Nintedanib Lacks Efficacy in a Spirometry‐Confirmed and Bleomycin‐Induced Mouse Model of Idiopathic Pulmonary Fibrosis

Nintedanib, a multitargeted tyrosine kinase inhibitor, is approved for idiopathic pulmonary fibrosis (IPF) for its ability to slow lung function decline. This study systematically evaluated the effects of nintedanib across three independent treatment intervention studies in the single-dose bleomycin (BLEO) mouse model of IPF. In each study, male C57BL/6J mice received a single intratracheal instillation of BLEO (n = 15-18) or saline (n = 10). Animals were randomised and stratified by body weight, and treatment assignment was assessed using noninvasive whole-body plethysmography 6 days after BLEO administration. BLEO-IPF mice were administered (PO, BID) vehicle, nintedanib (50 or 60 mg/kg), or an activin receptor-like kinase 5 inhibitor (ALK5i, SB525334, 60 mg/kg) for up to 21 days. In all studies, nintedanib consistently failed to improve lung health, as evaluated by lung function tests, biochemistry, histology and RNA sequencing. Plasma concentrations of nintedanib showed no correlation to any efficacy endpoint applied. Lung transcriptome signatures in nintedanib-treated BLEO-IPF mice indicated upregulated mRNA expression of p-glycoprotein, a known nintedanib efflux transporter, suggesting limited lung exposure of nintedanib in the model. In comparison, ALK5i significantly improved lung function and exhibited robust antifibrotic efficacy. Collectively, these findings challenge the use of nintedanib as a benchmarking drug in the single-dose BLEO-IPF mouse model.