May 30, 2012 (Milan, Italy)A new formulation of reconstituted human apolipoprotein A1 (apoA1) can "dramatically enhance cholesterol efflux from macrophages to serum," according to presentations on the product at the European Atherosclerosis Society 2012 Congress last weekend.

The new formulation, known as CSL-112, which is in development by CSL Laboratories, is currently in phase 2 trials in ACS patients.

Not all forms of HDL are equally as effective in promoting reverse cholesterol transport, which is why simply increasing HDL may not always be effective in reducing heart disease, explained Dr Andreas Gille (CSL, Victoria, Australia). He suggested that the disappointing results seen so far with the cholesteryl ester transfer protein (CETP) inhibitors may be because although these compounds lead to an increase in HDL, the HDL formed may not be capable of promoting cholesterol efflux.

"But we have clearly shown that our formulation of apoA1 produces HDL that is functional in promoting the efflux of cholesterol from macrophages, so our product should be able to prove or disprove the HDL hypothesis," he added.

ApoA1 is the delivery protein for HDL cholesterol, and CSL's formulation has been reconstituted with phospholipids to resemble native HDL, Gille reported.

He described studies showing that CSL-112 enhanced cholesterol efflux from macrophages when added to human serum samples from volunteers with both normal and high cholesterol levels.

He presented data showing that this effect was predominantly mediated by ABCA1--a protein that carries cholesterol across the cell membrane. When incubated with human plasma, CSL-112 increased levels of prebeta1-HDL, the substrate for ABCA1, in a dose-related manner. Gille also reported studies in rabbits in which CSL-112 infusions caused "immediate strong enhancement of cholesterol efflux."

He concluded: "Given the property of CSL-112 to robustly and rapidly enhance the capacity of plasma/serum to promote cholesterol efflux, CSL-112 may thus provide a novel option for rapid reduction of atherosclerotic burden and the potential of cardiovascular-event reduction in ACS."

In a second presentation, Dr Samuel Wright (CSL, King of Prussia, PA) explained that one of the difficulties of trying to give apoA1 is that it is rapidly cleared from the bloodstream, so the CSL product has been formulated with phospholipids to keep sustained levels in the plasma and has a half-life of three to four days.

Several Competitors

The idea of giving a form of apoA1 is not new, but previous attempts have not been successful. CSL's previous version (CSL-111) was discontinued because of liver toxicity, and other similar products have also run into problems. But there is now a second generation of apoA1 products in development, including CSL-112 and a synthetic version from Kinemed and a recombinant version from Cerenis, as well as the apoA1 Milano products in development by the Medicines Company and SemBioSys.

Asked how CSL-112 differs from CSL's first version, Wright was reluctant to give away much information. He said: "We believe we have understood in detail the nature of the other molecule, and we are confident that the new product will have a good profile." He added that phase 1 studies have been completed and should be presented later this year.

Commenting on the CSL-112 presentations for heartwire , lipid expert, Dr Alan Tall (Columbia University, New York) said he thought the approach "had a lot of promise."

UK professor of cardiovascular disease prevention Dr Kausik Ray (St George's, University of London, UK) commented to heartwire : "Cholesterol efflux was increased by three- or fourfold. That is impressive. And there seems to be a plausible explanation. But these were mainly in vitro studies. We will have to wait and see if it is meaningful or not. But yes, I would certainly say it looks promising."


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