Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278

Michael W Gill; Brian J Murphy; Peter T W Cheng; Lakshmi Sivaraman; Myrtle Davis; Lois Lehman-McKeeman

doi:10.1016/j.taap.2022.115885

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. 2022 Mar 1:438:115885. doi: 10.1016/j.taap.2022.115885. Epub 2022 Jan 26.

Authors

Michael W Gill¹, Brian J Murphy², Peter T W Cheng³, Lakshmi Sivaraman⁴, Myrtle Davis⁵, Lois Lehman-McKeeman⁶

Affiliations

¹ Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, USA. Electronic address: [email protected].
² Discovery Biology, Bristol Myers Squibb, Princeton, NJ, USA.
³ Discovery Chemistry, Bristol Myers Squibb, Princeton, NJ, USA.
⁴ Nonclinical Safety, Bristol Myers Squibb, New Brunswick, NJ, USA.
⁵ Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, USA.
⁶ Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, USA.

PMID: 35090952
DOI: 10.1016/j.taap.2022.115885

Abstract

In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA₁) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA₁ antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC₅₀ 1.8 μM), MRP3 (IC₅₀ 22 μM), and MRP4 (IC₅₀ 6.2 μM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 μM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 μM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC₅₀ 7.5 μM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC₅₀ ≥20 μM) and did not inhibit MDR3 activity (IC₅₀ >100 μM), nor did BMS-986234 inhibit BA efflux (≤50 μM) or mitochondrial function (≤30 μM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA₁ antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA₁ antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.

Keywords: Bile acids; Hepatobiliary toxicity; LPAR1; Lysophosphatidic acid receptor-1 antagonists; Mitochondrial function; Phospholipids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / metabolism
Bile Acids and Salts / metabolism
Biological Transport / physiology
Cell Line
Cell Line, Tumor
Chemical and Drug Induced Liver Injury / metabolism*
Digestive System Diseases / chemically induced*
Electron Transport / physiology
HEK293 Cells
Hep G2 Cells
Hepatocytes / drug effects
Humans
Idiopathic Pulmonary Fibrosis / drug therapy*
Liver / drug effects*
Mitochondria / drug effects
Receptors, Lysophosphatidic Acid / antagonists & inhibitors*

Substances

ATP Binding Cassette Transporter, Subfamily B
Bile Acids and Salts
Receptors, Lysophosphatidic Acid
multidrug resistance protein 3