Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

Abstract

Increased tumour necrosis factor-a levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma.In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n5132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted. Secondary end-points included morning peak expiratory flow, FEV1 % pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire.No significant differences were observed between ETN and placebo for any of the efficacy endpoints. ETN treatment was well tolerated, with no unexpected safety findings observed during the study.Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

“…The resulting cells were incubated with biotinylated antibodies against the lineage markers CD31, CD34, and CD45, and an AutoMACS column was used to deplete nonepithelial cells. AECs were then subjected to flow cytometry-based sorting as (21,22), but others not (23,52). It seems likely that this is because blockade of TNF is efficacious in only a subgroup of patients, which is consistent with our current finding that TNF is required in some, but not all, models of asthma.…”

Novel approaches to the management of noneosinophilic asthma

“…Neutralizing TNFα restores corticosteroid sensitivity in a mouse model of neutrophilic airway inflammation [Dejager et al 2015]. Several small clinical studies in severe asthma of the soluble TNF-α receptor blocker etanercept reported beneficial effects on clinical outcomes [Howarth et al 2005;Berry et al 2006], whereas larger studies with etanercept [Holgate et al 2011] and the TNF-α receptor blocker golimumab [Wenzel et al 2009] did not confirm a consistent beneficial clinical effect. When combined with concerns over increased risk of severe infections and malignancies with TNF-α receptor blocker treatment [Wenzel et al 2009] it is unlikely that this target will be developed further for the treatment of asthma.…”

Asthma phenotyping, therapy, and prevention: what can we learn from systems biology?

“…However, recent studies targeting tumor necrosis factor-α in human subjects have failed to show improved clinical end points (61).…”