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Oral treatment with PBI-4050 reduces kidney fibrosis Lyne Gagnon, Brigitte Grouix, Kathy Hince, Lilianne Geerts, Liette Gervais, Mikaël Tremblay, François Sarra-Bournet, Alexandra Felton, Shaun Abbott, Jean-Simon Duceppe, Martin Leduc, Boulos Zacharie, Christopher Penney and Pierre Laurin ProMetic BioSciences Inc., Laval, Québec, Canada p < 0.05 * 0.8 0.6 0.4 0.2 Fibroblast Proliferation & Differention Myofibroblast Proliferation, Survival & Migration EXTRACELLULAR MATRIX DEPOSITION FIBROSIS: ORGAN LOSS FUNCTION PBI-4050 IMPROVES KIDNEY FUNCTION Urine Protein (g/24 h) GROWTH FACTORS, BONE CYTOKINES & MARROW CHEMOKINES FIBROCYTES 21 153 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 Days 168 NX *p < 0.05 CKD: 5/6-NEPHRECTOMY INFLAMMATION DKD: db/db MODEL 0 Macrophages & Immune Cells * 1.0 GFR (ml/min) INJURY GFR 1.2 AKI: DOXORUBICININDUCED NEPHROPATHY CKD: 5/6-NEPHRECTOMY 190 NX + PBI-4050 Proteinuria * * * * 21 42 *p < 0.05 63 84 Days 105 NX KIDNEY Urinary MCP-1 Protein Level (% of Day 21) CKD: 5/6-NEPHRECTOMY PBI-4050 reduces fibrosis via the regulation of macrophages, T cells, fibrocytes/ fibroblasts/myofibroblasts and epithelial cells. In a pro-fibrotic phase, PBI-4050 plays a regulatory role by promoting a Type 1, anti-fibrotic cytokine production phenotype in macrophages and T cells, resulting in a reduction of the over-expression or overproduction of TGF-β, MCP-1, CTGF, IL-6 and IL-23. Interestingly, MCP-1 is also an important inducer of fibrocyte precursor migration in tissue. Fibrocyte differentiation, resident fibroblast activation and EMT are the key sources of activated myofibroblasts and successive accumulation of extracellular matrix protein deposition and fibrosis. PBI-4050 inhibits fibrocyte differentiation, fibroblast activation and EMT as demonstrated by a reduction in alpha smooth muscle actin (α-SMA), collagen I and SPARC mRNA expression. PBI-4050 also plays a role in tissue remodeling by regulating MMP and TIMP expression. CKD: 5/6-NEPHRECTOMY SUMMARY CONCLUSION Taken together, these preclinical results suggest that PBI-4050 offers the potential as a novel therapy for the treatment of kidney fibrosis. 126 153 NX + PBI-4050