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

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.

Single-cell transcriptome dynamics of the autotaxin-lysophosphatidic acid axis during muscle regeneration reveal proliferative effects in mesenchymal fibro-adipogenic progenitors

“…The involvement of the ENPP2-LPA-LPAR axis in inflammation and fibrosis is not new and several studies have shown its crucial participation (Tager et al, 2008;Castelino et al, 2011;Gan et al, 2011;Sakai et al, 2013;Ohashi and Yamamoto, 2015;He et al, 2018;Ninou et al, 2018); however, the mechanisms and cellular targets have been underexplored. Several ongoing studies suggest the ENPP2-LPA-LPAR axis as a prognostic indicator of injury-or radiation-induced fibrosis (NCT05031065), with some studying the safety, tolerance, and effectiveness of orally available ENPP2 inhibitors [BBT-877: NCT03830125; GLPG1690 (ziritaxestat): NCT02738801 and NCT03798366] or LPAR antagonists [BMS-986020: NCT01766817 (Decato et al, 2022); BMS-986278: NCT04308681], as a means of reducing tissue fibrosis and improving organ function in different patients cohorts. Because stromal cells of mesenchymal origin, e.g., FAPs and ASCs, highly express Lpar1, Enpp2, and key Plpp members, upcoming research should focus on better understanding the role of LPA axis in muscle homeostasis, inflammation, fibrosis, repair, and regeneration.…”

Designing Dual Inhibitors of Autotaxin-LPAR GPCR Axis

“…Due to aberrantly high levels of LPA and overexpression of LPAR1 in IPF patients, LPAR1 inhibitor such as BMS-986020 have also been evaluated in clinical trials for the treatment of IPF [ 39 , 40 ]. A 26-week clinical trial demonstrated that treatment of IPF patients with BMS-986020 results in significant improvement in forced vital capacity (NCT01766817) [ 39 , 41 ]. However, hepatobiliary toxicity has also been reported in some patients receiving BMS-986020.…”

Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications

“…In addition, the LPA receptor antagonist BrP-LPA was studied for the treatment of BC, leading to reduced cancer cell migration and tumor regression [ 116 ]. Other ATX inhibitors such as IOA-289 and PF8380, or BMS-986020, a LPAR1 antagonist, were developed and showed promising results in preclinical and clinical trials in other conditions [ 117 , 118 , 119 , 120 ]; however, they have not yet been tested in BC. Given the importance of ATX-LPA signaling, expanding research of these novel molecules in BC could lead to new therapeutic alternatives.…”