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Mitchell Goldman - One of the best experts on this subject based on the ideXlab platform.

  • Benralizumab for adolescent patients with severe eosinophilic asthma safety and efficacy after 3 years of treatment
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: William W. Busse, Eugene R Bleecker, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Mitchell Goldman, Ubaldo J Martin, Richard F Olsson, Laura Brooks, Bora Study Investigators
    Abstract:

    Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III Benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of Benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on Benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to Benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with Benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of Benralizumab treatment in adolescents) were consistent with previous findings.

  • relationship between Benralizumab exposure and efficacy for patients with severe eosinophilic asthma
    Clinical Pharmacology & Therapeutics, 2019
    Co-Authors: Yen Lin Chia, Bing Wang, Peter Barker, Mitchell Goldman, Li Yan, Lorin Roskos
    Abstract:

    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 (FEV1 ) 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 reduced efficacy; low CALIMA placebo AER possibly confounded this result. In population modeling, estimated Benralizumab 90% effective concentration for AER reduction was 927 ng/mL, below the Q8W dosage steady-state average PK concentration (1,066 ng/mL). Benralizumab treatment resulted in more rapid FEV1 improvement vs. placebo (estimated half-maximum time: 7.6 vs. 18 days); this response was greater for patients with greater baseline eosinophil counts. These results confirmed 30 mg Q8W is the optimal Benralizumab dosage for patients with severe eosinophilic asthma.

  • rapid onset of effect of Benralizumab on morning peak expiratory flow in severe uncontrolled asthma
    Annals of Allergy Asthma & Immunology, 2019
    Co-Authors: Geoffrey Chupp, Gary T Ferguson, Mitchell Goldman, James Zangrilli, Njira L Lugogo, Joel N Kline, I Hirsch, Frank Trudo
    Abstract:

    Abstract Background Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. Objective To assess Benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. Methods Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the Benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). Results Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of Benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. Conclusion In 3 phase 3 randomized clinical trials, Benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that Benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. Trial Registration ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

  • Benralizumab does not impair antibody response to seasonal influenza vaccination in adolescent and young adult patients with moderate to severe asthma results from the phase iiib alize trial
    Journal of Asthma and Allergy, 2018
    Co-Authors: Pamela L Zeitlin, Mila Leong, Jeremy Cole, Raburn M Mallory, Vivian H Shih, Richard F Olsson, Mitchell Goldman
    Abstract:

    Background and objectives Benralizumab is a humanized, afucosylated monoclonal antibody against the IL-5Rα. Initial monthly followed by every-other-month injections result in rapid and nearly complete eosinophil depletion. We evaluated whether three doses of Benralizumab modifies antibody response to seasonal influenza vaccination for adolescent/young adult patients with moderate to severe asthma. Methods ALIZE (NCT02814643) was a Phase IIIb randomized controlled trial of patients aged 12-21 years receiving medium- to high-dosage inhaled corticosteroids/long-acting β2-agonists. Patients received Benralizumab 30 mg or placebo at Weeks 0, 4, and 8, plus tetravalent influenza vaccination at Week 8. At Week 12, strain-specific antibody responses following vaccination were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Results A total of 103 patients were randomized and received Benralizumab (n=51) or placebo (n=52). There were no consistent differences in HAI or MN antibody responses at Week 12 between patients receiving Benralizumab or placebo. HAI geometric mean fold rises (GMFRs) for all influenza strains tested were 3.3-4.2 for Benralizumab vs 3.4-3.9 for placebo; MN GMFRs were 2.8-5.1 for Benralizumab vs 3.2-4.4 for placebo. A ≥4-fold rise in HAI from Weeks 8 to 12 occurred in 44.0%-56.0% and 30.6%-49.0% of patients receiving Benralizumab and placebo, respectively. At Week 12, 78.0%-100% vs 79.6%-100% of patients receiving Benralizumab and placebo, respectively, achieved a ≥40 HAI antibody titer. There were no significant safety findings. Conclusion Benralizumab did not impair the antibody response to seasonal virus vaccination in adolescents and young adult patients with moderate to severe asthma.

  • Benralizumab efficacy by atopy status and serum immunoglobulin e for patients with severe uncontrolled asthma
    Annals of Allergy Asthma & Immunology, 2018
    Co-Authors: Bradley E Chipps, Ian Hirsch, Paul Newbold, Frank Trudo, Mitchell Goldman
    Abstract:

    Abstract Background Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Objective To investigate the efficacy of Benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations. Methods We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting β 2 -agonists received 30 mg of subcutaneous Benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab-qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (≥150 kU/L) or low serum IgE ( Results Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26–61, P  = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018–0.232, P  = .0218) vs placebo for patients with at least 300 eosinophils/μL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with Benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate ( P  ≤ .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second ( P  ≤ .0041) vs placebo, respectively. Conclusion Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status.

Eugene R Bleecker - One of the best experts on this subject based on the ideXlab platform.

  • Benralizumab for adolescent patients with severe eosinophilic asthma safety and efficacy after 3 years of treatment
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: William W. Busse, Eugene R Bleecker, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Mitchell Goldman, Ubaldo J Martin, Richard F Olsson, Laura Brooks, Bora Study Investigators
    Abstract:

    Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III Benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of Benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on Benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to Benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with Benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of Benralizumab treatment in adolescents) were consistent with previous findings.

  • two year integrated steroid sparing analysis and safety of Benralizumab for severe asthma
    Journal of Asthma, 2019
    Co-Authors: Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Laura Brooks, Andrew Menziesgow, Dominick E Shaw, Esther Garcia Gil
    Abstract:

    Objective: Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with sever...

  • two year integrated efficacy and safety analysis of Benralizumab in severe asthma
    Journal of Asthma and Allergy, 2019
    Co-Authors: Mark J Fitzgerald, Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Peter Barker, Laura Brooks, Ubaldo J Martin
    Abstract:

    Background Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma. Objective We explored whether Benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile. Methods Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of Benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving Benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and <300 cells/μL). Results Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with Benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of Benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with Benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events. Conclusion This Benralizumab 2-year integrated analysis further supports long-term use of Benralizumab for patients with severe, uncontrolled eosinophilic asthma.

  • baseline patient factors impact on the clinical efficacy of Benralizumab for severe asthma
    European Respiratory Journal, 2018
    Co-Authors: Eugene R Bleecker, Mark J Fitzgerald, Mitchell Goldman, Paul Newbold, Ian Hirsch, Michael E Wechsler, Andrew Menziesgow, James Zangrilli
    Abstract:

    Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on Benralizumab efficacy for patients with severe asthma. This analysis used pooled data from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) Phase III studies. Patients aged 12–75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting β 2 -agonists received Benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks [Q4W]), Q4W, or placebo. Baseline factors that influenced Benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, prebronchodilator forced vital capacity (FVC), prior year exacerbations, and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in prebronchodilator forced expiratory volume in 1 s at treatment end relative to placebo. Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·μL −1 relative to the overall population. OCS use, nasal polyposis, and FVC −1 . Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to Benralizumab.

  • predictors of enhanced response with Benralizumab for patients with severe asthma pooled analysis of the sirocco and calima studies
    The Lancet Respiratory Medicine, 2018
    Co-Authors: Mark J Fitzgerald, Eugene R Bleecker, Paul Newbold, James Zangrilli, Ian Hirsch, Andrew Menziesgow, Paul Metcalfe, Mitchell Goldman
    Abstract:

    Summary Background 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. Methods 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. Findings 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; p Interpretation These results will help to guide clinicians when they are deciding whether to use Benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma. Funding AstraZeneca.

Peter Barker - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Benralizumab in chronic rhinosinusitis with nasal polyps a randomized placebo controlled trial
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: Claus Bachert, Peter Barker, Jody Tversky, Joseph K Han, Martin Desrosiers, Philippe Gevaert, Enrico Heffler, Claire Hopkins, David Cohen, Claire Emson
    Abstract:

    ABSTRACT Background Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). Objective We sought to assess the efficacy and safety of Benralizumab-mediated eosinophil depletion for treating CRSwNP. Methods The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with Benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Co-primary endpoints were change from baseline to week 40 in nasal polyp score (NPS) and patient-reported biweekly mean nasal blockage score (NBS). Results The study population comprised 413 randomized patients (Benralizumab, 207; placebo, 206). Benralizumab significantly improved NPS and NBS compared with placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test-22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was achieved for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. Conclusion Benralizumab added to standard-of-care therapy reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared with placebo in patients with CRSwNP.

  • Benralizumab for adolescent patients with severe eosinophilic asthma safety and efficacy after 3 years of treatment
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: William W. Busse, Eugene R Bleecker, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Mitchell Goldman, Ubaldo J Martin, Richard F Olsson, Laura Brooks, Bora Study Investigators
    Abstract:

    Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III Benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of Benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on Benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to Benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with Benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of Benralizumab treatment in adolescents) were consistent with previous findings.

  • comparison of autoinjector with accessorized prefilled syringe for Benralizumab pharmacokinetic exposure ames trial results
    Journal of Asthma, 2021
    Co-Authors: Ubaldo J Martin, Peter Barker, Rainard Fuhr, Pablo Forte, Milton J Axley, Magnus Aurivillius, Li Yan, Lorin Roskos
    Abstract:

    Objective: We compared the pharmacokinetic exposure following a single subcutaneous dose of Benralizumab 30 mg using either autoinjectors (AI) or accessorized prefilled syringes (APFS). APFS and AI...

  • safety of eosinophil depleting therapy for severe eosinophilic asthma focus on Benralizumab
    Drug Safety, 2020
    Co-Authors: David J Jackson, Peter Barker, Ubaldo J Martin, Stephanie Korn, Sameer K Mathur, Venkata G Meka, James Zangrilli
    Abstract:

    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 α (IL-5Rα)–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-5Rα–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.

  • onset of effect changes in airflow obstruction and lung volume and health related quality of life improvements with Benralizumab for patients with severe eosinophilic asthma phase iiib randomized controlled trial solana
    Journal of Asthma and Allergy, 2020
    Co-Authors: Reynold A Panettieri, Peter Barker, Richard F Olsson, Stephanie Korn, Tobias Welte, Kartik Shenoy, Margret Jandl, Edward Kerwin, Rosa Feijoo, Ubaldo J Martin
    Abstract:

    Objective In the SOLANA trial, we sought to physiologically characterize Benralizumab's onset of effect and maintenance of that effect for patients with severe eosinophilic asthma. Methods SOLANA (NCT02869438) was a multicenter, randomized, double-blind, parallel-group, placebo-controlled, Phase IIIb study conducted at 49 centers in six countries (Chile, Germany, Hungary, the Philippines, South Korea, and the United States). Eligible patients with baseline blood eosinophil counts ≥300 cells/µL were randomized to subcutaneous Benralizumab (30 mg) or placebo administered at Days 0, 28, and 56. The primary endpoint was the average change from baseline in prebronchodilator forced expiratory volume in 1 s (pre-BD FEV1) during the Day 28‒Day 84 period for Benralizumab vs placebo. Secondary endpoints included patient-reported outcomes (PROs). A subset of patients participated in a whole-body plethysmography substudy. Safety was also assessed. Results In total, 233 patients were randomized to Benralizumab (n=118) or placebo (n=115). Improvement from baseline in pre-BD FEV1 with Benralizumab 30 mg was not statistically significant compared with placebo (least-squares mean change difference [95% confidence interval] 57 mL [-22 to 135]; p=0.16). Compared with placebo, Benralizumab demonstrated early (Day 7) nonstatistically significant improvements in whole-body plethysmography assessments of hyperinflation and clinically meaningful improvements in PRO measures (Asthma Control Questionnaire 6 at Day 14 and St. George's Respiratory Questionnaire at Day 28), which were maintained over the treatment period. Benralizumab's safety profile was commensurate with previously reported studies. Conclusion The observed early changes in lung volume despite relatively small improvements in airflow obstruction suggest that the anti-inflammatory effect of Benralizumab may be manifested as deflation over time for patients with hyperinflation, who potentially have a greater degree of airway remodeling. This early effect could partially explain the rapid PRO improvements observed for certain patients.

Mark J Fitzgerald - One of the best experts on this subject based on the ideXlab platform.

  • Benralizumab for adolescent patients with severe eosinophilic asthma safety and efficacy after 3 years of treatment
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: William W. Busse, Eugene R Bleecker, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Mitchell Goldman, Ubaldo J Martin, Richard F Olsson, Laura Brooks, Bora Study Investigators
    Abstract:

    Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III Benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of Benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on Benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to Benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with Benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of Benralizumab treatment in adolescents) were consistent with previous findings.

  • two year integrated steroid sparing analysis and safety of Benralizumab for severe asthma
    Journal of Asthma, 2019
    Co-Authors: Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Laura Brooks, Andrew Menziesgow, Dominick E Shaw, Esther Garcia Gil
    Abstract:

    Objective: Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with sever...

  • two year integrated efficacy and safety analysis of Benralizumab in severe asthma
    Journal of Asthma and Allergy, 2019
    Co-Authors: Mark J Fitzgerald, Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Peter Barker, Laura Brooks, Ubaldo J Martin
    Abstract:

    Background Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma. Objective We explored whether Benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile. Methods Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of Benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving Benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and <300 cells/μL). Results Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with Benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of Benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with Benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events. Conclusion This Benralizumab 2-year integrated analysis further supports long-term use of Benralizumab for patients with severe, uncontrolled eosinophilic asthma.

  • baseline patient factors impact on the clinical efficacy of Benralizumab for severe asthma
    European Respiratory Journal, 2018
    Co-Authors: Eugene R Bleecker, Mark J Fitzgerald, Mitchell Goldman, Paul Newbold, Ian Hirsch, Michael E Wechsler, Andrew Menziesgow, James Zangrilli
    Abstract:

    Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on Benralizumab efficacy for patients with severe asthma. This analysis used pooled data from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) Phase III studies. Patients aged 12–75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting β 2 -agonists received Benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks [Q4W]), Q4W, or placebo. Baseline factors that influenced Benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, prebronchodilator forced vital capacity (FVC), prior year exacerbations, and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in prebronchodilator forced expiratory volume in 1 s at treatment end relative to placebo. Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·μL −1 relative to the overall population. OCS use, nasal polyposis, and FVC −1 . Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to Benralizumab.

  • predictors of enhanced response with Benralizumab for patients with severe asthma pooled analysis of the sirocco and calima studies
    The Lancet Respiratory Medicine, 2018
    Co-Authors: Mark J Fitzgerald, Eugene R Bleecker, Paul Newbold, James Zangrilli, Ian Hirsch, Andrew Menziesgow, Paul Metcalfe, Mitchell Goldman
    Abstract:

    Summary Background 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. Methods 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. Findings 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; p Interpretation These results will help to guide clinicians when they are deciding whether to use Benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma. Funding AstraZeneca.

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  • Benralizumab for adolescent patients with severe eosinophilic asthma safety and efficacy after 3 years of treatment
    The Journal of Allergy and Clinical Immunology, 2021
    Co-Authors: William W. Busse, Eugene R Bleecker, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Mitchell Goldman, Ubaldo J Martin, Richard F Olsson, Laura Brooks, Bora Study Investigators
    Abstract:

    Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III Benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of Benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on Benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to Benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with Benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of Benralizumab treatment in adolescents) were consistent with previous findings.

  • two year integrated steroid sparing analysis and safety of Benralizumab for severe asthma
    Journal of Asthma, 2019
    Co-Authors: Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Mark J Fitzgerald, Peter Barker, Laura Brooks, Andrew Menziesgow, Dominick E Shaw, Esther Garcia Gil
    Abstract:

    Objective: Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with sever...

  • two year integrated efficacy and safety analysis of Benralizumab in severe asthma
    Journal of Asthma and Allergy, 2019
    Co-Authors: Mark J Fitzgerald, Arnaud Bourdin, Eugene R Bleecker, William W. Busse, Gary T Ferguson, Peter Barker, Laura Brooks, Ubaldo J Martin
    Abstract:

    Background Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with Benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma. Objective We explored whether Benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile. Methods Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of Benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving Benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and <300 cells/μL). Results Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with Benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of Benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with Benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events. Conclusion This Benralizumab 2-year integrated analysis further supports long-term use of Benralizumab for patients with severe, uncontrolled eosinophilic asthma.

  • single use autoinjector functionality and reliability for at home administration of Benralizumab for patients with severe asthma greco trial results
    Journal of Asthma and Allergy, 2019
    Co-Authors: Gary T Ferguson, Peter Barker, Ubaldo J Martin, Magnus Aurivillius, Jeremy Cole, Paul Roussel, Greco Study Investigators
    Abstract:

    Purpose Accessorized prefilled syringes (APFS) have demonstrated functionality and reliability for subcutaneous (SC) delivery, including self-administration, of Benralizumab 30 mg in the clinic or at home. The multicenter, open-label GRECO study (NCT02918071) assessed functionality and reliability of a single-use autoinjector (AI) for at-home Benralizumab administration by patients or their caregivers. Patients and methods Adults with severe asthma received Benralizumab SC injections at the study site at Weeks 0, 4, and 8. The first dose was administered by health care providers. Patients/caregivers had the option of administering the second dose and were required to administer the third dose under supervision. At Weeks 12 and 16, patients/caregivers administered Benralizumab via AI at home. After each administration, patients/caregivers completed questionnaires concerning administration and device functioning. All AI devices used were returned for evaluation. Results A total of 595 AIs were used for 121 patients (mean age 48.5 years; 64% female) in the clinic and at home. Of 116 participants, 113 (97.4%; 95% confidence interval [CI]: 92.63-99.46) and 112 (96.6%; 95% CI: 91.41-99.05) successfully administered Benralizumab at home at Weeks 12 and 16, respectively; 108 (93.1%; 95% CI: 86.86-96.98) were successful on both occasions. Throughout the study, 10 (1.7%) AI administrations were unsuccessful: 8 (1.3%) because of user error, 1 (0.2%) with undetermined cause, and 1 (0.2%) because of a manufacturing defect. Benralizumab efficacy (assessed by Asthma Control Questionnaire 6 score) and pharmacokinetics for patients using the AI were comparable to published results for patients receiving Benralizumab via syringe in a clinical setting. No new or unexpected safety findings were observed. Conclusion AIs were functional, reliable, and performed well in the clinic and at home. Nearly all patients and caregivers successfully administered SC Benralizumab via AI. Benralizumab availability in AI and APFS could provide patients with choices for self-administration.

  • rapid onset of effect of Benralizumab on morning peak expiratory flow in severe uncontrolled asthma
    Annals of Allergy Asthma & Immunology, 2019
    Co-Authors: Geoffrey Chupp, Gary T Ferguson, Mitchell Goldman, James Zangrilli, Njira L Lugogo, Joel N Kline, I Hirsch, Frank Trudo
    Abstract:

    Abstract Background Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. Objective To assess Benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. Methods Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the Benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). Results Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of Benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. Conclusion In 3 phase 3 randomized clinical trials, Benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that Benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. Trial Registration ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).