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Autoimmune disorders make up a large number of human disorders which include more common disorders such as psoriasis, MS, RA and
steroid-resistant asthma, as well as rarer disorders such as Behcet's disease and autoimmune uveitis. Due to its Th17 activity, we believe VTP-43742 will be most effective in psoriasis, MS, Behcet's
disease and autoimmune uveitis. Psoriasis, a chronic autoimmune disorder of the skin, affects an estimated 7.4 million Americans. Based on various reports estimating the prevalence of diagnosis
per 100,000 people and the U.S. 2014 census, we estimate that, as of 2014, the number of Americans diagnosed with MS, Behcet's disease and autoimmune uveitis was 400,000, 16,500 and 5,400,
available therapies for the treatment of psoriasis include topical steroids, phototherapy or light therapy, systemic agents including oral retinoids, cyclosporine, and
methotrexate and finally
biologics that act by blocking the action of T cells, or by blocking various proteins in the immune system. We anticipate that VTP-43742 will be used for the treatment of mild to moderate psoriasis,
prior to antibody therapy, as well as for the treatment of severe psoriasis, in conjunction with or in replacement of antibody therapy.
We analyzed the ability of VTP-43742 to bind to RORgt in a biochemical binding assay. As shown in
Figure 8 below, the Ki value of VTP-43742 to RORgt, which measures how tightly the compound binds to its target, is high (3.7 nM). The binding affinity of
VTP-43742 to the other ROR isotypes, namely RORa and RORb, is much weaker as evidenced by the relatively higher Ki values,
which is important because significant toxicities are associated with inhibition of these two related receptors. Our internal studies have shown VTP-43742 to be greater than 1000-fold more potent for
RORgt as compared to RORa and RORb.
Figure 8: Binding affinity of VTP-43742 to isolated human ROR a, b, and
was also tested for its ability to block RORgt activity in Jurkat T cells, a well-established human T cell line for testing the functional
activity of compounds. This assay was used to determine the inverse agonist activity of RORgt ligands. As shown in Figure 9 below, VTP-43742 is a potent
inhibitor of RORgt activity in these cells with an IC50, which is the amount of drug necessary to inhibit the assay by 50%, of 17nM.
Figure 9: VTP-43742 is a potent (IC50=17nM) and effective inverse agonist in a RORgt-dependent reporter human T cell