Biomarkers for severe eosinophilic asthma

The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment. The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment. Biological therapies, in addition to regular controller medication, for patients with severe asthma are becoming the new standard of care for patients who were previously without alternative treatment options.1Global Initiative For Asthma. Global strategy for asthma management and prevention, 2017. Available at: www.ginasthma.org. Accessed July 1, 2017.Google Scholar Omalizumab, which neutralizes IgE, was the first biologic introduced for asthma in 2003 for patients who could not achieve asthma control with inhaled corticosteroids (ICSs), leukotriene inhibitors, and bronchodilators.1Global Initiative For Asthma. Global strategy for asthma management and prevention, 2017. Available at: www.ginasthma.org. Accessed July 1, 2017.Google Scholar, 2GenentechOmalizumab prescribing information. Genentech, South San Francisco (CA)2017Google Scholar, 3Lin C.H. Cheng S.L. 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Fox H. et al.Predicting and evaluating response to omalizumab in patients with severe allergic asthma.Respir Med. 2007; 101: 1483-1492Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar More recently, biologic therapies that disrupt IL-5 signaling and ultimately reduce eosinophil counts in blood and lung tissue (mepolizumab [GlaxoSmithKline, Research Triangle Park, NC] and reslizumab [Teva, Petach Tikva, Israel])7Buttner C. Lun A. Splettstoesser T. Kunkel G. Renz H. Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions.Eur Respir J. 2003; 21: 799-803Crossref PubMed Scopus (110) Google Scholar, 8Castro M. Mathur S. Hargreave F. Boulet L.P. Xie F. Young J. et al.Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.Am J Respir Crit Care Med. 2011; 184: 1125-1132Crossref PubMed Scopus (571) Google Scholar, 9Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. 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GlaxoSmithKline, Research Triangle Park (NC)2016Google Scholar, 13TevaReslizumab summary of product characteristics. Teva, Petach Tikva (Israel)2016Google Scholar In addition, benralizumab (AstraZeneca, Cambridge, United Kingdom), which is currently in development, depletes eosinophil counts by antibody-dependent cell-mediated cytotoxicity through binding to the α chain of the IL-5 receptor on the eosinophil surface.14Bleecker E.R. FitzGerald J.M. Chanez P. Papi A. Weinstein S.F. Barker P. et al.Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.Lancet. 2016; 388: 2115-2127Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar, 15FitzGerald J.M. Bleecker E.R. Nair P. Korn S. Ohta K. Lommatzsch M. et al.Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial.Lancet. 2016; 388: 2128-2141Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar, 16Ghazi A. Trikha A. Calhoun W.J. Benralizumab—a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity—a novel approach for the treatment of asthma.Expert Opin Biol Ther. 2012; 12: 113-118Crossref PubMed Scopus (144) Google Scholar In clinical trials all 3 anti-targeted IL-5 pathway therapies (mepolizumab, reslizumab, and benralizumab) reduced rates of exacerbations in patients with severe eosinophilic asthma.8Castro M. Mathur S. Hargreave F. Boulet L.P. Xie F. Young J. et al.Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.Am J Respir Crit Care Med. 2011; 184: 1125-1132Crossref PubMed Scopus (571) Google Scholar, 14Bleecker E.R. FitzGerald J.M. Chanez P. Papi A. Weinstein S.F. Barker P. et al.Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.Lancet. 2016; 388: 2115-2127Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar, 15FitzGerald J.M. Bleecker E.R. Nair P. Korn S. Ohta K. 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Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar In addition, mepolizumab and benralizumab have been shown to reduce or eliminate the dependency for oral corticosteroids (OCSs) without a loss of asthma control.20Bel E.H. Wenzel S.E. Thompson P.J. Prazma C.M. Keene O.N. Yancey S.W. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1136) Google Scholar, 21Nair P. Wenzel S. Rabe K.F. Bourdin A. Lugogo N.L. Kuna P. et al.Oral glucocorticoid-sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (613) Google Scholar Some overlap in the asthma phenotypes, principally severe allergic asthma and severe eosinophilic asthma, can lead to an overlap in eligibility for the different biological therapies.22Albers F.C. Mullerova H. Gunsoy N.B. Shin J.Y. Nelsen L.M. Bradford E.S. et al.Biologic treatment eligibility for real-world patients with severe asthma: the IDEAL study.J Asthma. 2017; ([Epub ahead of print])PubMed Google Scholar In circumstances in which the patient can be identified clearly as having a particular phenotype, the treatment options recommended in the Global Strategy for Asthma Management and Prevention (Global Initiative for Asthma [GINA]) guidelines are to prescribe anti-IgE and anti–IL-5 therapies, respectively.1Global Initiative For Asthma. Global strategy for asthma management and prevention, 2017. Available at: www.ginasthma.org. Accessed July 1, 2017.Google Scholar Integral to the successful clinical development of these drugs has been identification and use of biomarkers to identify patients likely to respond to treatment. A biomarker is any characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathologic processes, or responses associated with a therapeutic intervention.23Biomarkers Definitions Working GroupBiomarkers and surrogate endpoints: preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95Crossref PubMed Scopus (4684) Google Scholar There are several different types of biomarkers that include pharmacodynamic, predictive, diagnostic, and prognostic biomarkers. Pharmacodynamic biomarkers inform on the biological response to pharmacologic intervention. For example, the effect of anticoagulation treatments (eg, warfarin) for thromboembolic disease can be assessed by measuring prothrombin time as a pharmacodynamic biomarker.24Moore K.T. Byra W. Vaidyanathan S. Natarajan J. Ariyawansa J. Salih H. et al.Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects.Br J Clin Pharmacol. 2015; 79: 907-917Crossref PubMed Scopus (7) Google Scholar A predictive biomarker identifies patients likely to derive benefit from treatment or identify patients who are unlikely to respond, which thus influences clinical decisions. Although there are no predictive biomarkers for heart failure currently in routine use,25de Groote P. Pinet F. Bauters C. New technologies, new therapies: toward personalized medicine in heart failure patients?.Eur Heart J. 2013; 34: 636-637Crossref PubMed Scopus (2) Google Scholar predictive biomarkers are used routinely in oncology. For example, for patients with invasive breast cancer, overexpression or gene amplification of human epidermal growth factor receptor 2 is predictive of response to drugs targeted at the human epidermal growth factor receptor 2, such as trastuzumab, pertuzumab, and lapatinib.26Duffy M.J. Harbeck N. Nap M. Molina R. Nicolini A. Senkus E. et al.Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM).Eur J Cancer. 2017; 75: 284-298Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar Conversely, in patients with rheumatoid arthritis, a characteristic interferon type I genetic signature was found to be predictive of nonresponse to rituximab.27Raterman H.G. Vosslamber S. de Ridder S. Nurmohamed M.T. Lems W.F. Boers M. et al.The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.Arthritis Res Ther. 2012; 14: R95Crossref PubMed Scopus (133) Google Scholar A diagnostic biomarker identifies patients with a specific condition or disease, whereas a prognostic biomarker categories the risk of disease progression in the absence of treatment. In the case of heart failure, the presence of increased concentrations of B-type natriuretic peptide, which is produced in response to myocardial stress, has both positive and negative diagnostic value.28Gaggin H.K. Januzzi Jr., J.L. Biomarkers and diagnostics in heart failure.Biochim Biophys Acta. 2013; 1832: 2442-2450Crossref PubMed Scopus (253) Google Scholar B-type natriuretic peptide concentration on admission to the hospital also has a linear relationship with morbidity and mortality outcomes and is the gold standard prognostic biomarker for heart failure.28Gaggin H.K. Januzzi Jr., J.L. Biomarkers and diagnostics in heart failure.Biochim Biophys Acta. 2013; 1832: 2442-2450Crossref PubMed Scopus (253) Google Scholar In the case of asthma, early observations on the association between eosinophil overexpression and asthma severity were made in 1990 by Bousquet et al.29Bousquet J. Chanez P. Lacoste J.Y. Barneon G. Ghavanian N. Enander I. et al.Eosinophilic inflammation in asthma.N Engl J Med. 1990; 323: 1033-1039Crossref PubMed Scopus (2208) Google Scholar Multiple studies have since confirmed that blood, tissue, or sputum eosinophil counts can be used to characterize patients with severe asthma and eosinophilic inflammation.30Louis R. Lau L.C. Bron A.O. Roldaan A.C. Radermecker M. Djukanovic R. The relationship between airways inflammation and asthma severity.Am J Respir Crit Care Med. 2000; 161: 9-16Crossref PubMed Scopus (501) Google Scholar, 31Woodruff P.G. Khashayar R. Lazarus S.C. Janson S. Avila P. 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Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects.Am J Respir Crit Care Med. 1997; 155: 449-453Crossref PubMed Scopus (330) Google Scholar Through the drug development process for mepolizumab, investigators identified blood eosinophils, rather than sputum eosinophils, as the treatment target for mepolizumab, providing an accessible and multipurpose biomarker for severe eosinophilic asthma.18Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1528) Google Scholar, 19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 38Katz L.E. 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Maleeff B.E. et al.Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys.J Allergy Clin Immunol. 2001; 108: 250-257Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar the key T2 cytokine responsible for regulation of blood and tissue eosinophils.41Chung K.F. Targeting the interleukin pathway in the treatment of asthma.Lancet. 2015; 386: 1086-1096Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Mepolizumab prevents IL-5 from binding to the α chain of the IL-5 receptor complex expressed on the eosinophil cell surface and thus inhibits IL-5 signaling, blocking eosinophil survival and proliferation. Although the exact mechanism of action of IL-5 inhibitors is not fully elucidated, the desired physiologic goal is to neutralize the effect of activated eosinophils in blood and tissues, such as the lung. During the development of mepolizumab, the pharmacodynamic response was assessed in blood, sputum, and tissue eosinophils.18Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1528) Google Scholar, 19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 20Bel E.H. Wenzel S.E. Thompson P.J. Prazma C.M. Keene O.N. Yancey S.W. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1136) Google Scholar, 42Pouliquen I.J. Kornmann O. Barton S.V. Price J.A. Ortega H.G. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.Int J Clin Pharmacol Ther. 2015; 53: 1015-1027Crossref PubMed Scopus (66) Google Scholar, 43Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1533) Google Scholar Early studies showed that mepolizumab produced modest reductions in airway tissue and bone marrow eosinophil counts, suggesting limited pharmacodynamic effects in these compartments.9Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (750) Google Scholar Haldar et al43Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1533) Google Scholar then showed that treatment with 750 mg of intravenous mepolizumab in patients with severe asthma and sputum eosinophil counts of greater than 3% at least once in the previous 2 years reduced blood and sputum eosinophil counts during treatment, although sputum eosinophilia was present in 36% of exacerbations despite mepolizumab therapy. After this, the Dose Ranging Efficacy and safety With Mepolizumab in Severe Asthma (DREAM) study (NCT01000506) was conducted, which was a phase 2b/3 clinical trial of mepolizumab in patients with severe asthma and eosinophilic inflammation and included assessments of the pharmacodynamic response of mepolizumab.19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar The inclusion criteria for the DREAM study are shown in Fig 1. Patients in the DREAM study received either placebo or 75, 250, or 750 mg of intravenous mepolizumab, representing a 10-fold dose range. At the 750-mg intravenous dose, there were comparable reductions of 88% in blood and sputum eosinophil counts; however, for the 250-mg intravenous dose, the reduction in blood eosinophil counts was 86% compared with 65% for sputum, and for the 75-mg intravenous dose, the reduction in blood eosinophil counts was 78% compared with 32% for sputum (Fig 2).19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar All doses of mepolizumab had similar beneficial effects on the primary outcome measure, the rate of clinical significant asthma exacerbations.Fig 2Eosinophil, Feno, and exacerbation outcomes across the 10-fold dose range for mepolizumab in the DREAM study. *Collected from 94 patients in the DREAM sputum substudy. †Defined as worsening of asthma requiring use of OCSs for 3 or more days, admission, or a visit to the emergency room (ER). IV, Intravenous.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A second study42Pouliquen I.J. Kornmann O. Barton S.V. Price J.A. Ortega H.G. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.Int J Clin Pharmacol Ther. 2015; 53: 1015-1027Crossref PubMed Scopus (66) Google Scholar assessing a range of subcutaneous doses (12.5, 125, or 250 mg administered subcutaneously vs 75 mg administered intravenously) showed that this reduction in blood eosinophil count occurred 2 days after the first dose of mepolizumab, was dose dependent, and was not affected by administration route (intravenous vs subcutaneous) after adjusting for bioavailability. Overall, results from the DREAM study and Pouliquen et al42Pouliquen I.J. Kornmann O. Barton S.V. Price J.A. Ortega H.G. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.Int J Clin Pharmacol Ther. 2015; 53: 1015-1027Crossref PubMed Scopus (66) Google Scholar suggest that blood eosinophil but not sputum or tissue eosinophil counts are the key pharmacodynamic biomarker response to mepolizumab treatment in patients with severe eosinophilic asthma. This is reflected by the reduction in exacerbation rates with mepolizumab versus placebo in these patients. Since then, studies of mepolizumab in patients with hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic esophagitis all show a consistent pharmacodynamic effect of mepolizumab on eosinophils that can be measured easily and reproducibly by using blood eosinophil counts.18Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. et al.Mepolizumab treatment in patients with severe eosinophilic asthma.N Engl J Med. 2014; 371: 1198-1207Crossref PubMed Scopus (1528) Google Scholar, 19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 42Pouliquen I.J. Kornmann O. Barton S.V. Price J.A. Ortega H.G. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.Int J Clin Pharmacol Ther. 2015; 53: 1015-1027Crossref PubMed Scopus (66) Google Scholar, 44Stein M.L. Collins M.H. Villanueva J.M. Kushner J.P. Putnam P.E. Buckmeier B.K. et al.Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.J Allergy Clin Immunol. 2006; 118: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 45Straumann A. Conus S. Grzonka P. Kita H. Kephart G. Bussmann C. et al.Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.Gut. 2010; 59: 21-30Crossref PubMed Scopus (436) Google Scholar, 46Kim S. Marigowda G. Oren E. Israel E. Wechsler M.E. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome.J Allergy Clin Immunol. 2010; 125: 1336-1343Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 47Rothenberg M.E. Klion A.D. Roufosse F.E. Kahn J.E. Weller P.F. Simon H.U. et al.Treatment of patients with the hypereosinophilic syndrome with mepolizumab.N Engl J Med. 2008; 358: 1215-1228Crossref PubMed Scopus (487) Google Scholar In addition to blood eosinophil counts, other potential pharmacodynamic biomarkers, such as fraction of exhaled nitric oxide (Feno), were assessed during the development of mepolizumab.19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 43Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1533) Google Scholar Nitric oxide is released by several pulmonary cells, including epithelial cells, eosinophils, and macrophages, and nitric oxide levels have been shown to be increased in patients with conditions associated with inflammation, such as asthma and viral infections. In the DREAM study across the 10-fold dose range of 75 to 750 mg administered intravenously, there was no pharmacodynamic response with Feno (Fig 2).19Pavord I.D. Korn S. Howarth P. Bleecker E.R. Buhl R. Keene O.N. et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar This lack of response to Feno was also shown in the earlier mepolizumab study by Haldar et al.43Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1533) Google Scholar This suggests that Feno is not responsive to modulation through the IL-5 pathway and is potentially more relevant to different aspects of the T2 inflammatory response (eg, IL-13). Because the clinical efficacy of mepolizumab was similar across all doses of mepolizumab (75, 250, and 750 mg), it was decided to progress the lowest dose (75 mg administered intravenously) of mepolizumab in further phase 3 studies. The decision to take the lowest dose forward was supported by data that suggested that a dose of 75 mg administered intravenously (and the comparable exposure dose of 100 mg administered subcutaneously) was the minimum dose required to significantly reduce eosinophil counts.42Pouliquen I.J. Kornmann O. Barton S.V. Price J.A. Ortega H.G. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.Int J Clin Pharmacol Ther. 2015; 53: 1015-1027Crossref PubMed Scopus (66) Google Scholar In the subsequent clinical trials that have used the 100-mg subcutaneous dose (which has comparable systemic exposu