Immunoregulatory Therapeutics for Ulcerative Colitis BioTherapeutics, Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. Inflammatory bowel disease (IBD) is a chronic and disabling inflammatory disease of the gastrointestinal tract that afflicts 2 million Americans and over 5 million people worldwide. Current therapeutics are unsuccessful in maintaining remission and have been linked to serious side effects. BTI recently uncovered a novel chemical family that inhibits IL-18, an inflammatory cytokine produced by epithelial cells of the gastrointestinal tract to activate differentiation of IFNγ-producing Th1 cells and polarization of inflammatory macrophages. Our prototype NCE significantly reduced colonic scores and Th1 in the colonic lamina propria after DSS challenge and in the spontaneous Mdr1a-/- model of colitis, consistent with the proposed IL-18-blocking mechanism. This project will further characterize mechanisms of IL-18 signaling in IBD and validate the therapeutic efficacy of IL-18 inhibition in vivo and in human primary cells. The Specific Aims for this SBIR Phase I application are to: AIM 1. Evaluate the relative therapeutic efficacy of IL-18 inhibitors in vitro. We will assess the potency of IL-18 inhibition through binding and functional assays. AIM 2. Determine the therapeutic potential of IL-18 inhibition in mouse models of IBD. We will use the CD45RBhi adoptive transfer and DSS models of colitis to characterize the in vivo dose response to IL-18 inhibition through histological, transcriptional and immunological assays. AIM 3. Validate the responsiveness of in human UC patient cells to IL-18 signaling and inhibition. We will examine responses of healthy and UC PBMCs and LPMCs to IL-18 exposure and pharmacological inhibition. Expected successful outcomes will include: i) ≥ 50% reduction of IFNγ production in response to IL-18 after treatment in vitro; ii) ≥ 70% reduction of histological scores in adoptive transfer and DSS models of colitis; and iii) ≥ 50% reduction in IFNγ production in human UC PBMCs with IL-18 inhibition. The SBIR Phase II application will determine exposure-response relationships in therapeutic efficacy of IL-18 inhibition in chronic colitis models, conduct pharmacokinetic (PK) and safety studies in rats, evaluate the drug metabolism and off-target effects, and further validate the role of IL-18 as a therapeutic target in human UC and Crohn’s disease (CD). The long-term goal of this project is to develop a novel immunomodulatory therapeutic that is safer and more effective for treating IBD and provide a path towards commercialization of an asset with a target patient population of over 5 million with unmet clinical needs and a growing therapeutic market of $16 billion.

Public Health Relevance Inflammatory bowel disease (IBD) is a chronic and disabling inflammatory condition that targets the gastrointestinal tract and two clinical manifestations: Ulcerative colitis (UC) and Crohn’s disease (CD). In the United States alone, where current therapies are modestly successful and with significant side effects, 2 million people are afflicted by IBD, resulting in annual medical expenses that range between $14.6 and $31.6 billion. This SBIR Phase 1 will validate IL-18 as a novel therapeutic target for UC and develop the top lead IL-18 blocker, as a new immunomodulatory chemotype to address the unmet clinical need for safer and more effective oral therapeutics for UC.