Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease with limited effective treatment options. The LPA1 pathway has been implicated in the etiology and pathogenesis of IPF and is a promising therapeutic target for fibrotic diseases. LPA1 antagonists, including BMS‑986020 and BMS-986234, are being investigated for IPF. Differences in structure and pharmacology of LPA1 antagonists could impact their efficacy and safety profile. In a Phase 2 trial, BMS-986020 compared with placebo significantly slowed lung function decline but, in some patients, showed hepatobiliary effects; the mechanisms underlying these effects were investigated in vitro and in vivo. In vitro, BMS-986020 inhibits bile acid and phospholipid transporters, BSEP (IC50=4.8 µM), MRP4 (6.2 µM), and MDR3 (7.5 µM), which may reduce bile acid and phospholipid efflux, and alter bile composition and flow. BMS-986020 altered bile homeostasis in vivo, yielding elevated systemic bile acids in rats and humans. In contrast, a structurally distinct LPA1 antagonist BMS-986234, at projected clinically relevant concentrations, did not inhibit BSEP (IC50=19.6 µM), MRP4 (>50 µM), or MDR3 (>50 µM) in vitro, or inhibit bile acid efflux in human hepatocytes (≤50 µM). Additionally, BMS-986234 did not increase bile acids in rats or monkeys. In conclusion, the hepatobiliary effects observed with BMS‑986020 are likely off-target effects specific to this molecule and not mediated via antagonism of LPA1. These results suggest that structural variations in LPA1 antagonists may result in different safety profiles in patients with IPF and other fibrotic diseases.
- Copyright ©the authors 2017
