Atherosclerosis

The “hallmark” or “root cause” of atherosclerosis is thought to be the accumulation of cholesterol in arteries.  Cholesterol is delivered to arteries by low density lipoproteins (LDL).  The retention of LDL is thought to initiate a cascade of events including inflammation, decreases in endothelium-dependent vasorelaxation, promotion of plaque instability, and in later stages, narrowing of the vessel lumen.  Therefore, the removal of cholesterol from arteries is an important clinical goal, especially since plaque instability can cause plaque rupture, the major cause of most heart attacks.

Reduction of plasma LDL, and thus the delivery of cholesterol to arteries, is the foundation for treatment guidelines designed to lower the risk of coronary heart disease (CHD).  Despite the lowering of LDL with drugs (e.g. statins), however, significant residual risk for CHD still remains. The magnitude of the problem is illustrated by the fact that 1-2 million patients per year are hospitalized for either chest pain (unstable angina) or heart attack (myocardial infarction or MI), collectively referred to as the acute coronary syndromes (ACS).  Clinical studies suggest that 12% to 15% of ACS patients will have a subsequent event within 6 months. Therefore, complementary approaches that increase the removal of cholesterol from the arterial wall are being explored as therapeutic approaches for the acute treatment of atherosclerosis.

Proof-of-concept imaging studies in humans have demonstrated that rapid reductions (within weeks) in atherosclerotic plaque burden can be achieved in ACS patients by infusing synthetic HDL particles (apoA-I or apoA-IMilano complexed to phospholipids) to stimulate reverse cholesterol transport.  However, we believe that stimulating the endogenous production of HDL by driving cholesterol esterification may potentially provide a more “natural” way of enhancing the flux of cholesterol through the RCT pathway (see below).  ACP-501 need not be complexed to other lipids, has the potential to be administered subcutaneously, and unlike synthetic HDLs and other apoA-I mimetics does not elevate plasma triglycerides.  The goal of AlphaCore Pharma is to develop ACP-501 as a new pharmaceutical agent that has the potential to rapidly remove cholesterol from arteries, by stimulating RCT, thus reducing event rates in patients who have suffered an MI.

Preclinical Evidence that LCAT Enhances RCT and/or Decreases Atherosclerosis in Relevant Animal Models (i.e. CETP-Competent Species)

  • LCAT transgenic rabbits have elevated HDL and less atherosclerosis when fed a cholesterol diet (Hoeg, et al, 1996)
  • Hamsters overexpressing human LCAT have elevated HDL and increased biliary sterol excretion (Zhang, et al, 2004)
  • Overexpression of LCAT in rabbits causes regression of established atherosclerotic lesions (Van Craeyveld, et al, 2009)
  • Injection of LCAT (subcutaneous) enhances RCT, specifically, cholesterol efflux from peripheral tissues and fecal sterol excretion.  It also reduced atherosclerosis (Zhou, et al, 2009).

Clinical Evidence Supporting the Role of LCAT in RCT and Atherosclerosis

  • The severity of coronary heart disease (number of diseased vessels) is correlated with LCAT activity (Solajic-Bozicevic, et al, 1994)
  • Carriers of LCAT mutations have been shown by some investigators to have increased atherosclerosis (Ayyobi, et al, 2004; Hovingh, et al, 2005; Duivenvoorden, et al, 2010)
  • Pre-β-HDL levels (LCAT substrate) are elevated in patients with coronary heart disease (Miida, et al, 1996; Asztalos, et al, 2000; Lamon-Fava, et al, 2008; Tashiro, et al, 2009; Guey, et al, 2011)
  • There is an inverse correlation between pre-β-HDL levels and LCAT activity in patients with heart disease (Sethi, et al, 2010)
  • Infusion of ACP-501 increases HDL-cholesterol in patients with stable atherosclerosis (see October 9, 2012 Press Release)