Benralizumab after sub‐optimal response to mepolizumab in severe eosinophilic asthma
Authors: Joanne E. Kavanagh, Andrew P. Hearn, Grainne d’Ancona, Jaideep Dhariwal, Cris Roxas, Linda Green, Louise Thomson, Mariana Fernandes, Brian D. Kent, Alexandra M. Nanzer, David J. Jackson
Journal: Allergy (2020)

Mepolizumab and benralizumab are monoclonal antibodies (mAb) directed against anti-IL-5 and anti-IL5R, respectively, and their use reduces exacerbation rate and maintenance oral corticosteroid (mOCS) requirements in severe eosinophilic asthma (SEA).1-4 We recently reported that a minority of patients treated with mepolizumab experience a sub-optimal response including those with a higher baseline ACQ and mOCS requirement.1 It remains unclear if such patients may improve following a switch to benralizumab which provides a more complete depletion of airway eosinophils.5, 6 We retrospectively assessed patients with SEA treated at our specialist centre, who were switched from mepolizumab to benralizumab following a sub-optimal response defined as failing to achieve either: ≥50% reduction in mOCS dose; ≥50% reduction in annualized exacerbation rate (AER);and an ongoing requirement of ≥7.5 mg prednisolone/day or an AER of ≥3. Ethical approval to report on the outcomes of our routine clinical care using benralizumab without written consent was gained from the local Research Ethics Committee (15/LO/0886). Thirty-three patients were included in the analysis (mean age 52 ± 11, 55% female, BMI 32.1 ± 7.3, see Table S1). Values are mean (standard deviation) when normally distributed or median (interquartile range) when non-parametric. Overall, AER fell by 58% from 3.89 (±2.17) on mepolizumab to 1.64 (±1.57) on benralizumab (p < 0.001, Figure 1A and Table 1). Twenty-six patients were on mOCS at the end of mepolizumab treatment, and by 48-week benralizumab, 11/26 (42%) were able to discontinue, with 18/26 (69%) achieving ≥50% dose reduction (Figure 1B,C and Tables 1 and S2). There were statistically and clinically significant improvements in ACQ and AQLQ on benralizumab (Figure 1D,E). FEV1 improved from the end of mepolizumab to 48-week benralizumab; however, there was no improvement from premepolizumab levels (a fall in FEV1 was observed on mepolizumab in this cohort, Figure 1F). Three (9%) patients deteriorated on benralizumab, with an increase in mOCS dose of ≥5 mg od. A further 5 (15%) patients had no clear benefit (ie they had <50% reduction in annualized exacerbation rate or <50% reduction in mOCS dose compared to that at the end of mepolizumab treatment). There were no statistically significant differences in baseline characteristics between responders and those without a clear response (Table S3). Mepolizumab is known to reduce bone marrow and airway eosinophils by approximately 50%,7 and the phase 2b DREAM study highlighted a dose-related response in sputum eosinophil counts on mepolizumab.2 A sub-study of the OCS-sparing SIRIUS trial demonstrated the ongoing presence of sputum eosinophils and eosinophil progenitor (EoP) cells despite mepolizumab treatment, which was associated with a lower prednisolone sparing effect.8 Benralizumab has been shown to effectively deplete both blood and sputum eosinophil and EoP counts.6 It is therefore conceivable that a minority of patients may have a poor response to mepolizumab due to insufficient airway eosinophil depletion with the 100 mg dose of mepolizumab. In essence this notion is no different from the reality that within severe eosinophilic asthma, some patients require low dose maintenance oral steroids, whilst others require a higher dose to adequately suppress their airways inflammation. Our results appear to support this possibility and suggest that a more profound depletion in airway eosinophilia as occurs with benralizumab may offer additional clinical benefit in patients with particularly severe eosinophilic asthma. To our knowledge, this is the largest case series examining the clinical effectiveness of benralizumab in patients previously treated with mepolizumab. Our data suggest that SEA patients with a sub-optimal response to mepolizumab may benefit from switching to benralizumab. Indeed, some have a dramatic response becoming exacerbation-free and off all mOCS for asthma (Table S4). We report substantial and clinically meaningful improvements in exacerbation rate, oral corticosteroid use, asthma control and quality of life scores. Of note, a minority of patients had no clear benefit from switching to benralizumab and the mechanisms of this lack of response requires further research but may include unidentified airway infection or an IL-13 dominant type-2 pathway.9, 10 The major limitation of our data is that it is uncontrolled and retrospective but nonetheless represents real-world experience at a specialized asthma centre. Unfortunately, induced sputum was not routinely performed which would have added valuable insights into the mechanisms of poor response. Interestingly, the recently reported MEX study11 highlighted that approximately 50% of exacerbations in a large mepolizumab-treated asthmatic cohort were associated with persistent eosinophilic inflammation in sputum. This may in part explain the improved response with benralizumab. Aside from indirect treatment comparisons, no prospective data comparing the efficacy of mepolizumab and benralizumab exist but it is hoped that such head-to-head trials are conducted to aid clinicians in choosing between biologic therapies for SEA. Dr Kavanagh has nothing to disclose. Dr Hearn has nothing to disclose. Dr Dhariwal has nothing to disclose. Ms Roxas has nothing to disclose. Ms Green has nothing to disclose. Ms Thomson has nothing to disclose. Ms Fernandes has nothing to disclose. Ms D'Ancona reports personal fees from GSK, personal fees from Astrazeneca, outside the submitted work. Dr Kent reports personal fees from GSK, personal fees from Astrazeneca, outside the submitted work. Dr Nanzer reports personal fees from Astrazeneca, outside the submitted work. Dr Jackson reports personal fees from GSK, grants and personal fees from Astrazeneca, outside the submitted work. 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