PBI-4050 tested in an animal model of human type II diabetes

PBI-4050 tested in an animal model of human type II diabetes
uninephrectomized diabetic db/db mouse model
PBI-4050 significantly reduced:
• proteinuria
• kidney hyperfiltration,
• the expression of inflammatory/fibrotic markers in kidney and liver
• hepatic steatosis
Presented by: Dr. Lyne Gagnon
April 2 2014
Disclosure: Director, R&D - Biology, ProMetic BioSciences Inc.
1
1
2
Chronic model: Uni-nephrectomized diabetic
(db/db) mouse model
3
PBI-4050 reduces serum glucose to the C57BL/6 and sham level
Serum glucose measured on 5-hour starved mice
4
Treatment with PBI-4050 increases glucose metabolism in oral
glucose tolerance test at day 112
Serum glucose measured on 16-hour starved mice
5
Treatment with PBI-4050 reduces kidney
hyperfiltration in db/db mice at day 97
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Treatment with PBI-4050 reduces proteinuria
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Treatment with PBI-4050 increases urinary creatinine excretion
8
PBI-4050 reduces kidney mesangium lesions
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PBI-4050 reduces fibrotic markers expression in kidney
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PBI-4050 reduces lipid peroxidation in kidney
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PBI-4050 reduces liver steatosis
3.0
Liver Steatosis
2.5
p = 0.04
2.0
1.5
1.0
0.5
0
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Db/db
Db/db + PBI-4050
PBI-4050 reduces liver steatosis
C57BL/6
Db/db
Db/db + PBI-4050
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PBI-4050 reduces fibrotic markers expression in liver
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Conclusions: PBI-4050 offers the potential as
a novel therapy for DKD
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)
In liver
 Reduces steatosis
 Reduces fibrotic markers (TGF-, collagen 1, MMP-2 and TIMP-1 mRNA expression)
PBI-4050 is currently in Phase I and expected to be in
diabetic patients with Chronic Kidney Disease in early H2 2014
.
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PBI-4050 – Clinical status
Completed successful Pre-IND meeting with Health Canada for the treatment of
Diabetic patients with chronic kidney disease (DKD)
Clinical pathway confirmed for this primary indication and Pre-IND meeting with the FDA
is expected in Q2 2014.
Other Orphan Indications are also targeted and will be disclosed following our Pre-IND
meeting with the FDA.
Positive results in pulmonary fibrosis models have already been disclosed and new data
in kidney and liver fibrosis will be disclosed in April at 3 international conferences.
Phase I is expected to be completed in Q2 2014
The objectives of this randomised, double-blind, placebo-controlled, first in human,
single ascending dose study are to investigate safety tolerability and pharmacokinetics
of PBI-4050 administered orally once daily.
Phase Ib/II - expecting to be in patients in early H2 2014
In addition to monitoring safety and tolerability in patients for 3 months, this randomised, double-blind
placebo-controlled study will monitor early biomarkers to confirm that the beneficial effects
of PBI-4050 observed in several animal models can be translated to humans, and at what dose.
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Animal model of human Type II diabetes
Changes in BioMarkers after
few weeks of PBI-4050 treatment
↓ glucose in blood
↓ pro-inflammatory markers in blood
↓ pro-inflammatory markers in urine
↓ proteinuria
Phase Ib/II
To confirm PBI-4050
affects biomarkers in humans
in the same fashion;
to define dose range
• Proof of concept data in human
• Information on dosing
• Set the stage for phase II/III
Overtime the non-treated diabetic mice lose kidney
function as normal tissue is replaced by collagen
(colored in blue) = Fibrosis & loss of functionality
nontreated
= CKD /
= DKD
Other
Orphan
Indications
CKD / DKD
Chronic Kidney Disease
Diabetic Kidney Disease
PBI-4050
Diabetic mice treated with PBI-4050
maintain their renal function
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Acknowledgements
Biology
Dr. Brigitte Grouix
Lilianne Geerts
François Sarra-Bournet
Kathy Hince
André Doucet
Mikaël Tremblay
Alexandra Felton
Dr. Martin Leduc
Liette Gervais
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Frank Cesari
Lyne Marcil
Pierre Laurin
Chemistry
Dr. Christopher Penney
Dr. Boulos Zacharie
Dr. Shaun Abbott
Jean-Simon Duceppe

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