Abstract
BackgroundCHF6001 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).MethodsThis 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.ResultsOf 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).ConclusionThe 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 registrationThe study is registered on ClinicalTrials.gov (NCT03004417).
Highlights
CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor
The nature and severity of inflammation in chronic obstructive pulmonary disease (COPD) varies, and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients; a precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success [2]
Other pre-dose assessments on Days 1 and 32 were spirometry, forced oscillometry, and COPD Assessment Test (CAT), with Baseline Dyspnea Index recorded on Day 1 and Transition Dyspnea Index (TDI) on Day 32
Summary
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). The nature and severity of inflammation in COPD varies, and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients; a precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success [2]. Phosphodiesterase-4 (PDE4) is an enzyme that mediates the breakdown of cyclic adenosine monophosphate (cAMP), with PDE4 inhibition having anti-inflammatory effects in a broad range of cell types. The orally administered PDE4 inhibitor roflumilast prevents exacerbations in patients with COPD, is effective only in a specific subgroup: individuals with chronic bronchitis and a history of exacerbations [3,4,5,6]. Systemic exposure after oral administration can cause side effects such as nausea, weight loss and gastrointestinal disturbance, which may limit its use in clinical practice.
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