Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial

Allergic airways inflammation in asthma is characterized by an airway epithelial gene signature composed of POSTN,CLCA1, and SERPINB2. This Th2 gene signature is proposed as a tool to classify patients with asthma into Th2‐high and Th2‐low phenotypes. However, many asthmatics smoke and the effects of cigarette smoke exposure on the epithelial Th2 gene signature are largely unknown. Therefore, we investigated the combined effect of IL‐13 and whole cigarette smoke (CS) on the Th2 gene signature and the mucin‐related genes MUC5AC and SPDEF in air–liquid interface differentiated human bronchial (ALI‐PBEC) and tracheal epithelial cells (ALI‐PTEC). Cultures were exposed to IL‐13 for 14 days followed by 5 days of IL‐13 with CS exposure. Alternatively, cultures were exposed once daily to CS for 14 days, followed by 5 days CS with IL‐13. POSTN,SERPINB2, and CLCA1 expression were measured 24 h after the last exposure to CS and IL‐13. In both models POSTN,SERPINB2, and CLCA1 expression were increased by IL‐13. CS markedly affected the IL‐13‐induced Th2 gene signature as indicated by a reduced POSTN,CLCA1, and MUC5AC expression in both models. In contrast, IL‐13‐induced SERPINB2 expression remained unaffected by CS, whereas SPDEF expression was additively increased. Importantly, cessation of CS exposure failed to restore IL‐13‐induced POSTN and CLCA1 expression. We show for the first time that CS differentially affects the IL‐13‐induced gene signature for Th2‐high asthma. These findings provide novel insights into the interaction between Th2 inflammation and cigarette smoke that is important for asthma pathogenesis and biomarker‐guided therapy in asthma.

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“…2013; Brightling et al. 2015). In our exposure models, we noticed a marked decrease in periostin mRNA and protein levels upon CS exposure.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

et al. 2017

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“…Sub-grouping patients based on a serum biomarker and blood eosinophils has already been proven to be useful in asthma, where anti-IL-13 therapy appears to be most effective in the specific subgroup of patients with high serum levels of periostin. 110,111 Similarly, quantifying blood eosinophils in asthmatics has facilitated the identification of those patients that may best respond to IL-5 axis targeting drugs, such as mepolizumab and benralizumab. 93,112 The ability to endotype AD patients may contribute to precision medicine by allowing treatment to be tailored for individual patients.…”

Section: Valorisationmentioning

confidence: 99%

Biomarkers for atopic dermatitis

Thijs

Krastev

Weidinger

et al. 2015

Current Opinion in Allergy &Amp; Clinical Immunology

199

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“…Tralokinumab was tries in moderate-to-severe asthma patients with results in quality of life variation in subjects treated versus placebo [67]. Another randomized, double-blind, phase 2b study showed an acceptable safety profile for tralokinumab but a nonsignificant decline of asthma exacerbations [68].…”

Section: Anti-il-13mentioning

confidence: 99%

Severe Asthma: Moving from Phenotype to Endotype Classification with Updates on Treatment

Noujeim¹,

Bou‐Khalil²

2016

J Nurs Care

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Asthma has classically been categorized into several phenotypes to address the complexities of this disease. However, phenotypes only cover the clinically relevant aspects of the disease, but do not address the relationship between the disease and its etiology and pathophysiology. This led to the development of the term "endotypes" which links key pathogenic mechanisms with asthma phenotypes, and ultimately leads to better selection of treatment resulting in improved response. Although the exact pathogenesis of asthma is still under investigation, targeted-therapy based on asthma phenotypes and endotypes has shown some success, and the future appears promising for patients suffering from severe asthma since treatment is being tailored according to individual biology. We review in this manuscript the best evidence and updates currently available in the classification and treatment recommendations for severe asthma.

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Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial

Cited by 338 publications

References 29 publications

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

Biomarkers for atopic dermatitis

Severe Asthma: Moving from Phenotype to Endotype Classification with Updates on Treatment

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