Emerging biological therapies for treating chronic obstructive pulmonary disease: A pairwise and network meta-analysis

Abstract

Inflammation in chronic obstructive pulmonary disease (COPD) is often corticosteroid resistant and, thus, alternative anti-inflammatory approaches are needed. Since it is still not clear whether blocking specific pro-inflammatory factors may provide clinical benefit in COPD, we have performed a meta-analysis to quantify the impact of monoclonal antibodies (mABs) targeting the cytokine/chemokine-mediated inflammation in COPD.

A pairwise and network meta-analyses were performed by extracting data from randomized clicnial trials on COPD concerning the impact of mABs vs. placebo on the risk of exacerbation, forced expiratory volume in 1 s (FEV₁), and St. George's Respiratory Questionnaire (SGRQ).

Data on the interleukin (IL)-1β antagonist canakinumab, IL-1R1 antagonist MEDI8986, IL-5 antagonist mepolizumab, IL-5R antagonist benralizumab, IL-8 antagonist ABX-IL8, and TNF-α antagonist infliximab were found. Overall, mAB therapy had a moderate impact on the risk exacerbation, but not on FEV₁ and SGRQ. The pairwise meta-analysis performed in eosinophilic patients, and the network approach, indicated that mepolizumab elicited a beneficial effect against the risk of exacerbation, whereas benralizumab was more effective in improving both FEV₁ and SGRQ.

This study demonstrates that targeting the pathway activated by IL-5 may have a beneficial impact in eosinophilic COPD patients.

Introduction

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder in which the persistent respiratory symptoms and airflow limitation are due to a complex chronic inflammation that predominantly affects peripheral airways and lung parenchyma [1,2].

The inflammatory response to noxious particle and/or gases is prevalently orchestrated by the activation of inflammatory cells such as alveolar macrophages, neutrophils, T lymphocytes, and innate lymphoid cells recruited from the circulation. Furthermore, in some COPD patients there may also be increases in eosinophils. These inflammatory and structural cells, including epithelial and endothelial cells and fibroblasts, secrete several cytokines and chemokines [3]. These mediators have a relevant role in the pathogenesis and progression of COPD, since they recruit inflammatory cells from the circulation into the lungs, maintain inflammation, and lead to characteristic structural changes in the airways [2,3].

Relevant advances have been achieved for the identification of multiple cytokines and chemokines involved in chronic inflammatory disorders, but the effort to characterize a specific inflammatory profile in patients with COPD produced conflicting results [3]. In fact, some studies suggested that COPD is mainly characterized by a T-helper (Th)-1 and T-cytotoxic (Tc)-1 subtype (Th1/Tc1) pattern, whereas further researches found a predominant Th2/Tc2 phenotype [2]. Therefore, the cluster of cytokines and chemokines that orchestrate inflammation in COPD may involve tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13 IL-17, IL-18, IL-23, IL-33, and thymic stromal lymphopoietin (TSLP), and growth factors such as transforming growth factor (TGF)-β [2].

Little progress has been made in understanding the role of these factors in COPD, and how the multiple cytokine and chemokine network operate [3]. Nevertheless, the inhibition of these mediators, and the pathways that they activate, may represent a potential strategy to modulate the inflammatory processes that sustains the progression of COPD [4]. Moreover, since inflammation in COPD is largely corticosteroid resistant, alternative anti-inflammatory approaches are strongly needed [5,6]. Unfortunately, the currently available alternative anti-inflammatory strategies approved for the treatment of COPD are often limited by several transient mild-to-moderate adverse events, that may reduce the compliance to treatment [1,7]. As a consequence, to date there is a huge unmet medical need with regard to effective and well tolerated anti-inflammatory agents for treating patients with COPD [8].

Blocking cytokine and chemokines, their synthesis, antagonizing their receptors and targeting intracellular signalling pathways by using monoclonal antibodies (mABs) is a biological therapeutic approach that has been successful in the treatment of chronic inflammatory diseases, namely severe asthma, rheumatoid arthritis, and inflammatory bowel disease [6].

Indeed, mABs have advantages over small molecules, such as the high affinity and specificity for their targets, and the metabolic stability that allows them to be active for long time and have a long duration of action (from weeks to months). Furthermore, since their breakdown products are amino acids, they are not converted into toxic metabolites [9,10]. Consequently, several biological inhibitors of inflammatory mediators have been developed for targeting the cytokine/chemokine-mediated inflammation in COPD [2].

To date, it is still not clear whether blocking specific cytokines and chemokines may provide clinical benefit in COPD patients [3]. Therefore, we have performed a pairwise meta-analysis aimed to quantify the overall impact of mABs tested in randomized clinical trials (RCTs) with regard to functional and clinical outcomes of COPD. Furthermore, we have also carried out a network approach to compare and rank the effectiveness of specific mABs on the risk of COPD exacerbation, lung function, and health-related quality of life in eosinophilic COPD pateints.