Title: Oral treatment with a novel first-in-class
1Additional Information
Oral treatment with a novel first-in-class anti-fi
brotic 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(No Transcript)
3PBI-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)
4Chronic model Uni-nephrectomized diabetic
(db/db) mouse model
5PBI-4050 reduces serum glucose to the C57BL/6 and
sham level
Serum glucose measured on 5-hour starved mice
6Treatment with PBI-4050 increases glucose
metabolism in oral glucose tolerance test at day
112
Serum glucose measured on 16-hour starved mice
7PBI-4050 reduces liver steatosis
8PBI-4050 reduces liver steatosis
8
9PBI-4050 reduces fibrotic markers expression in
liver
10Treatment with PBI-4050 reduces kidney
hyperfiltration in db/db mice at day 97
11Treatment with PBI-4050 reduces proteinuria
12Treatment with PBI-4050 increases urinary
creatinine excretion
13PBI-4050 reduces kidney mesangium lesions
14PBI-4050 reduces fibrotic markers expression in
kidney
15PBI-4050 reduces lipid peroxidation in kidney
16Conclusions 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.
17NASH-Fibrosis Model CCl4-induced steatohepatitis
17
18 CCl4-induced liver fibrosis Effect of PBI-4050
19Day 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.
20PBI-4050 significantly reduces hepatic
concentration of hydroxyproline
P 0.007
21PBI-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)).
22PBI-4050 significantly reduces the histology
activity index (HAI)-Knodell score
p 0.008
23PBI-4050 significantly reduces the collagen score
in liver (MassonsTrichrome staining)
p 0.03
24PBI-4050 significantly reduces collagene
deposition in CCl4-induced liver fibrosis
(Massons trichrome stain)
- The Massons 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.
25PBI-4050 significantly reduces histological
lesions in CCl4-induced liver fibrosis (Massons
Trichrome)
26PBI-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.
27PBI-4050 significantly reduces histological
lesions in CCl4-induced liver fibrosis
(Hematoxyline-Eosin)
28Acknowledgements
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