PROMETIC ANNOUNCES PUBLICATION OF PBI-4050’s NOVEL ANTIFIBROTIC MECHANISM OF ACTION IN AMERICAN JOURNAL OF PATHOLOGY
- 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, QUEBEC, CANADA, – February 16, 2018 – 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: prometiclifesciencesinc.cmail20.com
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.'
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