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Evaluation of the Effect of PBI-4050 Alone or in Combination with Pirfenidone or Nintedanib on Blood Biomarkers Linked to the Fibrotic Process in IPF Patients
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A2439 - Evaluation of the Effect of PBI-4050 Alone or in Combination with Pirfenidone or Nintedanib on Blood Biomarkers Linked to the Fibrotic Process in IPF Patients
Author Block: L. Gagnon1, B. Grouix1, A. Laverdure1, L. Foulkes1, R. Sawtell1, A. Hagerimana1, P. Laurin1, M. R. Kolb2, J. Moran1, J. Parker1; 1Prometic Biosciences Inc., Laval, QC, Canada, 2McMaster University, Hamilton, ON, Canada.
Introduction: PBI-4050 is a lead candidate in pivotal phase 2/3 clinical trial for IPF. PBI-4050’s anti-fibrotic activity has been observed in various fibrosis models in different organs: lung, kidney, heart, liver, and pancreas. PBI-4050 has been shown to improve forced vital capacity (FVC) in an open-label phase 2 study in idiopathic pulmonary fibrosis (IPF). The main objective of this exploratory study was to determine whether treatment with PBI-4050 alters the level of key biomarkers in patients with IPF.
Methods: Subjects with a confirmed diagnosis of IPF received daily oral doses of 800 mg PBI-4050 with or without nintedanib or pirfenidone for 12 weeks. The biomarkers chosen for measurement can be divided into two main groups: cytokines and matrix metalloproteinases associated with fibrosis and inflammation.
Results: PBI-4050 was safe and well tolerated as a monotherapy or combined with nintedanib and pirfenidone. The mean change from baseline to week 12 in FVC in patients on PBI-4050 alone or PBI-4050 in combination with nintedanib was stable, -12 ml and +2 ml respectively, while it decreased significantly by -104.7 ml for PBI-4050 in combination with pirfenidone, due to a drug-drug interaction with pirfenidone. Bioanalysis of biomarkers showed no effect on MMPs. Significant increase (greater than 10%) for IL-9, IL-7 and MIP-1β was observed. Furthermore, three additional cytokines, IL-1Ra, IL-13 and G-CSF, showed interesting trends from baseline to week 12 where the change in concentration was over 10% increase and nearly statistically significant. A subgroup analysis demonstrated no change in mean CCL18 level with PBI-4050 alone but a trend towards an increase in the PBI-4050 in combination with pirfenidone (+7%, p=0.08), the group with sub-therapeutic dose of PBI-4050 and the poorer overall clinical response over the 12-week study. However, in the PBI-4050 combination with nintedanib group, the level of CCL18 decreased by 10% (p=0.03) over the 12 weeks, suggesting a potential mechanism by which PBI-4050 and the combination of PBI-4050 and nintedanib may further reduce fibrosis and improve prognosis for IPF patients.
Conclusions: PBI-4050 alone or in combination with nintedanib demonstrated promising efficacy. The results from the exploratory biomarkers analysis suggest the potential of PBI-4050 as an anti-fibrotic, anti-inflammatory and pro-tissue repair mechanism.
Author Block: L. Gagnon1, B. Grouix1, A. Laverdure1, L. Foulkes1, R. Sawtell1, A. Hagerimana1, P. Laurin1, M. R. Kolb2, J. Moran1, J. Parker1; 1Prometic Biosciences Inc., Laval, QC, Canada, 2McMaster University, Hamilton, ON, Canada.
Introduction: PBI-4050 is a lead candidate in pivotal phase 2/3 clinical trial for IPF. PBI-4050’s anti-fibrotic activity has been observed in various fibrosis models in different organs: lung, kidney, heart, liver, and pancreas. PBI-4050 has been shown to improve forced vital capacity (FVC) in an open-label phase 2 study in idiopathic pulmonary fibrosis (IPF). The main objective of this exploratory study was to determine whether treatment with PBI-4050 alters the level of key biomarkers in patients with IPF.
Methods: Subjects with a confirmed diagnosis of IPF received daily oral doses of 800 mg PBI-4050 with or without nintedanib or pirfenidone for 12 weeks. The biomarkers chosen for measurement can be divided into two main groups: cytokines and matrix metalloproteinases associated with fibrosis and inflammation.
Results: PBI-4050 was safe and well tolerated as a monotherapy or combined with nintedanib and pirfenidone. The mean change from baseline to week 12 in FVC in patients on PBI-4050 alone or PBI-4050 in combination with nintedanib was stable, -12 ml and +2 ml respectively, while it decreased significantly by -104.7 ml for PBI-4050 in combination with pirfenidone, due to a drug-drug interaction with pirfenidone. Bioanalysis of biomarkers showed no effect on MMPs. Significant increase (greater than 10%) for IL-9, IL-7 and MIP-1β was observed. Furthermore, three additional cytokines, IL-1Ra, IL-13 and G-CSF, showed interesting trends from baseline to week 12 where the change in concentration was over 10% increase and nearly statistically significant. A subgroup analysis demonstrated no change in mean CCL18 level with PBI-4050 alone but a trend towards an increase in the PBI-4050 in combination with pirfenidone (+7%, p=0.08), the group with sub-therapeutic dose of PBI-4050 and the poorer overall clinical response over the 12-week study. However, in the PBI-4050 combination with nintedanib group, the level of CCL18 decreased by 10% (p=0.03) over the 12 weeks, suggesting a potential mechanism by which PBI-4050 and the combination of PBI-4050 and nintedanib may further reduce fibrosis and improve prognosis for IPF patients.
Conclusions: PBI-4050 alone or in combination with nintedanib demonstrated promising efficacy. The results from the exploratory biomarkers analysis suggest the potential of PBI-4050 as an anti-fibrotic, anti-inflammatory and pro-tissue repair mechanism.
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