Am J Respir Crit Care Med. 2023 May 16. doi: 10.1164/rccm.202301-0071OC. Online ahead of print.
ABSTRACT
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.
PMID:37192443 | DOI:10.1164/rccm.202301-0071OC
