- PBI-4050 monotherapy and combination with nintedanib demonstrated promising results in the treatment of Idiopathic Pulmonary Fibrosis (IPF)
- Data on PBI-4050 regulation of proteins involved in human lung fibrosis
- Plasminogen administration shown to reduce acute lung injury (ALI) in an acute pancreatitis model
- PBI-4425 shown to reduce pulmonary emphysema in a scleroderma mouse model
LAVAL, Quebec – May 23, 2017 – Prometic Life Sciences Inc. (TSX: PLI) (OTCQX: PFSCF) (“Prometic” or the “Corporation”) presented new data at the 2017 American Thoracic Society (ATS) International Conference in Washington, D.C. The data presented included results from a Phase 2 clinical trial evaluating PBI-4050 in patients with idiopathic pulmonary fibrosis (“IPF”), and the benefits of plasminogen administration in reducing lung injury in a gold standard animal model of ALI/ARDS associated with acute pancreatitis.
PBI-4050 Phase 2 clinical data
During an oral presentation, Joseph Parker, M.D., senior director, clinical development at Prometic, explained that the lung function in 25 IPF patients receiving either PBI-4050 alone or PBI-4050 in combination with nintedanib remained stable as measured by the difference between the Forced Vital Capacity (FVC) at baseline and following 12 weeks of treatment (∆FVC of -12 ml and +2 ml, respectively). This contrasted significantly with the patients who received the PBI-4050 and pirfenidone combination treatment. In these patients, FVC declined significantly (n=15, ∆FVC of -102 ml). An apparent drug-drug interaction between pirfenidone and PBI-4050 resulted in a reduction of the therapeutic effect of each drug. PBI-4050’s absorption was reduced by over 50%, and stimulation of the metabolism of pirfenidone by PBI-4050 may have led to a sub-therapeutic level of pirfenidone. PBI-4050 + nintedanib provided a statistically significant benefit over PBI-4050 + pirfenidone (∆FVC of +2 ml vs. -102 ml respectively, p=0.0376). There was no statistical difference between PBI-4050 + nintedanib and PBI-4050 alone. PBI-4050 alone trended favorably compared to PBI-4050 + pirfenidone (∆FVC of -12 ml vs. -102 ml, p=0.1359).
|Change after 12 weeks of therapy||PBI-4050 Monotherapy
|PBI-4050 + Nintedanib
|PBI-4050 + Pirfenidone
|∆FVC (ml)||-12 ml*||+2 ml**||-102 ml|
*p = 0.1359 vs. PBI-4050 + Pirfenidone; n.s. vs. PBI-4050 + Nintedanib
** p = 0.0376 vs. PBI-4050 + Pirfenidone
“PBI-4050 presented a highly compelling safety and tolerability profile throughout all clinical trials,” said Dr. Parker. “Because PBI-4050 was well-tolerated and appeared to demonstrate a dose response relationship in the Phase 2 study, the planned pivotal Phase 2/3 trial will include three arms – two dose levels of PBI-4050 and placebo.”
Last month, Prometic confirmed the U.S. Food and Drug Administration’s (FDA) concurrence that only the combination of PBI-4050 and nintedanib would be required in the placebo-controlled Phase 2/3 clinical trial. Prometic also intends to initiate a second Phase 2/3 placebo-controlled trial in which IPF patients who failed to tolerate either nintedanib or pirfenidone would be randomized to receive either PBI-4050 or placebo (PBI-4050 Monotherapy). Prometic plans to initiate both studies in the second half of 2017.
PBI-4050 and effect on biomarkers in lung fibrosis
Martin Leduc, Ph.D., scientist at Prometic, presented data on the differentiating effect of PBI-4050 when compared to pirfenidone and nintedanib on biomarkers.
Abnormally activated small airway epithelial cells and interstitial fibroblasts are the principal effector cells in the pathogenesis of lung fibrosis. These cells produce a variety of proteins (biomarkers) involved in activities related to myofibroblast activation, inflammation and extracellular matrix accumulation and remodeling that all contribute to the pulmonary fibrosis process.
Plasminogen as potential treatment for Acute Lung Injury (ALI)
Data were presented by Lyne Gagnon, Ph.D., vice president of research and development at Prometic, on the efficacy of Prometic’s plasminogen in significantly reducing the lesions in the lung in the gold standard mouse model of acute pancreatitis. In this model, the circulating level of plasminogen was reduced, resulting in fibrin and fibrinous material being deposited in the lung. Prometic’s plasminogen treatment restored the plasminogen level in the animals and cleared the lung of fibrin deposits. Pathological lesions in the lungs of non-treated animals were similar to those seen in the lungs of human patients who develop ALI following acute pancreatitis.
PBI-4425, an analogue of PBI-4050, expected to enter clinical trials later this year, was shown to significantly reduce pulmonary emphysema and cutaneous hyperplasia in the tight-skin (TSK) mouse model for scleroderma. TSK animals develop cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The treatment of scleroderma is one of the indications potentially earmarked for PBI-4425.
Posters and oral presentation
- Phase 2, Open label, Single arm, Exploratory, Observational study to evaluate the safety and tolerability of PBI-4050 in patients with Idiopathic Pulmonary Fibrosis (IPF)
- PBI-4050 Reduces Expression of Fibrosis Biomarkers in the BioMAP SAEMyoF Primary Human Small Airway Epithelial Cells and Lung Myofibroblasts System
- Plasminogen Reduces Acute Lung Injury in an Acute Pancreatitis Model
- PBI-4425, a Novel First-in-class Anti-inflammatory/Antifibrotic Compound, Reduces Pulmonary Emphysema and Cutaneous Hyperplasia in Tight-skin (FBN1) Mouse
- PBI-4425, a Novel First-in-class Anti-inflammatory/Anti-fibrotic Compound, Inhibits Collagen I and CTGF Production in Human Fibroblasts, and Reduces Lung Fibrosis in the Bleomycin-Induced Lung Fibrosis Model
- Oral Treatment with PBI-4050 Reduces Acute Lung Injury in an Acute Pancreatitis Model
About acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions resulting in respiratory failure in critically ill patients. ALI is the term used to describe the pulmonary response to a broad range of injuries occurring either directly to the lung or as a consequence of injury or inflammation at other sites of the body, such as acute pancreatitis, severe burns, trauma or sepsis. ARDS represents the most severe subset of this condition. ALI and ARDS affect approximately 190,000 patients every year in the U.S., and are associated with a high mortality rate varying between 30% and 60%.
Prometic has previously disclosed that ALI and ARDS are two examples of acute critical care conditions it intends to pursue with its plasminogen product once it receives regulatory approval for use in congenital plasminogen deficiency, expected later this year.
About PBI-4050 & PBI-4425
PBI-4050 and PBI-4425 are Prometic’s orally active lead drug candidates targeting fibrosis. PBI-4050 is entering Phase 2/3 clinical trials after demonstrating efficacy and excellent safety profiles in three Phase 2 open label clinical trials. Prometic plans to initiate the next phase of clinical trials for PBI-4425 in the first quarter of 2018. Fibrosis is a complex process by which continuing inflammation causes vital organs to lose their function as normal tissue is replaced by fibrotic scar tissue. The proof-of-concept data generated to-date with PBI-4050 confirms its anti-fibrotic activity in several key organs including the kidneys, the heart, the lungs and the liver. PBI-4050 has on-going clinical trials in patients with metabolic syndrome and type 2 diabetes, cystic fibrosis with related diabetes and Alström Syndrome. The planned Phase 2/3 clinical trials scheduled to commence this year target patients with idiopathic pulmonary fibrosis (IPF) and chronic kidney disease (CKD). Twenty-six million patients in the U.S. alone are believed to suffer from CKD. Patients with severe CKD (stages 3 and 4) suffer from a progressive loss of their renal function leading to end-stage renal disease and the need for dialysis or kidney transplant. Cardiovascular complications are the most common cause of death in dialysis patients.
Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. Plasminogen is therefore vital in wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis.
About Prometic Life Sciences Inc.
Prometic Life Sciences Inc. (www.prometic.com) is a long-established biopharmaceutical company with globally recognized expertise in bioseparations, plasma-derived therapeutics and small-molecule drug development. Prometic offers its state-of-the-art technologies for large-scale purification of biologics, drug development, proteomics and the elimination of pathogens to a growing number of industry leaders. The company uses its own affinity technology, which provides for highly efficient extraction and purification of therapeutic proteins from human plasma, to develop best-in-class therapeutics and orphan drugs. Prometic is also active in developing its own novel small-molecule therapeutic products targeting unmet medical needs in the fields of fibrosis, anemia, neutropenia, cancer and autoimmune diseases/inflammation as well as certain nephropathies. Headquartered in Laval, Canada, Prometic has R&D facilities in the U.K., the U.S. and Canada, manufacturing facilities in the U.K. and commercial activities in the U.S., Canada, Europe, Russia, Asia and Australia.
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.