AlphaCore Pharma, a private biotechnology company focussed to develop recombinant human LCAT as a novel therapeutic agent has reported positive results from the phase I clinical trial by demonstrating the safety and tolerability of the drug ACP-501 (recombinant human LCAT). ACP-501 also met the study’s secondary endpoints by rapidly and substantially elevating HDL cholesterol, often referred to as “good” cholesterol.

The elevation of HDL cholesterol was due entirely to an increased formation of cholesteryl esters. This represents an increase in the unidirectional movement of tissue cholesterol, an important breakthrough in the development of a reverse cholesterol transport (RCT) therapy. RCT is the process by which cholesterol in the arterial wall is transported to the liver for excretion from the body.

“We are gratified that ACP-501 was shown to be safe in this trial, and moreover, that the changes in biomarkers are consistent with rapid enhancement of reverse cholesterol transport,” stated Bruce Auerbach, President of AlphaCore. “The increase in HDL cholesterol after administration of ACP-501 supports the notion that LCAT is a bottleneck in the reverse cholesterol transport process.” noted Auerbach.

The phase I single ascending dose study evaluated 16 volunteers with stable atherosclerosis. Four subjects in each of four cohorts were administered a single intravenous infusion of ACP-501 and followed for 28 days. No serious adverse events were reported for ACP-501.

The study site was the National Heart, Lung and Blood Institute (NIH) and investigators included Robert D Shamburek, MD (Principal Investigator), Alan Remaley, MD and Marcelo Amar, MD. ACP-501 is the first enzyme supplementation strategy targeting acute plaque stabilization. The data from this study support ongoing clinical development of ACP-501 in patients with high-risk atherosclerosis, including acute coronary syndromes.

Cholesterol must be removed from peripheral tissues or it will accumulate and cause disease. Cholesterol is removed from tissues and delivered to the liver for excretion from the body by a multistep process known as “Reverse Cholesterol Transport.” In the first step of RCT, small high-density lipoprotein particles (HDL3) in the bloodstream acquire cholesterol from tissues by a process known as “cholesterol efflux”.  In the second step, the enzyme lecithin: cholesterol acyltransferase (LCAT) converts the effluxed cholesterol to cholesteryl ester.

This newly formed cholesteryl ester moves from the HDL surface into the core of the HDL particle, and allows the maturation of HDL from small HDL3 to large HDL2. In the third step of RCT the LCAT-derived cholesteryl esters in HDL2 are either transferred to LDL in exchange for triglyceride, or removed directly by the liver via scavenger receptor-B1. LDLs are removed from the circulation by the classical LDL receptor pathway. Once in the liver the cholesteryl esters from both the LDL and HDL are hydrolyzed back to cholesterol, which can then be converted to bile acids or excreted as cholesterol into bile.

The ability of LCAT to drive cholesterol removal has been demonstrated in several animal species, most notably in rabbits, a species that shares many common steps of RCT with humans.  In rabbits the overexpression of LCAT through genetic manipulation or the injection of recombinant LCAT, results in HDL cholesterol elevation and, more importantly, increases RCT and reduces cholesterol accumulation in arteries.

ACP-501 is a recombinant human lecithin:cholesterol acyltransferase (rhLCAT), an enzyme in the bloodstream that participates in the RCT process.  ACP-501 is under development as a therapy for acute coronary syndromes, and other high-risk atherosclerosis conditions for the rapid removal of tissue cholesterol. AlphaCore Pharma’s approach to stimulating the flux through the RCT pathway is distinct from other HDL therapies developed to date. ACP-501 acts directly upon existing small HDL particles, which are already in abundance, and matures them into larger, cholesteryl ester-rich HDL particles, which are then ready for elimination from the body.

ACP-501 is also being developed to treat familial LCAT deficiency, as an orphan-designated enzyme replacement therapy, and other conditions where LCAT activity is low.