LPA1 antagonists BMS-986020 and BMS-986234 for idiopathic pulmonary fibrosis: Preclinical evaluation of hepatobiliary homeostasis

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.