Consistent lack of efficacy of nintedanib 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 per study) or saline (n=10 per study) and were randomized and stratified to treatment according to body weight and non-invasive whole-body plethysmography measured seven 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-mice indicated upregulated mRNA expression of p-glycoprotein (P-gp), a known nintedanib efflux transporter, suggesting limited lung bioavailability of nintedanib in the model. In comparison, ALK5i significantly improved lung function and exhibited robust anti-fibrotic efficacy in the model. Collectively, these findings challenge the use of nintedanib as a benchmarking drug in the BLEO-IPF model.