- PBI-4050 reduces the activation of hepatic stellate cells,
the major cells involved in liver fibrosis
- PBI-4050 decreases liver fibrosis through modulation of the
LKB1-AMPK-mTOR pathway
- AMPK acts as the "master regulator" of cellular energy
homeostasis and its role in reducing fibrosis is well
documented
LAVAL, QC, Aug. 10, 2018 /CNW Telbec/ - Prometic Life
Sciences Inc. (TSX: PLI) (OTCQX: PFSCF) ("Prometic")
today announced the publication of a paper further elucidating the
mechanism of action of its lead drug candidate, PBI-4050, on liver
fibrosis in the Journal of Pharmacology and Experimental
Therapeutics. The paper entitled "PBI-4050 reduces stellate
cell activation and liver fibrosis through modulation of
intracellular ATP levels and LKB1-AMPK-mTOR pathway"
details the antifibrotic signaling pathway modulated by
PBI-4050.
PBI-4050's clinical activity has already been demonstrated in
patients with severe liver fibrosis and liver cirrhosis; in the
ongoing Phase 2 clinical trial in patients with Alström syndrome,
PBI-4050 was shown to significantly reduce liver and cardiac
fibrosis.
The manuscript by Dr. Brigitte
Grouix et al. examines PBI-4050's antifibrotic
activity in liver fibrosis, a major cause of morbidity and
mortality worldwide The antifibrotic and antiproliferative activity
of PBI-4050 on activated hepatic stellate cells (HSCs), which have
a central role in fibrosis in experimental and human diseases, is
mediated through the modulation of intracellular ATP and the
LKB1-AMPK-mTOR-PPAR signaling axis, resulting in regulation of
excessive collagen deposition and remodeling, and decreased liver
fibrosis. It is well documented that AMPK acts as a central
protective molecule against liver fibrosis.
"In studying the mechanism of action of PBI-4050 in liver
diseases, including non-alcoholic steatohepatitis (NASH), we have
clearly demonstrated that PBI-4050 acts through a major signaling
AMPK pathway, thus linking metabolism to fibrosis", said Dr. Lyne
Gagnon, senior author of the paper and Prometic's vice president of
R&D. "Our data show the potential therapeutic effect of
PBI-4050 in liver fibrosis and NASH."
Pierre Laurin, chief executive
officer of Prometic added, "We have seen the benefits of PBI-4050
in reducing liver fibrosis in Alström syndrome patients. With this
further validation that the signaling pathway targeted by PBI-4050
is indeed at the core of the genesis of fibrosis in the liver, we
are very confident about its potential to address fibrosis-related
conditions such as IPF, Alström syndrome, and NASH. We look forward
to initiating our Phase 3 pivotal clinical trial for PBI-4050 in
IPF, and expanding the program in Alström syndrome."
The full publication can be accessed at :
http://jpet.aspetjournals.org/content/early/2018/08/09/jpet.118.250068
About NAFLD-NASH and Liver Fibrosis
Nonalcoholic fatty liver disease (NAFLD) is a condition where
normal liver tissue is replaced by more than 5-6 percent fat. In
NAFLD, the accumulation of fat can cause inflammation, cell death,
and scarring – a condition called non-alcoholic steatohepatitis or
NASH. Left untreated, NASH may progress to liver fibrosis and
ultimately to cirrhosis of the liver and hepatocellular
carcinoma.
About Alström Syndrome
Alström syndrome is a rare inherited autosomal recessive
syndrome characterized by the onset of obesity in childhood or
adolescence, Type 2 diabetes, often with severe insulin resistance,
dyslipidemia, hypertension and severe multi-organ fibrosis
involving the liver, kidney and heart. Alström syndrome is also
characterized by a progressive loss of vision and hearing, a form
of heart disease that weakens the heart muscle (dilated
cardiomyopathy), and short stature. This disorder can also cause
serious or life-threatening medical problems involving the liver,
kidneys, bladder, and lungs. The clinical manifestations of Alström
syndrome vary in severity, and not all affected individuals have
all of the features associated with the disorder.
More about the Fibrotic Process
Fibrosis is characterized by the excessive accumulation of
extracellular matrix (ECM) in damaged or inflamed tissues and is
the common pathological outcome of many inflammatory and metabolic
diseases. Numerous clinical conditions can lead to organ fibrosis
and functional failure; in many disorders, acute or persistent
inflammation is crucial to triggering and maintaining the fibrotic
response. The production of a variety of profibrotic
cytokines and growth factors by innate inflammatory cells results
in the recruitment and activation of ECM-producing myofibroblasts.
There is currently a great need for therapies that could
effectively target the complex pathophysiological pathways involved
in fibrosis. PBI-4050, a synthetic ligand of GPR40 and GPR84, acts
on cells involved in producing fibrosis: macrophages, fibroblasts
and epithelial cells, and has been shown to reduce fibrosis in
animal models of kidney, lung, heart, liver, pancreas and skin
fibrosis. GPR40 and GPR84 are both modulated in these models, but
in different ways. PBI-4050 stimulates GPR-40, and the importance
of this action has been validated in mice with deletion of the
GPR40 gene ("knockout") show increased fibrosis in standard models.
Conversely, PBI-4050 antagonizes the action of GPR-84, and, as
would be expected, GPR84 knockout mice show reduced fibrosis in
standard models.
More About PBI-4050
PBI-4050 is an orally active lead drug candidate with excellent
safety and efficacy profiles demonstrated in a large number of
animal models of fibrosis affecting different organs, including the
lung, liver, heart, kidney, and pancreas. These effects have been
replicated in Phase 2 studies in IPF, in metabolic syndrome with
type 2 diabetes and in Alström syndrome. PBI-4050 is entering
pivotal placebo-controlled phase 3 clinical trials for the
treatment of IPF and has already started placebo-controlled phase 2
trials in patients with metabolic syndrome and type 2 diabetes.
About Prometic Life Sciences Inc.
Prometic (www.prometic.com) is a publicly traded (TSX symbol:
PLI) (OTCQX symbol: PFSCF) biopharmaceutical corporation with two
drug discovery platforms focusing on unmet medical needs. The first
platform (small molecule therapeutics) stems from the discovery of
two receptors which we believe are at the core of how the body
heals: namely, promoting tissue regeneration and scar resolution as
opposed to fibrosis. One of the lead drug candidates emerging from
this platform, PBI-4050, is expected to enter pivotal phase 3
clinical trials for the treatment of Idiopathic Pulmonary Fibrosis
(IPF). The second drug discovery and development platform
(plasma-derived therapeutics) leverages Prometic's experience in
bioseparation technologies used to isolate and purify
biopharmaceuticals from human plasma. The Corporation's primary
goal with respect to this second platform is to address unmet
medical needs with therapeutic proteins not currently commercially
available, such as Ryplazim™ (plasminogen). We are also leveraging
this platform's higher recovery yield potential to advance
established plasma-derived therapeutics such as Intravenous
Immunoglobulin (IVIG). Furthermore, the Corporation is continuing
to secure its plasma supply through the execution of third party
contracts and expansion of its own collection activities for its
plasma processing needs. The Corporation also provides access to
its proprietary bioseparation technologies to enable pharmaceutical
companies in their production of non-competing biopharmaceuticals.
Recognized as a bioseparations expert, the Corporation derives
revenue from this activity through sales of affinity chromatography
media which contributes to offset the costs of its own R&D
investments.
We are headquartered in Laval, Quebec
(Canada) and have R&D facilities in Canada, the United
Kingdom ("UK") and the United
States ("USA"), manufacturing facilities in Canada and the Isle
of Man and corporate and business development activities in
Canada, the USA, and Europe.
Forward Looking Statements
This press release contains forward-looking statements about
Prometic's objectives, strategies and businesses that involve risks
and uncertainties. These statements are "forward-looking" because
they are based on our current expectations about the markets we
operate in and on various estimates and assumptions. Actual events
or results may differ materially from those anticipated in these
forward-looking statements if known or unknown risks affect our
business, or if our estimates or assumptions turn out to be
inaccurate. Such risks and assumptions include, but are not limited
to, Prometic's ability to develop, manufacture, and successfully
commercialize value-added pharmaceutical products, the availability
of funds and resources to pursue R&D projects, the successful
and timely completion of clinical studies, the ability of Prometic
to take advantage of business opportunities in the pharmaceutical
industry, uncertainties related to the regulatory process and
general changes in economic conditions. You will find a more
detailed assessment of the risks that could cause actual events or
results to materially differ from our current expectations in
Prometic's Annual Information Form for the year ended December 31, 2017 under the heading "Risk and
Uncertainties related to Prometic's business". As a result, we
cannot guarantee that any forward-looking statement will
materialize. We assume no obligation to update any forward-looking
statement even if new information becomes available, as a result of
future events or for any other reason, unless required by
applicable securities laws and regulations. All amounts are in
Canadian dollars unless indicated otherwise.
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SOURCE ProMetic Life Sciences Inc.