Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial.

Background: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma.

Methods: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses).

Multivariate Cluster Analyses to Characterize Asthma Heterogeneity and Benralizumab Responsiveness.

Background: An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions.

Objectives: Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach.

Methods: In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to analyze 11 clinical characteristics simultaneously.

BAL Fluid Eosinophilia Associates With Chronic Lung Allograft Dysfunction Risk: A Multicenter Study.

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death among lung transplant recipients. Eosinophils, effector cells of type 2 immunity, are implicated in the pathobiology of many lung diseases, and prior studies suggest their presence associates with acute rejection or CLAD after lung transplantation.

Research Question: Does histologic allograft injury or respiratory microbiology correlate with the presence of eosinophils in BAL fluid (BALF)? Does early posttransplant BALF eosinophilia associate with future CLAD development, including after adjustment for other known risk factors?

Study Design And Methods: We analyzed BALF cell count, microbiology, and biopsy data from a multicenter cohort of 531 lung recipients with 2,592 bronchoscopies over the first posttransplant year.

Clinical Implications of Longitudinal Blood Eosinophil Counts in Patients With Severe Asthma.

Background: The stability and variability of blood eosinophil counts (BECs) to phenotype patients with severe asthma is not fully understood.

Objective: This post hoc, longitudinal, pooled analysis of placebo-arm patients from 2 phase 3 studies evaluated the clinical implications of BEC stability and variability in moderate-to-severe asthma.

Methods: This analysis included patients from SIROCCO and CALIMA who received maintenance medium- to high-dosage inhaled corticosteroids plus long-acting β-agonists; 2:1 patients with BECs of 300 cells/μL or higher and less than 300 cells/μL were enrolled.

The commutability of enzyme linked immunosorbent assays for the quantification of serum eosinophil-derived neurotoxin (EDN).

Eosinophil-derived neurotoxin (EDN) is a surrogate biomarker of eosinophil activation and has considerable potential as a precision medicine biomarker in diseases where eosinophils may play a causative role. Clinical data for EDN have been generated using different quantitative immunoassays, but comparisons between these individual data sets are challenging as no internationally recognised EDN standards or orthogonal methods exist. In this study we aimed to compare commercial EDN assays from ALPCO, MBL, LSBio and CUSABIO for sample commutability.

Novel mechanisms of action contributing to benralizumab's potent anti-eosinophilic activity.

Background: Benralizumab is a humanised, anti-interleukin-5 receptor α monoclonal antibody with anti-eosinophilic activity. Lack of fucose (afucosylation) increases its affinity to CD16a and significantly enhances antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells. Although benralizumab proved clinically efficacious in clinical trials for patients with severe asthma and hypereosinophilic syndrome, in-depth characterisation of its anti-eosinophilic mechanisms of action remains elusive.

Eosinophil-derived neurotoxin: A biologically and analytically attractive asthma biomarker.

There is a growing body of evidence for the utility of eosinophil-derived neurotoxin (EDN) as a biomarker in asthma, including association with eosinophilic airway inflammation, assessment of disease severity and potential for predicting pathogenic risks, including exacerbations. However, to interpret any biomarker data with confidence, it is first important to understand the preanalytical factors and biological variation that may affect its reliable measurement and results interpretation. In this study we defined the healthy serum EDN reference range for men and women as 1.

The relationship between airway immunoglobulin activity and eosinophils in COPD.

In chronic obstructive pulmonary disease (COPD), the effects of inhaled corticosteroids are predicted by blood eosinophil counts. We previously briefly reported increased immunoglobulin (Ig)A and IgM levels in bronchoalveolar lavage (BAL) of COPD patients with higher (eosinophil ) compared to lower (eosinophil ) blood eosinophils (>250/μL versus < 150/μL), suggesting differences in adaptive immune function. An inverse relationship exists between eosinophil counts and airway pathogenic bacteria levels.

Eosinophils, basophils and type 2 immune microenvironments in COPD-affected lung tissue.

Although elevated blood or sputum eosinophils are present in many patients with COPD, uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils. Basophils have remained virtually unexplored in COPD. This study mapped tissue-infiltrating eosinophils, basophils and eosinophil-promoting immune mechanisms in COPD-affected lungs.

Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma.

Introduction: For patients with eosinophilic asthma with allergic characteristics, understanding the key drivers of exacerbations is important to identify optimal treatment strategies. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that significantly reduces exacerbation frequency for patients with severe, uncontrolled eosinophilic asthma. We evaluated the predictive value of baseline blood eosinophil counts vs.

Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies.

Background: Benralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab.

Methods: We analysed individual study and pooled results from GALATHEA and TERRANOVA.

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus-predominant subgroup.

Background: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio.

Sputum is reduced in COPD following treatment with benralizumab.

We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens or .

Benralizumab for the Prevention of COPD Exacerbations.

Background: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.

Methods: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment.

Modulation of blood inflammatory markers by benralizumab in patients with eosinophilic airway diseases.

Background: Benralizumab, a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor α, depletes eosinophils and basophils by enhanced antibody-dependent cell-mediated cytotoxicity. It demonstrated efficacy for patients with moderate to severe asthma and, in a Phase IIa trial, for chronic obstructive pulmonary disease (COPD) with eosinophilic inflammation. We investigated effects of benralizumab 100 mg every 8 weeks (first three doses every 4 weeks) subcutaneous on blood inflammatory markers through proteomic and gene-expression analyses collected during two Phase II studies of patients with eosinophilic asthma and eosinophilic COPD.

Periostin and Dipeptidyl Peptidase-4: Potential Biomarkers of Interleukin 13 Pathway Activation in Asthma and Allergy.

Periostin and dipeptidyl peptidase-4 (DPP-4) are proteins induced by type 2 cytokines interleukin (IL)-4 and IL-13 and show increased expression in asthma and diseases with type 2 inflammation, including atopic dermatitis and chronic rhinosinusitis. Both proteins can also be induced by other stimuli, such as profibrotic factors, which may confound their specificity as biomarkers of IL-13 pathway activation and type 2-driven disease. DPP-4 is important in glucose metabolism; therefore, serum concentrations may be confounded by the presence of concomitant metabolic disease.

Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma.

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma.This analysis used pooled data from the SIROCCO (ClinicalTrials.

Seasonal variability of exacerbations of severe, uncontrolled eosinophilic asthma and clinical benefits of benralizumab.

Background: Benralizumab is a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor alpha and induces direct, rapid, and nearly complete depletion of eosinophils via enhanced antibody-dependent cell-mediated cytotoxicity. In the United States, benralizumab is indicated for add-on maintenance treatment of patients ≥12 years old with severe asthma and an eosinophilic phenotype.

Objective: This study evaluated the effect of benralizumab treatment on seasonal asthma exacerbation rates for patients with severe, uncontrolled asthma.

Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles.

Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.

Objective: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations.

Methods: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center.

Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma.

Background: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.

Objective: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations.