BackgroundBackground 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) inhibitor, raises HDL-C levels, but the functional effects of these increases remain uncertain. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, raises HDL-C levels, but the functional effects of these increases remain uncertain. The ILLUSTRATE Trial was designed to assess whether torcetrapib plus atorvastatin would slow CAD progression, compared with atorvastatin alone. The ILLUSTRATE Trial was designed to assess whether torcetrapib plus atorvastatin would slow CAD progression, compared with atorvastatin alone. December 2, 2006: A 15,000 patient outcome trial was stopped because of a significant increase in all- cause mortality in the torcetrapib treatment group. December 2, 2006: A 15,000 patient outcome trial was stopped because of a significant increase in all- cause mortality in the torcetrapib treatment group.

446 atorvastatin patients464 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 mg to achieve LDL-C of 100±15 mg/dL Intravascular ultrasound with 40 MHz transducer Motorized 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 Atorvastatin monotherapy Torcetrapib 60mg- atorvastatin 24 months treatment

Ultrasound Determination of Atheroma Area Precise Planimetry of EEM and Lumen Borders Atheroma area Lumen area EEM area

Intravascular Ultrasound Efficacy Parameters Change in Atheroma Volume (Month 24) Atheroma Volume (baseline) Atheroma Volume = –  n Normalized Atheroma Volume Atheroma CSA Lumen CSA –  n  Number of slices in patient’s pullback x Median number of slices in all pullbacks = Change in Percent Atheroma Volume Atheroma CSA EEM CSA =  n Atheroma CSA EEM CSA – (Month 24) (baseline)  n   n   n  Atheroma area Lumen area EEM area

Baseline Demographics and Medications Titrated atorvastatin dosage 23mg in both treatment groups

Baseline Lipid Levels and Blood Pressure

Final Lipid Values and Percentage Change

Time Course: Change in LDL-C Levels Torcetrapib-Atorvastatin Atorvastatin Monotherapy Difference 19.9%

Time Course: Change in HDL-C Levels Torcetrapib-Atorvastatin Atorvastatin Monotherapy Difference 60.8%

Cumulative Histogram: Change in Systolic BP TorcetrapibAtorvastatin Atorvastatin Monotherapy LS Mean difference 4.6 mm Hg

Blood Pressure Related Adverse Events 10.6% 23.7% 8.2% 21.3% 3.2% 9.0% 0% 5% 10% 15% 20% 25% 30% Investigator reported HTN Pressure >140/90 mmHg Systolic BP Increase >15 mmHg Atorvastatin Torcetrapib

Primary Efficacy Parameter Change in Percent Atheroma Volume Change in percent atheroma volume † p value from ANCOVA Atorvastatin monotherapy Torcetrapib- atorvastatin *LS Mean change p = 0.72 †

Secondary IVUS Efficacy Parameters Change in Normalized Atheroma Volume (mm 3 ) Change in 10 mm Most Diseased Segment (mm 3 ) Atorvastatin Torcetrapib p = 0.12 † p = † † p value from ANCOVA*LS Mean change

Prespecified Subgroups: No Heterogeneity Men vs. women Men vs. women Age greater or less than 65 Age greater or less than 65 Smokers vs. Non-smokers Smokers vs. Non-smokers LDL-C greater or less than the median LDL-C greater or less than the median HDL-C greater or less than 40 mg/dL HDL-C greater or less than 40 mg/dL hsCRP greater or less than 3.0 mg/L hsCRP greater or less than 3.0 mg/L Presence or absence of diabetes Presence or absence of diabetes Presence or absence of metabolic syndrome Presence or absence of metabolic syndrome

Change In Percent Atheroma Volume (%) Subgroup With Significant Heterogeneity Atorvastatin monotherapy Torcetrapib-atorvastatin Interaction p value = Baseline Percent Atheroma Volume (PAV) above/below the median

Adverse Events: Safety Population (n=1188)

Relationship between LDL-C and Percent Atheroma Volume in Six Recent IVUS Trials Mean Low-Density Lipoprotein Cholesterol (mg/dL) Change in Percent Atheroma Volume (%) REVERSAL pravastatin REVERSAL atorvastatin CAMELOT placebo ACTIVATE placebo A-Plus placebo ASTEROID rosuvastatin ILLUSTRATE Atorvastatin ILLUSTRATE torcetrapib

ConclusionsConclusions Torcetrapib 60mg in combination with atorvastatin increased HDL-C by 61% and lowered LDL-C by 20%, compared with atorvastatin monotherapy. Torcetrapib 60mg in combination with atorvastatin increased HDL-C by 61% and lowered LDL-C by 20%, compared with atorvastatin monotherapy. However, torcetrapib also increased systolic blood pressure by an average of 4.6 mmHg. However, torcetrapib also increased systolic blood pressure by an average of 4.6 mmHg. Torcetrapib-atorvastatin did not reduce the progression of coronary atherosclerosis for the primary efficacy parameter, compared with atorvastatin alone. Torcetrapib-atorvastatin did not reduce the progression of coronary atherosclerosis for the primary efficacy parameter, compared with atorvastatin alone. Adverse events showed a numerical excess in the torcetrapib group, but these differences did not reach statistical significance (trial not powered for outcomes). Adverse events showed a numerical excess in the torcetrapib group, but these differences did not reach statistical significance (trial not powered for outcomes).

Failure of Torcetrapib: Interpretation 1)CETP inhibition may not generate HDL particles that function normally in facilitating reverse cholesterol transport. 2)The torcetrapib-mediated increase in BP may have counterbalanced any favorable effects on lipid levels. 3)The increased BP may reflect a more generalized toxicity, simultaneously preventing beneficial effects on progression and increasing adverse clinical outcomes. The absence of a beneficial effect for torcetrapib was particularly striking for the achieved LDL level of 70 mg/dL, 20% lower than atorvastatin monotherapy.

Some 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.”