Respir Res. 2026 Jul 15. doi: 10.1186/s12931-026-03809-w. Online ahead of print.
ABSTRACT
BACKGROUND: In a phase 2 trial (NCT04308681), treatment with admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 (LPA1) antagonist, reduced lung function decline in patients with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). In this exploratory analysis, we evaluated post-treatment changes in circulating biomarkers of lung fibrosis to elucidate mechanisms of admilparant action.
METHODS: Patients with IPF or PPF were randomized 1:1:1 to receive twice-daily admilparant (30 or 60 mg) or placebo for 26 weeks; background antifibrotics were allowed. The IPF and PPF cohorts were analyzed separately. Changes from baseline (CfB) in serum proteins associated with epithelial injury, inflammation, and fibrosis were measured by quantitative immunoassays at 4, 12, and 26 weeks, and compared between patients who received admilparant versus placebo. Pharmacodynamic biomarker changes were evaluated by clinical response status at week 26. Plasma samples from patients with IPF were assessed post hoc by SomaScan v4.1 proteomics assay. Statistical evaluations used linear mixed-effects models.
RESULTS: In the IPF cohort (n=276), nine serum proteins showed significant CfB (p<0.05) at week 26 in patients treated with 60-mg admilparant versus placebo, including increased adiponectin, MMIF, CD163, CEA, and ENRAGE, and decreased markers of epithelial injury and fibrosis (CA-125/MUC16, MMP-7, TN-C, PRO-FIB). In the PPF cohort (n=116), significant differences at week 26 (p<0.05) were observed for 11 serum proteins, including increased CEA and decreased periostin, IL6Rβ, CD163, KIM-1, multiple inflammatory markers (YKL-40, VCAM-1, PECAM-1, ferritin), and collagen degradation markers (C3M and C4M). Two serum proteins, CA-125 and TN-C, showed significantly greater CfB (p<0.05) in responders compared with non-responders in the IPF cohort. Plasma proteomic analysis identified differential expression (adjusted p<0.1) of adiponectin, CKMT1A, ANGPTL3, PDCD1LG2, and IGFBP6 at week 26 in patients with IPF treated with 60-mg admilparant versus placebo.
CONCLUSIONS: Treatment with 60-mg admilparant improved circulating biomarkers associated with epithelial injury and fibrosis in IPF, and with inflammation, fibrosis, and collagen degradation in PPF. Proteomic analysis identified additional biomarkers associated with mitochondrial and metabolic pathways in IPF. These findings expand our understanding of potential mechanisms of LPA1 antagonism with admilparant and identify biomarkers that may help evaluate treatment response and disease activity.
PMID:42458495 | DOI:10.1186/s12931-026-03809-w
