Idiopathic pulmonary fibrosis is an interstitial lung disease. Idiopathic pulmonary fibrosis commonly results in respiratory failure and death. Unfortunately, Idiopathic pulmonary fibrosis is one of the most aggressive forms of idiopathic interstitial pneumonia. As a result, idiopathic pulmonary fibrosis causes chronic, progressive fibrosis decline in lung function, progressive respiratory failure, and high mortality. Accurate diagnosis is essential to help with prognostication and optimize treatment selection. Idiopathic pulmonary fibrosis causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA1) pathway is implicated in idiopathic pulmonary fibrosis etiology. Particularly, BMS-986020 is a high-affinity LPA1 antagonist.
Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1-6) with pleiotropic activities on multiple cell types. Especially, LPA1 is the most ubiquitous LPA receptor in mammalian tissues, expressed in both osteoblasts and osteoclasts. The LPA1 pathway implicates in the etiology and pathogenesis of idiopathic pulmonary fibrosis. Furthermore, LPA1 is a promising therapeutic target for fibrotic diseases. In particular, BMS-986020 significantly slows lung function decline. In vitro, BMS-986020 inhibits bile acid and phospholipid transporters with IC50s of 4.8 µM, 6.2 µM, and 7.5 µM for BSEP, MRP4, and MDR3, respectively. Moreover, BMS-986020 reduces bile acid and phospholipid efflux, and alter bile composition and flow. Additionally, BMS-986020 altered bile homeostasis in vivo, yielding elevated systemic bile acids in rats.
In conclusion, the hepatobiliary effects observed with BMS 986020 are likely off-target effects specific to BMS-986020. These results suggest that structural variations in BMS-986020 may result in different safety profiles in idiopathic pulmonary fibrosis and other fibrotic diseases.
Palmer SM, et al. Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis. Chest. 2018 Nov;154(5):1061-1069.