Additional Information
Download
1 / 28

Oral treatment with a novel first-in-class - PowerPoint PPT Presentation


  • 210 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Oral treatment with a novel first-in-class' - adli


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

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


Pbi 4050 preclinical data in two liver fibrosis models
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)



Pbi 4050 reduces serum glucose to the c57bl 6 and sham level
PBI-4050 reduces serum glucose to the C57BL/6 and sham level

Serum glucose measured on 5-hour starved mice


Treatment with pbi 4050 increases glucose metabolism in oral glucose tolerance test at day 112
Treatment with PBI-4050 increases glucose metabolism in oral glucose tolerance test at day 112

Serum glucose measured on 16-hour starved mice


Pbi 4050 reduces liver steatosis
PBI-4050 glucose tolerance test at day 112reduces 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


Pbi 4050 reduces liver steatosis1
PBI-4050 glucose tolerance test at day 112reduces liver steatosis

C57BL/6

Db/db

Db/db + PBI-4050

8


Pbi 4050 reduces fibrotic markers expression in liver
PBI-4050 glucose tolerance test at day 112reduces fibrotic markers expression in liver





Pbi 4050 reduces kidney mesangium lesions
PBI-4050 excretionreduces kidney mesangium lesions


Pbi 4050 reduces fibrotic markers expression in kidney
PBI-4050 excretionreduces fibrotic markers expression in kidney



Conclusions pbi 4050 offers the potential as a novel therapy for hepatic steatosis in dkd
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.


NASH-Fibrosis Model therapy for hepatic steatosis in DKD

CCl4-induced steatohepatitis

17


C57BL6/J male therapy for hepatic steatosis in DKD

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)


Day 59 evidence of pre fibrosis
Day 59: Evidence of pre-fibrosis therapy for hepatic steatosis in DKD

  • 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.



Pbi 4050 significantly reduces the histology activity index hai knodell score
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)).



Pbi 4050 significantly reduces the collagen score in liver masson strichrome staining
PBI-4050 significantly reduces the collagen score in liver (Masson’sTrichrome staining)

p = 0.03


PBI-4050 significantly reduces collagene deposition in CCl (Masson’sTrichrome staining)4-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.


PBI-4050 (Masson’sTrichrome staining)significantlyreduceshistologicallesionsin CCl4-induced liverfibrosis (Masson’s Trichrome)

Control

CCL4)

CCL4 + PBI-4050 (200 mg/kg)

CCL4 + PBI-4050 (200 mg/kg)

Control

CCL4


PBI-4050 significantly reduces histological lesions in CCl (Masson’sTrichrome staining)4-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.


PBI-4050 (Masson’sTrichrome staining)significantlyreduceshistologicallesionsin CCl4-induced liverfibrosis (Hematoxyline-Eosin)

Control

CCL4)

CCL4 + PBI-4050 (200 mg/kg)

CCL4 + PBI-4050 (200 mg/kg)

Control

CCL4


Acknowledgements (Masson’sTrichrome staining)

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


ad