Merck announced that the extended-release niacin/laropiprant (cordaptive) co administered 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 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 co administered with simvastatin (pooled across 20 mg or 40 mg doses) reduced LDL-C by 48 per cent, increased HDL-C by 28 per cent, and reduced triglyceride levels by 33 per cent 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 per cent 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, associate chief and professor of medicine, Baylor College of Medicine, and co-author of 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) co administered with simvastatin 20 mg to 40 mg in weeks five through 12 (n = 590). Tolerability and the safety profile of Cordaptive co administered with simvastatin were also evaluated.
Reported lipid results in other treatment arms included a 17 per cent decrease in LDL-C, 23 per cent increase in HDL-C, and 22 per cent decrease in triglycerides with Cordaptive alone (n = 192); and a 37 per cent reduction in LDL-C, six per cent increase in HDL-C and 15 per cent reduction in triglycerides with simvastatin alone (pooled) (n = 585).
Reported side effects of interest included: liver enzyme elevations >3x ULN in ALT and/or AST (0.3 per cent with cordaptive co administered with simvastatin, 0.5 per cent with Cordaptive alone, and 1.0 per cent 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 per cent and 0.3 per cent, 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 per cent in the group treated with cordaptive co administered with simvastatin, 8.7 per cent with Cordaptive alone and 0.3 per cent with simvastatin alone.
Niacin-induced flushing is primarily caused by a prostaglandin, PGD2, a chemical that causes vasodilatation 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, MD, Clinical Research, Cardiovascular Disease, Merck Research Laboratories.
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 NDA for cordaptive has been accepted by the US FDA and the regulatory action is anticipated in the second quarter of 2008. Merck is also on track to file an NDA in 2008 for the company’s investigational compound MK 0524B.
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 per cent to three per cent.
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.
Researchers have said that patients were able to safely use Merck & Co.’s experimental Cordaptive drug to raise good HDL cholesterol alongside the company’s older Zocor cholesterol medicine.
Results of the Phase III trial involved about 1,400 patients and lasted 12 weeks. Cordaptive is a combination of an extended release form of niacin, a nutrient that raises heart-protective HDL, and an experimental drug called laropiprant that reduces the uncomfortable facial flushing which is a side effect of niacin.
Merck aims to seek approval next year for a separate product called MK-524B. It would combine Cordaptive in the same tablet with simvastatin, the active ingredient of Zocor which works by cutting the body’s production of LDL.
In the trial, levels of LDL fell 48 percent among patients receiving simvastatin as well as Cordaptive containing the full recommended two gram dose of niacin. That effectiveness against LDL, the primary goal of the trial, was deemed highly statistically significant.
Patients taking Cordaptive by itself in the trial experienced favorable, but less-impressive results: a 17 percent decrease in LDL, a 23 percent boost in HDL and a 22 percent drop in triglycerides.
Cordaptive is now awaiting U.S. marketing approval.
Use of cholesterol and blood pressure medicines by young adults appears to be rising rapidly — at a faster pace than among senior citizens, according to an industry report being released Tuesday.