Avanir unveils promising drugs for atherosclerosis
small molecules that, in animal models, reduce the fatty deposits
in blood vessel walls typically associated with atherosclerosis.
The results provide additional support for the view that the so-called reverse cholesterol transport pathway is a valid target for the development of new drugs to treat cardiovascular diseases.
Avanir's compounds are small molecule mimics of apoliprotein A1, a key component of reverse cholesterol transport which is involved in removing excess cholesterol from the body.
The animal studies showed that the lead compound in the series, dubbed AVP 26452, had favourable effects on plasma cholesterol levels by lowering harmful low-density lipoprotein (LDL) cholesterol while increasing high-density lipoprotein (HDL) cholesterol, which is thought to confer some protection against coronary artery disease.
Discussing the findings, Jagadish Sircar, vice president of drug discovery at Avanir, said that they tie in with reports that injectable versions of ApoA1 resulted in regression of vascular plaque in atherosclerosis patients following a short course of therapy.
"We believe our compounds could have similar benefits but may have more extensive applications as they are orally active," he added.
Unlike currently available drugs that focus on lowering plasma levels of LDL cholesterol, says Avanir, the new compounds are designed to have a more direct effect on the blood vessel wall by promoting reverse cholesterol transport.
This may be a more efficient mechanism to both prevent and reverse vascular disease because it actively removes cholesterol from the vessel wall rather than only preventing its accumulation. The top-selling statin class of cholesterol-lowering drugs, which work by preventing cholesterol synthesis in the body, have garnered worldwide sales approaching $20 billion (€16bn) a year.
In preclinical studies, AVP 26452 has demonstrated an ability to increase LDL-mediated cholesterol uptake in cultured human liver cells thereby facilitating the hepatic clearance of LDL.
It has also demonstrated an ability to decrease oxidised LDL-mediated cholesterol and cholesteryl ester accumulation in cultured human vascular smooth muscle cells, thereby protecting the cells from accumulation of excess cholesterol.
Meanwhile, in atherosclerosis-prone mice, AVP 26452 lowered plasma cholesterol associated with LDL. More importantly, following oral administration over 10 weeks, aortas from mice treated with the drug showed dose-dependent reduction in fatty atherosclerotic plaques compared to placebo-treated control mice.
Linda Curtiss of The Scripps Research Institute, who served as a scientific consultant for these studies, said: "if the animal data can be reproduced in humans, patients at risk of developing heart attacks or stroke may benefit from this approach."
