LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis

Benjamin E Decato, Diana Julie Leeming, Jannie Marie Bülow Sand, Aryeh Fischer, Shuyan Du, Scott M Palmer, Morten Karsdal, Yi Luo, Anne Minnich, Benjamin E Decato, Diana Julie Leeming, Jannie Marie Bülow Sand, Aryeh Fischer, Shuyan Du, Scott M Palmer, Morten Karsdal, Yi Luo, Anne Minnich

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model.

Methods: Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020.

Results: In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis.

Conclusions: BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://ichgcp.net/clinical-trials-registry/NCT01766817 .

Keywords: Biomarkers; Collagen; Extracellular matrix; Fibrosis; Idiopathic pulmonary fibrosis; LPA1 antagonist; Scar-in-a-Jar.

Conflict of interest statement

A Fischer, S Du, and Y Luo are employees of Bristol Myers Squibb and may own company stock and/or stock options. BE Decato was an employee of Bristol Myers Squibb at the time of the study. A Minnich is a consultant for Bristol Myers Squibb. SM Palmer served as Principal Investigator of the coordinating center of the previous BMS clinical trial (NCT01766817), and Duke University received research grant support to conduct that study. He has also received consulting fees from Altavant, Bristol Myers Squibb, Incyte Corporation, and Theravance Biopharma, Inc., and research grant support from Boehringer Ingleheim and Incyte Corporation. JMB Sand, DJ Leeming, and M Karsdal are employees of Nordic Bioscience and may hold company stock and/or stock options. M Karsdal and DJ Leeming are among the original inventors and patent holders for assays for PRO-C3 and C3M.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Diagram of Scar-in-a-Jar experimental system. Modified from Rønnow, SR, et al. Respir Res. 2020;21(1):108. Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). LDH lactate dehydrogenase; LPA lysophosphatidic acid; Sups supernatants; TGF-β1 transforming growth factor-beta 1
Fig. 2
Fig. 2
Lung fibrosis (as measured by QLF) correlations with FVC. Scatterplots and linear regression line predicting baseline (A) and CFB (B) whole lung percent fibrosis from baseline and CFB FVC, respectively. CFB change from baseline; ECM extracellular matrix; FVC forced vital capacity; QLF quantitative lung fibrosis
Fig. 3
Fig. 3
Heatmaps (A, B) and scatterplots and linear regression of ECM-neoepitope biomarker levels and pulmonary measures (C–E). A Heatmap of pairwise Spearman correlation of baseline ECM-neoepitope biomarker levels with baseline FVC and fibrosis measurements. B Heatmap of pairwise Spearman correlation of Week 26 ECM-neoepitope biomarker CFB with FVC and fibrosis CFB. Scatterplots and linear regression of baseline PRO-C4 and C6M levels by baseline whole lung QLF (C, D) and Week 26 CFB in C3M by Week 26 CFB in FVC, colored by treatment arm (E). *P < 0.05. CFB change from baseline; BID twice daily; FVC forced vital capacity; QD once daily; QLF quantitative lung fibrosis. ECM-neoepitope biomarker abbreviations are defined in Table 1
Fig. 4
Fig. 4
ECM-neoepitope biomarker CFB measurements in patients with IPF from the phase 2 trial NCT01766817. Patient numbers for each ECM-neoepitope biomarker stratified by treatment group and time point are indicated. BID twice daily; BL baseline; CFB change from baseline; ECM extracellular matrix; IPF idiopathic pulmonary fibrosis; QD once daily; SEM standard error of the mean; WK week. ECM-neoepitope biomarker abbreviations are defined in Table 1
Fig. 5
Fig. 5
Effects of BMS-986020 on LPA- or TGF-β1–stimulated fibrogenesis in the Scar-in-a-Jar in vitro model. Shown are ECM-neoepitope biomarkers over time for untreated, vehicle-, and BMS-986020–treated fibroblasts. Similar results were obtained in a prior experiment. ECM extracellular matrix; LPA lysophosphatidic acid; SEM standard error of the mean; Stim stimulation; TGF-β1 transforming growth factor-beta 1. ECM-neoepitope biomarker abbreviations are defined in Table 1

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