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will be beneficial for the treatment of multiple autoimmune disorders, specifically, psoriasis, MS, steroid-resistant asthma, Behcet's disease and autoimmune uveitis.
preclinical studies we have determined that VTP-43742 is a potent binder to RORgt that inhibits the conversion of naïve
T cells into Th17 cells and the secretion of multiple inflammatory proteins. It was shown to be greater than 1000-fold more potent for binding to RORgt
relative to two closely related receptors, RORa and RORb. Those preclinical studies have also shown that VTP-43742 inhibits
the secretion of IL-17 and other inflammatory proteins from Th17 cells, and is therapeutically beneficial in an animal model of autoimmunity. VTP-43742 is well absorbed after oral administration in
multiple animal species and has a long half-life in plasma, which we believe is consistent with once-a-day dosing in humans.
expect to begin the first single dose Phase 1 clinical trial for VTP-43742 in the first half of 2015 and expect to begin a two week Phase 1 proof-of-concept clinical
trial in psoriasis patients in the second half of 2015. The multiple dose Phase 1 clinical trial will be performed in psoriasis patients because psoriasis typically responds rapidly to therapy
and is straightforward to assess for improvement of disease activity. We expect results for this multiple dose Phase 1 proof-of-concept clinical trial by the end of 2015.
IL-17 was discovered in the 1990's as a pro-inflammatory protein, or cytokine. It has been implicated in multiple autoimmune disorders
including psoriasis, MS and RA. In 2000, it was determined that IL-17 is produced primarily by a subset of T cells, which are a type of lymphocyte, called Th17 cells. Th17 cells are normally involved
in mounting the immune response against disease causing organisms like fungi and bacteria. However, inappropriately regulated Th17 cells can attack normal human tissues, and have been shown to play a
significant role in multiple
autoimmune disorders. Persistent secretion of cytokines by Th17 cells, especially IL-17, promotes chronic inflammation by activating other cells to make additional inflammatory mediators such as tumor
necrosis factor, or TNF,-a, and the interleukins IL-1b, IL-6, and IL-8. Blockade of IL-17 activity by the monoclonal
antibodies ixekizumab, secukinumab and brodalumab has been shown to ameliorate autoimmune disorders both in human clinical trials and in preclinical models. These results have created interest in
identifying targets in Th17/IL-17 pathway that could be exploited to treat chronic inflammation and autoimmunity.
shown in Figure 6 below, Th17 cells are derived from naïve T cells. A mix of cytokines and growth factors induce RORgt
expression which helps to complete the differentiation process from naïve T cells to Th17 cells. The expression of RORgt drives the secretion of
IL-17 from Th17 cells along with a group of additional cytokines, and it also upregulates the IL-23 receptor, providing a positive feedback loop, further driving the activity of Th17 cells. These
cytokines are inflammatory mediators that, in turn, activate other inflammatory cells and the production of additional inflammatory molecules down stream of Th17 cells as depicted below.
Figure 6: Naive T cells differentiate into Th17 cells by action of multiple factors. Expression of RORgt in Th17 cells drives
expression of inflammatory cytokines that exacerbate autoimmune disease.