Development of a Multi-biomarker Prognostic Risk Score for Idiopathic Pulmonary Fibrosis (IPF) Based on Serum Proteins

Background: The Prognostic Lung Fibrosis Consortium (PROLIFIC) was formed to develop well-qualified assays suitable for use as prognostic biomarkers within the context of clinical trials for Idiopathic Pulmonary Fibrosis (IPF).

Methods: Luminex-based assays were developed under design control for 12 peripheral blood IPF biomarkers and qualified using pre-specified acceptance criteria. Biomarkers representing epithelial damage (CYFRA 21-1, SP-D, CA-125, CA-19-9, KL-6), fibrosis (MMP-7, TNC, POSTN), inflammation (CCL18, CXCL13, sICAM-1, and thrombosis (PAI-1) were measured in IPF patient baseline serum from the derivation cohort (Pulmonary Fibrosis Foundation Patient Registry, N=657) and the validation cohort (ISABELA studies, N=229). Single and multi-marker statistical analyses were performed for transplant free survival and FVC decline at one year, adjusting for sex, age, BMI, anti-fibrotic medication, smoking pack-years, % predicted FVC, and % predicted DLCO. Penalized logistic regression was used to select prognostic biomarkers using the LASSO method, and the resulting model was used to derive a multi-marker risk score.

Findings: FVC decline was significantly associated with baseline MMP-7, SP-D, KL-6, PAI-1, CA-19-9, CYFRA 21-1, CXCL13, and sICAM-1. Transplant-free survival was significantly associated with baseline SP- D, sICAM-1, TNC, and KL-6. A multi-marker prognostic model or PROLIFIC Prognostic Risk Score (PRS) for the composite outcome of death, lung transplant, or ≥10% relative FVC decline at 1 year was associated with baseline SP-D, CXCL13, TNC, and MMP-7 (derivation AUC=0.796, sensitivity=0.752, specificity=0.699; validation AUC=0.825, sensitivity=0.764, specificity=0.715).

Interpretation: The PROLIFIC PRS confirms the important serum proteins consistent with findings from previous analyses and yielded a subject-level prognostic risk score for transplant-free survival and FVC decline in IPF. The PROLIFIC consortium has submitted a Letter of Intent to the FDA Center for Drug Evaluation and Research to qualify the PROLIFIC PRS as a drug development tool under the Biomarker Qualification Program. The qualified biomarkers may be used as stratification or eligibility criteria in clinical trials and have the potential to provide valuable information that may reduce uncertainty in decisions made during drug development.