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VITAE PHARMACEUTICALS, INC filed this Form S-1 on 08/12/2014
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    RORgt as a Target in Autoimmunity

        The ROR protein family consists of three related receptor isotypes—RORa, RORb and RORg. RORa is expressed in many tissues, including brain, liver, thymus, and skeletal muscle. RORb has a limited expression pattern and is found mainly in the retina of the eye and the pineal gland, which is a small gland in the brain. RORg has a broad pattern of expression, similar to RORa. RORgt is a variant of the RORg gene and is found only in immune cells. Mice lacking RORa have a movement disorder due to deficiency and degeneration of specific brain cells. Similarly, lack of RORb in mice leads to blindness due to abnormal retinal development. Mice deficient in RORgt have impaired Th17 cell differentiation; however, these mice are otherwise healthy and are also resistant to many autoimmune disorders. We believe that these immuno-protective findings have stimulated a broad interest in developing RORgt inhibitors as a novel mechanism to control Th17 function to treat autoimmune disease. We believe that any viable product candidate needs to be highly specific for RORgt because of the potential safety concerns that are associated with inhibiting RORa or RORb activity.

        RORgt acts by binding to specific DNA sequences, called ROR Response Elements, or ROREs, to regulate the production of messenger RNA. When bound to the RORE of the IL-17 gene, RORgt stimulates the production of the IL-17 messenger RNA. As depicted in Figure 7 below, this activity of RORgt can be modulated by inverse agonists, or inhibitors, that block the activity of the receptor. These compounds bind to a specific ligand pocket in the receptor and suppress receptor activity.

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Figure 7: RORgt binds to DNA and initiates transcription of target genes, e.g., IL-17. An inverse agonist can bind to a specific pocket in RORgt and block its activity, leading to suppression of cytokine synthesis.

        Antibodies being developed to target the Th17/IL-23/IL-17 pathways have been extensively studied and have demonstrated efficacy in human trials in psoriasis, MS, RA and ankylosing spondylitis, which is an immune mediated inflammatory disease of the lower back. One of the anti-IL-17 antibodies, secukinumab, was shown to be superior to a TNF-a antibody in psoriatic patients. We believe that a small molecule, such as VTP-43742, that targets the same pathway by inhibiting the activity of RORgt in Th17 cells, may have the advantage of being orally active, affecting a broader spectrum of inflammatory proteins, having a lower cost of goods, and being easier to dose adjust or stop therapy when needed, and could compliment or compete with antibody approaches currently in development.

        The RORgt ligand pocket is well characterized and is particularly suitable for targeting with small molecules. Several inverse agonists of RORgt have been reported in medical and scientific literature. These compounds are effective in preclinical models of autoimmune disease and the anti-inflammatory effects observed with these RORgt blockers are similar to those seen with IL-17 antibodies. Many competing RORgt programs have struggled to achieve the potency and the requisite selectivity needed for a clinical candidate. There are subtle variations among the three ROR receptors in the ligand binding pocket. We have attempted to exploit these variations using Contour to develop VTP-43742. Our preclinical studies of VTP-43742 have shown that it is potent and is more than 1000-fold more potent at binding to RORgt than binding to RORa and RORb.

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