Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

MiRNA-495-3p Attenuates TNF-α Induced Apoptosis and Inflammation in Human Nucleus Pulposus Cells by Targeting IL5RA.

Intervertebral disc degeneration (IVDD) is considered to be the fundamental cause of the occurrence and development of lumbar disc herniation (LDH). The degeneration of IVDD is mainly caused by the participation of inflammatory factors. Thus, it is of great significance to analyze the pathogenesis of IVDD, which may guide clinical prevention and treatment of LDH. Our current study aims to identify the role of miR-495-3p in LDH and to further unravel the underlying mechanisms. Results in the current study showed that TNF-α treatment markedly inhibited cell viability of HNPC, increased the IL-1ß level, and decreased the mRNA level of miR-495-3p in HNPC in a time-dependent manner. Up-regulation of miR-495-3p promoted cell proliferation and inhibited inflammation and apoptosis in TNF-α-induced HNPCs. To investigate the underlying molecular mechanism through which miR-495-3p regulates TNF-α-induced inflammation and apoptosis in HNPCs, we explored the possible target gene of miR-495-3p. Bioinformatics analysis indicated that IL5RA, which is an important gene for TNF-α-induced HNPC injury, was also a target gene of miR-495-3p. A luciferase reporter assay was applied to test and verify the direct target association between miR-495-3p and IL5RA. The results discovered that down-regulation of miR-495-3p markedly reversed the anti-apoptosis and anti-inflammation of sh-IL5RA. In short, the present study evaluated the roles of miR-495-3p and IL5RA in IVDD development and progression. All the data indicated that miRNA-495-3p may play a protective role via inhibiting inflammation and apoptosis in human nucleus pulposus cells by targeting IL5RA pathway. Therefore, miRNA-495-3p may be a potential agent for LDH, and our study may provide a novel strategy in LDH treatment.

Effect of Anti-IL5, Anti-IL5R, Anti-IL13 Therapy on Asthma Exacerbations: A Network Meta-analysis.

BACKGROUND: Several new treatments for severe asthma have become available in the last decade; yet, little data exist to guide their use in specific patient populations. OBJECTIVE: A network meta-analysis was conducted comparing the efficacy of FDA-approved monoclonal antibody therapies in preventing exacerbations in patients with severe eosinophilic asthma. METHODS: PubMed and Ovid were searched from inception until July 2019 for randomized controlled trials that studied the efficacy of benralizumab, dupilumab, mepolizumab, and reslizumab, in preventing acute exacerbations of asthma. Studies were included if they reported data for patients with severe eosinophilic asthma (defined in this meta-analysis as absolute eosinophil count ≥ 250 cells/µL). Annualized rate ratios for asthma exacerbations (during treatment) were calculated and converted to log rate ratios. Direct and indirect treatment estimates (for inter-drug differences) were analyzed using frequentist network meta-analysis methodology in R and treatments were ranked based on P-scores. RESULTS: In total, nine studies were included in the final analysis. Network meta-analysis revealed that all drugs were superior to placebo in preventing rates of asthma exacerbation in the study population and no inter-drug differences existed. Dupilumab was found to have the greatest magnitudes of effect on decreasing log rate ratio of asthma exacerbation based on P-score (0.83). CONCLUSION: Benralizumab, dupilumab, mepolizumab, and reslizumab are all associated with decreased asthma exacerbations in patients with eosinophilic asthma, with no significant inter-drug differences.

Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma.

BACKGROUND: Fixed airflow obstruction (FAO) is associated with severe eosinophilic asthma. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: We evaluated FAO influence on benralizumab treatment response. METHODS: We performed a post hoc analysis of pooled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) data for patients with severe, uncontrolled asthma with baseline blood eosinophil counts of 300 or more cells/µL who received benralizumab 30 mg every 8 weeks or placebo. Demographics, baseline clinical characteristics, and treatment responses were evaluated by FAO status. FAO+ and FAO- were defined as ratios of postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity of less than 70% and 70% or more, respectively, at baseline. RESULTS: FAO+ prevalence was 63% (935/1493). With benralizumab, similar annual asthma exacerbation rate (AER) reductions vs placebo were achieved for FAO+ and FAO- patients (rate ratio [95% confidence interval (CI)] = 0.56 [0.44-0.71] and 0.58 [0.41-0.83], respectively), whereas annual AER reductions associated with emergency department visits or hospitalizations were greater for FAO+ vs FAO- patients (rate ratio [95% CI] = 0.55 [0.33-0.91] and 0.70 [0.33-1.48], respectively). Prebronchodilator FEV1 (95% CI) increase from baseline to end of treatment was greater for FAO+ vs FAO- patients receiving benralizumab compared with placebo (0.159 L [0.082-0.236] vs 0.103 L [-0.008 to 0.215]). Other lung function measures, patient-reported outcomes, and symptom improvements were also numerically greater for FAO+ vs FAO- patients. CONCLUSION: Benralizumab improved asthma control across several measures for patients with severe, uncontrolled eosinophilic asthma and FAO. TRIAL REGISTRATION: SIROCCO trial: NCT01928771 (URL: https://clinicaltrials.gov/ct2/show/NCT01928771) CALIMA trial: NCT01914757 (URL: https://clinicaltrials.gov/ct2/show/NCT01914757).

Engineering of Humanized Antibodies Against Human Interleukin 5 Receptor Alpha Subunit That Cause Potent Antibody-Dependent Cell-Mediated Cytotoxicity.

Patients with severe eosinophilic asthma (SEA; characterized by persistent eosinophilia in blood and airway tissues) experience frequent asthma exacerbations with poor clinical outcomes. Interleukin 5 (IL-5) and IL-5 receptor alpha subunit (IL-5α) play key roles in eosinophilia maintenance, and relevant therapeutic strategies include the development of antibodies (Abs) against IL-5 or IL-5α to control eosinophilia. Benralizumab, an anti-IL-5α Ab that depletes eosinophils mainly via Ab-dependent cell-mediated cytotoxicity and through blockage of IL-5 function on eosinophils, has been clinically approved for patients with SEA. Here, we report engineering of a new humanized anti-IL-5Rα Ab with potent biological activity. We first raised murine Abs against human IL-5Rα, humanized a leading murine Ab, and then further engineered the humanized Abs to enhance their affinity for IL-5Rα using the yeast surface display technology. The finally engineered version of the Ab, 5R65.7, with affinity (KD ≈ 4.64 nM) stronger than that of a clinically relevant benralizumab analogue (KD ≈ 26.8 nM) showed improved neutralizing activity toward IL-5-dependent cell proliferation in a reporter cell system. Domain level Ab epitope mapping revealed that 5R65.7 recognizes membrane-proximal domain 3 of IL-5Rα, distinct from domain I epitope of the benralizumab analogue. In ex vivo assays with peripheral eosinophils from patients with SEA and healthy donors, 5R65.7 manifested more potent biological activities than the benralizumab analogue did, including inhibition of IL-5-dependent proliferation of eosinophils and induction of eosinophil apoptosis through autologous natural-killer-cell-mediated Ab-dependent cell-mediated cytotoxicity. Our study provides a potent anti-IL-5Rα Ab, 5R65.7, which is worthy of further testing in preclinical and clinical trials against SEA as a potential alternative to the current therapeutic arsenal.

Targeting IL-5 in COPD.

Many patients with chronic obstructive pulmonary disease (COPD) continue to experience exacerbations despite receiving standard-of-care treatments. Novel approaches to COPD treatment focus on understanding and targeting molecular mechanisms of airway inflammation, airway obstruction, remodeling and lung destruction. Several identified phenotypes and endotypes of COPD will pave the future path for a more personalized approach to therapy. Although well known to be associated with neutrophilic inflammation, COPD may also be driven by eosinophilic inflammation both at stable states and during exacerbation. Targeting eosinophilic inflammation has been successful in managing severe eosinophilic asthma and may hold promise in certain phenotypes of COPD. The most promising biologic treatments at an advanced stage of development are agents blocking interleukin (IL)-5 or its receptor. This review examines our current understanding of the eosinophilic inflammation in COPD and the rationale for IL-5 targeting agents.

Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome.

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.).

Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma: A Systematic Literature Review and Network Meta-Analysis.

BACKGROUND: The interaction of IL-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials. OBJECTIVE: To indirectly compare reslizumab with benralizumab in similar patient populations using a network meta-analysis. METHODS: A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte-Carlo simulation method and a Bayesian statistical framework. RESULTS: Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels of greater than or equal to 300 cells/µL (n = 1537) and a reslizumab subgroup in Global Initiative for Asthma step 4/5 with 2 or more previous exacerbations and greater than or equal to 400 eosinophils/µL (n = 318). Safety was analyzed in the full population (N = 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab once every 4 weeks and there were reasonably high posterior probabilities that reslizumab is superior to benralizumab once every 4 weeks and once every 8 weeks for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations. CONCLUSIONS: This indirect comparison suggests that reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/µL; reslizumab, ≥400/µL) and 2 or more exacerbations in the previous year.

Anti-IL-5 and IL-5Ra: Efficacy and Safety of New Therapeutic Strategies in Severe Uncontrolled Asthma.

The current developments of the new biological drugs targeting interleukin 5 (IL-5) and IL-5 receptor allowed to expand the treatment options for severe hypereosinophilic asthma. Clinicians will then be able to choose between antibodies targeting either circulating IL-5 or its receptor expressed on eosinophils and basophils. The available clinical trials consistently reported favorable results about the reduction of exacerbations rate, improvement in quality of life, and sparing of the systemic steroid use, with a favorable safety profile. Two of these new drugs are administered subcutaneously, mepolizumab every 4 weeks and benralizumab every 8 weeks, whereas reslizumab is given intravenously monthly on a weigh-based dose. In the future, the research actions will be involved in the identification of a single biomarker or multiple biomarkers for the optimal choice of biological agents to be properly prescribed.

Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the treatment of asthma.

INTRODUCTION: In many severe asthmatics, eosinophils cause inflammation and airways hyperresponsiveness, resulting in frequent exacerbations, impaired lung function, and reduced quality of life. Interleukin-5 (IL-5) is a key cytokine for eosinophil growth, differentiation, recruitment, activation, and survival. Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the α subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma. Areas covered: The pharmacodynamic/pharmacokinetic profile of benralizumab and how it provided indications that permitted optimization of the design and timelines of the pivotal trials are described. Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5Rα itself. Afucosylation enhances its interaction with its binding site and facilitates its pharmacological activity. Other benefits of benralizumab are fast (within 24 h) depletion of peripheral blood eosinophils, potent suppressive activity of bone marrow eosinophils and eosinophil precursors, tissue eosinophil apoptosis regardless of the presence of eosinophil survival factors and even at low IL-5R densities. The fact that benralizumab is dosed subcutaneously and is equally effective when given every eight weeks instead than every four weeks provides patients with convenience of self-administration and make it appealing for patients who dislike injections.

Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma.

BACKGROUND: Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. METHODS: In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. RESULTS: Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. CONCLUSIONS: Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

IL-5 blocks apoptosis and tau hyperphosphorylation induced by Aß25-35 peptide in PC12 cells.

The primary features of Alzheimer's disease (AD) are extracellular amyloid plaques consisting mainly of deposits of amyloid ß (Aß) peptides and intracellular neurofibrillary tangles (NFTs). Sets of evidence suggest that interleukin-5 (IL-5) is involved in the pathogenesis of AD. Herein, we investigated the protective role of IL-5 in PC12 cells, to provide new insights into understanding this disease. Western blot was employed to assess the protein levels of Bax and phospho-tau as well as phospho-JAK2; MTT assay was performed to decipher cell viability. Treatment of IL-5 decreased Aß25-35-induced tau phosphorylation and apoptosis, effects blunted by JAK2 inhibition. IL-5 prevents Aß25-35-evoked tau protein hyperphosphorylation and apoptosis through JAK2 signaling.

Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study.

BACKGROUND: Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma. METHODS: We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting ß agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861. FINDINGS: Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per µL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo. INTERPRETATION: Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per µL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. FUNDING: MedImmune.

Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278. FINDINGS: We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per µL or more or 300 cells per µL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related. INTERPRETATION: Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia. FUNDING: MedImmune.

Establishment of humanized anti-interleukin-5 receptor alpha chain monoclonal antibodies having a potent neutralizing activity.

Human interleukin-5 is the key cytokine involved in regulating the production and function of human eosinophils. IL-5 binds to its specific receptor composed of two heterogeneous alpha and beta polypeptide chains (hIL-5Ralpha and betac) that are expressed on the cell surface. The hIL-5Ralpha specifically binds IL-5 without involvement of the betac. It has been suggested that neutralizing antibodies to hIL-5Ralpha could serve as a therapeutic agent in eosinophil-associated diseases. We describe here the creation and biologic activities of a mouse monoclonal antibody against hIL-5Ralpha that blocks the following IL-5 dependent activities (a) binding of the IL-5 ligand to its receptor, (b) IL-5 dependent growth of hIL-5R expressing cells, and (c) IL-5-induced adhesion of human eosinophils. We also describe the process for humanization of the mouse Mab towards development of a therapeutic MAb. The humanized version of the monoclonal antibody also displayed potent neutralizing activity against IL-5 dependent activities.