Orally delivered antagonists of Interleukin-23 receptor for treatment of inflammatory bowel disease

DESCRIPTION provided by applicant Inflammatory bowel disease IBD affects about of the worldandapos s population Due to its early onset and lack of adequate cure it requires lifelong treatment IBD impacts the gastrointestinal GI tract and manifests as two subtypes Crohnandapos s disease CD and ulcerative colitis UC In recent years anti TNF biological agents have revolutionized the treatment of IBD but these are not ideal drugs requiring administration by injection and in some instances hospitalization for intravenous infusion They have numerous systemically driven side effects including increased infections and anywhere from of patients either donandapos t respond or lose response Hence new therapeutic options to treat IBD are needed In this respect the recent identification of the IL pathway in chronic intestinal inflammation raises exciting new possibilities Ustekinemab targets both the IL and IL pathway and is efficacious in anti TNF resistant IBD patients However there is some concern of increased cardiovascular and cancer events as illustrated by the safety warning label on Ustekinumab and the removal of Briakinumab also targeting IL and IL These safety concerns are thought to be due to blocking the role of IL in host defense and cancer suppression whilst blocking IL signaling results in the observed efficacy IL is produced locally in the intestine and the upregulation of IL and its receptor is a primary step underpinning intestinal inflammation Since IBD represents a local inflammation of the intestinal tissue an ideal therapeutic would act from the luminal side to achieve high drug concentrations in diseased tissue enhanced efficacy whilst minimizing systemic bioavailability enhanced safety We have obtained exciting proof of concept data on the oral delivery of GI restricted drugs that are efficacious in a rodent model of disease These IL R antagonists are resistant to the proteolytic and reductive environment of the gastrointestinal tract resulting in high drug levels in diseased intestinal tissues after oral delivery and limited drug concentrations in the circulation This has the potential to transform the treatment paradigm for IBD by providing safe efficacious and durable drugs for life time treatment In this Phase I proposal we plan to Optimize the oral stability of PN a nM antagonist and optimize the potency of PN an orally stable though modestly potent nM antagonist Optimize intestinal and colonic tissue exposure of orally delivered leads and Evaluate efficacy of potent orally stable IL R antagonists in rodent models of disease This Phase I program is supported by a team that has a track record in the oral delivery of constrained peptides the proven capacity in translating early stage research to clinical outcomes a group of scientific and clinical advisors with significant experience in IBD and the appropriate research environment In addition all of the required methods are in place Phase II of the project will involve the evaluation and further optimization of lead candidates in disease models and eventual selection of Investigational New Drug candidates PUBLIC HEALTH RELEVANCE Inflammatory bowel disease which encompassed Crohnandapos s Disease and Ulcerative Colitis afflicts over million people in the United States and is estimated to cost $ billion in direct healthcare costs The disease has no cure has an onset early in life and requires life long treatment Current treatments are not effective or non durabl in many patients and have significant adverse effects This Phase I SBIR proposal describes the optimization of orally active local acting and GI restricted peptidic antagonists of IL receptor that will ultimately lead to more efficacious safe and durable treatment for IBD than current systemic approaches