Abstract
Rationale: Phosphodiesterase-4 (PDE4) inhibitors have demonstrated increased efficacy in patients with chronic obstructive pulmonary disease who had chronic bronchitis or higher blood eosinophil counts. Further characterization of patients who are most likely to benefit is warranted. Objective: To identify determinants of response to the PDE4 inhibitor tanimilast. Methods: A PDE4 gene expression signature in blood was developed by unsupervised clustering of the ECLIPSE study dataset (ClinicalTrials.gov ID: NCT00292552; Gene Expression Omnibus Series ID: GSE76705). The signature was further evaluated using blood and sputum transcriptome data from the BIOMARKER study (NCT03004417; GSE133513), enabling validation of the association between PDE4 signaling and target biomarkers. Predictivity of the associated biomarkers against clinical response was then tested in the phase-2b PIONEER tanimilast study (NCT02986321). Measurements and Main Results: The PDE4 gene expression signature developed in the ECLIPSE dataset classified subgroups of patients associated with different PDE4 signaling in the BIOMARKER cohort with an area under the receiver operator curve of 98%. In the BIOMARKER study, serum IL-8 was the only variable that was consistently associated with PDE4 signaling, with lower levels associated with higher PDE4 activity. In the PIONEER study, the exacerbation rate reduction mediated by tanimilast treatment increased up to twofold in patients with lower IL-8 levels; 36% versus 18%, reaching statistical significance at ⩽20 pg/ml (P = 0.035). The combination with blood eosinophils ⩾150 μl(-1) or chronic bronchitis provided further additive exacerbation rate reduction: 45% (P = 0.013) and 47% (P = 0.027), respectively. Conclusions: Using selected heterogeneous datasets, this analysis identifies IL-8 as an independent predictor of PDE4 inhibition, as tanimilast had a greater effect on exacerbation prevention in patients with chronic obstructive pulmonary disease who had lower baseline serum IL-8 levels. Testing of this biomarker in other datasets is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT00292552 [Gene Expression Omnibus Series ID: GSE76705], NCT03004417 [GSE133513], and NCT02986321).