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RATIONALE Phosphodiesterase-4 inhibitors (PDE4i) have demonstrated increased efficacy in COPD patients with chronic bronchitis or higher blood eosinophil counts. Further characterization of patients 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 (ClinTrial.gov: NCT00292552; Gene-Expression Series: 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 to different PDE4-signaling in the BIOMARKER cohort with Area-Under the Receiver-Operated-Curve of 98%. In the BIOMARKER study, serum interleukin-8 was the only variable consistently associated to PDE4-signaling, with lower levels associated to higher PDE4-activity. In the PIONEER study the exacerbation rate reduction mediated by tanimilast treatment increased up to 2-fold in patients with lower interleukin-8 levels; 36% vs 18%, reaching statistically significance ≤20pg/mL (p=0.035). The combination with blood eosinophils ≥150µL-1 or chronic bronchitis provided further additive exacerbation rate reduction: 45% (p=0.013) and 47% (p=0.027), respectively. CONCLUSIONS This analysis using selected heterogeneous datasets identifies interleukin-8 as an independent predictor of PDE4 inhibition, as tanimilast had a greater effect on exacerbation prevention in COPD patients with lower baseline serum interleukin-8. Testing of this biomarker in other datasets is warranted.