Sp102oral Treatment With Pbi-4050 Reduces Kidney Fibrosis

Introduction and Aims: PBI-4050, a novel first-in-class orally active compound which is currently in clinical phase Ib/II in CKD patients, displays antifibrotic activities via a novel mechanism of action. In a double-blind single ascending dose (400 to 2400 mg) in healthy volunteers, PBI-4050 was found to be safe and well tolerated up to 2400 mg without any significant adverse effects. Similarly, PBI-4050 was well tolerated in CKD patients with no SAEs observed at 800 mg. Methods: mRNA expression was investigated on TGF-β1-stimulated HK-2 and NHDF cells as well as in mouse and rat kidney tissue. Results: PBI-4050 reduces fibrosis via the regulation of macrophage, fibroblast and epithelial cells. In a pro-fibrotic phase, PBI-4050 plays a regulatory role on macrophages and T cells by promoting Type 1 anti-fibrotic cytokine production resulting in a reduction of the over-expression or over-production of TGF-β, MCP-1, CTGF, IL-6 and IL-23. In TGF-β-stimulated human fibroblast (NHDF), PBI-4050 reduces the expression of pro-fibrotic cytokines and growth factors (IL-6, MCP-1, CTGF, CCL11, IL-5, endothelin 1 (EDN1), EGF, PDGFα, VEGFα, Inhibin βE, TGF-β2); and of remodeling enzymes (LOX, MMP13, uPA, PA-1, TIMP3 and ILK). In TGF-β-stimulated human renal epithelial cells (HK-2), PBI-4050 reduces the expression of epithelial-to-mesenchymal transition markers (collagen III, ILK, MMP2, MMP9, TGF-β1, TGF-β1-2 and 3); of remodeling enzymes (LOX, MMP1, MMP2, MMP9, MMP13, tPA and TIMP3); and of growth factors (CTGF, EDN1, EGF, PDGFβ).