Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial

O'Byrne, Paul M.; Metev, Hristo; Puu, Margareta; Richter, Kai; Keen, Christina; Uddin, Mohib; Larsson, Bengt; Cullberg, Marie; Nair, Parameswaran

doi:10.1016/s2213-2600(16)30227-2

Cited by 213 publications

(146 citation statements)

References 29 publications

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“…Omalizumab, a monoclonal anti-Immunoglobulin E antibody, may be beneficial for some allergic asthmatics uncontrolled on therapy [38]. Mepolizumab and Reslizumab, both monoclonal anti-IL5 antibodies, reduce asthma exacerbations in those with severe eosinophilic asthma [39, 40], Different treatments, particularly for those with both-type 2 and non-Th2 inflammatory asthma, are under active development [41–43]. …”

Section: Introductionmentioning

confidence: 99%

Asthma heterogeneity and severity

Carr

Bleecker

2016

World Allergy Organization Journal

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Asthma is a common, chronic inflammatory airways disease characterized by a clinical syndrome of bronchial hyperresponsiveness, inflammation, and reversible airflow obstruction. Individuals with asthma can vary widely in clinical presentation, severity, and pathobiology. The incident factors, pathogenesis, prognosis, and treatment of asthma remain incompletely understood. Utilizing measurable characteristics of asthmatic patients, including demographic, physiologic, and biologic markers, can however identify meaningful phenotypic categories in asthma. Identification of these phenotypes may help improve precision therapeutics targeted toward an individual’s’ disease, and may identify strategies for preventing progression of disease severity.

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Section: Introductionmentioning

confidence: 99%

Asthma heterogeneity and severity

Carr

Bleecker

2016

World Allergy Organization Journal

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“…Although clinical data highlight the presence of neutrophils in severe, poorly controlled asthma, the presence does not naturally equate to causality. Consequently, the CXCR2 antagonist AZD5069 also proved ineffective in reducing the frequency of severe exacerbations or improving asthma symptoms or lung function when tested in a phase 2b trial in patients with uncontrolled, severe asthma 145. Manipulation of neutrophilic inflammation in a clinical setting has done little to support the notion that they may underlie the observed pathophysiology and represent a viable therapeutic target in asthma.…”

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confidence: 99%

The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?

Snelgrove

Patel

et al. 2018

Clin Experimental Allergy

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Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.

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“…A randomized, placebo-controlled clinical trial of the CXCR2 antagonist SCH527123 administered for 4 weeks to patients with severe asthma and sputum neutrophils > 40% resulted in a reduction of 36.3% in sputum neutrophil percentage, fewer mild exacerbations and a trend towards improvement in ACQ score [Nair et al 2012]. A clinical trial of the efficacy and safety of a CXCR2 antagonist AZD5069 in severe, uncontrolled persistent asthma reported that the addition of AZD5069 to combination ICS/long acting β 2 -agonist (LABA) treatment did not improve clinical outcomes despite a dose-dependent reduction in blood neutrophil counts [O'Byrne et al 2015]. A lack of improvement in clinical outcome despite a reduction in sputum neutrophil counts was reported with the CXCR2 antagonist AZD5069 in bronchiectasis [De Soyza et al 2015].…”

Section: Cxcr2 Antagonist Cxcr2mentioning

confidence: 99%