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Canadian IBD Today_Special Scientific Supplement_FINAL

Queen's School of Business Presentation

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2 Special Supplement, May 2023 C H R I S T O P H E R M A MD, MPH, FRCPC Christopher Ma is an academic gastroenterologist at the University of Calgary. He has advanced training in inflammatory bowel disease, clinical trial design, and analytic research methods. He has published over 170 peer-reviewed manuscripts and received over $6.5 million in research grant funding. His clinical and research focus is on patients with advanced Crohn's disease, ulcerative colitis, and eosinophilic esophagitis who require advanced medical therapies. Affiliations: Division of Gastroenterology & Hepatology, University of Calgary Department of Community Health Sciences, University of Calgary Alimentiv Inc., London, Ontario Introduction Targeting Th17-mediated inflammatory pathways through inhibition of interleukin (IL)-23 has emerged as an important therapeutic mechanism for patients with inflammatory bowel disease. Ustekinumab, a monoclonal antibody blocking both IL-12 and IL-23, was the first agent approved by Health Canada with this mechanism of action, initially for Crohn's disease (CD) in 2016 and subsequently for ulcerative colitis (UC) in 2020. Over the past decade, there has been increasing attention focused on selectively blocking IL-23, as the key activator of pathogenic Th17 inflammatory cells. Several monoclonal antibodies that target the unique p19 subunit of IL-23 (IL23p19 antagonists) have been developed for psoriasis and psoriatic arthritis, where IL-23 specific blockade results in substantially greater efficacy compared to targeting IL-12/23. 1 The first IL23p19 antagonist, risankizumab, has recently been approved in Canada for the treatment of moderate-to-severely active CD. Here, we describe the mechanism of action of risankizumab and how it differentiates from ustekinumab; review the pivotal clinical trial data that demonstrates the ability of risankizumab to achieve relevant clinical and endoscopic endpoints in both biologic treatment naïve and exposed patients; and summarize key safety data that helps inform decisions about the benefit-risk profile of this novel therapy. Th17 Immune Responses and the Mechanism of Action of Risankizumab IL-12 and IL-23 are heterodimeric cytokines that play important roles in both innate immunity and pathogenic inflammation, as master cytokines in the Th1 and Th17 pathways, respectively. IL-12 consists of two disulfide-bound subunits, p35 and p40, that bind to the IL12 receptor to induce downstream signalling. 2 IL-12 is predominantly secreted by antigen presenting cells, dendritic cells and macrophages, in response to microbial products such as lipopolysaccharide. IL-12 secretion activates natural killer (NK) cells and stimulates differentiation of naïve T-cells to interferon (IFN)-γ producing Targeting IL23p19 Using Risankizumab for the Management of Moderate-to-Severely Active Crohn's Disease: The Next Frontier?

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