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Background

Background. 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.

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Background

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  1. Background • 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. • The ILLUSTRATE Trial was designed to assess whether torcetrapib plus atorvastatin would slowCAD progression, compared with atorvastatin alone. • December 2, 2006: A 15,000 patient outcome trialwas stopped because of a significant increase in all-cause mortality in the torcetrapib treatment group.

  2. Intravascular ultrasound with 40 MHz transducer Motorized pullback at 0.5 mm/sec through >40 mm segment 4-10 week run-in atorvastatin 10-80 mgto achieve LDL-C of 100±15 mg/dL Atorvastatin monotherapy Torcetrapib 60mg-atorvastatin 24 monthstreatment 140 patients withdrew 135 patients withdrew 446 atorvastatin patients 464 torcetrapib patients 24 Month follow-up IVUS of originally imaged “target” vessel (n=910) 1188 patients at 137 centers in North America and EuropeSymptomatic CAD, coronary angiography with >20% stenosis

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

  4. EEM area Changein PercentAtheromaVolume AtheromaCSA AtheromaCSA    = – Lumen area EEMCSA EEMCSA (baseline) (Month 24) Atheroma area   n  n n n n n Change in Atheroma Volume Atheroma Volume Atheroma Volume – = (Month 24) (baseline) Intravascular Ultrasound Efficacy Parameters Median numberof slices inall pullbacks AtheromaCSA NormalizedAtheroma Volume LumenCSA – = x Number of slices in patient’s pullback

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

  6. Baseline Lipid Levels and Blood Pressure

  7. Final Lipid Values and Percentage Change

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

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

  10. Cumulative Histogram: Change in Systolic BP LS Mean difference 4.6 mm Hg Atorvastatin Monotherapy Torcetrapib Atorvastatin

  11. Atorvastatin Torcetrapib Blood Pressure Related Adverse Events 30% 23.7% 25% 21.3% 20% 15% 10.6% 9.0% 8.2% 10% 3.2% 5% 0% Systolic BPIncrease >15 mmHg Investigatorreported HTN Pressure>140/90 mmHg

  12. Primary Efficacy ParameterChange in Percent Atheroma Volume p = 0.72† Changein percent atheroma volume Atorvastatinmonotherapy Torcetrapib-atorvastatin †p value from ANCOVA *LS Mean change

  13. Atorvastatin Torcetrapib Secondary IVUS Efficacy Parameters Change in NormalizedAtheroma Volume (mm3) Change in 10 mm MostDiseased Segment (mm3) p = 0.023† p = 0.12† *LS Mean change †p value from ANCOVA

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

  15. Atorvastatin monotherapy Torcetrapib-atorvastatin Subgroup With Significant Heterogeneity Baseline Percent Atheroma Volume (PAV) above/below the median Interactionp value = 0.005 Change In Percent Atheroma Volume (%)

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

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

  18. Conclusions • 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. • 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).

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

  20. 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.”

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