Lysophosphatidic acid receptor 1 (LPAR1) antagonist BMS-986020 reduced serum extracellular matrix (ECM)-neoepitope biomarkers, elucidating a novel antifibrotic mechanism for the treatment of idiopathic pulmonary fibrosis (IPF), a new study published in Respiratory Research found.

In vitro, lysophosphatidic acid (LPA) is known to promote fibrogenesis, which is dependent on LPAR1 and inhibited by BMS-986020, a first-generation orally bioavailable LPAR1 antagonist. Decato et al conducted in vivo and in vitro analyses measuring serum ECM-neoepitope biomarkers in 140 patients with IPF to enhance the understanding of the impact of LPAR1 antagonism with BMS-986020 on ECM remodeling and lung function.

The effects of BMS-986020 on 9 ECM-neoepitope serum biomarkers were assessed in a post hoc analysis of a phase 2 trial (NCT01766817), and the direct effects of BMS-986020 on fibrogenesis were further evaluated in an in vitro scar-in-a-jar system.


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“ECM-neoepitope biomarker levels increased over the 6-month study duration in placebo-treated patients, reflecting disease worsening, but BMS-986020 treatment for 6 months decreased C1M, C3A, C3M, C4M2, C6M, PRO-C4, and VICM biomarker levels relative to baseline and placebo,” the authors wrote.

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LPA promotes normal wound healing and collagen deposition but, at increased levels, is also implicated in IPF pathogenesis. Pirfenidone and nintedanib are 2 known antifibrotic treatments for IPF that can slow forced vital capacity but are associated with tolerability considerations. For this reason, the blockade of LPAR1 shows promise in current clinical trials for its antifibrotic properties, particularly in lung fibrosis. A current phase 2 clinical trial using BMS-986020 demonstrated proof-of-mechanism in patients with IPF.

IPF is a progressive, debilitating lung disease characterized by epithelial damage and changes to the ECM composition, resulting in fibroblast activation and migration into the interstitium, collagen accumulation, and stiffening of the lung tissues. Consequently, this leads to lung fibrosis and fatal outcomes, with a life expectancy of 3 to 5 years after diagnosis.

Assessing ECM turnover using neoepitope biomarkers provides information about the balance between fibrogenesis and fibrinolysis in fibrotic conditions like IPF. Neoepitope biomarkers work by measuring new epitopes generated by protein formation or degradation.

References

Decato BE, Leeming DJ, Sand JMB, et al. LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis. Respir Res. 2022;23(1):61. doi:10.1186/s12931-022-01980-4

Safety and efficacy of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. ClinicalTrials.gov. January 11, 2013. Updated August 11, 2020. Accessed March 28, 2022.