WHITEHOUSE STATION, N.J., Nov. 5, 2007 -
Extended-release niacin/laropiprant (CORDAPTIVE™) coadministered with simvastatin had significant additive effects on reducing LDL-cholesterol (LDL-C), increasing HDL-cholesterol (HDL-C) and reducing triglyceride levels in a Phase III study with patients with primary hypercholesterolemia or mixed dyslipidemia. The results were presented today by Merck & Co., Inc. at the American Heart Association 2007 Scientific Sessions in Orlando, Fla.
In the study, 2 g (two 1-gram tablets) of CORDAPTIVE coadministered with simvastatin (pooled across 20 mg or 40 mg doses) reduced LDL-C by 48 percent, increased HDL-C by 28 percent, and reduced triglyceride levels by 33 percent following 12 weeks of treatment. The primary study endpoint was LDL-C reduction; secondary endpoints included increased HDL-C, triglyceride reduction and effects on other lipoproteins. A 1 g tablet of CORDAPTIVE contains 1 g of Merck-developed extended-release niacin and 20 mg of laropiprant – a novel flushing pathway inhibitor that is designed to reduce the flushing associated with niacin. All of the comparative lipid efficacy results were measured as mean percent change from baseline and were statistically significant, p < 0.001.
"The results in this study suggest that, if approved, CORDAPTIVE used with a statin could offer another approach to treat patients with dyslipidemia," said Christie M. Ballantyne, M.D., associate chief and professor of medicine, Baylor College of Medicine, and co-author of the study.
About the study
The double-blind, parallel, 12-week study with seven treatment arms in almost 1400 patients evaluated 1 g of CORDAPTIVE (1 g extended-release niacin/20 mg laropiprant) coadministered with simvastatin 10 mg to 40 mg in weeks one through four and 2 g of CORDAPTIVE (two 1-gram tablets each containing 1 g extended-release niacin/20 mg of laropiprant) coadministered with simvastatin 20 mg to 40 mg in weeks five through 12 (n = 590). Tolerability and the safety profile of CORDAPTIVE coadministered with simvastatin were also evaluated.
Reported lipid results in other treatment arms included a 17 percent decrease in LDL-C, 23 percent increase in HDL-C, and 22 percent decrease in triglycerides with CORDAPTIVE alone (n = 192); and a 37 percent reduction in LDL-C, six percent increase in HDL-C and 15 percent reduction in triglycerides with simvastatin alone (pooled) (n = 585).
About the tolerability of CORDAPTIVE
Reported side effects of interest included: liver enzyme elevations >3x ULN in ALT and/or AST (0.3 percent with CORDAPTIVE coadministered with simvastatin, 0.5 percent with CORDAPTIVE alone, and 1.0 percent with simvastatin alone), and increased median fasting plasma glucose values (4.0 mg/dL with CORDAPTIVE plus simvastatin, 4.0 mg/dL with CORDAPTIVE alone, and 1.0 mg/dL with simvastatin alone). There were no cases of creatine kinase (CK) levels >10x ULN in the group treated with CORDAPTIVE coadministered with simvastatin, which was not significantly different than that of the group treated with CORDAPTIVE or simvastatin alone (0.5 percent and 0.3 percent, respectively). All elevations were asymptomatic and resolved with discontinuation of treatment. There were no cases of myopathy, rhabdomyolysis or drug-related hepatitis.
Discontinuations due to flushing were 4.8 percent in the group treated with CORDAPTIVE coadministered with simvastatin, 8.7 percent with CORDAPTIVE alone and 0.3 percent with simvastatin alone.
Flushing pathway
Niacin-induced flushing is primarily caused by a prostaglandin, PGD2, a chemical that causes vasodilation in the skin and flushing symptoms, acting through the DP1 flushing pathway. Laropiprant selectively blocks the binding of PGD2 to its receptor, DP1. Research has shown blocking DP1 reduces flushing associated with niacin.
"It has been shown that niacin-based therapies reduce the risk of cardiovascular events. But even though niacin has broad lipid effects, the flushing side effect has been a barrier to many patients reaching the maximum 2 g dose," said John Paolini, M.D., Ph.D., Clinical Research, Cardiovascular Disease, Merck Research Laboratories.
About CORDAPTIVE
CORDAPTIVE is in development by Merck for the treatment of elevated LDL-C, low HDL-C and elevated triglycerides. Merck has previously announced that the New Drug Application for CORDAPTIVE has been accepted by the U.S. Food and Drug Administration (FDA), and regulatory action is anticipated in the second quarter of 2008. Merck is also on track to file a New Drug Application in 2008 for the Company's investigational compound MK 0524B.
About dyslipidemia
Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis, the number one cause of death among men and women and the primary reason for loss of quality of life in Western countries. Major modifiable risk factors for atherosclerotic disease include hypertension, diabetes, obesity, smoking and high levels of total cholesterol or LDL-C. Low levels of HDL-C also increase a person's chances of developing atherosclerosis. In fact, epidemiologic studies have shown that for every 1 mg/dL rise in HDL-C, the risk of developing cardiovascular disease decreases by two percent to three percent.
About cardiovascular risk factors
Cardiovascular disease (CVD) is a general term referring to diseases that affect the heart or blood vessels. Coronary heart disease (CHD), also known as coronary artery disease (CAD), is one of the most common forms of CVD and is the leading cause of death globally. Major risk factors for CVD include abnormal lipids, meaning not only high LDL-C ("bad" cholesterol) and triglyceride levels, but also low levels of HDL-C ("good" cholesterol). Researchers hypothesize that HDL takes part in the reverse transport of cholesterol from peripheral tissues in the body back to the liver for elimination. It is also theorized that HDL suppresses vascular inflammation associated with atherosclerosis and may potentially reduce the risk of injury to blood vessels through an anti-oxidative effect. Sixty-six percent of patients on current lipid lowering therapy have at least one lipid outside current recommendations.
Important considerations about simvastatin
Simvastatin, a cholesterol-modifying medicine from Merck, and marketed under the brand name ZOCOR®, is used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels.
Simvastatin should not be used by anyone allergic to any of its components, with liver disease, or by women who are pregnant, breast-feeding or likely to become pregnant. Muscle pain or weakness in people taking simvastatin should be reported to a doctor because these could be signs of a serious side effect. Doctors may perform blood tests before and periodically during treatment with simvastatin to check for liver problems. People taking 80 mg of simvastatin should receive an additional liver function test at three months. To help avoid serious side effects, discuss with your doctor medicine or food you should avoid while taking simvastatin. In most clinical trials, adverse reactions usually have been mild or transient. Most common side effects included headache (3.5 percent), abdominal pain (3.2 percent) and constipation (2.3 percent).
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
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.
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