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

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 probesets 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 matrixmetalloproteinases 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-12beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrixmetalloproteinases-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 classeffects.

Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

“…This allows CHF6001 to reach a therapeutic concentration in the target organ, the lung, with reduced systemic exposure, limiting systemic adverse effects. Indeed, CHF6001 inhaled twice daily (BID) has previously demonstrated lung-targeted anti-inflammatory effects in patients with COPD and a chronic bronchitis phenotype [ 10 , 11 ].…”

COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum

“…10 In a biomarker RCT conducted in COPD patients with chronic bronchitis receiving triple therapy (ICS/ long-acting β 2 agonist therapy (LABA) / long-acting muscarinic antagonist (LAMA)), tanimilast showed clear anti-inflammatory effects by modulating a range of airway biomarkers and inflammation pathways after 32 days of treatment. 8,11 Moreover, the ability of tanimilast to reduce sputum eosinophil counts was increased in patients with higher eosinophils levels in sputum (≥3%). 12 These data are compatible with previous RCT results with roflumilast showing inhibition of sputum eosinophil counts accompanied by a reduction in bronchial mucosal eosinophil numbers.…”

COPD sputum eosinophils: relationship to blood eosinophils and the effect of inhaled PDE4 inhibition

“…CHF6001 is an inhaled PDE4 inhibitor which showed anti-inflammatory effects in the airways after 32 days of treatment in COPD patients with chronic bronchitis on top of triple therapy [ 13 ]. In sputum, CHF6001 reduced the levels of certain cytokines and down-regulated inflammatory genes associated with eosinophil activation [ 14 ]. Previous studies with roflumilast showed inhibition of the total number of inflammatory cells in sputum, and inhibition of sputum eosinophil counts accompanied by a reduction in bronchial mucosal eosinophil numbers [ 8 , 15 ].…”