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ability of VTP-43742 to block endogenous RORgt activity was determined in an assay system which we believe to be more representative of the
treatment of humans. As shown in Figure 10 below, VTP-43742 was shown to be a potent inhibitor of RORgt dependent IL-17 production in lymphocytes in human
whole blood assays with an IC50 potency of 221 nM, which is the concentration of drug needed to inhibit this assay by 50%. The whole blood assay is an important measure to gauge the
effects that protein binding and cell penetration may have on a compound's activity. The assay is helpful in estimating drug levels needed to achieve RORgt
blockade in animals and humans.
Human Whole Blood Assay
Figure 10: VTP-43742 is a potent inhibitor of IL-17 in physiologically relevant primary human lymphocytes in whole blood.
autoimmune encephalomyelitis, or EAE, is a mouse model of MS that we believe can serve as a useful surrogate model for human MS since both are associated with inflammation
and demyelination, or loss of the protective sheath around nerves, along with a Th17 dependent disease process. VTP-43742 was tested in the EAE model to assess its effects on disease progression. It
was orally administered twice daily from the time of disease induction. As shown in Figure 11 below, VTP-43742 significantly reduced the clinical score in a dose-dependent manner consistent
with a decrease in inflammation and demyelination, where a higher clinical score represents a worsening condition in the animal model. The maximal reduction in clinical score (50%-60%) is similar to
that seen with other IL-17 targeted therapies including IL-17 monoclonal antibodies and RORgt gene knock-out mice. Since IL-17 expression is induced in
infiltrating T cells in the spinal cords of diseased animals, and RORgt regulates the expression of IL-17, spinal cords were harvested and analyzed for IL-17
expression. VTP-43742 showed a significant, dose-dependent decrease in the expression of IL-17.