Researchers uncovered the potential molecular mechanisms underlying BMS-986020-induced hepatobiliary toxicity, as published in Toxicology and Applied Pharmacology. Similar findings were not observed for 2 other lysophosphatidic acid receptor-1 (LPAR1) antagonists, BMS-986234 and BMS-986278, which were both structurally different from BMS-986020.
BMS-986020 was evaluated for idiopathic pulmonary fibrosis (IPF) in a phase 2 study (NCT01766817); however, problems with hepatobiliary toxicity dictated voluntary withdrawal from clinical development.
“The general lack of findings for BMS-986234 and BMS-986278 at projected clinically relevant exposures in multiple in vitro systems indicate that these LPAR1 antagonists are differentiated from BMS-986020 and are not expected to pose the same risk for hepatobiliary toxicity,” the authors said.
The mechanisms underlying BMS-986020-induced hepatobiliary toxicity included:
- Inhibition of plasma bile acids transport, which led to increased levels of plasma bile acids in the liver and hepatotoxicity
- Changes in bile’s biliary phospholipids composition, which led to biliary toxicity
- Direct drug-induced mitochondrial toxicity to hepatocytes and biliary epithelial cell
The retrospective analysis of plasma samples collected from patients with IPF treated with BMS-986020 in the clinical trial revealed dose-related increases in several individual bile acids (eg, glycine and taurine conjugates of cholic acid and chenodeoxycholic acid) when compared to the control group.
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These increases in plasma bile acids were positively correlated with the upregulation of liver function enzymes, such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase.
Moreover, results from in vitro studies indicated that BMS-986020 inhibited bile acid efflux transporters, including the canalicular bile salt export pump (potent inhibitor) and the basolateral transporters multidrug resistance-associated protein 4 (potent inhibitor) and multidrug resistance-associated protein 3 (moderate inhibitor).
It also inhibited the bile acid uptake transporter, sodium taurocholate cotransporting polypeptide (moderate inhibitor), and the conjugated bile acid uptake transporters organic anion transporting polypeptide 1B1 and organic anion transporting polypeptide 1B3 (potent inhibitor).
The putative inhibitory effect of BMS-986020 on biliary clearance was further evaluated by measuring taurocholic acid uptake and canalicular clearance. Results showed that biliary clearance was inhibited ≥68%, as so was taurocholic acid uptake.
Gill MW, Murphy BJ, Cheng PPT, Sivaraman L, Davis M, Lehman-McKeeman L. Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: contrasts with BMS-986234 and BMS-986278. Toxicol Appl Pharmacol. Published online January 26, 2022. doi:10.1016/j.taap.2022.115885
Safety and efficacy of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. ClinicalTrials.gov. January 11, 2013. Updated August 11, 2020. Accessed January 31, 2022.