Next-generation drug discovery in fibrosis and cancer

Fibrosis in IBD: an evolving unmet need beyond inflammation control

Michael Eberhardson, Senior medical director, AstraZeneca

Abstract: Inflammation is no longer the whole story in IBD. Fibrosis represents a major unmet clinical need beyond inflammation control. Even in the era of advanced biologics and small molecules, fibrosis remains a persistent and often irreversible driver of bowel damage, especially in Crohn’s disease, where strictures continue to lead to endoscopic intervention and surgery. This disconnect exposes one of the most important unresolved challenges in the field: patients may achieve inflammatory control while disease progression continues at the level of tissue architecture. At the center of this process is the extracellular matrix, not as a passive scar, but as an active and evolving regulator of repair, stiffness, signaling, and chronic fibrotic transformation. This presentation will argue for a shift in perspective from inflammation alone to tissue remodeling as one of the key therapeutic targets and fibrosis must become a priority in IBD research and care if we are to achieve genuine transformation of the treatment of IBD.

Extracellular matrix biomarkers as determinants of response and resistance in solid tumors

Saurabh Gupta, Senior director, Bristol-Myers Squibb

Abstract: TBD

CSF-1R inhibition shows efficacy in multiple preclinical fibrosis models

Michael Clupper, Research investigator, Incyte

Abstract: Multi-organ fibrosis is a dominant pathological characteristic of chronic graft-vs-host disease (cGvHD) that can result in severe quality-of-life impairment or lethality. In cGvHD, activated macrophages mediate inflammation and drive fibrotic progression via release of profibrotic mediators such as TGF-β and PDGF. The colony stimulating factor 1 receptor (CSF-1R) is expressed on monocytes and macrophages; in cGvHD, signaling through CSF-1R is required for monocyte recruitment and differentiation, as well as macrophage activation. Here, we show that blockade of CSF-1R signaling with an αCSF-1R monoclonal antibody was sufficient to ameliorate fibrotic pathology in two mouse models of fibrosis with distinct pathologenic etiologies. In a cGvHD mimetic mouse model, αCSF-1R treatment significantly decreased fibrosis in both skin and lung tissue, while in a silicosis model, αCSF-1R treatment decreased macrophage infiltration and BALF levels of leukocytes and profibrotic mediators.