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Press Release Source: Merck & Co., Inc.

Merck/Schering-Plough Pharmaceuticals Announces New Clinical Trial for VYTORIN -ezetimibe/simvastatin-

Tuesday November 9, 8:38 am ET

Nov. 9, 2004--

Large Trial to Evaluate VYTORIN(TM) in Reducing Major Cardiovascular Events Through Intensive Lowering of LDL Cholesterol in Patients with Acute Coronary Syndromes

Merck/Schering-Plough Pharmaceuticals today announced a large scale clinical outcomes trial that will be conducted for VYTORIN(TM) (ezetimibe/simvastatin). The trial known as IMPROVE IT (Improved Reduction of Outcomes: VYTORIN Efficacy International Trial) will evaluate the risk reduction provided by VYTORIN 10/40 mg as compared to Zocor (simvastatin) 40 mg in reducing death and major coronary events in approximately 10,000 patients with acute coronary syndromes (ACS). In clinical trials, VYTORIN has been shown to provide superior LDL cholesterol lowering as compared to Lipitor or Zocor. The intent of the study is to determine whether VYTORIN provides incremental reductions in cardiovascular events in these patients as compared to simvastatin. The primary endpoint of the trial is the composite of death, myocardial infarction (MI), rehospitalization for ACS or revascularization (occurring 30 days or more after the initial event).

"The purpose of IMPROVE IT is to evaluate the potential incremental impact of VYTORIN versus simvastatin alone in reducing mortality and morbidity in high risk patients with ACS by dramatically lowering LDL cholesterol through dual inhibition," said Eugene Braunwald, M.D., F.A.C.C., Distinguished Hersey Professor of Medicine, Harvard Medical School, chairman TIMI Study Group, Brigham and Women's Hospital.

Study Design

IMPROVE IT is a multi-center, randomized, double-blind active comparator study that will enroll approximately 10,000 patients with ACS, including unstable angina (UA), non-ST-segment elevation acute myocardial infarction (NSTEMI) and ST-segment elevation acute myocardial infarction (STEMI). Patients will be randomized to either VYTORIN 10/40 mg or simvastatin 40 mg per day. Patients will be followed for over two years.

"There is growing clinical evidence that intensive lipid lowering provides additional benefits to high-risk patients. IMPROVE IT will potentially provide further clinical evidence on how best to manage high-risk patients with ACS. It will also further characterize the clinical profile of VYTORIN beyond its already demonstrated significant efficacy in LDL cholesterol reduction," said Robert M. Califf, M.D., F.A.C.C., professor of medicine, director, Duke Clinical Research Institute, Duke University Medical Center.

About Acute Coronary Syndromes

ACS includes unstable angina (UA), non ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) patients. ACS is usually caused by the buildup of plaque (deposits of fat-like substances) in the coronary arteries of the heart. These plaques may tear or rupture, leading to the formation of a blood clot which may partly or completely block the blood flow in a coronary artery, abruptly limiting the supply of oxygenated blood to a portion of heart muscle. Patients with UA often experience severe constricting pain in the chest occurring at rest, but testing does not show evidence of heart muscle damage. However, the development of UA is a warning sign that a heart attack may soon occur. NSTEMI, the most common form of heart attack, presents similarly to UA but is accompanied by evidence of heart muscle damage. In STEMI, an abrupt complete blockage of the coronary artery causes more extensive damage to the heart muscle. The treatment of ACS includes improving blood supply to the heart muscle, preventing further clot formation, and, ultimately, preventing further progression of coronary atherosclerosis. According to the American Heart Association, it is estimated that approximately 1.5 million patients are annually admitted for symptoms of ACS in the United States alone.

Full indications and contraindication for VYTORIN

VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B(1), 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.

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.

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 (Greater than 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 (Greater than 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).

Additional Outcomes Trials for VYTORIN

In addition to the IMPROVE-IT trial, Merck/Schering-Plough Pharmaceuticals is conducting three other large-scale clinical outcomes trials. They are:

The trial known as SHARP (Study of Heart And Renal Protection) will evaluate the effects of lowering LDL-C with ZETIA 10 mg and simvastatin 20 mg daily versus placebo in 9,000 patients with chronic kidney disease. The study will assess the effect of this combination therapy on the time to the first major vascular event (i.e., heart attack, stroke, or revascularization) and on progression to end-stage renal disease among pre-dialysis patients, as well as assessing safety and tolerability in the different treatment arms.

The trial known as SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) is a placebo controlled study that will examine the reduction in mortality and morbidity of patients with aortic stenosis with the co-administration of ZETIA and simvastatin 40 mg.

The trial known as ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) will evaluate ZETIA 10 mg and simvastatin 80 mg versus simvastatin 80 mg alone in reversing the atherosclerotic thickening of the carotid artery in patients with high cholesterol.