Effects of nintedanib on circulating biomarkers of idiopathic pulmonary fibrosis

Abstract

Background Biomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial. Methods Subjects with IPF were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures. Results 346 subjects were treated (116 randomised to nintedanib, 230 to placebo). Surfactant protein D (SP-D) and cancer antigen 125 (CA-125), markers of epithelial injury, decreased in subjects treated with nintedanib versus placebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94, 95% CI 0.89–0.99; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75, 95% CI 0.71–0.81; p<0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in forced vital capacity over 12 weeks was attributable to the change in CA-125. A small increase in C3A (collagen 3 degraded by ADAMTS-1/4/8) and a small decrease in C3M (collagen 3 degraded by matrix metalloproteinase-9), markers of extracellular matrix turnover, were observed in subjects treated with nintedanib versus placebo. Conclusions Effects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.