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NEW ORLEANS, March 8, 2004 - Results from Phase III clinical trials showed that patients taking ezetimibe with simvastatin experienced significantly greater reductions in LDL (“bad”) cholesterol across the dosing ranges studied compared to reductions seen in patients taking Lipitor (atorvastatin) or ZOCOR® (simvastatin), alone. Results from the studies, conducted in support of VYTORINTM (ezetimibe/simvastatin), an investigational medicine, were presented here today at the 53rd Annual Scientific Meeting of the American College of Cardiology (ACC). Ezetimibe and simvastatin, the active ingredients in VYTORIN, achieve dual inhibition of two sources of cholesterol by inhibiting both cholesterol production in the liver and cholesterol absorption in the intestine.

“Results from these studies showed that ezetimibe with simvastatin provided significantly greater reductions in LDL cholesterol compared to atorvastatin or simvastatin alone. These results suggest that, if approved, this investigational medicine would offer physicians a different treatment option which targets two sources of cholesterol through dual inhibition of both cholesterol production and absorption,” said Christie Ballantyne, M.D., FACC, FACP, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Baylor College of Medicine/The Methodist DeBakey Heart Center in Houston.

Study Results
Ezetimibe with simvastatin provided greater LDL-C reductions
compared to Lipitor
Results from a 24-week, 788-patient study of ezetimibe 10 mg taken with simvastatin (doses ranging from 10 mg to 80 mg) compared to atorvastatin monotherapy (doses ranging from 10 mg to 80 mg) showed significantly greater LDL-C reductions in patients taking ezetimibe with simvastatin compared to patients taking atorvastatin alone across the dosing ranges. The average LDL-C levels at baseline across treatment groups ranged from 179 mg/dL to 181 mg/dL.

The primary endpoint of this study was the efficacy comparison after the first six-week treatment period. After six weeks of therapy, patients taking ezetimibe 10 mg with simvastatin 10 mg and patients taking ezetimibe 10 mg with simvastatin 20 mg experienced greater LDL-C reductions (46 percent and 50 percent, respectively) compared to atorvastatin 10 mg, which produced a 37 percent reduction (p <0.01 for each versus atorvastatin). In addition, as each treatment group was titrated through the dosing ranges (by doubling the respective statin dose up to a maximum of 80 mg), ezetimibe with simvastatin consistently provided greater LDL-C reductions than atorvastatin at all points in the treatment period.

Study patients underwent a four-week diet/placebo run-in period and were then randomized to three treatment groups, each of which underwent four sequential, six-week treatment periods: (1) atorvastatin 10 mg in Period One, titrated to A20 mg, A40 mg, and A80 mg in Periods Two through Four (n=262); (2) ezetimibe with simvastatin 10 mg (10/10) in Period One, titrated to EZE/S20 mg (10/20), EZE/S40 mg (10/40), and EZE/S80 mg (10/80) in Periods Two through Four (n=263); and (3) ezetimibe with simvastatin 20 mg (10/20) in Period One, titrated to EZE/S40 (10/40) mg for Periods Two and Three, then EZE/S80 mg (10/80) in Period Four (n=263).

Results from this study also showed greater mean HDL-C increases across the treatment periods in patients taking ezetimibe with simvastatin (mean of 10 percent, range 8 to 12 percent) compared to patients taking atorvastatin alone (mean of 6 percent, range 5 to 8 percent).

Ezetimibe with simvastatin was well tolerated and had an overall safety profile similar to atorvastatin monotherapy in the study; there were no clinically or statistically significant differences in the incidence of muscle enzyme elevations (5 to 10 times or more than 10 times the upper limit of normal) or consecutive liver enzyme elevations (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] more than 3 times the upper limit of normal).

Ezetimibe with simvastatin provided greater LDL-C reductions
compared to ZOCOR
In another study, patients taking ezetimibe with simvastatin experienced significantly greater LDL-C reductions across the doses tested compared to ZOCOR alone. Ezetimibe 10 mg with simvastatin 20 mg achieved a 51 percent LDL-C reduction compared to reductions of 35 percent and 42 percent, respectively, for simvastatin 20 mg and 40 mg
(typical starting doses for simvastatin) alone. In pooled results across the dosing ranges, patients taking ezetimibe with simvastatin experienced significantly greater LDL cholesterol.