Abstract
Background Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. Methods In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757. Findings Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group). Interpretation Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. Funding AstraZeneca and Kyowa Hakko Kirin.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2128-2141 |
| Number of pages | 14 |
| Journal | The Lancet |
| Volume | 388 |
| Issue number | 10056 |
| DOIs | |
| State | Published - Oct 29 2016 |
| Externally published | Yes |
ASJC Scopus subject areas
- Medicine(all)
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In: The Lancet, Vol. 388, No. 10056, 29.10.2016, p. 2128-2141.
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TY - JOUR
T1 - Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA)
T2 - a randomised, double-blind, placebo-controlled phase 3 trial
AU - FitzGerald, J. Mark
AU - Bleecker, Eugene R.
AU - Nair, Parameswaran
AU - Korn, Stephanie
AU - Ohta, Ken
AU - Lommatzsch, Marek
AU - Ferguson, Gary T.
AU - Busse, William W.
AU - Barker, Peter
AU - Sproule, Stephanie
AU - Gilmartin, Geoffrey
AU - Werkström, Viktoria
AU - Aurivillius, Magnus
AU - Goldman, Mitchell
N1 - Funding Information: The results of the CALIMA study showed that 56 weeks of add-on therapy with benralizumab 30 mg Q4W and Q8W significantly reduced the annual rate of asthma exacerbations by up to 36% for patients with severe asthma and elevated blood eosinophils that were inadequately controlled on existing standard of care therapy. Both benralizumab dosing regimens also significantly improved lung function and, when administered every 8 weeks, significantly improved patient-reported total asthma symptom scores relative to baseline and placebo. Furthermore, benralizumab rapidly depleted blood eosinophils to the limits of detection. Together, these findings are consistent with the established mechanism of action of benralizumab 18 and validate the approach of targeting the interleukin-5 receptor α to deplete blood eosinophils and improve clinical outcomes for this difficult-to-treat group of patients. Our findings confirm and support results from the phase 3 SIROCCO study, ). Despite similar trial designs and target patient groups included in the primary analyses, reductions in exacerbation rates seemed to be greater in the SIROCCO study than in the CALIMA study. A potential explanation for this difference in efficacy between the trials is not completely clear. However, subgroup analyses suggested that heterogeneity in regional exacerbation rates in CALIMA might have contributed to the size of treatment effect of benralizumab to a greater extent in CALIMA than in SIROCCO. This finding was substantially the consequence of patients from the eastern Europe and rest of world (ie, South America) regions who had fewer exacerbations in the year before study entry (ie, less severe baseline disease) compared with patients from the other regions, and because these patients had a very low rate of exacerbations during the treatment period, irrespective of benralizumab regimen. In support of this explanation, we found that patients who had experienced three or more exacerbations in the previous year (ie, greater asthma severity at baseline), and who were under-represented in the eastern Europe and rest of world (South America) regions, had the greatest effects of benralizumab treatment. Exacerbation reductions in this subgroup of CALIMA patients (three or more exacerbations in year before study) mirror annual asthma exacerbation rate reduction results of the SIROCCO study—ie, 45% and 51% for the Q4W and Q8W regimens, respectively, in both studies. 28 in which 48 weeks of add-on benralizumab 30 mg (Q4W and Q8W) resulted in substantial improvements in asthma exacerbations, lung function, and symptom control for patients with severe, uncontrolled asthma with baseline blood eosinophils 300 cells per μL or greater ( table 5 28 In addition to regional heterogeneity and exacerbation history, the efficacy results of the CALIMA trial seemed to be affected by a strong placebo response. At baseline, the exacerbation rate of the placebo group of the primary analysis population was 2·7, which had fallen to 0·93 by the end of treatment. This response could have led to an underestimation of the treatment benefit of benralizumab in CALIMA. Our findings confirm and extend results obtained in earlier clinical studies of benralizumab. In CALIMA, benralizumab treatment resulted in direct, rapid, and nearly complete eosinophil depletion at 4 weeks, the first sampling timepoint, consistent with phase 1 and 2 study results showing such depletion to occur as early as day 1, 21–23 which is consistent with the potent depletion of eosinophils seen in CALIMA. In the phase 2B dose-ranging study, depletion of eosinophil counts was associated with a 41% (80% CI 11–60) reduction in the annual exacerbation rate, as well as improved lung function and symptom control, for patients with severe, uncontrolled asthma treated with 52 weeks benralizumab 100 mg Q8W, compared with placebo. Moreover, the reduction in exacerbation rate relative to placebo was 57% (80% CI 33–72) for the subset of patients with baseline blood eosinophils 300 cells per μL or greater. The results from CALIMA and SIROCCO allow more confident predictions of benralizumab efficacy in this patient subpopulation, as well as estimates of treatment benefits for patients receiving high-dosage inhaled corticosteroids plus LABA with baseline blood eosinophils less than 300 cells per μL. These results also provide support for assessments of benralizumab in the treatment of other diseases with an eosinophilic component. The results obtained in the CALIMA trial add to a growing body of data that supports the use of anti-interleukin-5 pathway drugs in the management of patients with severe, uncontrolled asthma. By contrast with benralizumab, which acts directly on the eosinophil interleukin-5 receptor to cause eosinophil apoptosis, reslizumab and mepolizumab target the interleukin-5 molecule, thereby leading to passive reduction of eosinophils. One advantage of the former approach is that benralizumab could circumvent the induction of increased cytokine production associated with anti-cytokine antibodies. 29 A further advantage is that the direct action of benralizumab results in greater depletions of blood eosinophils than the indirect action of medications that target the interleukin-5 ligand. 18 In phase 3 studies, reslizumab and mepolizumab treatment resulted in substantial reductions in exacerbation rates with attendant reductions in circulating eosinophils. 13–16 Although direct comparison of different biologics is not possible in the absence of dedicated, head-to-head comparative trials, improvements in exacerbation rates seem to be comparable to those reported for patients treated with reslizumab or mepolizumab. However, these findings should be viewed in light of the asthma profiles of the patients recruited into the respective studies, who probably had more severe asthma at baseline than did patients enrolled in CALIMA. The reslizumab studies focused on patients with greater eosinophil counts (ie, baseline blood eosinophils in excess of 400 cells per μL) who might be expected to be more responsive to therapy. 13 Patients were recruited to the DREAM and MENSA mepolizumab studies with greater baseline inhaled corticosteroid dosages than patients in CALIMA (ie, ≥880 μg vs ≥500 μg fluticasone formulation or equivalent, respectively), which indicates more severe asthma. 14–16 Moreover, patients enrolled in mepolizumab studies had greater baseline and on-treatment exacerbation rates than patients enrolled in CALIMA, 14–16 which indicates a more severe exacerbation phenotype. The improvements in exacerbation rates indicated by the post-hoc analysis of CALIMA patients with a more severe exacerbation history (ie, three or more exacerbations in the previous year), mirror efficacy results obtained for the overall population in the SIROCCO study, 28 as well as the mepolizumab and reslizumab studies. 13–16 Increases in lung function with benralizumab treatment seemed to be comparable or greater than those observed for mepolizumab and reslizumab, 13,15 with improvements observed as early as 4 weeks, the first timepoint assessed. We also found small improvements in ACQ-6 and AQLQ(S)+12 scores for patients treated with the benralizumab Q8W regimen, which are consistent with results obtained for mepolizumab and reslizumab. 13,15 However, the clinical benefit of small improvements such as these is uncertain. In addition to drugs that target the interleukin-5 pathway, other biologic agents are in clinical development for the treatment of uncontrolled asthma. Dupilumab is a human anti-interleukin-4 receptor α monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling. This agent has increased lung function and reduced severe exacerbations for patients with uncontrolled, persistent asthma in a phase 2 study. 30 Benralizumab was well tolerated, as shown by the low discontinuation rate and an anticipated safety profile in the CALIMA study based on the results of the phase 2B study. 23 Few adverse events were considered to be drug related, and discontinuations due to benralizumab were uncommon. Anti-drug antibody responses were infrequent, and there was no indication that positive anti-drug antibody responses were associated with hypersensitivity or affected efficacy outcomes. Our study has some limitations. CALIMA enrolment enriched the study population of patients with baseline blood eosinophils 300 cells per μL or greater (via 2:1 randomisation). Therefore, this study was not designed to compare outcomes for patients with baseline blood eosinophils 300 cells per μL or greater with patients with lower blood eosinophil counts. In addition, the CALIMA study was not powered to detect differences between the two benralizumab dosing regimens. Patients enrolled in CALIMA and SIROCCO were eligible to join the 2-year BORA safety extension study ( NCT02258542 ). This study will provide data for the longer term use of benralizumab, which cannot be provided by CALIMA or SIROCCO. Finally, because of small sample sizes, we were unable to assess whether benralizumab resulted in efficacy for different patient subgroups of interest (eg, black or African American, adolescent, and atopic patients). The results obtained from this study, together with those obtained in SIROCCO, provide strong evidence of the clinical value of benralizumab treatment in the management of patients with severe or uncontrolled asthma and blood eosinophils 300 cells per μL or greater. Benralizumab, an anti-eosinophil monoclonal antibody that targets the interleukin-5 receptor α, represents a new mechanism of action to address the unmet needs of these patients. Contributors JMF, ERB, and MG conceived and designed the study. PB, SS, GG, MA, VW, and MG collected the data. All authors had access to and analysed and interpreted the data. All authors participated in the development and critical review of the report. All authors provided final approval for publication submission and are accountable for the accuracy and integrity of the work. Declaration of interests JMF is a member of advisory boards for AstraZeneca, Novartis, Teva, ALK, and Boehringer Ingelheim; and has also been paid honoraria for lecturing at symposia organised by these companies. ERB has undertaken clinical trials through his employer, Wake Forest School of Medicine, for AstraZeneca, MedImmune, Boehringer Ingelheim, Pfizer, Cephalon/Teva, Forest, Genentech, GSK, Johnson & Johnson (Janssen), Novartis, and Sanofi; and has also served as a paid consultant for AstraZeneca, MedImmune, Boehringer Ingelheim, Pfizer, GSK, Forest, Novartis, Regeneron, and Sanofi. PN is a member of advisory boards for AstraZeneca, Sanofi, Teva, and Roche; and has also received honoraria from these companies and from Novartis and Boehringer Ingelheim for lectures at symposia. SK reports being a member of advisory boards for AstraZeneca, Teva, Roche, and Novartis and has received honoraria from these companies for lectures at symposia. KO declares no competing interests. ML received honoraria for lectures and advisory boards from ALK Abelló, Allergopharma, AstraZeneca, Bencard, Berlin-Chemie, Boehringer Ingelheim, Boston Scientific, Chiesi, GSK, Janssen-Cilag, MSD, Mundipharma, Novartis, Nycomed/Takeda, Sanofi, TEVA, and UCB. GTF reports grants and personal fees from Novartis, AstraZeneca, Pearl Therapeutics, and Sunovian, as well as grants from Forest and personal fees from GlaxoSmithKline. WWB reports personal fees from Novartis, Genentech, Roche, Boehringer Ingelheim, Sanofi, AstraZeneca, Teva, 3M, Boston Scientific, Circassia, ICON, and GlaxoSmithKline, outside of the submitted work. PB, GG, MA, VW, and MG are employees of AstraZeneca. SS is an employee of Optimum Statistics Inc and provided statistical analyses and support under contract to AstraZeneca, through inVentiv Health Clinical. Acknowledgments Funding for this study was provided by AstraZeneca and Kyowa Hakko Kirin. We would like to thank the investigators, health-care providers, research staff, and patients who participated in the CALIMA study. We would like to acknowledge Mark Odorisio (AstraZeneca, Gaithersburg, MD, USA), Nick Adye (AstraZeneca, Cambridge, UK), and Irma Dzhindzhikhashvili (AstraZeneca, Warsaw, Poland) for their clinical operations leadership in this study. We also thank Ian Hirsch (AstraZeneca, Gaithersburg, MD, USA) for biometrics management and support of statistical analyses and programming. Writing and editing assistance, including preparation of a draft report under the direction and guidance of the authors, incorporating author feedback, and manuscript submission, was provided by Neil M Thomas (Endpoint Medical Communications, Brighton, UK) and Michael A Nissen (AstraZeneca). This support was funded by AstraZeneca. Publisher Copyright: © 2016 Elsevier Ltd
PY - 2016/10/29
Y1 - 2016/10/29
N2 - Background Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. Methods In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757. Findings Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group). Interpretation Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. Funding AstraZeneca and Kyowa Hakko Kirin.
AB - Background Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. Methods In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757. Findings Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group). Interpretation Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. Funding AstraZeneca and Kyowa Hakko Kirin.
UR - http://www.scopus.com/inward/record.url?scp=84994910846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994910846&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(16)31322-8
DO - 10.1016/S0140-6736(16)31322-8
M3 - Article
C2 - 27609406
AN - SCOPUS:84994910846
SN - 0140-6736
VL - 388
SP - 2128
EP - 2141
JO - The Lancet
JF - The Lancet
IS - 10056
ER -