Relationship Between Benralizumab Exposure and Efficacy for Patients With Severe Eosinophilic Asthma.
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ABSTRACT:
SUBMITTER: Chia YL
PROVIDER: S-EPMC6767326 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
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Relationship Between Benralizumab Exposure and Efficacy for Patients With Severe Eosinophilic Asthma.
Chia Yen Lin YL Yan Li L Yu Binbing B Wang Bing B Barker Peter P Goldman Mitchell M Roskos Lorin L
Clinical pharmacology and therapeutics 20190322 2
We evaluated the relationship between benralizumab (30 mg every 4 and 8 weeks (Q4W, Q8W)) pharmacokinetic (PK) exposure and end points of asthma exacerbation rates (AERs) and change from baseline in prebronchodilator forced expiratory volume in 1 second (FEV<sub>1</sub> ) for patients with severe, uncontrolled eosinophilic asthma in the SIROCCO/CALIMA phase III trials. In empirical assessment, AER ratios in SIROCCO were similar across PK quartiles. However, the lowest PK quartile in CALIMA had r ...[more]
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Project description:PurposeIn the Phase III SIROCCO trial (NCT01928771), benralizumab significantly reduced asthma exacerbations and improved lung function and symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate efficacy and safety of benralizumab for Korean patients in SIROCCO.MethodsSIROCCO was a randomized, double-blind, parallel-group, placebo-controlled trial of 1,204 patients aged 12-75 years with severe asthma uncontrolled by high-dosage inhaled corticosteroids/long-acting β₂-agonists (ICS/LABA). Patients received benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W; first 3 doses Q4W) or placebo Q4W for 48 weeks. The primary analysis population comprised patients with blood eosinophil counts ≥ 300 cells/μL. This subgroup analysis evaluated Korean patients from this group.ResultsOf 122 Korean patients randomized, 86 had blood eosinophil counts ≥ 300 cells/μL. Benralizumab reduced the annual asthma exacerbation rate by 70% (Q4W: rate estimate 0.79, rate ratio 0.30 [95% confidence interval {CI}, 0.13-0.65], nominal P = 0.003; n = 28) and 85% (Q8W: rate estimate 0.40, rate ratio 0.15 [95% CI, 0.06-0.36], nominal P < 0.001; n = 30) vs. placebo (rate estimate 2.67, n = 28). Prebronchodilator forced expiratory volume in 1 second was increased with benralizumab treatment by 0.270 L (Q4W: 95% CI, 0.039-0.500, nominal P = 0.023; n = 28) and 0.362 L (Q8W: 95% CI, 0.143-0.582, nominal P = 0.002; n = 30) vs. placebo (n = 27). Total asthma symptom score was similar for patients receiving either benralizumab Q4W (-0.27 [95% CI, -0.83 to 0.30], nominal P = 0.356; n = 27) or benralizumab Q8W (0.10 [95% CI, -0.44 to 0.65], nominal P = 0.708; n = 30) vs. placebo (n = 28). Drug-related adverse events were experienced by 2%, 8%, and 5% of patients in the placebo, benralizumab Q4W, and benralizumab Q8W arms.ConclusionsBenralizumab reduced annual asthma exacerbation rates, increased lung function, and was well-tolerated by Korean patients with severe, uncontrolled eosinophilic asthma.
| S-EPMC6557768 | biostudies-literature
Project description:BackgroundBenralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA.MethodsFrom July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients' characteristics, parameters, numbers of exacerbations and maintenance OCS doses.ResultsAmong the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab.ConclusionBenralizumab treatment improved and controlled asthma symptoms based on the GETE score.
| S-EPMC7398222 | biostudies-literature
Project description:BackgroundCompEx Asthma, a composite end-point for asthma exacerbations, captures clinically relevant, diary-based acute worsening events (AWEs) (defined as deterioration in daily peak expiratory flow concurrent with deterioration in asthma symptoms and/or rescue therapy use) and severe exacerbations (SevEx) (defined by American Thoracic Society/European Respiratory Society guidelines). We hypothesised that CompEx and SevEx would show similar benralizumab treatment effects and correlations to blood eosinophil counts in patients with severe asthma.MethodsThis post hoc analysis of pooled 12-month data from two phase 3 studies included patients aged ≥16 years with severe, uncontrolled asthma who were randomised to benralizumab 30 mg or placebo. Annualised event rates were analysed using a negative binomial model. The impact of blood eosinophil count on treatment effect was assessed.ResultsAmong patients with a blood eosinophil count ≥300 cells·µL-1 (n=913), benralizumab reduced the annualised event rate versus placebo for CompEx (1.57 versus 2.57; risk ratio 0.61, 95% CI 0.53-0.70, p<0.001), SevEx (0.94 versus 1.55; risk ratio 0.60, 95% CI 0.52-0.70, p<0.001) and AWE (0.92 versus 1.57; risk ratio 0.59, 95% CI 0.48-0.72, p<0.001), with greater treatment effects observed for higher blood eosinophil counts. In patients with blood eosinophil count ≥300 cells·µL-1, benralizumab was associated with shorter median event duration (CompEx: 10.5 days versus 17.0 days; SevEx: 10.0 days versus 15.0 days; AWE: 5.0 days versus 6.0 days).ConclusionsBenralizumab reduced the risk of CompEx events with treatment effects similar to those for SevEx and AWEs across a range of blood eosinophil counts. Use of CompEx supports the evaluation of benralizumab and other novel drugs in clinical studies.
| S-EPMC10945385 | biostudies-literature
Project description:IntroductionFor 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.MethodsAnalyses 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 (< 150, ≥ 150 to < 300, ≥ 300 to < 450, ≥ 450 cells/µL) and IgE concentration quartiles (< 62.0, ≥ 62.0 to < 176.2, ≥ 176.2 to < 453.4, and ≥ 453.4 kU/L). We compared AERs for patients receiving benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) vs. placebo for overlapping baseline blood eosinophil count categories and serum IgE concentration quartiles via a regression approach and by continuously using locally weighted regression smoothing analysis.ResultsExacerbation risk for patients with severe asthma receiving placebo increased with increasing baseline blood eosinophil counts but not with increasing serum IgE concentrations. Addition of baseline atopy status did not influence the relationship between IgE concentrations and exacerbation risk for patients receiving placebo. Patients with blood eosinophil counts ≥ 300 cells/µL had consistent decreases in exacerbation risk with benralizumab relative to placebo across all serum IgE concentration quartiles.ConclusionBaseline blood eosinophil counts, but not serum IgE concentrations, are an important predictor of exacerbation risk. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in exacerbation risk, regardless of IgE concentrations.Clinical trial registrationClinicalTrials.gov: SIROCCO, NCT01928771; CALIMA, NCT01914757.
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Project description:PurposeTo characterize the clinical phenotypes of severe eosinophilic asthma based on early responsiveness to benralizumab in terms of forced expiratory volume in 1 second (FEV1) improvement.Patients and methodsSixty-four participants diagnosed with severe eosinophilic asthma and who had completed 4 months of benralizumab treatment were included in this analysis. Pre-treatment clinical factors were compared between responders and non-responders according to improvements in ACT or FEV1. Correlations between the sums of increased Type 2-related inflammatory parameters and changes of ACT or FEV1 were also evaluated before and after the 4-month treatment. A two-step cluster analysis was performed to identify distinct phenotypes related to benralizumab responsiveness in terms of FEV1.ResultsAt the 4-month timepoint, all parameters, except for FeNO, were significantly improved after benralizumab treatment. FEV1 responders were associated with higher levels of Type 2-related inflammatory parameters. An improvement in FEV1 but not in ACT was clearly associated with increases in the sums of increased type 2-related inflammation parameters (p = 0.0001). The cluster analysis identified 5 distinct phenotypes of severe eosinophilic asthma according to the variable FEV1 responsiveness to benralizumab. The greatest response was found in the distinct phenotype of severe eosinophilic asthma, which was characterized by modest increase in total IgE and FeNO relative to blood eosinophils with least exposure to smoking.ConclusionThis study, to the best of our knowledge, is the first cluster analysis to report distinct phenotypes related to clinical benralizumab response in a real-world population with severe eosinophilic asthma. These results may help to predict responsiveness to benralizumab in patients with severe eosinophilic asthma.
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Project description:Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor ? (IL-5R?)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5R?-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation. The integrated analyses of benralizumab safety data from the phase III SIROCCO and CALIMA trials and subsequent BORA extension trial for patients with asthma, and the phase III GALATHEA and TERRANOVA trials for patients with chronic obstructive pulmonary disease, form the principal basis for this review.
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Project description:Despite several therapeutic choices, 10-20% of patients with severe uncontrolled asthma do not respond to maximal best standard treatments, leading to a healthcare expenditure of up to 80% of overall costs for asthma. Today, there are new important therapeutic strategies, both pharmacological and interventional, that can result in improvement of severe asthma management, such as omalizumab, bronchial thermoplasty and other biological drugs, for example, mepolizumab, reslizumab and benralizumab. The availability of these new treatments and the increasing knowledge of the different asthmatic phenotypes and endotypes makes correct patient selection increasingly complex and important. In this article, we discuss the features of benralizumab compared with other anti-interleukin-5 biologics and omalizumab, the identification of appropriate patients, the safety profile and future developments.
| S-EPMC5933597 | biostudies-literature
Project description:IntroductionAsthma associated with eosinophilic granulomatosis with polyangiitis (EGPA) is often severe and corticosteroid-dependent, leading to significant morbidity. Mepolizumab and benralizumab are humanized monoclonal antibodies targeting interleukin 5 (IL-5) and its receptor, respectively. They have been shown to be effective in steroid-sparing in patients with severe eosinophilic asthma.ObjectiveOur aim was to evaluate the efficacy and safety of mepolizumab and benralizumab prescribed for severe asthma in patients with EGPA under "real-world" conditions.MethodsThis was a retrospective analysis of patients with EGPA and persistent asthma who received either mepolizumab 100 or 300 mg administered every 4 weeks, or benralizumab 30 mg administered every 4 weeks for the initial 3 injections and followed by an injection every 8 weeks thereafter, whilst combined with oral glucocorticoids. The follow-up every 6 ± 3 months included an assessment of clinical manifestations, pulmonary function tests and eosinophil cell count. The primary outcome was the proportion of patients at 12 months receiving a daily oral dose of prednisone or equivalent of 4 mg or less with a BVAS of 0.ResultsTwenty-six patients were included. After 12 months of treatment with mepolizumab or benralizumab, 32% of patients met the primary outcome and were receiving less than 4 mg of prednisone per day with a BVAS of 0. The median dose of prednisone was 10 mg per day at baseline, 9 mg at 6 months, and 5 mg at 12 months (p ≤ 0.01). At 12 months, 23% of patients were weaned off corticosteroids, while an increase or no change in dose was observed in 27% of patients. The median eosinophil count was significantly reduced from 365 cells/mm3 to 55 cells/mm3 at 6 months and 70 cells/mm3 at 12 months, respectively. No significant change was observed in FEV1. After 12 months of treatment, 14% of patients had had an average of 1 exacerbation of asthma, compared with 52% of patients before baseline. The tolerability profile was favorable.ConclusionIn this real-world study in patients with severe asthma and a history of EGPA asthma, mepolizumab and benralizumab had a significant steroid-sparing effect and reduced asthma exacerbation, but no significant effect on lung function.
| S-EPMC10998444 | biostudies-literature
Project description:BackgroundPatients with severe, uncontrolled asthma experience debilitating symptoms that result in meaningful reductions to health-related quality of life. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that reduces exacerbations and improves asthma symptoms for patients with severe, uncontrolled eosinophilic asthma.ObjectiveThe objective of this study was to evaluate improvements in daily asthma-related health status outcomes following treatment with benralizumab.MethodsPooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) Phase III studies were analyzed. Patients aged 12-75 years with severe, uncontrolled asthma, and blood eosinophil counts (BEC) ≥300 and ≥150 cells/µL were evaluated. Patients received subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W, first three doses Q4W) or placebo and completed a daily diary reporting rescue medication use, night-time awakening requiring rescue medication use, perceived tiredness, and asthma-related activity impairment. Outcome measures were compared across treatment arms from baseline to end of treatment (EOT) using a mixed-effect model for repeated measures analyses.ResultsPatients with BEC ≥300 cells/µL receiving benralizumab Q8W had greater improvements in all patient-reported outcomes at EOT relative to baseline than patients receiving placebo (all nominal P≤0.013). Effects were reported as early as 3 days following the initial dose and sustained throughout treatment for daily and night-time rescue medication use and night-time awakenings requiring rescue medication. For patients with BEC ≥300 and ≥150 cells/ µL, sustained improvements in activity impairment items (all nominal P<0.05) were achieved with benralizumab Q8W at week 2.ConclusionBenralizumab produces sustained reductions by as early as 3 days in rescue medication use and activity impairment for patients with severe, uncontrolled eosinophilic asthma.
| S-EPMC6350639 | biostudies-literature
Project description:BackgroundBenralizumab, a humanized, anti-interleukin-5 (anti-IL-5) receptor α monoclonal antibody that directly and rapidly depletes eosinophils, has shown significant efficacy in reducing asthma exacerbations and improving lung function in moderate to severe eosinophilic asthma patients. However, there is some controversy regarding the adverse events (AEs) of benralizumab and a comprehensive analysis of these AEs has not been performed. This study aimed to assess the incidence of these AEs in published randomized controlled trials (RCTs).MethodsWe searched for RCTs in the Embase, PubMed and Cochrane databases that compared benralizumab with placebo in moderate to severe eosinophilic asthma patients. The outcome was the incidence of AEs during the observation period.ResultsEight RCTs were analyzed in this study. Patients treated with benralizumab had a lower risk of overall AEs (risk ratio (RR) 0.94; 95% confidence interval (CI) 0.90-0.98), serious adverse events (SAEs) (RR 0.82; 95% CI 0.68-0.98), asthma exacerbation (RR 0.72, 95% CI 0.61-0.85), bronchitis (RR 0.76, 95% CI 0.59-0.96) and sinusitis (RR 0.64, 95% CI 0.48-0.85), but had a higher risk of headache (RR 1.42, 95% CI 1.07-1.87) and pyrexia (RR 2.26, 95% CI 1.32-3.87) than patients treated with placebo. No increased incidence of death, hypersensitivity, injection-site reactions, nasopharyngitis, rhinitis, upper respiratory tract infection, influenza, cough, nausea, back pain or arthralgia was observed with benralizumab compared with placebo.ConclusionsBenralizumab reduced the risk of SAEs, asthma exacerbation, bronchitis and sinusitis, and aggravated the risk of headache and pyrexia. Other AEs were comparable between the benralizumab group and placebo group. Therefore, benralizumab is a relatively safe drug, but vigilance regarding AEs is imperative during long-term treatment.
| S-EPMC6709166 | biostudies-literature