Journal Article

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis

Kornmann, Oliver, Watz, Henrik, Emirova, Aida, Leaker, Brian, Afolabi, Ebenezer K., Lucci, Germano, Bassi, Michele, Govoni, Mirco, Colgan, Brendan, Jellema, Gera L., Petruzzelli, Stefano, Nandeuil, Marie Anna, Beeh, Kai Michael, Vezzoli, Stefano, Singh, Dave

2020

Overview

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 < 0.05) with 800 and 1600 μg BID, 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, 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.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Activity recognition / Administration, Inhalation / Aged / Anti-Inflammatory Agents - administration & dosage / Biomarkers / Biomarkers - blood / Biomarkers - metabolism / Blood / Bronchitis / Bronchitis, Chronic - drug therapy / Bronchitis, Chronic - metabolism / Care and treatment / Chronic obstructive lung disease / Chronic obstructive pulmonary disease / Clinical medicine / Cross-Over Studies / Cytokines / Development and progression / DNA microarrays / Female / Gene expression / Genetic aspects / Genomes / Health aspects / Humans / Inflammation / Inflammation Mediators / Inhibitors / Interleukin 12 / Interleukins / Lungs / Macrophage inflammatory protein / Macrophage inflammatory protein 1 / Male / Matrix metalloproteinase / Matrix metalloproteinases / Medicine / Medicine & Public Health / Oxidative stress / para-Aminobenzoates / Pattern recognition / Phosphodiesterase / Phosphodiesterase 4 inhibitors / Phosphodiesterase 4 Inhibitors - administration & dosage / Phosphodiesterase 4 Inhibitors - therapeutic use / Phosphodiesterases / Pneumology/Respiratory System / Proteins / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - metabolism / Quality control / Sputum / Sputum - cytology / Sputum - metabolism / Sulfonamides / Therapy / Transcriptome / Tumor necrosis factor / Tumors / Vitamin D