Merck and Schering-Plough Respond To Issues Raised About ENHANCE Clinical Trial
WHITEHOUSE STATION, N.J., KENILWORTH, N.J., Jan. 25, 2008 - Merck and Schering-Plough said today that they strongly object to mischaracterizations about the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. "While the ENHANCE trial was time consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial. We took numerous actions to assure the quality of the reading of the ultrasound images," said Thomas Koestler, Ph.D., president, Schering-Plough Research Institute.
VYTORIN® (ezetimibe/simvastatin) and ZETIA® (ezetimibe) have been studied extensively in patients with elevated cholesterol. Clinical studies conducted to date have demonstrated that VYTORIN and ZETIA significantly decreased LDL cholesterol in patients with elevated cholesterol, along with a healthy diet. In addition, the safety and tolerability profiles of VYTORIN and ZETIA are set forth in the approved labeling. The approval of VYTORIN and ZETIA in many markets around the world is based on their demonstrated safety and tolerability profiles, and ability to lower LDL-cholesterol.
"We stand behind VYTORIN and ZETIA and stand behind our science that has brought these cholesterol-lowering medications to millions of people around the world," said Peter S. Kim, Ph.D., president, Merck Research Laboratories.
Many patients with elevated cholesterol cannot achieve their cholesterol treatment goals with diet and exercise. Many of these patients also cannot achieve their treatment goals with statins alone.
Clinical studies, which are included in the attached prescribing information, have demonstrated that VYTORIN lowered patients' LDL cholesterol more than atorvastatin, rosuvastatin, or simvastatin at the doses studied. When added to a statin, ZETIA provided additional LDL-cholesterol lowering compared to the statin alone. Unlike some statins, ZETIA has not been shown to prevent heart disease or heart attacks. VYTORIN contains two medicines: ZETIA and Zocor® (simvastatin). It has not been shown to reduce heart attacks or strokes more than simvastatin alone.
"More than 20 years of clinical research has demonstrated that lowering LDL cholesterol, along with a healthy diet and other therapeutic lifestyle changes, is the cornerstone of lipid treatment for patients at risk for heart disease," said Dr. Koestler. "VYTORIN and ZETIA are important treatment options that can help appropriate patients lower their LDL cholesterol."
Regarding the ENHANCE trial
The ENHANCE study involved 720 patients with a rare form of inherited high cholesterol known as Heterozygous Familial Hypercholesterolemia (HeFH) that affects less than 0.2 percent of the population. This imaging trial looked at the effects of ezetimibe/simvastatin versus simvastatin on the intima media thickness (IMT) measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two-year period.
As indicated in the January 14, 2008 announcement, in ENHANCE, there was no statistically significant difference in the mean change in the primary measure of the study, between the maximum approved doses of ezetimibe/simvastatin and simvastatin alone. ENHANCE was not an outcomes trial; that is, it did not attempt to measure whether the combination of ezetimibe and simvastatin reduced the risk of heart attacks or strokes more than simvastatin alone. The IMPROVE-IT study, an ongoing outcomes trial, is being conducted to answer that question in patients with acute coronary syndrome.
In ENHANCE, ezetimibe/simvastatin achieved significantly greater LDL cholesterol reduction compared to simvastatin alone.
ENHANCE began in October 2002 and the last patient visit occurred in April 2006. Following the last patient visit, the study required the meticulous examination of approximately 30,000 ultrasound images of the carotid arteries and 10,000 ultrasound images of the femoral arteries.
The ENHANCE trial employed a novel non-invasive methodology to assess IMT using digital single-frame ultrasound imagery of the arteries. Examination of these images was a challenging process and the data analysis took significantly longer than expected. Numerous steps were taken in 2006 and 2007 to address quality issues and finalize the data analysis.
Until December 31, 2007, the study remained blinded; that is, neither the patients nor the researchers nor the companies knew the group of patients that received each therapy. On that date, statisticians for Schering-Plough Research Institute first became unblinded. Additional personnel at the companies were made aware of the findings during the first two weeks of January, 2008.
On January 14, 2008, the companies announced the results of the primary endpoint and other results.
An abstract has been submitted on the ENHANCE trial to the American College of Cardiology with the expectation that the data will be presented and discussed in an appropriate scientific context at their annual meeting in March, 2008.
The companies look forward to participating in rigorous scientific debates on this important issue in the months ahead. "We are committed to conducting clinical research with the highest integrity and quality, and reporting the results as quickly as possible," said Dr. Koestler.
"We remain committed to the advancement of the study of high LDL cholesterol, its relationship to heart disease, and the availability of effective therapies in the interest of patients and healthcare providers everywhere," said Dr. Kim.
To further clarify issues surrounding the timeline of the ENHANCE study, a chronology of events is attached.
Additional background about the ENHANCE trial
ENHANCE was a multinational, randomized, double-blind, active comparator trial that used digitized single-frame ultrasound technology for imaging purposes. There were 357 HeFH patients randomized to ezetimibe/simvastatin 10/80 mg and 363 HeFH patients to simvastatin 80 mg. The study collected approximately 30,000 carotid artery and 10,000 femoral artery images from these patients. HeFH is characterized by markedly elevated plasma concentrations of LDL cholesterol; typically well above the 95th percentile for age and sex.
Single-frame ultrasound images were analyzed from the right and left carotid arteries at three sites (the common carotid, the internal carotid and the carotid bulb) and at numerous time points (baseline, 6, 12, 18 and 24 months). Images from the right and left common femoral arteries were analyzed at these same time points as well.
Important information about VYTORIN
VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo Bi, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
VYTORIN is also 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 (≥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.
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).
Important information about ZETIA
ZETIA is a prescription medication and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by women who are nursing or pregnant or who may become pregnant, or by anyone with active liver disease. Statins should not be taken by anyone with these conditions. If you have ever had liver problems or are pregnant or nursing, your doctor will decide if ZETIA is right for you. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment.
Due to the unknown effects of increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown) associated with ZETIA; however myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks.
When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes, more than three times the upper limit of normal, were slightly higher than those with the statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA was co-administered with fenofibrate, consecutive elevations in liver enzymes more than three times the upper limit of normal, were 2.7percent, and 4.5 percent in patients treated with fenofibrate alone. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.
In clinical trials, most frequent side effects for ZETIA alone vs. placebo included: back pain (4.1percent vs. 3.9 percent), arthralgia (3.8 percent vs. 3.4 percent), and fatigue (2.2 percent vs. 1.8 percent); for ZETIA plus statin vs. statin or placebo alone: back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent), abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent), and fatigue (2.8 percent vs. 1.4 percent vs. 1.9 percent).
About Merck/Schering-Plough Pharmaceuticals
Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY outside the U.S.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
Schering-Plough disclosure notice
The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to potential market for VYTORIN and ZETIA (ezetimibe). Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part II, Item 1A. "Risk Factors" in the Schering-Plough's third quarter 2007 10-Q.Â
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