Print Page  Close Window

SEC Filings

S-1
VITAE PHARMACEUTICALS, INC filed this Form S-1 on 08/12/2014
Entire Document
 

Table of Contents

        In addition to augmenting RCT, activation of LXR receptors has also been shown to decrease the production of inflammatory proteins in macrophages. LXR agonism exerts general inhibitory action on the synthesis of inflammatory proteins. Inflammation in an atherosclerotic plaque makes the endothelial surface over the plaque prone to formation of blood clots and predisposes the plaque to rupture, and a ruptured plaque often leads to blood clots. Thus, LXR activation interferes with the pathology of atherosclerosis by directly activating genes to promote RCT, which decreases the amount of cholesterol in the plaque, and by inhibiting pro-inflammatory gene expression, which reduces plaque associated inflammation.

    Market Opportunity

        According to the American Heart Association, as of 2005, there were approximately 1.4 million hospital discharges in the United States due to ACS. According to an article published in the American Journal of Managed Care, the economic impact of ACS is estimated to be greater than $150 billion annually and the direct medical cost for ACS is estimated at $75 billion, with a significant portion associated with drug therapy. The goal of treating ACS after the acute event is to preserve patency of the coronary artery. After an ACS event, patients are usually treated with an anti-blood clotting agent and a cholesterol lowering agent. We believe that VTP-38443, when used in combination with existing therapies used to treat patients with ACS, may have a significant therapeutic benefit, by decreasing the propensity for formation of blood clots on the surface of a plaque.

    Preclinical Data

        The ability of VTP-38443 to bind to LXRa and LXRb was determined in biochemical binding assays. As shown in Figure 14 below, VTP-38443 is a potent binder to LXRb (12 nM), which is 22-fold more potent than binding to LXRa (262 nM). VTP-38443 was also tested for its ability to induce LXR-mediated activity in a cell-based assay. As shown in Figure 14 below, VTP-38443 is a potent agonist of LXRb with an EC50, which is the amount of drug necessary to achieve 50% of the maximum effect, of 19 nM. Consistent with the binding assays, VTP-38443 was approximately 20-fold more potent for LXRb activity compared to LXRa. Compounds with greater selectivity have a larger margin between having beneficial effects on an atherosclerotic plaque and the side effect of increased triglyceride synthesis.

GRAPHIC

Figure 14: VTP-38443 binds to and activates LXRb more potently than LXRa in binding and cell-based assays.

        The ability of VTP-38443 to induce key LXR target genes and to promote cholesterol efflux has been determined in a human fibroblast cell line. As shown in Figure 15 below, VTP-38443 is a potent agonist for increasing the expression of ABCA1 mRNA, which encodes ABCA1 proteins, in human cells. In other cell based experiments, we have demonstrated that this increase is associated with an increased removal of cholesterol from human cells in an HDL dependent manner.

93