ATS 2018 Perspectives - Episode 9
At the 2018 American Thoracic Society (ATS) International Conference in San Diego, California, Prometic Life Sciences presented new clinical data assessing PBI-4050 on blood biomarkers for treatment of idiopathic pulmonary fibrosis (IPF), concluding that PBI-4050 alone or in combination with nintedanib demonstrated promising efficacy.
The recent analysis revealed that PBI-4050, the lead candidate in a pivotal phase 2/3 clinical trial, significantly increased levels of biomarkers known for antifibrotic effects, suggesting the potential as an antifibrotic, anti-inflammatory and pro-tissue repair mechanism.
“The drug turned out to be very safe, and I think it will offer a nice combination,” Joe Parker, MD, senior director, Prometic Life Sciences, told MD Magazine. “If it proves effective in the larger trial, it’ll be a nice alternative either as monotherapy or in combination with nintedanib to be more effective than current therapy, and maybe with less side effects.”
The main objective of the exploratory study was to determine whether treatment with PBI-4050 alters the level of key biomarkers in 41 enrolled patients. Subjects with a confirmed diagnosis of IPF received daily oral doses of 800 mg PBI-4050 with (n = 9) or without nintedanib (n = 16) or pirfenidone (n = 16) for 12 weeks. Baseline characteristics were similar to those in previous randomized controlled studies.
After 2 weeks, 1 subject on PBI-4050 and pirfenidone withdrew because of an unrelated treatment-emergent adverse effect of IPF exacerbation and is not included in the analysis.
Biomarkers chosen for measurement were divided into 2 main groups: cytokines and matrix metalloproteinases associated with fibrosis and inflammation.
Researchers concluded that PBI-4050 was safe and well tolerated as a monotherapy or in combination with nintedanib and pirfenidone.
The mean change from baseline to week 12 in forced vital capacity (FVC) on PBI-4050 both alone or 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 because of a drug-to-drug interaction.
Researchers observed a significant increase (greater than 10%) for IL-9, IL-7 and MIP-1β, reflecting a change in the balance between a profibrotic and an inflammatory, wound-healing environment.
“This [PBI-4050] would provide an alternative option for patients who are actually intolerant of 1 of the 2 current drugs,” Parker added. “It also would allow for patients on nintedanib, if they are still progressing on their drug, to have another option to improve their rate of declines and they would be better in that regard."
Patients who responded to PBI-4050 treatment were recorded as having significantly higher serum plasminogen levels indicating the importance of plasminogen in IPF.
Daily oral treatment with 800 mg PBI-4050 with or without nintedanib or pirfenidone for 12 weeks demonstrated a strong safety profile in those with IPF. There no deaths, no patients experiencing a decline of 10% of their FVC and no treatment-emergent adverse effects required study drug discontinuation.
The most common treatment adverse effect was diarrhea in all groups, however, it was less significant in patients receiving PBI-4050 alone.
PBI-4050 alone and in combination with nintedanib indicated promising efficacy when compared to those receiving PBI-4050 in combination with pirfenidone.
The effects of the small molecule candidate demonstrated in animal models have been replicated in phase 2 studies in IPF, metabolic syndrome with type 2 diabetes and Alström syndrome, and is currently involved in pivotal placebo-controlled phase 3 clinical trials for treatment of IPF.