A novel thermogel for topical treatment of ulcerative colitis with microbialmetabolite mimicry.

PROJECT SUMMARY About one million people in the U.S. are affected by ulcerative colitis (UC), a chronic inflammatory disease that significantly affects health-related quality of life and can ultimately lead to colorectal cancer. The disease is variable across patients for severity (mild, moderate, or severe), extent (proctitis, distal UC, and pancolitis), and course (relapsing-remitting or chronically active). Medical management of UC is focused on reducing inflammation and achieving mucosal healing by first inducing and then maintaining remission. Moderate-to- severe UC is currently treated during flares and for short courses with corticosteroids (frequently, prednisone or budesonide), and for more sustained treatment with anti-TNF-α agents, anti-integrins, anti-IL-12/IL-23, and small molecules, which have risks of severe adverse effects and often result in non-response. Alternative dosage forms, such as topical formulations, are preferable to systemic therapies because they target the actual site of disease, achieving higher concentrations in the colonic mucosa with lower systemic exposure and fewer side effects. However, current topical approaches still suffer several limitations. Suppositories are only active in the rectum, and foams can only reach the sigmoid colon. Current enemas are able to reach as proximal as the splenic flexure but are not well-tolerated by patients due to retention issues, urgency, and the need for prolonged use. Intact Therapeutics is developing a novel topical therapeutic product (INT-102) for the treatment of moderate-to-severe, distal UC. INT-102 offers the unique combination of 1) a novel microbial metabolite- derived agonist of the Pregnane X Receptor (PXR), which has been demonstrated to regulate the inflammatory response, and 2) an innovative proprietary thermosensitive delivery platform (TDP) designed to achieve superior drug delivery to the distal colon. The proposed formulation will be used to treat inflammation refractory to first- line treatments while eschewing the side effects of current systemic therapies and overcoming the limitations hindering the use of current topical therapeutics for moderate-to-severe UC. This SBIR Phase I project proposes to develop the formulation with the lowest effective concentration of this new active drug (Aim 1), assess its pharmacokinetics in vivo (Aim 2), and demonstrate its safety and efficacy profile in a murine UC model (Aim 3). This work will be preparatory of a Phase II project in which Intact will evaluate the pharmacodynamics of the new formulation, validate efficacy in additional colitis models and UC patient explant culture (testing the drug efficacy related to inhibiting the target pathway), and conduct a comprehensive toxicology assessment in GLP IND- enabling studies. By offering a new effective treatment for moderate-to-severe UC, Intact Therapeutics will improve the health and quality of life of UC patients.