Mirco Govoni1, Michele Bassi2, Stefano Vezzoli2, Germano Lucci2, Aida Emirova2, Marie Anna Nandeuil2, Stefano Petruzzelli2, Gera L Jellema3, Ebenezer K Afolabi3, Brendan Colgan4, Brian Leaker5, Oliver Kornmann6, Kai Michael Beeh7, Henrik Watz8, Dave Singh9. 1. Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi, Parma, Italy. M.Govoni@chiesi.com. 2. Global Clinical Development, Personalised Medicine and Biomarkers, Chiesi, Parma, Italy. 3. Almac Diagnostics, Craigavon, UK. 4. Celerion, Belfast, UK. 5. The Heart Lung Centre, London, UK. 6. IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany. 7. Insaf Respiratory Research Institute, Wiesbaden, Germany. 8. Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. 9. Medicines Evaluation Unit, The University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK.
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.
RCT Entities:
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.
Authors: Espen E Groth; Melanie Weber; Thomas Bahmer; Frauke Pedersen; Anne Kirsten; Daniela Börnigen; Klaus F Rabe; Henrik Watz; Ole Ammerpohl; Torsten Goldmann Journal: Respir Res Date: 2020-10-19
Authors: Dave Singh; Henrik Watz; Kai Michael Beeh; Oliver Kornmann; Brian Leaker; Brendan Colgan; Germano Lucci; Aida Emirova; Marie Anna Nandeuil; Debora Santoro; Deborah Balzano; Mirco Govoni Journal: Eur Respir J Date: 2020-08-06 Impact factor: 16.671
Authors: Dave Singh; Michele Bassi; Deborah Balzano; Germano Lucci; Aida Emirova; Marie Anna Nandeuil; Gera Jellema; Ebenezer K Afolabi; Brian Leaker; Oliver Kornmann; Kai Michael Beeh; Henrik Watz; Mirco Govoni Journal: J Cell Mol Med Date: 2020-12-09 Impact factor: 5.295