Merckâ€™s Investigational CETP-Inhibitor, MK-0859 (anacetrapib), Produced Positive Effects on Lipids with No Observed Blood Pressure Changes in Phase IIb Study
WHITEHOUSE STATION, N.J. -- In Phase IIb study results presented by Merck & Co., Inc., anacetrapib (formerly known as MK-0859), its investigational selective cholesteryl ester transfer protein (CETP) inhibitor, significantly reduced LDL-cholesterol (LDL-C) and Apolipoprotein B (Apo B) and increased HDL-cholesterol (HDL-C) and Apolipoprotein A-1 (Apo A-1) both as monotherapy and in combination with atorvastatin 20 mg compared to placebo in patients with dyslipidemia. These results were presented today at the 16th International Symposium on Drugs Affecting Lipid Metabolism (DALM).
The primary endpoint of the eight-week study was LDL-C reduction, with secondary endpoints of HDL-C increases and effects on other lipoproteins and apolipoproteins and blood pressure evaluated across ten treatment groups. In the study, anacetrapib monotherapy at doses of 10 mg, 40 mg, 150 mg and 300 mg reduced LDL-C levels by 16 percent, 27 percent, 40 percent, and 39 percent, and increased HDL-C levels by 44 percent, 86 percent, 139 percent, and 133 percent compared to placebo (two and four percent, respectively) in a dose dependent manner. Anacetrapib co-administered with atorvastatin, across all doses studied, also produced significant incremental reductions in LDL-C and increases in HDL-C compared to atorvastatin alone. The comparative lipid results in the study were statistically significant (p<0.001 vs. placebo for all doses).
â€œThe favorable lipid effects seen in this study with multiple doses of anacetrapib were significant, and confirm the continued evaluation of the clinical benefits of CETP inhibitors in the treatment of dyslipidemia," said Daniel Bloomfield, M.D., Clinical Research, Merck Research Laboratories. "The decreased LDL-C concentrations, increased HDL-C concentrations and no demonstrable increase in blood pressure seen with anacetrapib are particularly encouraging results of this study." In addition to these Phase IIb study results, Merck continues to carefully evaluate all of its data and other available information as its plans for anacetrapib are evaluated.
About the lipid changes study endpoints
This double-blind, randomized, parallel-group dose-ranging study evaluated lipid level changes and the safety profile of anacetrapib, administered as monotherapy or co-administered with atorvastatin 20 mg, in 589 patients with dyslipidemia (primary hypercholesterolemia or mixed hyperlipidemia).
The changes in lipoproteins - Apo B (a component of LDL-C) and Apo A-1 (a component of HDL-C) - were consistent with the LDL-C and HDL-C changes seen in the study.
About the tolerability of anacetrapib
Anacetrapib was not associated with a mean increase in blood pressure in any treatment arm. The incidence rates of individual adverse events were similar across the placebo, atorvastatin and active treatment groups (â‰¤ 5.5 percent). There were sparse and non-dose-related incidences of clinically important elevations in ALT, AST and CPK. There were no treatment-related serious adverse events or deaths. Treatment-related discontinuations were rare (â‰¤ 5 percent) and no patients discontinued due to serious treatment-related adverse events. There were no reports of hepatitis, myopathy or rhabdomyolysis observed in this study.
About CETP inhibition
CETP inhibitors work by inhibiting cholesteryl ester transfer protein (CETP), a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins, resulting in higher HDL-cholesterol levels (the "good" cholesterol-containing particle) and reducing LDL-cholesterol levels (the "bad" cholesterol). It is hypothesized that increased CETP activity may increase the risk for atherosclerosis (the formation of plaques in arteries) and coronary heart disease (CHD) due to increased LDL-C formation, especially in people with elevated triglycerides.
Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis. 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 personâ€™s chances of developing atherosclerosis.
About cardiovascular risk factors
Cardiovascular disease (CVD) is a general term referring to diseases that affect the heart or blood vessels. CHD, also known as coronary artery disease (CAD), is one of the most common forms of CVD. Major risk factors for CVD include abnormal blood lipids, meaning high LDL-C and triglyceride levels and low HDL-C levels. Researchers hypothesize that HDL-C takes part in the reverse transport of LDL-C from peripheral tissues in the body back to the liver for elimination. It is also theorized that HDL-C suppresses vascular inflammation associated with atherosclerosis and may potentially reduce the risk of injury to blood vessels through an anti-oxidative effect.
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