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

doi:10.1186/s12931-022-01980-4

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

Respir Res. 2022 Mar 18;23(1):61. doi: 10.1186/s12931-022-01980-4.

Authors

Benjamin E Decato¹, Diana Julie Leeming², Jannie Marie Bülow Sand², Aryeh Fischer¹, Shuyan Du¹, Scott M Palmer³, Morten Karsdal², Yi Luo¹, Anne Minnich⁴

Affiliations

¹ Research & Early Development, Bristol Myers Squibb, 3401 Princeton Pike, Princeton, NJ, 08648, USA.
² Nordic Bioscience, Herlev Hovedgade 205-207, 2730 Herlev, Denmark.
³ Duke University Medical Center, 2085 Msrb2 2 Genome Ct., Durham, NC, 27710, USA.
⁴ Research & Early Development, Bristol Myers Squibb, 3401 Princeton Pike, Princeton, NJ, 08648, USA. anne.minnich@bms.com.

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://clinicaltrials.gov/ct2/show/NCT01766817 .

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

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers / blood
Collagen / drug effects*
Collagen / metabolism
Epitopes / blood
Female
Humans
Idiopathic Pulmonary Fibrosis / drug therapy*
Idiopathic Pulmonary Fibrosis / pathology
In Vitro Techniques
Male
Middle Aged
Models, Biological
Receptors, Lysophosphatidic Acid / antagonists & inhibitors*
Respiratory System Agents / administration & dosage*
Vital Capacity / drug effects

Substances

Biomarkers
Epitopes
Receptors, Lysophosphatidic Acid
Respiratory System Agents
Collagen

Associated data

ClinicalTrials.gov/NCT01766817