Abstract
BackgroundCardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis.ObjectivesThis study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l).MethodsThis was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD).ResultsWe screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups.ConclusionsIn this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.
Highlights
Chronic Obstructive Pulmonary Disease (COPD) is a complex condition, which is associated with extra-pulmonary manifestations, such as systemic inflammation and cardiovascular disease, that increase patient morbidity and mortality [1]
This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation
The treatment effect of losmapimod compared to placebo was not significant, at -0Á05 for to-blood ratio (TBR), p = 0Á42, and +0Á40% for flow-mediated dilatation (FMD), p = 0Á70
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a complex condition, which is associated with extra-pulmonary manifestations, such as systemic inflammation and cardiovascular disease, that increase patient morbidity and mortality [1]. P38 mitogen-activated protein kinases (MAPK) are signalling molecules that regulate cellular responses to extra-cellular stresses [2]. They regulate pro-inflammatory cytokines, and have a key role in the initiation and development of inflammatory diseases, including COPD and atherosclerosis [2] [3]. Losmapimod (GW856553 Brentford UK), a selective p38α/β MAPK inhibitor has been evaluated as an anti-inflammatory therapy in different patient populations including COPD and cardiovascular disease. P38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis
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