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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. serum immunoglobulin E (IgE) concentrations on exacerbation risk and the association of these variables with benralizumab treatment effect. Methods Analyses were performed with data pooled from the phase III SIROCCO and CALIMA benralizumab trials. Crude annual asthma exacerbation rates (AERs) were determined for placebo as a function of baseline blood eosinophil counts and serum IgE concentrations with prespecified blood eosinophil count categories (, Plain Language Summary Many patients with severe asthma have elevated numbers of eosinophils (a subset of white blood cells) and raised serum concentrations of immunoglobulin E (IgE; antibodies). Elevated eosinophil counts together with IgE concentrations are associated with more frequent asthma attacks. Benralizumab is a drug that almost completely depletes eosinophils and significantly reduces asthma attacks for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. The individual influence of eosinophils and IgE on benralizumab efficacy has been published. In this study, we further extend the analyses to evaluate the interrelationship of eosinophil counts and IgE concentrations with asthma attack frequency and benralizumab efficacy for patients with severe, uncontrolled asthma. We evaluated the association of blood eosinophil counts and IgE concentrations with asthma attack frequency for patients with severe asthma who received high-dosage inhaled corticosteroids plus additional controller medications but did not receive benralizumab in the benralizumab clinical trials. We observed that increased blood eosinophil counts were associated with greater asthma attack frequency, while serum IgE concentrations had no influence on asthma attack frequency. We also evaluated patients who received benralizumab and determined that benralizumab can reduce the occurrence of these attacks for patients with elevated blood eosinophil counts regardless of their serum IgE concentrations. Frequency of asthma attacks also decreased with benralizumab for patients with elevated serum IgE concentrations, but serum IgE concentrations did not influence benralizumab efficacy. Benralizumab is an efficacious treatment for patients with uncontrolled eosinophilic asthma, regardless of their IgE concentrations. Electronic Supplementary Material The online version of this article (10.1007/s12325-019-01191-2) contains supplementary material, which is available to authorized users.

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. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum γP:F ratio. Methods Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate‐to‐severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters. Results Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n = 20), high γP:F ratio, increased H influenzae, low diversity measures and increased pro‐inflammatory mediators when compared to the larger Haemophilus‐low cluster (n = 121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the γP:F ratio consistently differentiated between clusters. Conclusion Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The γP:F ratio was able to distinguish the Haemophilus‐high versus Haemophilus‐low subgroups, whether the Haemophilus‐high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation., Sputum microbiomic cluster analysis and TDA demonstrates 2 subgroups of stable severe asthma and moderate‐to‐severe COPD differentiated according to dominance of Haemophilus. The Haemophilus‐high group had no defining clinical characteristics but had lower microbial diversity and increased levels of sputum TNFα and IL1β. γProteobacteria:Firmicutes (γP:F) differentiated the clusters and was the most predictive biomarker of the Haemophilus‐high group.

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 Streptococcus pneumoniae were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens S. pneumoniae or Haemophilus influenzae. Thus, benralizumab may have an indirect effect upon airway bacterial load.

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. Methods Serum samples for proteomic analysis and whole blood for gene expression analysis were collected at baseline and 52 weeks (asthma study) or 32 weeks (COPD study) post-treatment. Proteomic analyses were conducted on a custom set of 90 and 147 Rules-Based Medicine analytes for asthma and COPD, respectively. Gene expression was profiled by Affymetrix Human Genome U133 plus 2 arrays (~ 54 K probes). Gene set variation analysis (GSVA) was used to determine transcriptomic activity of immune signatures. Treatment-related differences between analytes, genes, and gene signatures were analyzed for the overall population and for patient subgroups stratified by baseline blood eosinophil count (eosinophil-high [≥300 cells/μL] and eosinophil-low [

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 high) compared to lower (eosinophil low) blood eosinophils (>250/μL versus high (n = 20) and eosinophil low (n = 21) patients. Bronchial B-cell numbers were measured by immunohistochemistry. B-cell activity was assessed in bronchial samples and following exposure to BAL from eosinophil high and eosinophil low patients. BAL levels of non-typeable Haemophilus influenza (NTHi)-specific immunoglobulins were quantified. Results showed airway expression of IgA, IgG1 and IgM were lower in eosinophil low compared to eosinophil high patients, with lower levels of NTHi-specific IgA and IgM. Bronchial B-cell numbers were similar in both groups, but B-cell activity was lower in eosinophil low patients. In conclusion, COPD eosinophil low patients show differences in adaptive immune function compared to COPD eosinophil high patients. These differences may cause different microbiomes in these COPD phenotypes.

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 1.98 to 26.10 ng/mL, with no significant gender differences. Smoking did not impact the mean EDN levels and no circadian rhythm was identified for EDN, unlike blood eosinophils (EOS) where levels peaked at 00:00h. EDN expression in different cell types was investigated and shown to occur primarily in eosinophils, indicating they are likely to be the main cellular repository for EDN. We also confirm that the quantification of serum EDN is not influenced by the type of storage tube used, and it is stable at ambient temperature or when refrigerated for at least 7 days and for up to one year when frozen at -20°C or -80°C. In summary, EDN is a stable biomarker that may prove useful in precision medicine approaches by enabling the identification of a subpopulation of asthma patients with activated eosinophils and a more severe form of the disease.

Background: Integrated analyses of Phase III trials are important in characterizing patients (pts) who have the greatest long-term benefits with benralizumab. Aims and Objectives: To examine relationship of exacerbation (EX) frequency during 2 years of benralizumab treatment with baseline (BL) characteristics and efficacy. Methods: We performed post-hoc subgroup integrated analysis of 48-week SIROCCO (Bleecker, Lancet 2016) and 56-week CALIMA (FitzGerald, Lancet 2016) with 56-week BORA extension study (Busse, Lancet Respir Med 2019). Pts receiving benralizumab 30 mg SC every 8 weeks who had BL blood eosinophil counts ≥300 cells/μL were assessed. Pts were evaluated based on EXs experienced during the 2-year analysis period (0, 1, ≥2). Results: BL pre-bronchodilator [BD] FEV1 (%), pre-BD FEV1/FVC, and prior requirement for mechanical ventilation were significantly different for pts with 0–≥2 EXs, with additional significant differences for pts with 0 vs. 2 EXs (table). Greater improvements in ACQ-6 and AQLQ(S)+12 scores were observed for pts with 0 vs. 1/≥2 EXs, while lesser improvement in FEV1 and ACQ-6 and AQLQ(S)+12 scores was observed for the ≥2 EX group vs. the other groups by 16 weeks and was sustained for 2 years. Conclusions: Pts who remained EX-free during 2 years of benralizumab treatment were older at asthma onset, had better lung function, smaller ICU asthma admission rate and BMI, and less gastroesophageal reflux.

SummaryBackgroundBenralizumab 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.MethodsWe analysed individual study and pooled results from GALATHEA and TERRANOVA. At study enrolment, patients from GALATHEA and TERRANOVA were aged 40–85 years, had moderate to very severe airflow limitation, had elevated blood eosinophil counts, and at least two exacerbations or one severe exacerbation in the previous year despite dual inhaled therapy (inhaled corticosteroids plus long-acting β2-agonists or long-acting β2-agonists plus long-acting muscarinic antagonists) or triple inhaled therapy (inhaled corticosteroids plus long-acting β2-agonists plus long-acting muscarinic antagonists). We analysed data for 3910 patients who received benralizumab (30 mg or 100 mg subcutaneously every 8 weeks; first three doses every 4 weeks) or placebo with dual or triple therapy to identify factors consistently associated with annual exacerbation rate reduction. We evaluated the annual exacerbation rate for benralizumab versus placebo as the primary endpoint. GALATHEA and TERRANOVA are registered with ClinicalTrials.gov, NCT02138916 and NCT02155660, respectively.FindingsFor 2665 patients with elevated blood eosinophil counts, treatment effect with benralizumab every 8 weeks at 100 mg, but not at 30 mg, occurred for patients with a history of more frequent exacerbations, poorer baseline lung function, or greater baseline lung function improvement with short-acting bronchodilators. Patients with baseline blood eosinophil counts of 220 cells per μL or greater with: three or more exacerbations in the previous year receiving benralizumab every 8 weeks versus placebo, had rate ratios (RRs) of 0·69 (95% CI 0·56–0·83) for 100 mg and 0·86 (0·71–1·04) for 30 mg; postbronchodilator FEV1 of less than 40% had RRs of 0·76 (0·64–0·91) for 100 mg and 0·90 (0·76–1·06) for 30 mg; and postbronchodilator response of at least 15% had RRs of 0·67 (0·54–0·83) for 100 mg and 0·87 (0·71–1·07) for 30 mg. When combined factors were examined, patients with elevated baseline blood eosinophil counts, with three or more exacerbations in the previous year, and who were receiving triple therapy were identified as likely to benefit from benralizumab 100 mg every 8 weeks versus placebo (RR 0·70 [95% CI 0·56–0·88]). Benralizumab 30 mg every 8 weeks did not benefit patients meeting these criteria compared with placebo (RR 0·99 [95% CI 0·79–1·23]).InterpretationElevated blood eosinophil counts combined with clinical characteristics identified a subpopulation of patients with COPD who had reductions in exacerbations with benralizumab treatment. These hypothesis-generating analyses identified the potential efficacy of benralizumab 100 mg for this subpopulation. These findings require prospective evaluation in clinical trials.FundingAstraZeneca.

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. Firstly, we analytically validated the ALPCO enzyme linked immunosorbent assay (ELISA) and demonstrated appropriate analytical characteristics, including an intra/inter-assay precision coefficient-of-variation of between 1.9 and 6.8%. EDN purified from blood proved to be a good quality control material, whereas recombinant EDN, expressed in E.coli, did not react in the ALPCO immunoassay. Using healthy and asthma patient serum samples we confirmed that the ALPCO assay correlated well with the MBL assay, with a coefficient of determination (R2) of 0.92. However, the results from LSBio and CUSABIO assays were not commutable to the other assays.

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. This review evaluates the potential of these biomarkers for anti-IL-13-directed therapy in asthma and diseases with type 2 inflammation.

BackgroundBenralizumab 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.MethodsHere, we further investigated the mechanisms involved in benralizumab's anti-eosinophilic activities by employing relevant primary human autologous cell co-cultures and real-time-lapse imaging combined with flow cytometry.ResultsIn the presence of NK cells, benralizumab induced potent eosinophil apoptosis as demonstrated by the upstream induction of Caspase-3/7 and upregulation of cytochromec. In addition, we uncovered a previously unrecognised mechanism whereby benralizumab can induce eosinophil phagocytosis/efferocytosis by macrophages, a process called antibody-dependent cellular phagocytosis. Using live cell imaging, we unravelled the stepwise processes leading to eosinophil apoptosis and uptake by activated macrophages. Through careful observations of cellular co-culture assays, we identified a novel role for macrophage-derived tumour necrosis factor (TNF) to further enhance benralizumab-mediated eosinophil apoptosis through activation of TNF receptor 1 on eosinophils. TNF-induced eosinophil apoptosis was associated with cytochromecupregulation, mitochondrial membrane depolarisation and increased Caspase-3/7 activity. Moreover, activated NK cells were found to amplify this axis through the secretion of interferon-γ, subsequently driving TNF expression by macrophages.ConclusionsOur data provide deeper insights into the timely appearance of events leading to benralizumab-induced eosinophil apoptosis and suggest that additional mechanisms may contribute to the potent anti-eosinophilic activity of benralizumabin vivo. Importantly, afucosylation of benralizumab strongly enhanced its potency for all mechanisms investigated.

Background Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1β. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD. Methods This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study. Subjects aged 45–75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks. The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation). Secondary endpoints were severe AECOPD rate and St George’s Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation). Results Of subjects randomised to placebo (n = 164) and MEDI8968 (n = 160), 79.3% and 75.0%, respectively, completed the study. There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores. Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome. The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar. The most common TEAE was worsening of COPD. Conclusions In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life. Trial registration ClinicalTrials.gov, NCT01448850, date of registration: 06 October 2011. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0633-7) contains supplementary material, which is available to authorized users.

Introduction and objectives Understanding the key drivers of exacerbations for patients with overlapping eosinophilic and allergic severe asthma is important for identifying the optimal treatment strategy. Benralizumab every 8 weeks (Q8W; first three doses every 4 weeks) decreases the annual asthma exacerbation rate (AAER) for patients with severe, uncontrolled asthma with baseline blood eosinophil counts (BBEC) ≥300 cells/µL and serum IgE concentrations ≥150 or Methods For the first objective, pooled analyses of 1,937 patients who received placebo in the benralizumab (Phase III SIROCCO and CALIMA and Phase IIb), tralokinumab (Phase III STRATOS 1 and 2 and Phase IIb), and tezepelumab (Phase II PATHWAY) exacerbation studies of approximately 1-year duration were performed. Crude AAER by BBEC and serum IgE concentrations were estimated for all patients and by atopy status. For the second objective, pooled analyses of SIROCCO and CALIMA patients receiving benralizumab 30 mg Q8W or placebo were performed. AAER was evaluated for overlapping BBEC and serum IgE concentrations via a negative binomial regression approach. Results For the pooled placebo analysis, AAER increased with increasing BBEC but did not increase with increasing serum IgE concentrations (figure), which was also regardless of atopy status. For the pooled SIROCCO/CALIMA analysis population with BBEC ≥300 cells/μL, benralizumab resulted in similar improvements in AAER vs. placebo across all baseline serum IgE concentration quartile groups (figure). Similar results were observed for patients with BBEC ≥150 cells/μL. Conclusions BBEC are important predictors of exacerbation risk. However, this was not observed with serum IgE concentrations. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in the risk of exacerbations compared with placebo, regardless of serum IgE concentrations.

Background: Severe asthma is heterogeneous, with different phenotypes and endotypes. Aims and Objectives: We identified subsets of benralizumab-treated patients (pts) with severe asthma by assignment to Severe Asthma Research Program (SARP) clinical clusters. Methods: Pts (N=2,281) from SIROCCO (Lancet 2016:2115; n=1,082) and CALIMA (Lancet 2016:2128; n=1,199) were assigned to clusters via a discriminant function based on 11 predictors. Drug responses were compared with the Kruskal-Wallis test (nominal p-values). Results: Pts met criteria for 4 of 5 SARP clusters. Cluster 2 pts (n=393) were 81% atopic with early onset moderate asthma (mean age 15 yrs). Cluster 4 pts (n=386) were 82% atopic with early onset severe asthma (mean age 11 yrs). Cluster 3 pts (n=641) were 50% atopic with late-onset severe asthma (mean age 47 yrs). Cluster 5 pts (n=861) were 55% atopic with late-onset asthma (mean age 33 yrs) and persistent airflow obstruction. All clusters had annual exacerbation rate reductions for combined benralizumab arms vs. placebo, which were greater in late-onset asthma clusters (Cluster 3, −48%; 5, −50%; p Conclusions: Benralizumab improved lung function and reduced exacerbations in all clusters, with greater effects in late-onset asthma Clusters 3 and 5 vs. early onset Clusters 2 and 4. This supports the importance of understanding asthma heterogeneity and responsiveness to targeted therapies.

Background: In GALATHEA/TERRANOVA Phase III trials (N Engl J Med. 2019; May 20), exacerbation reduction with benralizumab for patients with COPD did not reach statistical significance. Aims and Objectives: We evaluated baseline factors to identify patients demonstrating greater benralizumab efficacy. Methods: We pooled data from GALATHEA/TERRANOVA (N=3,910) for patients randomized to placebo or benralizumab (56 weeks). We ran prespecified statistical analyses to detect baseline factors that identified patients demonstrating greater reduction of moderate to severe COPD exacerbations with benralizumab 30 mg or 100 mg. Results: We identified several baseline efficacy factors: history of frequent exacerbations, lesser post-BD FEV1, greater post-BD FEV1 response, prior triple inhaled therapy use (figure). These factors identified greater efficacy with benralizumab 100 mg vs. placebo for patients with baseline eosinophils ≥220 cells/µL than for the overall population. Patients receiving benralizumab 100 mg with a combination of prior triple inhaled therapy use, baseline blood eosinophils ≥220 cells/µL, and ≥3 exacerbations (previous 12 months) demonstrated the greatest response (rate ratio vs. placebo [95% CI]: 0.70 [0.56, 0.88]). Conclusions: We identified a subpopulation of patients with specific traits who demonstrated a clinically meaningful benralizumab response. A Phase III trial is ongoing to evaluate benralizumab efficacy for these patients.

BACKGROUND: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. METHODS: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient’s background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12. RESULTS: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse. CONCLUSIONS: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.)

Introduction Allergic disease is commonly associated with asthma. We compared demographics and baseline clinical characteristics of patients with and without allergic disease from the benralizumab SIROCCO (NCT01928771) and CALIMA (NCT01914757) Phase III studies. Methods Patients were aged 12–75 years and had severe, uncontrolled asthma despite receiving high-dosage inhaled corticosteroids/long-acting β2-agonists. Incidence of allergic disease was determined from medical history and respiratory disease characteristics in trial databases. Results Of 2,295 patients, 1,908 (83.1%) had ≥1 allergic condition and 387 (16.9%) had no allergic conditions. Key baseline characteristics differed between patients with and without allergic disease. Compared to patients without allergic disease, patients with allergic disease had greater blood eosinophil counts, serum IgE concentrations, incidence of experiencing ≥3 exacerbations in the previous year, and incidence of nasal polyposis (nasal polyposis was not a search term for allergy incidence). Patients with allergic disease also had longer time since asthma diagnosis than patients without allergic disease (mean [SD]: 20.0 [14.8] years vs. 15.8 [13.8] years, respectively) and younger age at asthma diagnosis (29.5 [18.5] years vs. 37.1 [17.8] years, respectively). There were no differences in any baseline lung function criteria, ACQ-6 score, or BMI. Conclusions Most patients in SIROCCO and CALIMA had comorbid allergic disease. Baseline characteristics associated with enhanced response to benralizumab were distributed across populations with and without allergic disease. Patients with allergic disease had greater blood eosinophil counts and incidences of previous exacerbations and nasal polyps; patients without allergic disease had later onset of asthma.

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. Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades Global Initiative for Chronic Obstructive Lung Disease stages I–IV; never-smokers/smokers served as controls. Automated immunohistochemistry and in situ hybridisation identified immune cells, the type 2 immunity marker GATA3 and eotaxins (CCL11, CCL24). Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD. The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3+ cells, including type 2 helper T-cell lymphocytes and type 2 innate lymphoid cells. A similarly localised and interleukin-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice. Both mice and patients displayed spatially confined eotaxin signatures with CCL11+ fibroblasts and CCL24+ macrophages. In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that is likely to have implications for personalised treatment., Highly localised Th2- and eosinophil-rich pockets were identified in COPD-affected lungs, which increased in number with increasing disease severity and included basophils. This exemplifies a novel type of heterogeneity in the immunopathology of COPD. http://bit.ly/2HexTco

Eosinophilic inflammation is frequently associated with increased asthma severity. Benralizumab is a humanized, afucosylated, anti-interleukin-5Rα monoclonal antibody that selectively depletes eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity.To study effects of benralizumab on eosinophil counts and activity following administration to asthma patients.Sera were collected from asthma patients enrolled in two clinical studies. Placebo or benralizumab was subcutaneously administered to patients in Phase I (100 or 200 mg, multiple doses; N = 14; NCT00659659) and Phase IIa (25, 100, or 200 mg every 4 weeks; N = 24; NCT00783289) studies. Sera were also collected from healthy volunteers (N = 20) for comparison. Blood eosinophils, IL-5, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), eotaxin/chemokine (C-C motif) 11 (CCL11), eotaxin-2/CCL24, tumor necrosis factor (TNF), and interferon-γ (IFN-γ) were measured at baseline and post-treatment.Increased EDN concentrations were observed in sera of patients from both studies relative to healthy volunteers (p 0.05). At baseline, sera EDN concentrations correlated with blood eosinophil counts (rs = 0.5; p 0.05). Benralizumab reduced blood eosinophil numbers and sera EDN and ECP relative to baseline (p 0.05). No changes in TNF or IFN-γ were observed, while serum IL-5, eotaxin/CCL11, and eotaxin-2/CCL24 increased after benralizumab administration vs. placebo (p 0.05).In two independent studies, serum IL-5, EDN, and ECP were modulated following benralizumab. Eosinophil depletion after benralizumab also resulted in significant reductions in EDN and ECP concentrations, suggesting that cytotoxic granule proteins were not released after eosinophil reduction.

Background Atopic, eosinophilic, and T H 2-high asthma phenotypes may overlap, but the extent is unknown. Understanding the overlap across these phenotypes may be useful in guiding asthma patient care. Objective To examine the frequency and overlap of atopic, eosinophilic, and T H 2-high asthma phenotypes. Methods We analyzed 2005 to 2006 data from the National Health and Nutrition Examination Survey. Patients with asthma were identified based on the participant self-report. Eosinophilic asthma was defined as a blood eosinophil cutoff point of ≥150, 300, or 400/μL. Atopic asthma was defined as having an allergen-specific IgE level of ≥0.35 IU/mL for any of the 9 perennial allergens tested. T H 2-high asthma was defined as a total serum IgE of ≥100 IU/mL and a blood eosinophil count of ≥140/μL. Results The study included 269 children and 310 adults. Depending on the eosinophil cutoff used, 31% to 78% of children and 21% to 69% of adults with asthma were classified as having eosinophilic asthma. In addition, 63% of children and 61% of adults were classified as having atopic disease and 48% of children and 37% of adults as having T H 2-high asthma. At a higher eosinophil cutoff point, a greater proportion of eosinophilic asthma can be classified as atopic or T H 2 high, but a lower proportion of atopic or T H 2-high asthma can be classified as eosinophilic. Approximately 70% or more of children and adults with asthma were 1 of these 3 phenotypes. Conclusion A considerable overlap among eosinophilic, atopic, and T H 2-high asthma phenotypes exists in a general asthma population.

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 Streptococcus pneumoniae were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens S. pneumoniae or Haemophilus influenzae. Thus, benralizumab may have an indirect effect upon airway bacterial load.

Background: COPD patients with higher sputum or blood eosinophil counts have greater clinical response to corticosteroids and suffer lower bacterial colonisation (Kolsum et al, Respir Res 2017). Recently we have shown that these patients have higher levels of immunoglobulin (Ig) A and M proteins in their bronchoalveolar lavage (Kolsum et al, JACI 2017). Aims: To compare immunoglobulin and plasma cell gene expression in bronchial brushings from eosinophil high and low COPD patients. Methods: 21 eosinophil low (blood count 250/µl) COPD patients were recruited for bronchoscopy. Following RNA sequencing, the STAR pipeline was used to quantify bronchial brush gene expression. Differentially expressed genes and immune-related signatures were compared in eosinophil high vs low groups by ANOVA. Results: Genes relating to IgA and IgM had greater expression in eosinophil high patients (Table 1). A plasma cell gene signature (TNFRSF17, IGKC, IGKV4-1, IGHA1) was on average expressed higher in eosinophil high patients (p=0.03) Conclusions: COPD patients with higher blood eosinophils, have more IgA, IgM and increased plasma cell gene signature in the bronchial airway. While this may play a role in reducing bacterial colonisation in these patients, further work is required to determine if this is a direct role of eosinophils or whether this is secondary to the higher, local inflammation observed in eosinophilic COPD patients.

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. Methods This was a post hoc analysis of pooled data from the phase III SIROCCO (ClinicalTrials.gov identifier: NCT01928771) and CALIMA (NCT01914757) trials. The primary analysis population was patients ages 12-75 years treated with high-dosage inhaled corticosteroids and long-acting beta-2 agonists who had baseline blood eosinophil counts of ≥300 cells/μL. Patients received benralizumab 30 mg subcutaneously every 4 weeks or every 8 weeks (the first three doses every 4 weeks) or placebo every 4 weeks. Crude exacerbation rates (asthma exacerbations per patient-year) were determined for each month and season. Marginal asthma exacerbation rates and exacerbation rate ratios were estimated by season or month by using a negative binomial model that included covariates for study code, treatment, region, use of maintenance oral corticosteroids, and number of exacerbations in the previous year. Hemispheric seasons were accounted for by normalizing the study site locations. Results Observed crude exacerbation rates were higher in the fall and winter than in the spring and summer for all the patients. For the patients who received placebo, benralizumab every 4 weeks, and benralizumab every 8 weeks, crude exacerbation rates were the following: fall, 1.52, 0.86, and 0.81, respectively; winter, 1.44, 0.91, and 0.82, respectively; spring, 1.11, 0.66, and 0.52, respectively; and summer, 1.02, 0.55, and 0.51, respectively. Rate reductions in seasonal marginal annual exacerbation rates were 37-50% versus placebo at each season (p Conclusion Benralizumab significantly and consistently reduced asthma exacerbations across all seasons versus placebo for patients with severe, uncontrolled eosinophilic asthma.

Background Paper-based diaries and self-report of symptom worsening in COPD may lead to underdetection of exacerbations. Epidemiologically, COPD exacerbations exhibit seasonal patterns peaking at year-end. We examined whether the use of a BlackBerry-based daily symptom diary would detect 95% or more of exacerbations and enable characterization of seasonal differences among them. Methods Fifty participants with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I to IV COPD began a community-based study in December 2007. Another 30 began in December 2008. Participants transmitted daily symptom diaries using a BlackBerry. Alerts were triggered when symptom changes, missed diary transmissions, or medical care for a respiratory problem occurred. Participant encounters were initiated if COPD exacerbations were suspected. Participants used their BlackBerrys to report returns to normal breathing. Results Participants transmitted 99.9% of 28,514 possible daily diaries. All 191 (2.5/participant-year) COPD exacerbations meeting Anthonisen criteria were detected. During 148 of the 191 exacerbations (78%, 1.97/participant-year), patients were hospitalized and/or ordered prednisone, an antibiotic, or both. Respiratory viruses were detected in 78 of the 191 exacerbations (41%). Those coinciding with a respiratory viral infection averaged 12.0 days, and those without averaged 8.9 days (P < .04), with no difference in Anthonisen score. Respiratory symptom scores before exacerbations and after normal breathing return showed no differences. Exacerbations were more frequent during the Christmas period than the rest of the year but were not more frequent than in the rest of winter alone. Conclusions Smartphone-based collection of COPD symptom diaries enables near-complete identification of exacerbations at inception. Exacerbation rates in the Christmas season do not reach levels that necessitate changes in disease management.

Introduction: In Phase III studies, benralizumab, a humanized anti–interleukin-5 receptor α, anti-eosinophil (EOS) monoclonal antibody, significantly reduced asthma exacerbations and improved asthma control for patients (pts) with severe, uncontrolled asthma. Aims and Objectives: We evaluated the effect of baseline blood EOS counts and exacerbation history on benralizumab response. Methods: This was a post-hoc analysis of pooled data from SIROCCO (Lancet. 2016;388:2115–27; 48 weeks [N=1,204]) and CALIMA (Lancet. 2016;388:2128–41; 56 weeks [N=1,091]) of pts with severe, uncontrolled asthma receiving benralizumab 30 mg every 4 weeks (Q4W), every 8 weeks (Q8W, Q4W for the first 3 doses), or placebo. Pts had ≥2 exacerbations in the previous year. The primary endpoint was annual exacerbation rate (AER) by baseline blood EOS count and exacerbation history. Results: AER decreased with benralizumab vs. placebo at every EOS threshold, with a response/EOS threshold relationship for Q8W dosing (table). More exacerbations in the past year were associated with a greater response to benralizumab. Similar trends emerged for lung function and asthma symptom improvements. Conclusions: For pts with severe, uncontrolled asthma, greater baseline blood EOS counts and more frequent exacerbations were associated with greater treatment effects. These results should help refine patient selection for benralizumab treatment.

Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor α monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma. We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories.This study is a pooled analysis of the results from the randomised, double-blind, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase 3 studies. In these studies, patients with severe, uncontrolled asthma were randomly assigned (1:1:1) to receive subcutaneous benralizumab 30 mg, either every 4 weeks or every 8 weeks (with first three doses given every 4 weeks), or placebo every 4 weeks. The primary endpoint was annual exacerbation rate (AER) ratio versus placebo, analysed by baseline eosinophil counts (≥0, ≥150, ≥300, or ≥450 cells per μL) and by number of exacerbations (two vs three or more) during the year before enrolment. The analyses were done in accordance with the intention-to-treat principle.Of 2295 patients, 756 received benralizumab every 4 weeks, 762 received benralizumab every 8 weeks, and 777 patients received placebo. AER among patients with baseline blood eosinophil counts of at least 0 cells per μL was 1·16 (95% CI 1·05-1·28) in patients who received placebo versus 0·75 (0·66-0·84) in patients who received benralizumab every 8 weeks (rate ratio 0·64, 0·55-0·75; p0·0001). In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per μL, AER was 0·73 (0·65-0·82); rate ratio versus placebo was 0·63 (0·54-0·74; p0·0001). The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups. Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations.These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma.AstraZeneca.

Objective: Benralizumab, an anti-eosinophilic monoclonal antibody, in combination with high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS/LABA), significantly reduced asthma exacerbations, improved lung function, and reduced symptoms for patients with severe, uncontrolled asthma with blood eosinophil counts ≥300 cells/μL in the Phase III SIROCCO and CALIMA studies. To understand the efficacy and safety of benralizumab for patients with eosinophil-driven disease with blood eosinophil counts lower than 300 cells/μL, we evaluated the effect of applying an eosinophil cutoff of ≥150 cells/μL.Methods: Adult patients with uncontrolled asthma despite high-dosage ICS/LABA ± additional asthma controller(s) received subcutaneous benralizumab 30 mg every 8 weeks (Q8W; first three doses every 4 weeks) or placebo for 48 (SIROCCO) or 56 (CALIMA) weeks. Efficacy measures including annual exacerbation rate, prebronchodilator FEV1, and total asthma symptom score were analyzed by baseline blood eos...

Asthma is a heterogeneous condition characterised by chronic inflammation and airway remodelling. T2-mediated airway inflammation, characterised by IL4, IL5 and IL13, has been the recent focus of pharmacotherapy, with a host of targeted biologic agents now available to clinicians [1]. The anti-IL5R agent, benralizumab, causes depletion of eosinophils and basophils via antibody dependent cell-mediated cytotoxicity (ADCC) in blood; however, the mechanism of action in the tissue is uncertain. Benralizumab has reduced exacerbations and improved lung function in clinical trials. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: L. Chachi has nothing to disclose. Conflict of interest: S. Diver has nothing to disclose. Conflict of interest: H. Kaul reports grants from AirPROM, during the conduct of the study. Conflict of interest: M.C. Rebelatto is an employee of and owns shares in AstraZeneca. Conflict of interest: A. Boutrin is an employee of and holds stock options in AstraZeneca. Conflict of interest: P. Nisa has nothing to disclose. Conflict of interest: P. Newbold is an employee of and owns shares in AstraZeneca. Conflict of interest: C. Brightling reports grants and personal fees for consultancy from GlaxoSmithKline, AstraZeneca/Medimmune, Novartis, Chiesi, Roche/Genentech and Boehringer Inglheim, personal fees for consultancy from Vectura, Theravance, PreP, Gilead, Sanofi/Regeneron, Teva, Gossamer and 4DPharma, grants from Pfizer and Mologic, outside the submitted work.

Introduction L’asthme est frequemment d’origine allergique. Nous avons compare les caracteristiques demographiques et cliniques des patients avec et sans maladie allergique inclus dans les etudes de phase III SIROCCO ( NCT01928771 ) et CALIMA ( NCT01914757 ). Methodes Les patients etaient âges entre 12 et 75 ans et avaient un asthme severe, non controle en depit d’un traitement par une association de steroides inhales et de beta-2 mimetiques de longue duree d’action a fortes doses. L’incidence de la maladie allergique etait determinee a partir de l’historique medical et des caracteristiques de la maladie respiratoire. Resultats Sur 2295 patients inclus, 1908 (83,1 %) avaient au moins une condition allergique et 387 (16,9 %) n’avaient pas de condition allergique. Les caracteristiques a l’inclusion differaient entre les patients avec et sans condition allergique. Compares avec les patients sans maladie allergique, les patients avec une maladie allergique avaient un compte d’eosinophiles, une concentration serique d’IgE, une frequence d’exacerbations superieure ou egale a 3 dans l’annee precedente et une incidence de polypose nasale superieure. Les patients ayant une maladie allergique avaient aussi une duree depuis le diagnostic de l’asthme superieure a ceux sans maladie allergique (20,0 ans [SD :14,8] vs 15,8 ans [13,8] respectivement). Il n’y avait pas de differences entre les 2 groupes en termes de fonction respiratoire, de score ACQ-6 et d’indice de masse corporelle. Discussion La plupart des patients inclus dans les etudes SIROCCO et CALIMA avaient une maladie allergique. Les caracteristiques a l’inclusion associees a une reponse accrue au benralizumab etaient reparties entre les patients avec et sans maladie allergique. Les patients ayant une maladie allergique avaient un compte eosinophile, une prevalence d’exacerbations dans l’annee precedente et de polypes nasaux plus important ; les patients sans maladie allergique avaient un âge au diagnostic de l’asthme plus tardif. The authors have provided permission for Gabriel Thabut to present on their behalf.