Circulating biomarkers and progression of idiopathic pulmonary fibrosis: data from the INMARK trial.

Background: We used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF).
Methods: Subjects with IPF and forced vital capacity (FVC) ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models.
Results: Of 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM (C-reactive protein (CRP) degraded by matrix metalloproteinase (MMP)-1/8), C3M (collagen 3 degraded by MMP-9), CRP, KL-6 (Krebs von den Lungen-6) and SP-D (surfactant protein D) were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2-64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0-64.5% of the test set were correctly classified.
Conclusions: Among subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.
Competing Interests: Conflict of interest: T.M. Maher reports consulting fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Roche/Genentech, Theravance and Veracyte; and payment for presentations from Boehringer Ingelheim and Roche/Genentech. R.G. Jenkins has received grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Pliant and RedX; consulting fees from Bristol Myers Squibb, Daewoong Pliant, RedX, Resolution Therapeutics and Veracyte; payment for presentations from AstraZeneca, Chiesi, patientMpower and Roche; has served on a data safety monitoring or advisory board for Boehringer Ingelheim, Galapagos and Vicore; and has a leadership role with Action for Pulmonary Fibrosis and NuMedii. V. Cottin reports grants from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CSL Behring, Ferrer, GlaxoSmithKline, Pliant, PureTech, RedX, Roche, Sanofi and Shionogi; payment for presentations and support for attending meetings from Boehringer Ingelheim, Ferrer and Roche; and has served on a data safety monitoring or advisory board for Celgene/Bristol Myers Squibb, FibroGen, Galapagos, Galecto and Roche. Y. Nishioka reports grants and payment for presentations from Boehringer Ingelheim. I. Noth reports grants from Veracyte; royalties from UpToDate; consulting fees from Boehringer Ingelheim, Genentech and Sanofi; patents for a gene signature predictor of FVC and for PCSK6 (pending); and has served on a data safety monitoring board for Yale University. M. Selman was a member of an adjudication committee for Celgene. C. Ittrich, C. Diefenbach, S. Stowasser and E.S. White are employees of Boehringer Ingelheim. The remaining authors have nothing to disclose.
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