Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)

Abstract

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7á-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion 33

Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

“…Developed by Pfizer, it is currently undergoing clinical trials (phase III). Its safety has been shown in rat, dogs, and humans (90). In clinical trials involving a cohort of men and women with hyperlipidemia and hypoalphalipoproteinemia, avasimibe significantly reduced total triglyceride and VLDL cholesterol (91), but not total plasma cholesterol.…”

“…Avasimibe (CI-1011) is a member of the group of ACAT inhibitors that present enhanced solubility and was reviewed recently (90). Developed by Pfizer, it is currently undergoing clinical trials (phase III).…”

ACAT1/SOAT1 as a Therapeutic Target for Alzheimer's Disease

“…For instance, the 'ACAT inhibitor' CI-976 ( Figure 1A) was shown to inhibit multiple membrane trafficking steps, at least in part by inhibiting the enzyme activity of lysophospholipid acyltransferase 3 [128], which is an MBOAT member [23]. The 'ACAT inhibitor' CI-1011 orally fed to animals or to men decreased the plasma concentrations of total triglyceride [129], presumably because CI-1011 also inhibits the enzyme activity of diacylglycerol acyltransferase 1, a different MBOAT member [23]. Currently K604 is the only small molecule ACAT1-specific inhibitor available.…”

3D Ultrasound Measurement of Change in Carotid Plaque Volume

“…4 Another potential example of such novel therapy is the inhibitors of acyl-coenzyme A:cholesterol acyltransferase, which are powerfully antiatherosclerotic in animal models but have little effect on plasma lipids in human subjects. [5][6][7][8][9] Without a way of measuring efficacy, it would not be possible to develop such drugs because the duration and cost of studies based on vascular end points such as myocardial infarction or stroke would be excessive. Therefore, it will be necessary to use intermediate end points based on progression of atherosclerosis for dose-finding studies and for early proof of principle studies to demonstrate efficacy and thereby make it feasible to go on to larger studies based on end points.…”