coronary score on quantitative coronary angiography.score on quantitative coronary angiography.

80 mg group discontinued80 mg group discontinued

6 week follow-up6 week follow-up

80 mg group discontinued80 mg group discontinued

6 week follow-up6 week follow-up

RR

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ERASE Trial: Primary EndpointERASE Trial: Primary Endpoint

-3.4%

-1.6%

-4%

-3%

-2%

-1%

0%

1%

-3.4%

-1.6%

-4%

-3%

-2%

-1%

0%

1%

Percent Change in Atheroma Volume from Percent Change in Atheroma Volume from Baseline to 6 weeksBaseline to 6 weeks

• The primary endpoint The primary endpoint of percent change in of percent change in atheroma volume from atheroma volume from baseline to 6 weeks baseline to 6 weeks did not differ between did not differ between treatment groups treatment groups (-3.4% in the CSL-111 (-3.4% in the CSL-111 group vs. -1.6% in the group vs. -1.6% in the placebo group, placebo group, p=0.48)p=0.48)

PlaceboPlaceboCSL-111CSL-111

Cha

nge

in a

ther

oma

volu

me

(%)

Cha

nge

in a

ther

oma

volu

me

(%)

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p = 0.48p = 0.48

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ERASE Trial: Secondary EndpointERASE Trial: Secondary Endpoint

-5.3

-2.3

-6

-5

-4

-3

-2

-1

0

1

-5.3

-2.3

-6

-5

-4

-3

-2

-1

0

1

Absolute Change in Atheroma Volume from Absolute Change in Atheroma Volume from Basleine to 6 weeksBasleine to 6 weeks

• The absolute change The absolute change in atheroma volume in atheroma volume from baseline to 6 from baseline to 6 weeks also did not weeks also did not differ between differ between treatment groups treatment groups (-5.3mm(-5.3mm33 in the CSL- in the CSL-111 group vs. -2.3 mm111 group vs. -2.3 mm33 in the placebo group, in the placebo group, p=0.39)p=0.39)

PlaceboPlaceboCSL-111CSL-111

Abs

olut

e ch

ange

in a

ther

oma

Abs

olut

e ch

ange

in a

ther

oma

volu

me

(mm

volu

me

(mm

33 ))

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p = 0.39p = 0.39

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ERASE Trial: Secondary EndpointsERASE Trial: Secondary Endpoints

• Mean change in plaque characterization index Mean change in plaque characterization index on IVUS was -0.0097 for CSL-111 and +0.0128 on IVUS was -0.0097 for CSL-111 and +0.0128 for placebo (p=0.01).for placebo (p=0.01).

• Reduction in coronary score on angiography Reduction in coronary score on angiography was significantly less with CSL-111 compared was significantly less with CSL-111 compared with placebo (-0.039 mm for CSL-111 vs. -with placebo (-0.039 mm for CSL-111 vs. -0.071 mm for placebo, p=0.03).0.071 mm for placebo, p=0.03).

• Mean change in plaque characterization index Mean change in plaque characterization index on IVUS was -0.0097 for CSL-111 and +0.0128 on IVUS was -0.0097 for CSL-111 and +0.0128 for placebo (p=0.01).for placebo (p=0.01).

• Reduction in coronary score on angiography Reduction in coronary score on angiography was significantly less with CSL-111 compared was significantly less with CSL-111 compared with placebo (-0.039 mm for CSL-111 vs. -with placebo (-0.039 mm for CSL-111 vs. -0.071 mm for placebo, p=0.03).0.071 mm for placebo, p=0.03).

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ERASE Trial: LimitationsERASE Trial: Limitations

• The 80 mg CSL-111 group was discontinued due to high The 80 mg CSL-111 group was discontinued due to high rates of abnormal liver function tests, including alanine rates of abnormal liver function tests, including alanine aminotransferase >5 times the upper limit of normal aminotransferase >5 times the upper limit of normal (ULN) in 50% of the group and aspartate (ULN) in 50% of the group and aspartate aminotransferase >5 times ULN in 33% of the group.aminotransferase >5 times ULN in 33% of the group.

• The lipid effects of the agent in the study were not The lipid effects of the agent in the study were not reported.reported.

• A larger trial would be required to evaluate the clinical A larger trial would be required to evaluate the clinical safety and efficacy of this agent.safety and efficacy of this agent.

• The 80 mg CSL-111 group was discontinued due to high The 80 mg CSL-111 group was discontinued due to high rates of abnormal liver function tests, including alanine rates of abnormal liver function tests, including alanine aminotransferase >5 times the upper limit of normal aminotransferase >5 times the upper limit of normal (ULN) in 50% of the group and aspartate (ULN) in 50% of the group and aspartate aminotransferase >5 times ULN in 33% of the group.aminotransferase >5 times ULN in 33% of the group.

• The lipid effects of the agent in the study were not The lipid effects of the agent in the study were not reported.reported.

• A larger trial would be required to evaluate the clinical A larger trial would be required to evaluate the clinical safety and efficacy of this agent.safety and efficacy of this agent.

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ERASE Trial: SummaryERASE Trial: Summary

• Among patients with recent acute coronary Among patients with recent acute coronary syndromes, treatment with the novel reconstituted syndromes, treatment with the novel reconstituted HDL agent CSL-111 was not associated with a HDL agent CSL-111 was not associated with a reduction in atheroma volume compared with reduction in atheroma volume compared with placebo.placebo.

• Treatment with CSL-111 was associated with a Treatment with CSL-111 was associated with a change in atheroma volume within the treatment change in atheroma volume within the treatment arm from baseline to 6 week follow-up.arm from baseline to 6 week follow-up.

• Among patients with recent acute coronary Among patients with recent acute coronary syndromes, treatment with the novel reconstituted syndromes, treatment with the novel reconstituted HDL agent CSL-111 was not associated with a HDL agent CSL-111 was not associated with a reduction in atheroma volume compared with reduction in atheroma volume compared with placebo.placebo.

• Treatment with CSL-111 was associated with a Treatment with CSL-111 was associated with a change in atheroma volume within the treatment change in atheroma volume within the treatment arm from baseline to 6 week follow-up.arm from baseline to 6 week follow-up.

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