Research & Early Development, Bristol Myers Squibb, 3401 Princeton Pike, Princeton, NJ, 08648, USA.
Nordic Bioscience, Herlev Hovedgade 205-207, 2730 Herlev, Denmark.
Respir Res. 2022 Mar 18;23(1):61. doi: 10.1186/s12931-022-01980-4.
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 (LPA) 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 LPA 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.
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.
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 LPA-induced fibrogenesis.
BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .
特发性肺纤维化（IPF）是一种使人虚弱的肺部疾病，其治疗选择有限。一项 2 期临床试验（NCT01766817）表明，与安慰剂相比，每日两次给予 BMS-986020（溶血磷脂酸受体 1（LPA）拮抗剂）治疗可使 IPF 患者的用力肺活量（FVC）斜率在 26 周内显著降低。本分析旨在通过 2 期研究的事后分析以及体外纤维化模型，更好地了解 LPA 拮抗作用对细胞外基质（ECM）-新表位生物标志物和肺功能的影响。
在 IPF 患者中测量了 9 种 ECM-新表位生物标志物的血清水平。使用线性混合模型评估了生物标志物与基线和基线 FVC 变化的相关性，以及与高分辨率计算机断层扫描测量的定量肺纤维化的相关性，以及与治疗臂之间的差异。使用 Scar-in-a-Jar 体外纤维化模型进一步阐明 BMS-986020 的抗纤维化机制。
在 140 名 IPF 患者中，基线 ECM-新表位生物标志物水平不能预测 FVC 进展，但与基线 FVC 和肺纤维化测量值显著相关。与安慰剂相比，BMS-986020 治疗后大多数血清 ECM-新表位生物标志物水平显著降低，并且一些降低与 FVC 和/或肺纤维化改善相关。在 Scar-in-a-Jar 体外模型中，BMS-986020 可有效抑制 LPA 诱导的纤维化。
BMS-986020 降低了先前与 IPF 预后相关的血清 ECM-新表位生物标志物。体外，LPA 促进纤维化，该纤维化依赖于 LPA 并被 BMS-986020 抑制。这些数据共同阐明了药理学 LPA 阻断的新型抗纤维化作用机制。试验注册临床Trials.gov 标识符：NCT01766817；首次发布：2013 年 1 月 11 日；https://clinicaltrials.gov/ct2/show/NCT01766817。
