Research Project
7999519
DESCRIPTION (provided by applicant): 5-Aminosalicylic acid (5-ASA) and its analogs such as the prodrug sulfasalazine are front line therapy for Inflammatory Bowel Disease (IBD), which include both Crohn's disease and ulcerative colitis. 5-ASA is only moderately efficacious in putting patients into remission and the doses of 5-ASA required are quite high (4-5g/day). 5-ASA has been shown to inhibit a range of cell-mediated immune functions, and it is now believed that the anti-inflammatory effects of 5-ASA are driven by the inhibition of activation of nuclear Factor-?B (NF-?B), a central mediator of inflammatory processes (McDermott 2000). The Catabasis platform addresses inflammation in a unique way by targeting pro- and anti-inflammatory pathways simultaneously inside the cell. The primary mechanism of action of the Catabasis NCEs is selective modulation of the NF-?B axis. The CAT1000 series of molecules achieves synergistic activity by chemically linking two known therapeutics-a salicylate analog and the ?-3 fatty acid DHA. One of the lead compounds in this series, CAT1920, is a conjugate which chemically links 5-ASA with DHA. CAT1920 inhibits NF-?B driven inflammation in a macrophage cell line and also inhibits TNF? secretion in an in vivo screening model of acute inflammation. In a preliminary study in an indomethacin-induced rat model of IBD, CAT1920 showed efficacy at doses of 100 and 300 mg/kg. Further optimization of the formulation of CAT1920 has resulted in improved exposures of CAT1920, which we believe will translate to improved efficacy at lower doses in this model. The primary aim of this Phase 1 SBIR proposal is to establish CAT1920 as a therapeutic agent for the treatment of IBD. Studies in the indomethacin rat IBD model with the improved formulation will be coupled with the determination of the PK/PD relationship for CAT1920. We will elucidate the molecular mechanism of action of CAT1920 through in vitro characterization in the human intestinal epithelial cell model Caco-2. The effects of CAT1920 on modulating both pro- and anti-inflammatory gene expression will be analyzed by whole genome microarray profiling. From a refined causal modeling analysis of the gene expression data, we will identify a panel of relevant biomarker genes that predict the effects of CAT1920 in intestinal epithelial cells, and we will confirm the modulation of this gene panel in enterocytes from CAT1920 treated animals. Further development of CAT1920 and identification of back-up compounds will be part of a future Phase II SBIR application, including studies to address initial toxicology in multiple species to support IND studies. PUBLIC HEALTH RELEVANCE: Inflammatory Bowel Diseases (IBD) are chronic inflammatory diseases of the digestive tract which include Crohn's Disease and ulcerative colitis. IBD affects 1.4 million patients in the United States and the incidence is increasing and the age of onset is decreasing. Treatment options are primarily focused on immunomodulation and are limited due to lack of efficacy, development of resistance, large required doses (up to 4 g/day) and significant safety concerns. Even with the availability of several classes of drugs used to treat IBD, there remains a significant unmet medical need for novel mechanism of action (MOA) therapeutics that have improved efficacy. The proposal presented in this Phase I SBIR grant application will establish the mechanism of action of CAT1920 and its utility as a novel, safe and efficacious therapeutic for the treatment of IBD.
