VYTORIN (TM) superior again to Lipitor at lowering LDL (bad) cholesterol

10/28/04

Greater LDL cholesterol reduction with VYTORIN (TM) compared to Lipitor resulted in greater goal attainment at most common doses

For Immediate Release WHITEHOUSE STATION and KENILWORTH, N.J., Oct. 28, 2004 -- Results from a new clinical trial conducted in 1,902 patients with high cholesterol showed that VYTORINTM (ezetimibe/simvastatin) provided greater reduction in LDL ("bad") cholesterol across the dosing ranges compared to Lipitor. At the most commonly used starting doses of these two therapies, VYTORIN 10/20 mg decreased LDL cholesterol by 51 percent compared with 36 percent for Lipitor 10 mg (p<0.001).

In a subgroup of high risk patients (CHD or CHD risk equivalent), significant differences in LDL cholesterol reductions at these doses resulted in more patients achieving a goal of less than 100 mg/dL with VYTORIN as compared to Lipitor; specifically, 82 percent of high risk patients on VYTORIN 10/20 mg (n=106) achieved a cholesterol lowering goal of less than 100 mg/dL as compared to only 47 percent for patients on Lipitor 10 mg (n=106, p<0.001). High risk patients in the study with a goal of less than 100 mg/dL who were taking VYTORIN 10/20 mg had a baseline LDL cholesterol of 166 mg/dL as compared to patients taking Lipitor 10 mg who had a baseline of 169 mg/dL.

The results were presented this week at the 15th International Symposium on Drugs Affecting Lipid Metabolism (DALM), in Venice, Italy. Additional results from the study showed that VYTORIN 10/40 mg decreased LDL cholesterol by 59 percent compared to 48 percent for Lipitor 40 mg in the subgroup of high risk patients. These patients had a baseline LDL cholesterol values of 169 mg/dL and 175 mg/dL respectively (p<0.001). In a post-hoc analysis of these data, significant differences in LDL cholesterol reductions, at all doses compared, resulted in more high risk patients achieving LDL cholesterol levels less than 70 mg/dL with VYTORIN as compared to Lipitor. In particular, 57 percent of high risk patients taking VYTORIN 10/40 mg (n=112) achieved a LDL cholesterol goal of less than 70 mg/dL as compared with 23 percent of the patients (n=115) taking Lipitor 40 mg (p<0.001).

"In this study, VYTORIN was significantly more effective than Lipitor in reducing LDL cholesterol at all doses compared and for attaining LDL cholesterol treatment goals pooled across the dosing range," said Christie Ballantyne, M.D., director of the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, Texas, and lead investigator of the study. "This study gives further support to the new option that VYTORIN, which reduces both the production and the absorption of cholesterol, provides to physicians in the treatment of high LDL cholesterol."

VYTORIN was approved by the FDA on July 23, 2004 for the treatment of high LDL cholesterol in patients with primary hypercholesterolemia or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. VYTORIN is the first and only product approved to treat the two sources of cholesterol by inhibiting the production of cholesterol in the liver and blocking the absorption of cholesterol in the intestine, including cholesterol from food. The active ingredients in VYTORIN are ezetimibe and simvastatin. The recommended starting dose of VYTORIN is 10/20 mg (10 mg ezetimibe/20 mg simvastatin).

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

Study results also demonstrated VYTORIN increased HDL cholesterol by a greater degree than Lipitor

In other results observed in the six week study, VYTORIN 10/40 mg and 10/80 mg also provided significantly greater increases in HDL ("good") cholesterol of 9 percent and 8 percent respectively as compared to the HDL cholesterol increase of 4 percent and 1.4 percent respectively seen in patients taking Lipitor 40 mg and 80 mg (p<0.001). Increased HDL cholesterol in patients treated with VYTORIN 10/10 mg (7.7 percent) and 10/20 mg (7.2 percent) was numerically higher compared to Lipitor 10 mg (6.9 percent) and 20 mg (5.1 percent). However, these differences did not reach statistical significance.

Study showed VYTORIN was well tolerated and had lower incidence of liver function elevations than Lipitor

Both VYTORIN and Lipitor were well tolerated in the study. The percentage of patients with clinical and laboratory adverse experiences was generally comparable between the two treatment groups. However, there was a significantly greater incidence of consecutive elevations in liver enzymes (ALT and/or AST) greater than or equal to three times the upper limit of normal in the pooled Lipitor group (1.2 percent, 11 out of 939 patients) compared with the pooled group of patients who took VYTORIN (0.1 percent, 1 out of 933 patients) (p<0.001). There were no clinically or statistically significant differences in the incidence of muscle enzyme elevations and no patients in the study were diagnosed with myopathy.

Post-hoc analysis of C Reactive Protein (CRP) reduction showed VYTORIN achieved a 25 percent reduction, comparable to Lipitor A post-hoc analysis of archived baseline and post–baseline blood samples was performed on 1,832 of the study's enrolled patients. Results from this analysis showed that averaged across all doses, both VYTORIN and Lipitor demonstrated a mean 25 percent reduction on CRP after six weeks of treatment.

"In addition to providing greater LDL cholesterol lowering than with Lipitor and in a pooled analysis, a greater increase in HDL, VYTORIN was shown in this study to provide comparable reductions in C-Reactive Protein, "said Dr. Ballantyne. "While the exact meaning of CRP reduction is unknown, given the ongoing discussions around CRP, this is an interesting study finding. Further studies are needed to confirm these findings."

CRP is considered an emerging risk marker for CHD. In an American Heart Association/Centers for Disease Control Scientific Statement published in the January 2003 issue of Circulation, high-sensitivity CRP was recognized as a potentially valuable marker and an optional adjunct to major risk factors in the assessment of risk for coronary disease in patients at moderate cardiovascular risk. (1) The relationship between reductions in CRP and reduction of CHD risk has not been established.

Study design

The study was a multicenter, randomized, double-blind, active controlled parallel-group study of 1,902 patients designed to evaluate the efficacy and safety of VYTORIN as compared to Lipitor across their respective dosing ranges. The primary efficacy endpoint was the percent change from baseline to the end of the 6-week treatment period in LDL cholesterol for patients treated with VYTORIN or Lipitor averaged across all doses. The study enrolled men and women 18 to 79 years of age with an LDL cholesterol level at or above drug treatment thresholds established by the NCEP ATP III who were deemed eligible if they met the following criteria: established coronary heart disease (CHD) or CHD risk equivalent, or two or more risk factors conferring a 10-year risk for CHD greater than 20 percent (by Framingham score) with an LDL cholesterol greater than or equal to 130 mg/dL; no established CHD or CHD risk equivalent, with two or more risk factors conferring a 10-year risk for CHD greater than or equal to 10 percent and less than or equal to 20 percent with an LDL cholesterol greater than or equal to 130 mg/dL; no established CHD or CHD risk equivalent, with two or more risk factors conferring a 10-year risk for CHD less than 10 percent with an LDL cholesterol greater than or equal to 160 mg/dL; and no established CHD or CHD risk equivalent, with less than two risk factors, and with LDL cholesterol greater than or equal to190 mg/dL. Other criteria included fasting serum triglyceride (TG) level less than or equal to 350 mg/dL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine kinase (CK) level less than or equal to 1.5 times the upper limit of normal, serum creatinine level less than or equal to 1.5 mg/dL, and a hemoglobin A1C less than 9 percent in patients with diabetes.

Full indication for VYTORIN

VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia. VYTORIN also is indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (=3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48 week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (=3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

In clinical studies VYTORIN was well tolerated with a low incidence of adverse events

VYTORIN has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

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