Oral corticosteroid (OCS) treatment for severe asthma is associated with substantial disease burden. Thus, OCS dosage reduction is desirable. Relative efficacy of biologics in reducing OCS treatment for severe, uncontrolled asthma is not fully characterized.
We performed a matching‐adjusted indirect comparison (MAIC) to assess the relative effects on OCS treatment reduction of three biologic asthma treatments.
In MAIC of benralizumab vs. mepolizumab and vs. dupilumab, patient‐level data from the Phase III benralizumab OCS‐sparing trial, ZONDA, were weighted to match treatment effect–modifying patient characteristics in comparator trials.
After matching adjustment, mean difference between benralizumab and mepolizumab for OCS reduction was 6.08% (95% CI −22.22‐34.38;
Following patient baseline characteristics matching across clinical trials, benralizumab demonstrated efficacy comparable to mepolizumab and dupilumab for OCS dosage reduction, OCS elimination, and annual exacerbation rate reduction. Comparatively low effective sample sizes indicated substantial differences for patient populations between ZONDA and mepolizumab and dupilumab trials.
This study was funded by AstraZeneca.
Patients with severe asthma have substantial disease burden and are susceptible to frequent exacerbations.
OCS‐sparing potential has been demonstrated by three biologics approved for treatment of severe asthma: benralizumab, an interleukin (IL)‐5 receptor alpha–directed cytolytic monoclonal antibody; mepolizumab, an anti–IL‐5 monoclonal antibody; and dupilumab, a monoclonal antibody that inhibits IL‐4 and IL‐13.
Although these data are useful to clinicians, data comparing the OCS‐sparing potential of benralizumab, mepolizumab, and dupilumab would be even more helpful in interpreting comparative efficacy for patients with severe asthma receiving OCS maintenance treatment. However, there have been no head‐to‐head trials with these treatments.
Indirect treatment comparison (ITC) via matching‐adjusted indirect comparison (MAIC) allows for comparison of treatments across clinical trials.
MAIC is a population‐adjusted ITC designed to reduce bias by matching patient‐level data from clinical trials of one treatment with aggregate data reported for comparator trials.
This second publication in a series of MAIC analyses of data for patients with severe, uncontrolled asthma compares benralizumab with mepolizumab and with dupilumab for effects on mean percentage of OCS dosage reduction, patients who achieved elimination of OCS treatment, and annualized exacerbation rate.
This MAIC analysis followed guidance for well‐designed, population‐adjusted ITCs.
Benralizumab was compared with mepolizumab and with dupilumab for three outcomes: OCS dosage reduction (at 24 weeks and at the end of the trial), percentage of patients able to eliminate OCS treatment at 24 weeks, and annual rate of clinically significant exacerbations. End‐of‐trial values were from week 28 for ZONDA and week 24 for SIRIUS and LIBERTY ASTHMA VENTURE. Odds ratios for elimination of OCS treatment were calculated based on the overall trial populations, not just the subsets of patients eligible for complete OCS reduction based on baseline OCS dosage. Annual rates of clinically significant exacerbations were estimated as rate ratios for active treatments vs. placebo.
All analyses were conducted with SAS version 9.1 (SAS Institute Inc, Cary, NC, USA) and R version 3.0.3 (R Foundation for Statistical Computing, Vienna).
We compared study population differences between ZONDA
ZONDA
Relative treatment effects of benralizumab vs. mepolizumab and vs. dupilumab were estimated with standard ITC methodologies.
To identify important variability across study methods, we examined study characteristics including sample size and patient selection criteria (Appendix
Evidence networks were generated from the benralizumab ZONDA trial and the mepolizumab SIRIUS trial for placebo‐anchored comparison of benralizumab vs. mepolizumab, and from the ZONDA trial and the dupilumab LIBERTY ASTHMA VENTURE trial for placebo‐anchored comparison of benralizumab vs. dupilumab
The ZONDA and SIRIUS studies were broadly similar in overall design, inclusion/exclusion criteria, trial setting, blinding procedures (Appendix
Comparison of baseline characteristics of patients included in benralizumab (ZONDA) and mepolizumab (SIRIUS) studies
Characteristics | ZONDA | SIRIUS | ||
---|---|---|---|---|
Benralizumab 30 mg Q8W | Placebo | Mepolizumab 100 mg Q4W | Placebo | |
Age, years | 52.9 (10.1) | 49.9 (11.7) | 49.8 (14.1) | 49.9 (10.3) |
Male (%) | 35.6 | 36.0 | 36.0 | 55.0 |
BMI, kg/m2 | 30.2 (6.5) | 28.7 (5.2) | 27.8 (5.9) | 29.5 (6.1) |
Pre‐bronchodilator FEV1 predicted, % | 59.0 (17.9) | 62.0 (16.5) | 59.6 (17.0) | 57.8 (18.5) |
Pre‐bronchodilator FEV1/FVC, % | 59.0 (12.0) | 62.0 (13.0) | 63.0 (12.4) | 61.0 (11.7) |
Pre‐bronchodilator FEV1, L | 1.8 (0.6) | 1.9 (0.7) | 1.9 (6.6) | 2.0 (8.2) |
Reversibility, % | 25.1 (19.0) | 23.2 (18.0) | 24.9 (19.3) | 23.7 (18.6) |
ACQ‐5 score | 2.4 (1.2) | 2.7 (0.9) | 2.2 (1.3) | 1.99 (1.2) |
Exacerbations in previous year | 3.1 (2.8) | 2.5 (1.8) | 3.3 (3.4) | 2.9 (2.8) |
0 exacerbations (%) | 0 | 0 | 17.0 | 15.0 |
1 exacerbation (%) | 28.8 | 32.0 | 16.0 | 17.0 |
≥ 2 exacerbations (%) | 71.2 | 68.0 | 67.0 | 68.0 |
Never‐smokers (%) | 83.6 | 77.3 | 59.0 | 62.0 |
OCS dosage, prednisolone equivalent, mg/d | 14.3 (7.8) | 14.2 (6.4) | 12.4 (7.2) | 13.2 (6.3) |
Blood eosinophil count, cells/µL | 509.0 (320.2) | 656.0 (589.0) | 413.0 (386.2) | 347.0 (303.3) |
Omalizumab use (%) | 12.3 | 10.7 | 33.0 | 33.0 |
Nasal polyps (%) | 27.4 | 37.3 | 23.0 | 26.0 |
Atopic (%) | 39.7 | 49.3 | – | – |
Data presented as mean (SD) unless otherwise indicated.
Abbreviations: ACQ‐5: Asthma Control Questionnaire 5; BMI: body mass index; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; OCS: oral corticosteroid; Q4W: every 4 weeks; Q8W: every 8 weeks (first 3 doses Q4W); SD: standard deviation.
Data extracted from the respective publication. All other values are extracted from the respective clinical study reports.
Baseline and sensitivity analysis characteristics of ZONDA patients before and after adjusting to SIRIUS patients for the analysis of percentage reduction in OCS dosage, percentage of patients with OCS elimination, and annual rate of clinically significant exacerbations
Characteristics | ZONDA | SIRIUS (aggregate reported data) | ZONDA (after adjusting to SIRIUS) |
---|---|---|---|
Benralizumab 30 mg Q8W + placebo N = 148 | Mepolizumab 100 mg Q4W + placebo N = 135 | Base‐case ESS = 72 Sensitivity ESS = 44 | |
Maintenance OCS dosage, prednisolone equivalent, mg/d | 14.21 (7.06) | 12.79 (6.74) | 12.79 (5.39) |
Blood eosinophil count, cells/µL | 583.05 (478.99) | 380.73 (348.15) | 380.73 (278.68) |
Exacerbations in the previous year | 2.78 (2.36) | 3.10 (3.10) | 3.10 (2.48) |
Nasal polyps (%) | 32.43 | 24.50 | 24.50 |
BMI, kg/m2 | 29.47 (5.94) | 28.66 (5.97) | 28.66 (4.78) |
ACQ‐5 score | 2.69 (1.15) | 2.07 (1.22) | 2.07 (0.83) |
History of omalizumab use (%) | 11.49 | 33 | 33 |
Data presented as mean (SD) unless otherwise indicated. Data in bold indicate variables used only in the sensitivity analysis.
Abbreviations: ACQ‐5: Asthma Control Questionnaire 5; BMI: body mass index; ESS: effective sample size; OCS: oral corticosteroid; Q4W: every 4 weeks; Q8W: every 8 weeks (first three doses Q4W); SD: standard deviation.
Data for the ZONDA population are calculated from individual patient data.
One patient was missing a baseline blood eosinophil count; six patients were missing information on 100% OCS reduction.
In comparing benralizumab vs. mepolizumab, the following variables were selected for matching in the base‐case model: eosinophil count, exacerbations in the previous year, OCS dosage, body mass index (BMI), and presence of nasal polyps. These variables, plus history of omalizumab use and ACQ‐5 score, were used in the sensitivity analysis. After adjustment for SIRIUS population characteristics, ZONDA baseline characteristics were well‐matched to the mepolizumab population (Table
Comparisons were performed at week 24. Because ZONDA (28 weeks) was longer than SIRIUS (24 weeks), additional analyses were conducted for end of study. From baseline to week 24, in the base‐case analysis, reduction of mean OCS dosage was 36% (95% CI 19‐54) greater with benralizumab treatment compared with placebo in ZONDA before matching adjustment and 22% (95% CI 4‐40) greater after matching adjustment to the mepolizumab population. From baseline to end of study, reduction of mean OCS dosage was 37% (95% CI 21‐53) greater with benralizumab treatment compared with placebo before matching and 21% (95% CI 5‐38) greater after matching to the mepolizumab population. Mepolizumab treatment reduced mean OCS dosage by 16% (95% CI −6‐38) more than placebo from baseline to week 24, which was also the end of study. After matching, mean differences in OCS reduction between benralizumab and mepolizumab at 24 weeks and at study end were 6.08% (95% CI −22.22‐34.38;
Indirect treatment comparisons of benralizumab and mepolizumab for (A) percentage reduction in oral corticosteroid (OCS) dosage, (B) percentage of patients with OCS elimination, and (C) reduction in annual rate of clinically significant exacerbations. CI: confidence interval; Q4W: every 4 wk; Q8W: every 8 wk (first three doses every 4 wk)
In a sensitivity analysis where adjustments for ACQ‐5 score and omalizumab use were added to the model as matching variables, reduction of mean OCS dosage was 28.14% (95% CI 8.94‐47.33) and 31.00% (95% CI 14.93‐47.07) greater with benralizumab treatment compared with placebo at week 24 and end of study, respectively. Mean differences in OCS reduction between benralizumab and mepolizumab at 24 weeks and at study end were 11.94% (95% CI −17.20‐41.08;
From baseline to week 24, odds ratios for OCS elimination with benralizumab Q8W vs. placebo were 4.06 (95% CI 1.67‐9.88) before matching and 4.80 (95% CI 1.62‐14.26) after matching adjustment to the mepolizumab population. Odds ratio for complete OCS dosage reduction for mepolizumab vs. placebo was 2.07 (95% CI 0.67‐6.44) from baseline to week 24. After matching, patients receiving benralizumab were not statistically significantly different (odds ratio 2.32 [95% CI 0.48‐11.15]) from those receiving mepolizumab for achieving OCS elimination (Figure
In the sensitivity analysis, before matching, the odds ratio for benralizumab vs. placebo was 6.25 (95% CI 1.63‐23.96). After matching, benralizumab had an odds ratio of 3.02 (95% CI 0.52‐17.49) vs. mepolizumab for achieving OCS elimination.
Benralizumab reduced the annual rate of clinically significant exacerbations vs. placebo by 70% (rate ratio [RR] 0.30, 95% CI 0.19‐0.49) in ZONDA before matching adjustment and by 62% (RR 0.38, 95% CI 0.21‐0.69) after matching adjustment to the mepolizumab population
The ZONDA and LIBERTY ASTHMA VENTURE studies were broadly similar in overall design, inclusion/exclusion criteria, trial setting, blinding procedures (Appendix
Comparison of baseline characteristics of patients included in benralizumab (ZONDA) and dupilumab (LIBERTY ASTHMA VENTURE) studies
Characteristics | ZONDA | LIBERTY ASTHMA VENTURE | ||
---|---|---|---|---|
Benralizumab 30 mg Q8W | Placebo | Dupilumab 300 mg Q2W | Placebo | |
Age, years | 52.9 (10.1) | 49.9 (11.7) | 51.9 (12.5) | 50.7 (12.8) |
Male (%) | 35.6 | 36.0 | 39.8 | 39.3 |
BMI, kg/m2 | 30.2 (6.5) | 28.7 (5.2) | 28.88 (5.91) | 29.77 (6.00) |
Pre‐bronchodilator FEV1 predicted, % | 59.0 (17.9) | 62.0 (16.5) | 51.64 (15.28) | 52.69 (15.14) |
Pre‐bronchodilator FEV1, L | 1.8 (0.6) | 1.9 (0.7) | 1.53 (0.53) | 1.63 (0.61) |
ACQ‐5 score | 2.4 (1.2) | 2.7 (0.9) | 2.42 (1.24) | 2.58 (1.09) |
Exacerbations in previous year | 3.1 (2.8) | 2.5 (1.8) | 2.01 (2.08) | 2.17 (2.24) |
OCS dosage, prednisolone equivalent, mg/d | 14.3 (7.8) | 14.2 (6.4) | 10.75 (5.90) | 11.75 (6.31) |
Blood eosinophil count, cells/µL | 509.0 (320.2) | 656.0 (589.0) | 370.0 (316) | 325 (298) |
Blood eosinophil count < 150 cells/µL (%) | 0 | 0 | 21.4 | 35.5 |
Blood eosinophil count ≥ 150 to < 300 cells/µL (%) | 16.4 | 14.7 | 32 | 26.2 |
Blood eosinophil count ≥ 300 cells/µL (%) | 83.6 | 85.3 | 46.6 | 38.3 |
Nasal polyps (%) | 27.4 | 37.3 | 32.0 | 35.5 |
Chronic rhinosinusitis (%) | 35.6 | 38.7 | 22.3 | 28 |
Omalizumab use (%) | 12.3 | 10.7 | – | – |
Atopic status (%) | 39.7 | 49.3 | – | – |
Data presented as mean (SD) unless otherwise indicated.
Abbreviations: ACQ: Asthma Control Questionnaire 5; BMI: body mass index; FEV1: forced expiratory volume in 1 s; OCS; oral corticosteroid; Q2W: every 2 wk; Q8W: every 8 wk (first three doses every 4 wk); SD: standard deviation.
Baseline characteristics of ZONDA patients before and after adjusting to LIBERTY ASTHMA VENTURE patients for the analysis of mean percentage reduction in OCS dosage and percentage of patients with OCS elimination
Characteristics | ZONDA | LIBERTY ASTHMA VENTURE (aggregate reported data) | ZONDA (after adjusting to LIBERTY ASTHMA VENTURE) |
---|---|---|---|
Benralizumab 30 mg Q8W + placebo N = 148 | Dupilumab 300 mg Q2W + placebo N = 210 | Benralizumab 30 mg Q8W SC + placebo ESS = 36 | |
BMI, kg/m2 | 29.47 (6.06) | 29.34 (5.96) | 29.34 (3.66) |
ACQ‐5 score | 2.67 (1.16) | 2.50 (1.16) | 2.5 (0.71) |
Exacerbations in previous year | 2.82 (2.39) | 2.09 (2.16) | 2.09 (1.33) |
OCS dosage adjusted at baseline, mg/d | 14.2 (7.05) | 11.26 (6.12) | 11.26 (3.76) |
Blood eosinophil count, cells/µL | 592.22 (483.84) | 347 (307) | 347 (188.45) |
Nasal polyps (%) | 32.39 | 33.80 | 33.81 |
Data presented as mean (SD) unless otherwise indicated.
Abbreviations: ACQ‐5: Asthma Control Questionnaire 5; BMI: body mass index; ESS: effective sample size; OCS: oral corticosteroid; Q2W: every 2 wk; Q8W: every 8 wk (first three doses every 4 wk); Abbreviation: SD, standard deviation.
Data for the ZONDA population are calculated from individual patient data.
One patient was missing a baseline blood eosinophil count; six patients were missing information on 100% OCS reduction.
For the benralizumab vs. dupilumab comparison of mean percentage OCS dosage reduction and percentage of patients with OCS elimination, the following variables were selected for matching: BMI, ACQ‐5 score, exacerbations in the previous year, OCS dosage, and presence of nasal polyps. After adjustment for LIBERTY ASTHMA VENTURE population characteristics, ZONDA baseline characteristics were well‐matched to the dupilumab population (Table
Baseline characteristics of ZONDA patients before and after adjusting to LIBERTY ASTHMA VENTURE patients for the analysis of annual exacerbation rate
Characteristics | ZONDA | LIBERTY ASTHMA VENTURE (aggregate reported data) | ZONDA (after adjusting to LIBERTY ASTHMA VENTURE) |
---|---|---|---|
Benralizumab 30 mg Q8W + placebo N = 148 | Dupilumab 300 mg Q2W + placebo N = 210 | Benralizumab 30 mg Q8W + placebo ESS = 36 | |
BMI, kg/m2 | 29.47 (5.94) | 29.34 (5.96) | 29.34 (3.72) |
ACQ‐5 score | 2.69 (1.15) | 2.50 (1.16) | 2.50 (0.72) |
Mean number of exacerbations in previous year | 2.78 (2.36) | 2.09 (2.16) | 2.09 (1.35) |
OCS dosage adjusted at baseline, prednisolone equivalent, mg/d | 14.21 (7.06) | 11.26 (6.12) | 11.26 (3.82) |
Blood eosinophil count, cells/µL | 583.05 (478.99) | 347 (307) | 347 (191.48) |
Nasal polyps (%) | 32.43 | 33.8 | 33.8 |
Data presented as mean (SD) unless otherwise indicated.
Abbreviations: ACQ‐5: Asthma Control Questionnaire 5; BMI: body mass index; ESS: effective sample size; OCS: oral corticosteroid; Q2W: every 2 wk; Q8W: every 8 wk (first three doses every 4 wk); SD: standard deviation.
Data for the ZONDA population are calculated from individual patient data.
One patient was missing a baseline blood eosinophil count.
From baseline to week 24 in ZONDA, reduction in mean OCS dosage was 36% (95% CI 19‐54) greater with benralizumab compared with placebo before matching and 27% (95% CI 12‐43) greater with benralizumab compared with placebo after matching adjustment to the dupilumab population. Mean OCS dosage reduction was 28% (95% CI 16‐41) greater from baseline to week 24 with dupilumab treatment compared with placebo. After matching, mean difference in OCS reduction between benralizumab and dupilumab was −0.71% (95% CI −20.56‐19.15) (Figure
Indirect treatment comparisons of benralizumab and dupilumab for (A) percentage reduction in oral corticosteroid (OCS) dosage, (B) percentage of patients with OCS elimination, and (C) reduction in annual rate of clinically significant exacerbations. CI: confidence interval; Q2W: every 2 wk; Q8W: every 8 wk (first three doses every 4 wk)
Odds ratios for OCS elimination for benralizumab vs. placebo were 4.06 (95% CI 1.67‐9.88) before matching and 6.19 (95% CI 1.63‐23.49) after matching. Odds ratio for OCS elimination for dupilumab vs. placebo was 2.74 (95% CI 1.47‐5.10). After matching to the LIBERTY ASTHMA VENTURE population, odds ratio for benralizumab vs. dupilumab was not statistically significant (2.26 [95% CI 0.52‐9.84]) for achieving OCS elimination (Figure
Benralizumab treatment reduced annual exacerbation rate vs. placebo by 70% (RR 0.30, 95% CI 0.19‐0.49) in ZONDA before matching adjustment and by 79% (RR 0.21, 95% CI 0.09‐0.47) after matching adjustment to the dupilumab population (Figure
Our study used the MAIC technique to evaluate OCS dosage reduction and exacerbation outcomes of benralizumab treatment compared with those of mepolizumab and dupilumab, two other biologics for the treatment of severe, uncontrolled asthma. After matching adjustment to balance baseline characteristics between the ZONDA (benralizumab) and SIRIUS (mepolizumab) populations, there were no statistically significant differences between the two treatments. No significant differences were observed between benralizumab vs. mepolizumab and vs. dupilumab before matching.
ESS ranged from 25% to 49% of the original sample size in these analyses. This represented a substantial reduction from the original trial populations (ZONDA, N = 148; SIRIUS, N = 135; LIBERTY ASTHMA VENTURE, N = 210). Greater differences between original study population size and ESS for a MAIC comparison indicate greater differences in characteristics of patients in the trials being compared.
These results extend our previous baseline‐adjusted analysis of the Phase III benralizumab and mepolizumab exacerbation studies. In those studies, reduction in asthma exacerbation rates was similar for both treatments, and improvements in FEV1 were numerically greater with benralizumab, but the differences were not statistically significant.
A recently published report by Busse et al used ITC analysis to suggest that mepolizumab was associated with significantly greater improvements than benralizumab in clinically significant exacerbations and asthma control.
The three OCS‐sparing studies of monoclonal antibody treatments for severe, uncontrolled asthma examined in this analysis varied in important ways, including differences in inclusion/exclusion criteria and baseline patient characteristics that would have biased standard ITCs. However, by matching individual patient data from the benralizumab ZONDA trial to important aggregate baseline characteristics from the comparator trial via MAIC analysis, the re‐weighted, matching‐adjusted data can provide an estimate of what the outcome would have been if the comparator trial had included a benralizumab arm. MAIC is a more powerful tool than meta‐regression in adjusting for the impact of treatment‐effect modifiers, because the use of individual patient data for adjustment offers more information about patient‐level associations than does the aggregate‐level adjustments used in standard ITCs.
These OCS‐sparing trials varied in defining which patients were eligible for OCS elimination. In the ZONDA trial, patients had to have a baseline optimized OCS dosage ≤ 12.5 mg/d; in the SIRIUS and LIBERTY ASTHMA VENTURE trials, the thresholds were < 25 mg/d and ≤ 30 mg/d, respectively. This component could not be adjusted with MAIC methodology, so the results should be interpreted with caution. Moreover, patient characteristics that were not measured in these trials, and could therefore not be accounted for in matching, may have played an undetermined role in these outcomes. ESS was substantially reduced from the original trial populations (ZONDA, N = 148; SIRIUS, N = 135; LIBERTY ASTHMA VENTURE, N = 210). Moreover, the optimization and OCS‐tapering schemes also differed. Faster schemes inherently led to better OCS‐sparing effect in a given (and presently quite short) time, usually at the price of greater exacerbation rates in the placebo arm. Undoubtedly, from a patient perspective, longer term OCS‐sparing effects of new treatments are a welcome development, as OCS dependence usually lasts years. Adrenal insufficiency is a frequent cause of OCS weaning failure, and this event was not specifically addressed in these trials. This limitation could have potentially impacted the size of the treatment effect observed in this MAIC analysis.
MAIC provides a more reliable comparison of benralizumab vs. mepolizumab and vs. dupilumab than aggregate data alone. Matching eliminates biases that might arise in a standard ITC because of cross‐trial differences. This MAIC analysis demonstrated that, after adjustment for differences in baseline population characteristics, reductions in OCS dosage, percentages of patients achieving OCS elimination, and annual asthma exacerbation rates were comparable between mepolizumab, dupilumab, and benralizumab.
A. Bourdin received personal fees, nonfinancial support, and other support from AstraZeneca, Novartis, Chiesi Pharmaceuticals, and Actelion; grants, personal fees, and other support from GSK; grants, personal fees, nonfinancial support, and other support from Boehringer Ingelheim; personal fees and other support from Teva and Regeneron; other support from Gilead; and personal fees and nonfinancial support from Roche, outside the submitted work. D. Husereau is a board or advisory committee member for GSK and AstraZeneca and has received financial support from AstraZeneca. N. Molinari has nothing to declare. S. Golam, L. Lindner, and X. Xu are full‐time employees of AstraZeneca. MK Siddiqui is an employee of PARAXEL International and performed the analysis on behalf of AstraZeneca.
An abstract describing these results was presented as a poster at the European Respiratory Society (ERS) International Congress 2019.
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The authors thank Lance Brannman, PhD, James G. Zangrilli, MD, and Ian Hirsch, PhD, of AstraZeneca for conceptual input in the early stages of this work and Pragya Shukla, MS, of PARAXEL International for contributions to the design and conduct of the analyses. Editorial support was provided by Jennie G. Jacobson, PhD, CMPP, and Caryne Craige, PhD, of JK Associates, Inc, and Michael A. Nissen, ELS, of AstraZeneca. This support was funded by AstraZeneca.
Data underlying the findings described in this manuscript may be requested in accordance with AstraZeneca's data‐sharing policy described at