BackgroundBackgroundBackgroundBackground• HDL-C levels are inversely related to CV event rates.HDL-C levels are inversely related to CV event rates.

• Torcetrapib, a cholesteryl ester transfer protein (CETP) Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, raises HDL-C levels, but the functional effects inhibitor, raises HDL-C levels, but the functional effects of these increases remain uncertain.of these increases remain uncertain.

• The ILLUSTRATE Trial was designed to assess The ILLUSTRATE Trial was designed to assess whether torcetrapib plus atorvastatin would slowwhether torcetrapib plus atorvastatin would slowCAD progression, compared with atorvastatin alone.CAD progression, compared with atorvastatin alone.

• December 2, 2006: A 15,000 patient outcome trialDecember 2, 2006: A 15,000 patient outcome trialwas stopped because of a significant increase in all-was stopped because of a significant increase in all-cause mortality in the torcetrapib treatment group.cause mortality in the torcetrapib treatment group.

446 atorvastatin patients 464 torcetrapib patients

135 patients withdrew140 patients withdrew

24 Month follow-up IVUS of originally imaged “target” vessel (n=910)

4-10 week run-in atorvastatin 10-80 mgto achieve LDL-C of 100±15 mg/dL

Intravascular ultrasound with 40 MHz transducerMotorized pullback at 0.5 mm/sec through >40 mm segment

1188 patients at 137 centers in North America and Europe Symptomatic CAD, coronary angiography with >20% stenosis

Atorvastatinmonotherapy

Torcetrapib 60mg-atorvastatin

24 monthstreatment

Ultrasound Determination of Atheroma AreaUltrasound Determination of Atheroma AreaUltrasound Determination of Atheroma AreaUltrasound Determination of Atheroma Area

Precise Planimetry of EEM and Lumen BordersPrecise Planimetry of EEM and Lumen Borders

Atheroma area

Lumenarea

EEM area

Intravascular Ultrasound Efficacy ParametersIntravascular Ultrasound Efficacy ParametersIntravascular Ultrasound Efficacy ParametersIntravascular Ultrasound Efficacy Parameters

Change inAtheroma Volume (Month 24)

Atheroma Volume

(baseline)

Atheroma Volume= –

nNormalizedAtheromaVolume

AtheromaCSA LumenCSA– n

Number of slices in patient’s pullbackx

Median numberof slices in

all pullbacks=

Changein PercentAtheromaVolume

AtheromaCSA

EEMCSA =

n AtheromaCSA

EEMCSA –

(Month 24) (baseline)

n

n n

Atheroma area

Lumenarea

EEM area

Baseline Demographics and MedicationsBaseline Demographics and MedicationsBaseline Demographics and MedicationsBaseline Demographics and Medications

Characteristic Atorvastatin

monotherapy (n=597)

Torcetrapib- atorvastatin

(n=591) p value

Age 57.0 56.9 0.96

Male 70.5% 70.4% 0.96

BMI 30.3 30.6 0.41

Current Smokers 18.8% 17.3% 0.50

History of Hypertension 77.6% 74.5% 0.21

Prior Statin Use 91.0% 90.7% 0.88

History of Diabetes Mellitus 22.3% 20.1% 0.37

Aspirin usage 94.3% 93.7% 0.68

Titrated atorvastatin dosage 23mg in both treatment groups

Baseline Lipid Levels and Blood PressureBaseline Lipid Levels and Blood PressureBaseline Lipid Levels and Blood PressureBaseline Lipid Levels and Blood Pressure

Characteristic Atorvastatin

Monotherapy (n=597)

Torcetrapib- atorvastatin

(n=591) p value

Total Cholesterol (mg/dL) 157.5 157.7 0.91

LDL-cholesterol (mg/dL) 84.3 83.1 0.35

HDL-cholesterol (mg/dL) 45.2 46.0 0.34

LDL-C/HDL-C ratio 1.90 1.88 0.39

Triglycerides (mg/dL) 123.9 122.0 0.66

C-reactive Protein (mg/L) 1.8 2.1 0.04

Systolic BP (mmHg) 120.0 119.8 0.81

Diastolic BP (mmHg) 73.4 73.3 0.70

Final Lipid Values and Percentage ChangeFinal Lipid Values and Percentage Change Final Lipid Values and Percentage ChangeFinal Lipid Values and Percentage Change

Lipid Value (mg/dL)

Atorvastatin monotherapy

(n=446)

Torcetrapib -Atorvastatin

(n=464)

p value*

Final Value

Change (%)

Final Value

Change (%)

Total Cholesterol 157.2 1.9% 167.5 7.2% <0.001

LDL-cholesterol 87.2 6.6% 70.1 -13.3% <0.001

HDL-cholesterol 43.9 -2.2% 72.1 58.6% <0.001

LDL-C/HDL-C ratio 2.03 NA 0.93 NA <0.001

Triglycerides 110 -8.2% 104 -14.3% <0.001

C-Reactive Protein 1.5 -0.2 1.85 -0.1 0.19

40

50

60

70

80

90

100

0 1 3 6 9 12 15 18 21 24

Time (months)

LDL cholesterol Level (mg/dL)

Time Course: Change in LDL-C LevelsTime Course: Change in LDL-C Levels

Torcetrapib-AtorvastatinTorcetrapib-Atorvastatin

Atorvastatin Monotherapy

Difference 19.9%

20

30

40

50

60

70

80

90

0 1 3 6 9 12 15 18 21 24

Time (months)

HDL-cholesterol Level (mg/dL)

Time Course: Change in HDL-C LevelsTime Course: Change in HDL-C Levels

Torcetrapib-AtorvastatinTorcetrapib-Atorvastatin

Atorvastatin Monotherapy

Difference 60.8%

0%

20%

40%

60%

80%

100%

>-20 -15 -10 -5 0 5 10 15 20 25

Change in Systolic Blood Pressure (mmHg)

Percentage of Subjects (%)

Cumulative Histogram: Change in Systolic BPCumulative Histogram: Change in Systolic BP

TorcetrapibTorcetrapibAtorvastatinAtorvastatin

AtorvastatinMonotherapy

LS Mean difference4.6 mm Hg

Blood Pressure Related Adverse EventsBlood Pressure Related Adverse EventsBlood Pressure Related Adverse EventsBlood Pressure Related Adverse Events

10.6%

23.7%

8.2%

21.3%

3.2%

9.0%

0%

5%

10%

15%

20%

25%

30%

Investigatorreported HTN

Pressure>140/90 mmHg

Systolic BPIncrease >15 mmHg

Atorvastatin

Torcetrapib

Primary Efficacy ParameterPrimary Efficacy Parameter

Change in Percent Atheroma VolumeChange in Percent Atheroma VolumePrimary Efficacy ParameterPrimary Efficacy Parameter

Change in Percent Atheroma VolumeChange in Percent Atheroma Volume

0.19

0.12

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Changein percentatheromavolume

†p value from ANCOVA

Atorvastatinmonotherapy

Torcetrapib-atorvastatin

*LS Mean change

p = 0.72†

Secondary IVUS Efficacy ParametersSecondary IVUS Efficacy ParametersSecondary IVUS Efficacy ParametersSecondary IVUS Efficacy Parameters

-9.5

-6.3

-16

-12

-8

-4

0

-3.3

-4.2

-7

-6

-5

-4

-3

-2

-1

0

Change in NormalizedAtheroma Volume (mm3)

Change in 10 mm MostDiseased Segment (mm3)

Atorvastatin Torcetrapib

p = 0.12†p = 0.023†

†p value from ANCOVA*LS Mean change

Prespecified Subgroups: No HeterogeneityPrespecified Subgroups: No HeterogeneityPrespecified Subgroups: No HeterogeneityPrespecified Subgroups: No Heterogeneity

• Men vs. womenMen vs. women

• Age greater or less than 65Age greater or less than 65

• Smokers vs. Non-smokersSmokers vs. Non-smokers

• LDL-C greater or less than the medianLDL-C greater or less than the median

• HDL-C greater or less than 40 mg/dLHDL-C greater or less than 40 mg/dL

• hsCRP greater or less than 3.0 mg/LhsCRP greater or less than 3.0 mg/L

• Presence or absence of diabetesPresence or absence of diabetes

• Presence or absence of metabolic syndromePresence or absence of metabolic syndrome

0.19

0.61

-0.37

0.21

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

PAV <median PAV ≥median

ChangeIn PercentAtheromaVolume

(%)

Subgroup With Significant HeterogeneitySubgroup With Significant HeterogeneitySubgroup With Significant HeterogeneitySubgroup With Significant Heterogeneity

Atorvastatin monotherapy Torcetrapib-atorvastatin

Interactionp value = 0.005

Baseline Percent Atheroma Volume (PAV) above/below the median

Adverse Events: Safety Population (n=1188)Adverse Events: Safety Population (n=1188)Adverse Events: Safety Population (n=1188)Adverse Events: Safety Population (n=1188)

Atorvastatin Monotherapy

(n=597)

Torcetrapib- Atorvastatin

(n=591)

Death 6 (1.0%) 8 (1.4%)

CHD death 1 (0.2%) 1 (0.2%)

Nonfatal myocardial infarction 16 (2.7 %) 13 (2.2%)

Fatal or nonfatal stroke 8 (1.3%) 2 (0.3%)

Hospitalization for unstable angina 34 (5.7%) 47 (8.0%)

Coronary revascularization 95 (15.9%) 114 (19.3%)

Peripheral vascular disease 13 (2.2%) 10 (1.7%)

Hospitalization for CHF 4 (0.7%) 9 (1.5%)

Composite: CHD death, MI, stroke, and unstable angina

57 (9.5%) 62 (10.5%)

Composite: CHD death, MI, stroke, unstable angina, and revasculariztion

117 (19.6%) 124 (21.0%)

Relationship between LDL-C and Percent Relationship between LDL-C and Percent Atheroma Volume in Six Recent IVUS TrialsAtheroma Volume in Six Recent IVUS TrialsRelationship between LDL-C and Percent Relationship between LDL-C and Percent

Atheroma Volume in Six Recent IVUS TrialsAtheroma Volume in Six Recent IVUS Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

Changein PercentAtheromaVolume

(%)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

ACTIVATEplacebo

A-Plusplacebo

ASTEROIDrosuvastatin

ILLUSTRATEAtorvastatin

ILLUSTRATEtorcetrapib

ConclusionsConclusionsConclusionsConclusions• Torcetrapib 60mg in combination with atorvastatin Torcetrapib 60mg in combination with atorvastatin

increased HDL-C by 61% and lowered LDL-C by 20%, increased HDL-C by 61% and lowered LDL-C by 20%, compared with atorvastatin monotherapy.compared with atorvastatin monotherapy.

• However, torcetrapib also increased systolic blood However, torcetrapib also increased systolic blood pressure by an average of 4.6 mmHg.pressure by an average of 4.6 mmHg.

• Torcetrapib-atorvastatin did not reduce the progression Torcetrapib-atorvastatin did not reduce the progression of coronary atherosclerosis for the primary efficacy of coronary atherosclerosis for the primary efficacy parameter, compared with atorvastatin alone.parameter, compared with atorvastatin alone.

• Adverse events showed a numerical excess in the Adverse events showed a numerical excess in the torcetrapib group, but these differences did not reach torcetrapib group, but these differences did not reach statistical significance (trial not powered for outcomes).statistical significance (trial not powered for outcomes).

Failure of Torcetrapib: InterpretationFailure of Torcetrapib: InterpretationFailure of Torcetrapib: InterpretationFailure of Torcetrapib: Interpretation

1)1)CETP inhibition may not generate HDL particles that CETP inhibition may not generate HDL particles that function normally in facilitating reverse cholesterol function normally in facilitating reverse cholesterol transport.transport.

2)2)The torcetrapib-mediated increase in BP may have The torcetrapib-mediated increase in BP may have counterbalanced any favorable effects on lipid levels.counterbalanced any favorable effects on lipid levels.

3)3)The increased BP may reflect a more generalized The increased BP may reflect a more generalized toxicity, simultaneously preventing beneficial effects on toxicity, simultaneously preventing beneficial effects on progression and increasing adverse clinical outcomes.progression and increasing adverse clinical outcomes.

The absence of a beneficial effect for torcetrapibThe absence of a beneficial effect for torcetrapibwas particularly striking for the achieved LDL levelwas particularly striking for the achieved LDL level

of 70 mg/dL, 20% lower than atorvastatin monotherapy.of 70 mg/dL, 20% lower than atorvastatin monotherapy.

Some Final ThoughtsSome Final ThoughtsSome Final ThoughtsSome Final Thoughts

In 20 years since introduction of statins, no new classes of anti-atherosclerotic drugs have been introduced.

We continue to believe that raising drugs to raise HDL-C levels represents promising therapeutic targets.

It remains uncertain whether the unfavorable torcetrapib results were due to the “molecule” or the “mechanism”

Although discouraging, we do not think these results preclude the possibility that another CETP inhibitor will produce favorable effects, but they do “raise the bar.”