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

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 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 Overall design: Sputum cells and whole blood samples were profiled on Affymetrix U133 Plus 2.0 microarrays. Induced sputum was collected for analysis at pre-dose and 2 h post-dose on Days 20 or 26 or 32. Whole blood was collected for analysis at pre-dose on Day 1 and 2 h post-dose on Day 32. In blood, 51, 54 and 55 post-dose samples for placebo, 800 and 1600 µg twice daily, respectively and 45, 48, 45 pre-dose samples for placebo, 800 (mid) and 1600 µg (high) twice daily, respectively, have been used for analysis. In sputum 43, 41 and 41 post-dose samples for placebo, 800 and 1600 µg twice daily, respectively, and 30, 36, 38 pre dose samples for placebo, 800 and 1600 µg twice daily, respectively, have been used for analysis