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Oral treatment with a novel first-in-class

Additional Information. Oral treatment with a novel first-in-class anti-fibrotic compound PBI-4050 reduces hepatic steatosis and improves kidney function in the diabetic db/db mouse model. Presented by: Dr. Lyne Gagnon AASLD Conference Washington November 2-4, 2013.

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Oral treatment with a novel first-in-class

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  1. Additional Information Oral treatment with a novel first-in-class anti-fibrotic compound PBI-4050 reduces hepatic steatosis and improves kidney function in the diabetic db/db mouse model. Presented by: Dr. Lyne Gagnon AASLD Conference Washington November 2-4, 2013 Also including the results on the effect of PBI-4050 in CCl4-induced liver fibrosis Disclosure: ProMetic BioSciences Inc. 1

  2. PBI-4050 preclinical data in two liver fibrosis models Chronic model Uni-nephrectomized diabetic (db/db) mouse model (Slides 4-16) NASH-fibrosis model CCl4-induced steatohepatitis (Slides 17-27)

  3. Chronic model: Uni-nephrectomized diabetic (db/db) mouse model

  4. PBI-4050 reduces serum glucose to the C57BL/6 and sham level Serum glucose measured on 5-hour starved mice

  5. Treatment with PBI-4050 increases glucose metabolism in oral glucose tolerance test at day 112 Serum glucose measured on 16-hour starved mice

  6. PBI-4050 reduces liver steatosis 3.0 2.5 2.0 1.5 1.0 0.5 0 p = 0.04 Liver Steatosis Db/db Db/db + PBI-4050

  7. PBI-4050 reduces liver steatosis C57BL/6 Db/db Db/db + PBI-4050 8

  8. PBI-4050 reduces fibrotic markers expression in liver

  9. Treatment with PBI-4050 reduces kidney hyperfiltration in db/db mice at day 97

  10. Treatment with PBI-4050 reduces proteinuria

  11. Treatment with PBI-4050 increases urinary creatinine excretion

  12. PBI-4050 reduces kidney mesangium lesions

  13. PBI-4050 reduces fibrotic markers expression in kidney

  14. PBI-4050 reduces lipid peroxidation in kidney

  15. Conclusions: PBI-4050 offers the potential as a novel therapy for hepatic steatosis in DKD In liver • Reduces steatosis • Reduces fibrotic markers (TGF-, collagen 1, MMP-2 and TIMP-1 mRNA expression) In kidney • Reduces kidney hyperfiltration, proteinuria, albuminuria • Increases urinary creatinine excretion • Reduces histological lesions in the mesangium • Reduces fibrotic markers expression (IL-6, collagen 1, TIMP-1 and MMP-2 mRNA expression) • Reduces oxidative stress (lipid peroxidation) PBI-4050 has now enter into clinical program.

  16. NASH-Fibrosis Model CCl4-induced steatohepatitis 17

  17. C57BL6/J male CCl4-induced liver fibrosis: Effect of PBI-4050 Study design IP injection of 2ml/kg of CCl4 10% in olive oil, twice a week for 8, 12 or 16 weeks Day 59: Euthanasiaand analysis Day 1: Oral administration of vehicle or PBI-4050 (day 1 to day 59)

  18. Day 59: Evidence of pre-fibrosis • The effect of PBI-4050 was studied on the pre-fibrosis/ fibrosis development in CCl4-induced hepatic fibrosis. • Fibrosis was estimated with the measurement of hydroxyproline which is a direct measure of collagen (marker of fibrosis) in the liver (next slide). PBI-4050 reduces liver fibrosis.

  19. PBI-4050 significantly reduces hepatic concentration of hydroxyproline P = 0.007

  20. PBI-4050 significantly reduces the histology activity index (HAI)-Knodell score • Intoxication with CCl4 results in hepatocyte damage, necrosis, inflammation, and fibrosis, which spreads to link the vascular structures that feed into and drain the hepatic sinusoid (the portal tract and central vein radicle, respectively), and over 8-30 weeks results in the development of fibrosis to hepatocellular carcinoma. • Knodell score is the combined scores for necrosis, inflammation and fibrosis. Histology activity index (HAI) evaluates: • Periportal +/- bridging necrosis (bridging between portal-portal and portal-central linkage); • Intralobular degeneration (acidophil bodies, ballooning, focal necrosis-scattered foci of hepatocellular necrosis) and focal necrosis; • Portal inflammation, and • fibrosis (fibrous portal expansion, or bridging fibrosis (portal-portal or portal-central linkage or cirrhosis (loss of normal hepatic lobular architecture with fibrous septae separating and surrounding nodules)).

  21. PBI-4050 significantly reduces the histology activity index (HAI)-Knodell score p= 0.008

  22. PBI-4050 significantly reduces the collagen score in liver (Masson’sTrichrome staining) p = 0.03

  23. PBI-4050 significantly reduces collagene deposition in CCl4-induced liver fibrosis (Masson’s trichrome stain) • The Masson’s trichrome stain the cytoplasm, keratin, muscle fibers and intracellular fibers in red colour; nuclei in black colour and collagen (fibrous tissue) in blue color. • All control mice revealed a normal distribution of collagen. • Extensive collagen deposition and bridging fibrosis were evident in CCl4-treated animals. • Significant reduction of collagen deposition and bridging formation between portal-portal or portal-central was observed in PBI-4050 treated animals.

  24. PBI-4050 significantlyreduceshistologicallesionsin CCl4-induced liverfibrosis (Masson’s Trichrome) Control CCL4) CCL4 + PBI-4050 (200 mg/kg) CCL4 + PBI-4050 (200 mg/kg) Control CCL4

  25. PBI-4050 significantly reduces histological lesions in CCl4-induced liver fibrosis (Hematoxylin-Eosin stain) • The hematoxylin eosin stains the cytoplasm in red colour; nuclei with blue colour and show the steatosis and lymphocyte infiltration in stained tissue. • A moderate steatosis and a severe inflammation are observed as compared to control (non-CCl4) mice. Treatment with PBI-4050 reduces inflammatory infiltration in hepatic lobes.

  26. PBI-4050 significantlyreduceshistologicallesionsin CCl4-induced liverfibrosis (Hematoxyline-Eosin) Control CCL4) CCL4 + PBI-4050 (200 mg/kg) CCL4 + PBI-4050 (200 mg/kg) Control CCL4

  27. Acknowledgements Biology Dr. Brigitte Grouix Lilianne Geerts François Sarra-Bournet Kathy Hince André Doucet Mikaël Tremblay Alexandra Felton Dr. Martin Leduc Liette Gervais Frank Cesari Lyne Marcil Pierre Laurin Chemistry Dr. Christopher Penney Dr. Boulos Zacharie Dr. Shaun Abbott Jean-Simon Duceppe

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