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Patients with COPD who have higher eosinophil numbers in the airways and peripheral blood demonstrate a greater clinical response to inhaled corticosteroids (ICS) [1–3]. Furthermore, the effect of the oral phosphodiesterase-4 (PDE4) inhibitor roflumilast on exacerbations in severe COPD patients with chronic bronchitis, who are treated with ICS and long-acting bronchodilators, also appears to be greater at higher blood eosinophil counts [4]. The mechanisms responsible for these differential drug effects remain to be defined, but may relate to increased type-2 inflammation and/or decreased presence of colonising airway bacteria in COPD patients with more eosinophils [5, 6], leading to different responses to anti-inflammatory drugs. An association between blood and sputum eosinophils has been observed in some, but not all studies [7–12]. Accurate sputum eosinophil count measurement requires good quality samples to make cytospins where eosinophils can be clearly counted; variable quality of sputum samples, particularly in multicentre studies, will affect the ability to show a relationship with blood eosinophil counts., PDE4 inhibition reduces sputum eosinophils in those COPD patients with higher eosinophil counts. This evidence supports an effect of PDE4 inhibitors on eosinophilic inflammation. https://bit.ly/3airXw7

Background Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Methods Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study. Results CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. Conclusions Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis 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 minimising unwanted systemic class-effects. Trial registration ClinicalTrial.gov, EudraCT, 2015–005550-35. Registered 15 July 2016.

Background: CHF6001 is a selective inhaled PDE4i (NEXThaler®). The aim of this study was to assess the effects of CHF6001 on markers of inflammation in sputum and blood. Methods: In this randomized, double-blind, 3-way crossover study, moderate-to-severe COPD subjects with chronic bronchitis (CB) received CHF6001 1600 or 3200µg daily or placebo for 32 days on top of ICS/LABA/LAMA therapy. CHF6001 concentrations and biomarkers of inflammation were analyzed in sputum supernatant and whole blood, plasma or serum. A post-hoc microarray gene expression analysis in blood and sputum cells was also carried out. Results: 61 patients were randomized. CHF6001 sputum concentrations were ~2000-fold higher than in plasma. In sputum supernatant, both doses significantly (p Conclusion: Both doses of CHF6001 significantly decreased a number of key biomarkers of airway inflammation in COPD patients with CB. Moreover, these effects were essentially localized to the lung with inhaled delivery limiting systemic exposure

Background CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD). Methods This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32. Results Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo. In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide). Conclusion The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy. Trial registration The study is registered on ClinicalTrials.gov (NCT03004417). Electronic supplementary material The online version of this article (10.1186/s12931-019-1142-7) contains supplementary material, which is available to authorized users.