The Development of RORgt Immunomodulators Targeting the TH17 Axis in IBD- Phase 2

DESCRIPTION provided by applicant In our SBIR Phase research program we discovered two novel ROR t inverse agonist lead series and showed efficacy in two animal models of inflammatory bowel disease IBD IBD is a significant health burden reducing the quality of life of million people in the United States alone Th cells are a lineage of T helper cells that have recently been identified as critical mediators of the immunopathology of several human inflammatory disease states including IBD The orphan nuclear receptor ROR t has been shown to be the master controller of the differentiation of Th cells ROR t knockout animals are highly resistant to several autoimmune diseases In healthy people Th cells are chiefly located in the lamina propria of the small intestine In IBD patients this compartmentalization breaks down and Th cells migrate and expand in number at inflamed tissue sites throughout the gut Antagonism of the transcriptional activity of ROR t blocks the differentiation of CD T cells into the Th cell lineage Thus ROR t inverse agonists reduce the Th cell population at sites of inflammation Th cells secrete large quantities of IL A IL F IL TNF and other inflammatory cytokines ROR t drives the production of these cytokines and it has been demonstrated that ROR t inverse agonists reduce the secretion of these cytokines from pre existing Th cells Therefore small molecule inverse agonists of ROR t will effectively treat IBD by reducing the Th cell population and IL A F production We discovered novel and potent ROR t inverse agonists that functionally block the ex vivo differentiation of human Th cells Importantly we demonstrate in two IBD animal efficacy models that our most advanced lead compound significantly attenuates the disease Analyses of the proximal target biomarkers shows that the compound effects are occurring via the expected mechanism of action inverse agonism of ROR t Based on the success of the Phase SBIR work we propose the following aims optimize the pharmacological properties and oral bioavailability of novel ROR t inverse agonists using our proprietary BindingSIGHTS drug design platform to guide a medicinal chemistry testing cycle determine the ex vivo T cell functional activity of ROR t inverse agonists on human Th Th Th and Treg cells evaluate the therapeutic efficacy of orally bioavailable ROR t inverse agonists in animal models of IBD evaluate the safety toxicity of the most advanced compounds to nominate candidates for Investigational New Drug IND enabling studies Together these studies will provide orally bioavailable therapeutics for IBD that will facilitate subsequent human clinical trials PUBLIC HEALTH RELEVANCE Th cells are a lineage of T helper cells that have recently been identified as critical mediators of the immunopathology of several human inflammatory disease states including inflammatory bowel disease IBD The orphan nuclear receptor ROR t has been shown to be the master controller of the differentiation of Th cells The goal of the proposed research is to optimize the pharmacological properties of small molecule ROR t inverse agonists The improved properties will provide sufficient oral bioavailaibility and half life to yield once per day dosing of human IBD patients The results of these studies will be one or more patentable new chemical entities NCEs that are candidates for IND studies