The American Heart Association Presented by Dr. Steven E. Nissen ACTIVATE Trial Acyl-coenzyme A: cholesterol acyltransferase (ACAT) Inhibition on the Progression of Coronary Atherosclerosis (ACTIVATE) Trial Presented at The American Heart Association Scientific Session 2005 Presented by Dr. Steven E. Nissen

ACTIVATE Trial: Background ACAT1 is found predominantly in macrophages. ACAT2 is present in the liver and in the intestinal mucosa. By inhibiting ACAT1, the goal was to make more free cholesterol available for reverse cholesterol transport, and thereby reduce lipid accumulation in lesions.

ACTIVATE Trial 534 patients with symptomatic coronary artery disease with a stenosis >20% on coronary angiography 31% female, mean age 60 years, mean follow-up 18 months Placebo controlled. Randomized. Blinded. Pactimibe (100 mg per day for 18 months) n=266 Placebo n=268 IVUS (baseline and 18 month follow-up) 408/534 patients had baseline and 18 month IVUS available Primary Endpoint: Change in percent atheroma volume at 18 months Secondary Endpoint: Change in absolute atheroma volume at 18 months in the total segment and in the most diseased 10mm segment Presented at AHA 2005

ACTIVATE Trial: Final LDL p=0.15 At baseline, LDL cholesterol was 95 mg/dL, HDL cholesterol was 43 mg/dL, and CRP was 3 mg/L. There was no significant difference between groups in change in CRP or LDL at 18 month follow-up. Final LDL was 91.3 mg/dL in the pactimibe group (+0.6 mg/dL vs baseline) and 86.4 mg/dL in the placebo group (-3.4 mg/dL vs baseline) +0.6 mg/dL vs baseline -3.4 mg/dL vs baseline Presented at AHA 2005

ACTIVATE Trial: Primary Endpoint Change in percent atheroma volume at 18 months p=0.77 The primary endpoint of change in percent atheroma volume at 18 months did not differ significantly between the pactimibe group and the placebo group (0.69 vs 0.59, p=0.77) Presented at AHA 2005

ACTIVATE Trial: Secondary Endpoints Change in absolute atheroma volume in 10mm segment with greatest disease (mm3) p=0.01 For the secondary endpoint of change in absolute total atheroma volume at 18 months, the pactimibe group had 1.3 mm3 of regression, whereas the placebo group had 5.6 mm3 of regression (p=0.04) Analysis of the 10 mm segment with the greatest disease showed that the pactimibe group had 1.3 mm3 of regression and the placebo group had 3.2 mm3 of regression (p=0.01) Change in absolute total atheroma volume (mm3) p=0.04 mm3 Presented at AHA 2005

ACTIVATE Trial: Clinical Events Composite of clinical events (%) p=0.53 There was no difference in the composite of cardiovascular death, non-fatal MI, stroke, hospitalization for unstable angina, or coronary or carotid revascularization (23.8% vs 26.5%, p=0.53) or any component of the clinical composite endpoint. Presented at AHA 2005

ACTIVATE Trial: Limitations Approximately 60 patients in each arm did not return for repeat IVUS, and ascertainment was therefore not complete Unclear if the promotion of disease progression is a class effect or specific to this drug

ACTIVATE Trial: Summary Among patients with symptomatic coronary artery disease, treatment with the novel ACAT inhibitor pactimibe was not associated with a reduction in atherosclerosis progression compared with placebo at 18 month follow-up. While there was no difference in the primary endpoint, there was actually more disease regression with placebo than with pactimibe in the secondary endpoints of absolute atheroma volume. Given these pro-atherogenic findings with pactimibe, the future of ACAT inhibition as a target treatment for atherosclerosis is unclear, although it is possible that changes in the balance between ACAT 1 and ACAT 2 inhibition could produce different results. Presented at AHA 2005