- 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 :
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.
SOURCE ProMetic Life Sciences Inc.
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