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

Respiratory Research. 2020;21(1):1-11 DOI 10.1186/s12931-020-1329-y

 

Journal Homepage

Journal Title: Respiratory Research

ISSN: 1465-9921 (Print); 1465-993X (Online)

Publisher: BMC

LCC Subject Category: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the respiratory system

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Mirco Govoni (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Michele Bassi (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Stefano Vezzoli (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Germano Lucci (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Aida Emirova (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Marie Anna Nandeuil (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Stefano Petruzzelli (Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi)

Gera L. Jellema (Almac Diagnostics)

Ebenezer K. Afolabi (Almac Diagnostics)

Brendan Colgan (Celerion)

Brian Leaker (The Heart Lung Centre)

Oliver Kornmann (IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases)

Kai Michael Beeh (Insaf Respiratory Research Institute)

Henrik Watz (Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL))

Dave Singh (Medicines Evaluation Unit, The University of Manchester, Manchester University NHS Foundation Trust)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 17 weeks

 

Abstract | Full Text

Abstract 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.