CETP MAKING A COME BACK
Merck's Investigational Anacetrapib Phase IIb Study Results Presented at American Heart Association Annual Scientific Sessions
Persistent Lipid Effects Remained in the Higher Dose Arms After Cessation Of Therapy in Patients with Dyslipidemia
Press Release
Source: Merck
On 9:00 am EST, Tuesday November 17, 2009
ORLANDO, Fla.--(BUSINESS WIRE)--In a phase IIb study in 589 patients with primary hypercholesterolemia or mixed hyperlipidemia treated with anacetrapib as monotherapy or co-administered with atorvastatin, there were persistent lipid effects in the higher dose arms in both the monotherapy and co-administration treatment groups eight weeks after stopping active therapy with anacetrapib. These findings were announced today at the American Heart Association (AHA) Annual Scientific Sessions in Orlando, Florida.
Anacetrapib is an investigational oral compound currently in Phase III trials that works by inhibiting the activity of CETP in the blood. CETP inhibition with anacetrapib decreases LDL-cholesterol (LDL-C) levels and increases HDL-cholesterol (HDL-C) levels. The effect of CETP inhibition on cardiovascular risk has yet to be established.
“The study findings add to the data from the initial Phase IIb efficacy and safety results published in the American Heart Journal in February 2009,” said Yale Mitchel, M.D., vice president, Cardiovascular Disease Clinical Research, Merck Research Laboratories. “A phase III trial, titled DEFINE, is ongoing to further evaluate the safety and efficacy of anacetrapib in patients with coronary heart disease and will provide important information on this compound.”
About the Study
The results presented today represent the second part of a randomized, double-blind, placebo-controlled, parallel-group dose-ranging study. In part 1 of the study, 539 patients aged 18–75 years and with moderate elevations in LDL-C were randomized to either anacetrapib (at 10, 40, 150, or 300 mg doses) plus placebo, or anacetrapib (at 10, 40, 150, or 300 mg doses) plus atorvastatin 20 mg for eight-week period.
In part 2 of the study, treatment with anacetrapib was stopped and patients continued to receive either placebo or atorvastatin 20 mg for an additional eight weeks. The effect of withdrawal of the drug on lipid efficacy (LDL-C, HDL-C, total cholesterol, non-HDL-C, apo B, apo A-1), CETP levels and safety were assessed. Safety was assessed through physical examination, vital signs, laboratory evaluations, electrocardiograms, blood pressure measurements and adverse event (AE) assessments.
In the reversal phase of the study, eight weeks after cessation of therapy persistent lipid effects remained in the higher dose arms (150 mg and 300 mg) for both the anacetrapib monotherapy and co-administration treatment groups. These effects may be due to persistent drug levels which are likely related to the high lipid solubility of the drug. Also in the study, there were no patterns of clinically important blood pressure elevations or adverse experiences in the treatment groups.
Percent changes from baseline eight weeks after cessation of therapy were:
Anacetrapib monotherapy (relative to placebo):
10 mg 40 mg 150 mg 300 mg
LDL-C reduction 0% -1.2% -9.3% -15.3%
HDL-C increase 3.7% 18.6% 40.5% 43.4%
Total cholesterol reduction -0.3% 3.8% 1.9% -1.2%
Anacetrapib + atorvastatin (20mg):
10 mg 40 mg 150 mg 300 mg
LDL-C reduction 1.7% -3.9% -11.2% -11.9%
HDL-C increase 2.6% 13.1% 40.7% 41.8%
Total cholesterol reduction 1.0% -0.8% 0.1% -0.6%
About CETP Inhibition
Cholesterol ester transfer protein (CETP) is a plasma protein which plays a critical role in the cholesterol transport pathway. CETP transfers cholesteryl esters from anti-atherogenic high-density lipoprotein cholesterol (HDL-C) to pro-atherogenic low-density lipoprotein cholesterol (LDL-C) in exchange for triglycerides. Low levels of HDL-C are associated with an increased risk of atherosclerosis (the formation of plaques in arteries) and coronary heart disease (CHD). Research has shown that inhibition of CETP is associated with decreased LDL-C levels and increased HDL-C levels. The benefit of CETP inhibition on CHD risk has not been demonstrated.
