Objectives Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of signalling pathways involved in embryonic development, including the Hedgehog (Hh) pathway. Hh can promote multiple profibrotic processes including myofibroblast differentiation, expression of extracellular matrix genes, migration, and survival. Vismodegib is a small-molecule inhibitor of the Hedgehog (Hh) signalling pathway approved for the treatment of basal cell carcinoma. We sought to evaluate the activity of Hh signalling in IPF lung tissue and identify blood biomarkers of Hh pathway activity in IPF patients.

Methods Gene expression in biopsies from IPF and control unused donor lungs, and in fibroblasts stimulated with Shh in vitro. CXCL14 protein was measured in plasma from IPF patients and from solid tumour patients treated with vismodegib in a phase 1b clinical trial (NCT00968981).

Results We observed significantly increased expression levels of Hh pathway genes including SMO, PTCH2, GLI1, and GLI2 in IPF vs control lungs. To identify candidate systemic biomarkers of Hh pathway activity, we compared transcriptional data from IPF lung biopsies and fibroblasts stimulated in vitro with Shh. The gene most significantly upregulated in both datasets was CXCL14, which encodes a soluble secreted chemokine whose expression is inhibited in vitro by the addition of vismodegib. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In solid tumour patients, circulating CXCL14 levels were significantly reduced upon treatment with vismodegib.

Conclusions We observed strong evidence for Hedgehog pathway activity in IPF lungs. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of vismodegib in IPF. The ISLAND trial is a phase 2 randomised, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of vismodegib in IPF patients. ISLAND will enrol 129 patients with IPF, randomised 2:1 to vismodegib or placebo for 60 weeks. The primary efficacy objective is to evaluate the effect of vismodegib on mean change in forced vital capacity (FVC). Secondary outcome measures include IPF and/or Hh-associated biomarkers, progression-free survival, and change in quantitative lung fibrosis on HRCT. Enrollment is expected to start in October 2014.