- New, previously undescribed pathway critical to fibrosis
development with two receptors acting as "dual master
switches"
- Studies in knockout mice demonstrate that GPR40 is
protective and GPR84 is deleterious in fibrotic diseases
- PBI-4050's anti-fibrotic mechanism of action demonstrated to
occur via simultaneous stimulation of GPR40 and inhibition of
GPR84
LAVAL, QC, Feb. 16, 2018 /PRNewswire/ - Prometic
Life Sciences Inc. (TSX: PLI) (OTCQX: PFSCF)
("Prometic") today announced the publication in the
American Journal of Pathology, the official journal of the
American Society of Investigational Pathology, of the novel
antifibrotic mechanism of action of its small molecule lead drug
candidate, PBI-4050. The paper entitled "A Newly Discovered
Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40
and GPR84" documents the discovery of an antifibrotic pathway
involving these two receptors. PBI-4050 is now entering pivotal
phase 3 clinical trials in patients with idiopathic pulmonary
fibrosis ("IPF") following the confirmation of the trial design in
a recent clinical development Type C meeting with the US Food and
Drug Administration (FDA).
The manuscript of Dr. Lyne Gagnon et al. examines
PBI-4050's ligand affinity in vitro and in vivo for
the fatty acid receptors, GPR40 and GPR84. GPR40 and GPR84 are
known to be involved in diverse physiological processes related to
metabolic regulation and to inflammation, but the fundamental
importance of these receptors in the fibrosis pathways had not been
recognized until now. In this study, the authors uncovered a novel
antifibrotic pathway involving these receptors, showing that GPR40
is protective and GPR84 is deleterious in fibrotic diseases.
Importantly, this study also shows that PBI-4050 acts as an agonist
of GPR40 and an antagonist of GPR84. Through its binding to these
receptors, PBI-4050 significantly attenuated fibrosis in many
injury contexts, as evidenced by the global antifibrotic activity
observed in the kidney, liver, heart, lung, pancreas, or skin. This
paper explains the unique and novel mechanism of action of
PBI-4050, a first-in-class compound, in fibrosis-related
diseases.
"In studying the mechanism of action of PBI-4050, we have
clearly demonstrated the contribution of two fatty acid receptors,
GPR40 and GPR84, in the regulation of cells involved in fibrosis,
including macrophages, epithelial cells and fibroblasts," said Dr.
Lyne Gagnon, primary author of the paper and Prometic's
Vice-President of R&D Pre-clinical. "Our data show that GPR40
and GPR84 modulate fibrotic disease progression. Therefore, by
targeting this novel antifibrotic pathway, PBI-4050 and its
analogues have the potential to delay or even reverse the
progression of fibrotic diseases."
Pierre Laurin, Chief Executive
Officer of Prometic added, "We have seen the benefits of PBI-4050
in the treatment of fibrotic diseases. Now, having an understanding
of the unique mechanism of action of PBI-4050, we are more
confident than ever in its potential to help patients suffering
from fibrosis-related conditions such as IPF and Alström Syndrome.
We look forward to initiating our Phase 3 pivotal clinical trial
for PBI-4050 in IPF, expanding the program in Alström Syndrome and
to advancing follow-on analogues of PBI-4050 in clinical programs
targeting other large fibrosis-related unmet medical needs."
The full publication can be accessed at:
http://ajp.amjpathol.org/article/S0002-9440(17)30804-0/fulltext
About Idiopathic Pulmonary Fibrosis (IPF) and Acute
Exacerbation
Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating,
and ultimately fatal disease characterized by a progressive decline
in lung function. It is a specific type of interstitial lung
disease in which the small air sacs of the lung, the "alveoli,"
gradually become replaced by fibrotic (scar) tissue and is the
cause of worsening dyspnea (shortness of breath). IPF is usually
associated with a poor prognosis. The term "idiopathic" is used
because the cause of pulmonary fibrosis is still unknown. IPF
usually occurs in adult individuals of between 50 and 70 years of
age, particularly those with a history of cigarette smoking, and
affects men more often than women. IPF affects approximately
130,000 people in the United
States, with about 48,000 new cases diagnosed annually.
Nearly 40,000 people with IPF die each year, a mortality rate
similar to breast cancer. The 5-year mortality rate for patients
with IPF is estimated to range from 50% to 70%. Acute exacerbation
of IPF (AE-IPF) is defined as a sudden acceleration of the disease
or an idiopathic acute injury superimposed on diseased lung tissue
that leads to a significant decline in lung function. An AE-IPF is
associated with a mortality rate as high as 85%, with mean survival
periods between 3 to 13 days.
More about 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 trigger the fibrotic response. The
production of various 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 pathophysiological
pathways involved in fibrosis. PBI-4050, a synthetic ligand of
GPR40 and GPR84, acts on cells involved in the fibrotic pathway:
macrophages, fibroblasts and epithelial cells. Moreover, PBI-4050
reduces fibrosis in animal models of kidney, lung, heart, liver,
pancreas and skin fibrosis. GPR40 and GPR84 are both modulated in
models of fibrotic diseases and mice with a deletion in GPR40 have
increased renal interstitial fibrosis in response to ischemia,
unilateral ureteral obstruction (UUO), and adenine-induced
nephropathy models, while GPR84 knockout mice have reduced kidney
fibrosis in a model of adenine-induced nephropathy.
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. The effects of PBI-4050
demonstrated in animal models 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 metabolic syndrome and
type 2 diabetes patients.
About Prometic Life Sciences Inc.
Prometic Life Sciences Inc. (www.prometic.com) is a
biopharmaceutical corporation with two drug discovery platforms
focusing on unmet medical needs in the field of fibrosis and orphan
diseases. The first platform, small molecule therapeutics, stems
from the discovery of two receptors GPR40/GPR84 acting as "dual
master switches" which are at the core of the healing process as
opposed to fibrosis. The second platform, plasma-derived
therapeutics, leverages Prometic's vast experience in bioseparation
technologies to address unmet medical needs with therapeutic
proteins not currently commercially available, such as Ryplazim™
(plasminogen human). Prometic is also leveraging the second
platform higher recovery yield advantage to develop some more
established plasma-derived therapeutics with significant growth in
demand such as Intravenous Immunoglobulin (IVIG) and provides
access to its proprietary bioseparation technologies to enable
pharmaceutical companies in their production of non-competing
biopharmaceuticals. Globally 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. Headquartered in Laval (Canada), Prometic has R&D facilities
in the UK, the U.S. and Canada, manufacturing facilities in the UK
and commercial activities in the U.S., Canada, Europe and Asia.
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, 2016, 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.
SOURCE ProMetic Life Sciences Inc.