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calcineurin inhibitors. Though effective, they both have been shown to have serious side effects in some patients. For glucocorticoids, these side effects include thinning of the skin and loss of
barrier function, adrenal suppression caused by drug absorption through the skin, and contraindications for use on the face and other sensitive areas of skin. For calcineurin inhibitors, these side
effects include a burning sensation upon application and a black box warning for the potential to induce cancer. Two calcineurin inhibitors approved for sale in 2001 had combined annual sales of
greater than $450 million in 2004. These two treatments were required to add a "black box warning" in 2005 for risk of cancer, and combined annual sales dropped. In 2013, the combined annual
sales of these two products were
approximately $240 million. We believe that VTP-38543 can be developed as a first-in-class therapy that controls inflammation and improves the skin barrier function in these patients while
avoiding the side effects associated with existing treatments.
The ability of VTP-38543 to bind to LXR was determined in biochemical binding assays. VTP-38543 is a potent binder to
LXRb (26 nM). VTP-38543 was also tested for its ability to induce LXR-mediated activity in a cell-based assay. VTP-38543 is a potent partial agonist of
LXRb with an EC50 of 16 nM.
also assessed the ability of VTP-38543 to reduce inflammation in a mouse ear model of inflammation. As shown in Figure 20 below, the chemical tetradecanoylphorbol acetate, or
TPA, induced a strong inflammatory response (Figure 20B) as shown by the infiltration of neutrophils (small arrows) and increased ear swelling as indicated by the width of the double headed
arrow. Topical treatment with VTP-38543 significantly reduced both neutrophil infiltration and swelling (Figure 20D). The effect was comparable to the reduction observed upon topical treatment
with a potent glucocorticoid, clobetasol (Figure 20C).
Figure 20: VTP-38543 is efficacious in a chemically induced mouse ear model of inflammation. A: Vehicle treated, no chemical induction. B: Vehicle
treated + chemical (TPA) induction. C: Glucocorticoid (clobetasol) + TPA induction. D: VTP-38543 + TPA induction.
and SREBP1c are key LXR target genes that are involved in lipid transport and lipid synthesis. Mice lacking ABCG1 or SREBP1c display abnormal barrier formation. As shown in
Figure 21 below, topical application of VTP-38543 to the skin of hairless mice increased expression of both genes.