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Sputum and blood transcriptomics characterization of the PDE4 inhibitor CHF6001 in COPD

ABSTRACT: The aim of the present study was to characterize the gene expression profile of the phosphodiesterase-4 inhibitor CHF6001 on top of inhaled triple therapy in sputum cells and whole blood of chronic bronchitis patients. Samples for analyses were collected from a multicenter, three-period, three-way, placebo-controlled, double-blind, complete block crossover study. Eligible patients underwent three, 32-day treatment periods during which they received CHF6001 800 or 1600 µg twice daily (total daily doses of 1600 or 3200 µg) or matching placebo, all via multi-dose dry-powder inhaler (NEXThaler). Treatment periods were separated by a 28–42 day washout. Eligible patients were male or female, ≥40 years of age, current or ex-smokers with a smoking history ≥10 pack-years, a diagnosis of COPD, post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥30% and <70% predicted, ratio of FEV1 to forced vital capacity (FVC) <0.70, COPD Assessment Test score ≥10, and a history of chronic bronchitis (defined as chronic cough and sputum production for more than three months per year for at least two years) and treated with inhaled triple ICS/LABA/LAMA therapy for at least two months prior to enrollment. CHF6001 had no effect in blood, but a strong effect in sputum with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-value adjusted for False Discovery Rate<0.05) for 800 and 1600µg , respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (>87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumor necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. In conclusion inhaled PDE4-Inhibition by CHF6001 on top of triple therapy in patients with chronic bronchitis patients significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimizing unwanted systemic class-effects

ORGANISM(S): Homo sapiens

PROVIDER: GSE133513 | GEO | 2020/03/30

REPOSITORIES: GEO

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Sputum and blood transcriptomics characterization of the PDE4 inhibitor CHF6001 in COPD

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