ORIGINAL RESEARCH

Ability of Serum IgE Concentration to PredictExacerbation Risk and Benralizumab Efficacyfor Patients with Severe Eosinophilic Asthma

David J. Jackson . Marc Humbert . Ian Hirsch . Paul Newbold .

Esther Garcia Gil

Received: October 24, 2019 / Published online: December 14, 2019� The Author(s) 2019

ABSTRACT

Introduction: For patients with eosinophilicasthma with allergic characteristics, under-standing the key drivers of exacerbations isimportant to identify optimal treatment strate-gies. Benralizumab is an interleukin-5 receptoralpha–directed cytolytic monoclonal antibodythat significantly reduces exacerbation fre-quency for patients with severe, uncontrolledeosinophilic asthma. We evaluated the predic-tive value of baseline blood eosinophil counts vs.serum immunoglobulin E (IgE) concentrations

on exacerbation risk and the association of thesevariables with benralizumab treatment effect.Methods: Analyses were performed with datapooled from the phase III SIROCCO andCALIMA benralizumab trials. Crude annualasthma exacerbation rates (AERs) were deter-mined for placebo as a function of baselineblood eosinophil counts and serum IgE con-centrations with prespecified blood eosinophilcount categories (\ 150, C 150 to\300, C 300to\450, C 450 cells/lL) and IgE concentrationquartiles (\62.0, C 62.0 to \176.2, C 176.2 to\453.4, and C 453.4 kU/L). We comparedAERs for patients receiving benralizumab 30 mgevery 8 weeks (first three doses every 4 weeks)vs. placebo for overlapping baseline bloodeosinophil count categories and serum IgEconcentration quartiles via a regressionapproach and by continuously using locallyweighted regression smoothing analysis.

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11211308.

Electronic Supplementary Material The onlineversion of this article (https://doi.org/10.1007/s12325-019-01191-2) contains supplementary material, which isavailable to authorized users.

D. J. Jackson (&)Guy’s Severe Asthma Centre, Guy’s & St Thomas’NHS Trust, Great Maze Pond, London, UKe-mail: David.Jackson@gstt.nhs.uk

D. J. JacksonAsthma UK Centre, School of Immunology &Microbial Sciences, King’s College London, Strand,London, UK

M. HumbertAP-HP, Service de Pneumologie, Hopital Bicetre, 78Rue du General Leclerc, Le Kremlin-Bicetre, France

I. Hirsch � P. NewboldAstraZeneca, One MedImmune Way, Gaithersburg,MD, USA

E. Garcia GilAstraZeneca, Avgda. Diagonal, Barcelona, Spain

Adv Ther (2020) 37:718–729

https://doi.org/10.1007/s12325-019-01191-2

Results: Exacerbation risk for patients withsevere asthma receiving placebo increased withincreasing baseline blood eosinophil counts butnot with increasing serum IgE concentrations.Addition of baseline atopy status did not influ-ence the relationship between IgE concentra-tions and exacerbation risk for patientsreceiving placebo. Patients with blood eosino-phil counts C 300 cells/lL had consistentdecreases in exacerbation risk with benral-izumab relative to placebo across all serum IgEconcentration quartiles.Conclusion: Baseline blood eosinophil counts,but not serum IgE concentrations, are animportant predictor of exacerbation risk.Patients with severe eosinophilic asthma treatedwith benralizumab had consistent reductions inexacerbation risk, regardless of IgEconcentrations.Clinical Trial Registration: ClinicalTrials.gov:SIROCCO, NCT01928771; CALIMA,NCT01914757.

Keywords: Asthma; Benralizumab; CALIMA;Eosinophils; Exacerbations; ImmunoglobulinE; Interleukin-5 receptor; SIROCCO

Key Summary Points

Why carry out this study?

Patients with eosinophilic asthma canhave elevated serum IgE concentrations

Eosinophilia is associated with asthmaexacerbations, which can be reduced withbenralizumab, an interleukin-5 receptoralpha–directed anti-eosinophilmonoclonal antibody

We aimed to determine the importance ofelevated blood eosinophil counts andserum IgE concentrations on exacerbationrisk and their influence on benralizumab’sability to reduce exacerbation frequencyfor patients with eosinophilic asthma anda range of serum IgE concentrations

What was learned from the study?

Elevated blood eosinophil counts, but notserum IgE concentrations, are associatedwith increased exacerbation risk forpatients with severe, uncontrolled asthma

Benralizumab reduces exacerbation riskfor patients with elevated bloodeosinophil counts regardless of serum IgEconcentrations and, therefore, should beconsidered for patients with uncontrolledeosinophilic asthma with allergiccharacteristics

PLAIN LANGUAGE SUMMARY

Many patients with severe asthma have elevatednumbers of eosinophils (a subset of white bloodcells) and raised serum concentrations ofimmunoglobulin E (IgE; antibodies). Elevatedeosinophil counts together with IgE concentra-tions are associated with more frequent asthmaattacks. Benralizumab is a drug that almostcompletely depletes eosinophils and signifi-cantly reduces asthma attacks for patients withsevere, uncontrolled asthma and elevated bloodeosinophil counts. The individual influence ofeosinophils and IgE on benralizumab efficacyhas been published. In this study, we furtherextend the analyses to evaluate the interrela-tionship of eosinophil counts and IgE concen-trations with asthma attack frequency andbenralizumab efficacy for patients with severe,uncontrolled asthma. We evaluated the associ-ation of blood eosinophil counts and IgE con-centrations with asthma attack frequency forpatients with severe asthma who received high-dosage inhaled corticosteroids plus additionalcontroller medications but did not receivebenralizumab in the benralizumab clinical tri-als. We observed that increased blood eosino-phil counts were associated with greater asthmaattack frequency, while serum IgE concentra-tions had no influence on asthma attack fre-quency. We also evaluated patients who

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received benralizumab and determined thatbenralizumab can reduce the occurrence ofthese attacks for patients with elevated bloodeosinophil counts regardless of their serum IgEconcentrations. Frequency of asthma attacksalso decreased with benralizumab for patientswith elevated serum IgE concentrations, butserum IgE concentrations did not influencebenralizumab efficacy. Benralizumab is an effi-cacious treatment for patients with uncon-trolled eosinophilic asthma, regardless of theirIgE concentrations.

INTRODUCTION

Asthma is a heterogenous disease that affectsmore than 339 million people worldwide [1–3].Allergic asthma is a common phenotype ofasthma, and several factors such as elevatedimmunoglobulin E (IgE) concentrations andeosinophilia play an important role in thepathology of this disease [2–5]. A total of 47% ofadults have both eosinophilic ([ 150 cells/lL)and atopic asthma (with elevated IgE concen-trations), while 78% of adults with atopicasthma also have eosinophilic asthma [5]. It is,therefore, important to identify the character-istics of individual patients with severe asthmato determine the optimal treatment regimen.

Omalizumab (Genentech, Inc., South SanFrancisco, CA, USA), a humanized anti-IgEmonoclonal antibody, is approved as add-ontherapy for patients aged 6 years or older withmoderate to severe persistent, uncontrolledasthma with positive skin test or in vitro reac-tivity to a perennial aeroallergen [6]. In thephase III EXTRA clinical trial, omalizumabreduced exacerbation rates relative to placeboby 25% for patients with severe allergic asthma[7]. In a post hoc analysis of this study, patientswith allergic asthma and blood eosinophilcounts C 260 cells/lL had a 32% reduction inasthma exacerbation rate with omalizumabrelative to placebo, compared with a 9%reduction for patients with blood eosinophilcounts \260 cells/lL [8]. Exacerbation ratereductions with omalizumab were similarregardless of serum IgE concentrations [9, 10].

Benralizumab (AstraZeneca, Cambridge, UK)is an interleukin-5 receptor alpha–directedcytolytic monoclonal antibody that inducesdirect, rapid, and nearly complete depletion ofeosinophils via enhanced antibody-dependentcell-mediated cytotoxicity [11, 12]. Benral-izumab 30 mg every 8 weeks (Q8W; first threedoses every 4 weeks [Q4W]) is indicated for theadd-on maintenance treatment of patients withsevere asthma aged 12 years and older, and withan eosinophilic phenotype [13]. In the 48-weekSIROCCO and 56-week CALIMA phase III stud-ies, significant reductions in annual asthmaexacerbation rates (AERs) by 51% (p\ 0.0001)and 28% (p = 0.0188), respectively, wereachieved with benralizumab Q8W comparedwith placebo for patients with severe, uncon-trolled asthma and baseline blood eosinophilcounts C 300 cells/lL [14, 15]. In addition, sig-nificant improvements were also achieved withbenralizumab Q8W relative to placebo in pre-bronchodilator forced expiratory volume in 1 s(FEV1) (0.159 L [p = 0.0006] and 0.116 L[p = 0.0102], respectively) at the end of treat-ment (EOT) [14, 15].

Benralizumab Q8W has also been demon-strated to reduce exacerbations and improvelung function for patients with severe, uncon-trolled asthma with blood eosinophil countsC 300 cells/lL and with either high serum IgEconcentrations (C 150 kU/L; 53% of patients) orlow serum IgE concentrations (\150 kU/L; 47%of patients), with or without atopy (based onPhadiatop [Phadia AB/Thermo Fisher Scientific,Uppsala, Sweden] test results), or for those whomet the criteria similar to patients who mightqualify for omalizumab treatment (serum IgEconcentrations 30–700 kU/L and with atopy) orthose who did not meet these criteria [16]. AERsdecreased by 42% (high serum IgE concentra-tions; p\0.0001), 43% (low serum IgE con-centrations; p = 0.0004), 40% (with atopy;p\0.0001), 46% (without atopy; p = 0.0001),46% (met criteria; p = 0.0002), and 39% (didnot meet criteria; p\0.0001) with benral-izumab Q8W relative to placebo [16].

However, this dichotomous analysis haslimitations, as it does not allow evaluation ofdifferences in treatment effects across the fullrange of IgE concentrations. Unlike with blood

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eosinophil counts, there is lack of consensus onan IgE cut-off value that defines high vs. lowconcentrations. To address this and determinebenralizumab efficacy for patients across a rangeof IgE concentrations, including very high, wecategorized the study population into quartiles,an approach used to assess the effect of omal-izumab on exacerbations [10]. We analyzedpooled data from the SIROCCO and CALIMAstudies to determine the influence of baselineblood eosinophil counts and serum IgE, across arange of concentrations, on exacerbation riskfor patients with severe, uncontrolled asthma.Furthermore, as the influences of baseline bloodeosinophil counts and serum IgE concentra-tions on exacerbation risk and benralizumabefficacy were previously studied independently,although variable concentrations of thesebiomarkers coexist for patients, we evaluatedthese two biomarkers together. We aimed toassess the potential utility of benralizumab forpatients with eosinophilic asthma with allergiccharacteristics.

METHODS

Study Design and Participants

SIROCCO and CALIMA were randomized, dou-ble-blind, parallel-group, placebo-controlled,international, phase III studies [14, 15]. Thestudy designs consisted of an enrollment visit(week-4), a 4-week screening and run-in phase,randomization (week 0), treatment period fromweeks 0 to 48 (SIROCCO) or 56 (CALIMA), and afinal follow-up visit 8 weeks (SIROCCO) or4 weeks (CALIMA) after the EOT period.

Enrollment criteria for the studies have beenpublished [14, 15]. Male and female patients12–75 years of age, weighing at least 40 kg, andwith physician-diagnosed asthma that requiredtreatment with medium- to high-dosageinhaled corticosteroids (ICS) and long-acting b2-agonists (LABA) for at least 12 months beforeenrollment were included. Patients had two ormore asthma exacerbations within 12 monthsbefore the date of enrollment that requiredsystemic corticosteroid therapy or a temporaryincrease in usual maintenance oral

corticosteroid dosages [14, 15]. Before anypatients enrolled, an independent ethics com-mittee or institutional review board at eachstudy center approved the clinical study proto-col, and the national regulatory authority eitherapproved the clinical study protocol or receiveda notification according to local regulations (seeelectronic supplementary materials). Studieswere conducted in accordance with the Decla-ration of Helsinki, the International Conferenceon Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for HumanUse and Good Clinical Practice guidelines, andthe ethics committee at each participating site[14, 15]. All patients provided written informedconsent at enrollment.

Treatments

In SIROCCO and CALIMA, patients were ran-domized 1:1:1 to receive placebo Q4W, benral-izumab 30 mg subcutaneously Q4W, orbenralizumab 30 mg subcutaneously Q8W (firstthree doses Q4W). Patients with baseline bloodeosinophil counts C 300 cells/lL and\300 cells/lL were recruited at a ratio of approximately 2:1,respectively.

Outcomes

In the present study, we performed analyses forpatients who received placebo or the indicatedbenralizumab dosage (30 mg Q8W) in additionto high-dosage ICS and LABA (defined as fluti-casone propionate C 500 mg/day or equivalenttotal daily dosage) pooled from the SIROCCOand CALIMA studies.

AERs were determined as a function ofbaseline blood eosinophil counts or serum IgEconcentrations, either separately or combined.An exacerbation was defined as asthma wors-ening that led to either systemic corticosteroiduse (or temporary increase in a stable oral cor-ticosteroid background dosage) for at least3 days or a single depot-injectable dose of cor-ticosteroid; an asthma-related emergencydepartment or urgent care visit (duration\24 h) that required systemic corticosteroiduse; or an asthma-related inpatient hospital

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admission (duration C 24 h). Asthma worsen-ing was defined as any new or increased symp-toms or signs that were concerning to thepatient or related to an asthma daily diary alert[14, 15].

Baseline blood eosinophil counts were eval-uated as a continuous function, by categoriesprespecified in the SIROCCO and CALIMAstudies (\150, C 150 to\300, C 300 to\450,and C 450 cells/lL) and also for the SIROCCOand CALIMA primary population (C 300 cells/lL). Baseline serum IgE concentrations wereevaluated as a continuous function or by quar-tiles (\ 62.0, C 62.0 to \ 176.2, C 176.2 to\453.4, and C 453.4 kU/L). Evaluation of AERsas a function of serum IgE concentrations wasalso determined on the basis of baseline atopystatus. Atopy was defined as a positive Phadi-atop test reaction. The Phadiatop test is a multi-allergen inhalant screening blood test withextracts for house dust mites, cat and dog dan-der, mold spores, and tree, grass, and weedpollen.

Statistical Analysis

This analysis was performed for the full analysisset according to the intention-to-treat principlefor the pooled SIROCCO and CALIMA studies.The full analysis set included all randomizedpatients who received any study treatment,regardless of their protocol adherence andcontinued participation in the study. The simi-larity of the SIROCCO and CALIMA studiesallowed for their results to be pooled [14, 15].Similarities included study design (the onlydifference being treatment period: 48 weeks forSIROCCO and 56 weeks for CALIMA), inclusionand exclusion criteria (except CALIMA includedpatients who used medium-dosage ICS), treat-ment, randomization, stratification, and out-comes. Included patients had similar baselineclinical characteristics across the trials. Thispermitted us to obtain more accurate estimatesof the relationship of baseline blood eosinophilcounts and serum IgE concentrations withAERs, both for placebo and for benralizumabrelative to placebo. Analyses were performedwith SAS 9.4 (SAS Institute, Cary, NC, USA).

We used locally weighted regressionsmoothing analysis with corresponding confi-dence intervals (CIs) to determine the relation-ship between AERs with blood eosinophilcounts and serum IgE concentrations. We ana-lyzed AERs and corresponding ratios via a neg-ative binomial model, with adjustments forstudy, treatment, region, prior exacerbations,and oral corticosteroid use at time of random-ization. The log of each patient’s correspondingfollow-up time was used as an offset variable inthe model to adjust for different exposure timesduring which the events occurred. We deter-mined the estimated treatment effect (i.e., rateratio of benralizumab vs. placebo), correspond-ing CI, and two-sided p value for the rate ratio.

RESULTS

Demographics and baseline clinical character-istics of SIROCCO and CALIMA patients were,in general, balanced between treatment groupsoverall [14–16].

There was a positive relationship betweenbaseline blood eosinophil counts and AERs forpatients in the placebo arm (with backgroundhigh-dosage ICS/LABA) (Fig. 1). However, therewas no relationship between increasing baselineserum IgE concentrations and AERs (Fig. 2).Baseline atopy status did not influence therelationship between baseline serum IgE con-centrations and AERs (Fig. 3). Benralizumabreduced AERs for each of these patient popula-tions, with greater benralizumab response withincreasing blood eosinophil counts and consis-tent improvements with increasing serum IgEconcentrations (Figs. 1, 2, 3).

When we evaluated the relationship betweenblood eosinophil counts and serum IgE con-centrations in combination, greater baselineblood eosinophil counts (i.e., C 450 cells/lL)were associated with larger AERs than lesserbaseline blood eosinophil counts (i.e.,\150 cells/lL), regardless of baseline serum IgEconcentrations (Table 1) for patients receivingplacebo. AERs increased with increasing base-line blood eosinophil count categories for mostserum IgE concentration quartiles, althoughthere was some variability. AERs were not

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greater in the fourth quartile of baseline serumIgE concentrations compared with the firstquartile, and no obvious pattern in AER changeswas observed with increasing baseline IgE con-centrations across baseline blood eosinophilcount categories.

Patients with eosinophilic asthma(C 300 cells/lL) treated with benralizumab hadconsistent decreases in AER relative to placeboregardless of baseline serum IgE concentrationquartiles (Table 2, Fig. 4). Rate ratios rangedfrom 0.47 (95% CI 0.31, 0.72; p = 0.0004) to

Fig. 1 LOESS plot analysis of association between base-line blood eosinophil counts and exacerbation frequency(full analysis set). CI confidence interval, LOESS locallyestimated scatterplot smoothing, Q8W every 8 weeks (first

three doses every 4 weeks). Shaded areas represent 95% CI.Baseline blood eosinophil counts [ 1000 cells/lL areincluded in the model but not presented in the figure

Fig. 2 LOESS plot analysis of association between base-line serum IgE concentrations and exacerbation frequency(full analysis set). CI confidence interval, IgE immunoglob-ulin E, LOESS locally estimated scatterplot smoothing,

Q8W every 8 weeks (first three doses every 4 weeks).Shaded areas represent 95% CI. IgE concentrations[ 2000 kU/L are included in the model but not presentedin the figure

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0.56 (95% CI 0.37, 0.84; p = 0.0057) acrossbaseline serum IgE concentration quartiles(Table 2).

DISCUSSION

IgE and eosinophils play distinct roles in thepathogenesis of allergic asthma [4, 17],

although there is probably some overlap inthese mechanisms because cross-linking of IgEalso leads to increased eosinophil counts. IgE isassociated with the acute and chronic phases ofthe disease. In the acute phase, allergens stim-ulate the production of IgE, and cross-linking ofIgE promotes the inflammatory cascade associ-ated with development of allergic asthma,leading to a significant increase in eosinophil

Fig. 3 LOESS plot analysis of association of baselineserum IgE concentrations and atopy status with exacerba-tion frequency (full analysis set). CI confidence interval,IgE immunoglobulin E, LOESS locally estimated

scatterplot smoothing, Q8W every 8 weeks (first threedoses every 4 weeks). Shaded areas represent 95% CI. IgEconcentrations [ 2000 kU/L are included in the modelbut not presented in the figure

724 Adv Ther (2020) 37:718–729

counts in the chronic phase of the disease[4, 17]. The relevance of each component in thedevelopment and progression of allergic asthmasymptoms, such as exacerbation frequency andreduced lung function, is unclear and maylikely be different for each patient.

In this study, we evaluated the influence ofbaseline blood eosinophil counts and serum IgEconcentrations on exacerbation frequency witha data set pooled from the phase III SIROCCOand CALIMA trials for benralizumab. Whileincreasing baseline blood eosinophil countswere directly associated with greater AERs forpatients receiving placebo at the end of thestudies, baseline serum IgE concentrations hadno influence on AERs. These results suggest thattreatments that decrease eosinophils mayreduce exacerbation frequency for patients witheosinophilic asthma with allergic characteris-tics, regardless of serum IgE concentrations.This conclusion was supported by our findingsthat benralizumab treatment resulted in sub-stantial reductions in exacerbation rates forpatients with severe, uncontrolled eosinophilicasthma regardless of serum IgE concentrations.These results expand on earlier findings thatpatients with blood eosinophil countsC 300 cells/lL with either serum IgE concen-trations C 150 or \ 150 kU/L, with or withoutatopy, or who might or might not qualify foromalizumab treatment had substantial reduc-tions (C 40%) in exacerbation frequencies [16].

Omalizumab is an approved add-on treat-ment for patients with moderate to severe,

uncontrolled allergic asthma with elevatedserum IgE concentrations [18]. Similar to find-ings for omalizumab [9], baseline serum IgEconcentrations do not predict benralizumabresponse. However, unlike omalizumab [7, 9],increasing baseline blood eosinophil counts areclearly associated with greater benralizumabefficacy. Overall, these studies suggest thatomalizumab treatment may be efficacious forreducing symptoms of allergic asthma that arestimulated by the cross-linking of specific IgE inresponse to an allergic trigger. For patients witheosinophilic asthma with allergic characteris-tics, alternative treatments, such as benral-izumab, may be needed.

Mepolizumab, a marketed human anti–interleukin-5 monoclonal antibody for patientswith severe eosinophilic asthma [19], has beenevaluated in two separate studies for patientswho either received [20] or were qualified atstudy entry [21] to receive omalizumab treat-ment. In a post hoc analysis of the phase IIIMENSA trial [22], patients who received omal-izumab had a 57% exacerbation rate reductionwith mepolizumab vs. placebo (compared with47% for those who did not receive omalizumab)[20]. In a post hoc meta-analysis of data fromthe phase III MENSA [22] and MUSCA [23] tri-als, mepolizumab reduced exacerbation rates vs.placebo by 57% and 55% for patients who werequalified or unqualified for omalizumab (basedon prescribing and dosing criteria), respectively[21]. Together with our findings, this supportsthe use of agents that target eosinophils directly

Table 1 Effect of baseline blood eosinophil counts and serum IgE concentrations on annual asthma exacerbation rates forpatients receiving placebo (full analysis set)

Serum IgE concentration (kU/L) Crude AER

Baseline blood eosinophil count (cells/lL)

< 150 ‡ 150 to < 300 ‡ 300 to < 450 ‡ 450

\ 62.0 1.25 (n = 53) 0.91 (n = 57) 1.28 (n = 32) 1.44 (n = 43)

C 62.0 to\ 176.2 1.57 (n = 34) 0.94 (n = 45) 1.15 (n = 46) 1.84 (n = 66)

C 176.2 to\ 453.4 1.10 (n = 30) 1.93 (n = 42) 1.19 (n = 45) 1.38 (n = 80)

C 453.4 0.80 (n = 29) 0.84 (n = 31) 1.10 (n = 39) 1.33 (n = 90)

AER annual asthma exacerbation rate, IgE immunoglobulin E

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(benralizumab) or indirectly (mepolizumab) toreduce eosinophils for the treatment of patientswith eosinophilic asthma with allergiccharacteristics.

A limitation of this study was the smallnumbers of patients for the different subgroups,

which restricted interpretation of the findingswith no consistent trends. Another limitationwas that this post hoc analysis was not part ofthe general testing strategy. Because of this, allcomparator results of benralizumab vs. placebouse nominal p values, and no formal statistical

Table 2 Annual asthma exacerbation rate reductions with benralizumab vs. placebo based on baseline serum IgE con-centrations (full analysis set; baseline blood eosinophil counts C 300 cells/lL)

Serum IgE concentration (kU/L) Placebo Benralizumab Q8W

\ 62.0

Number of patients analyzed 75 73

Rate estimate (95% CI) 1.40 (1.00, 1.96) 0.71 (0.46, 1.09)

Absolute difference estimate vs. placebo (95% CI) – - 0.69 (- 1.21, - 0.17)

Rate ratio vs. placebo (95% CI) – 0.51 (0.31, 0.84)

Nominal p vs. placebo – 0.0079

C 62.0 to\ 176.2

Number of patients analyzed 112 109

Rate estimate (95% CI) 1.66 (1.26, 2.18) 0.79 (0.56, 1.10)

Absolute difference estimate vs. placebo (95% CI) – - 0.87 (- 1.38, - 0.37)

Rate ratio vs. placebo (95% CI) – 0.47 (0.31, 0.72)

Nominal p vs. placebo – 0.0004

C 176.2 to\ 453.4

Number of patients analyzed 125 106

Rate estimate (95% CI) 1.37 (1.07, 1.76) 0.71 (0.52, 0.97)

Absolute difference estimate vs. placebo (95% CI) – - 0.67 (- 1.06, - 0.27)

Rate ratio vs. placebo (95% CI) – 0.52 (0.35, 0.76)

Nominal p vs. placebo – 0.0008

C 453.4

Number of patients analyzed 129 128

Rate estimate (95% CI) 1.22 (0.92, 1.62) 0.68 (0.48, 0.96)

Absolute difference estimate vs. placebo (95% CI) – - 0.54 (- 0.93, - 0.15)

Rate ratio vs. placebo (95% CI) – 0.56 (0.37, 0.84)

Nominal p vs. placebo – 0.0057

Estimates were calculated via a negative binomial model, with adjustments for study, treatment, region, prior exacerbations,and oral corticosteroid use at time of randomization. The log of each patient’s corresponding follow-up time was used as anoffset variable in the model to adjust for different exposure times during which the events occurredCI confidence interval, IgE immunoglobulin E, Q8W every 8 weeks (first three doses every 4 weeks)

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significance can be inferred. Lastly, this studywas not performed for patients who were diag-nosed with allergic asthma, and any associationof improvements with benralizumab for thispatient population is speculative.

CONCLUSIONS

Blood eosinophil counts, but not serum IgEconcentration, predict exacerbation risk. Exac-erbation rate reductions with benralizumab forpatients with eosinophilia and elevated serumIgE concentrations and/or atopy indicate apotential benefit of benralizumab for patientswith eosinophilic asthma with allergic charac-teristics. Physicians should consider eosinophil-depleting therapies for patients with uncon-trolled asthma and elevated blood eosinophilcounts, regardless of serum IgE concentrations.

ACKNOWLEDGEMENTS

We thank the patients who participated in theSIROCCO and CALIMA studies.

Funding. AstraZeneca (Cambridge, UK) fun-ded this study and the journal’s Rapid ServiceFee and Open Access publication. All authorshad full access to all of the data in this studyand take complete responsibility for the integ-rity of the data and accuracy of the dataanalysis.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapprovals for this version to be published.

Authorship Contributions. All authors con-ceived and designed the study. Ian Hirsch, PaulNewbold, and Esther Garcia Gil acquired thedata. All authors analyzed and interpreted thedata. All authors participated in the develop-ment and review of the manuscript and gavethe approval to submit for publication.

Medical Writing, Editorial, and OtherAssistance. Writing and editing support,including preparation of the draft manuscript

Fig. 4 Effect of baseline serum IgE concentrations onannual asthma exacerbation rate reduction with benral-izumab vs. placebo (full analysis set; baseline bloodeosinophil counts C 300 cells/lL). CI confidence interval,IgE immunoglobulin E, Q quartile, Q8W every 8 weeks(first three doses every 4 weeks). Estimates were calculated

via a negative binomial model, with adjustments for study,treatment, region, prior exacerbations, and oral corticos-teroid use at time of randomization. The log of eachpatient’s corresponding follow-up time was used as anoffset variable in the model to adjust for different exposuretimes during which the events occurred. ap\ 0.01

Adv Ther (2020) 37:718–729 727

under the direction and guidance of theauthors, incorporation of author feedback, andmanuscript submission, was provided by AlanSaltzman, PhD, CMPP (JK Associates, Inc.,Conshohocken, PA, USA), and Michael A. Nis-sen, ELS (AstraZeneca, Gaithersburg, MD, USA).This support was funded by AstraZeneca.

Disclosures. David J. Jackson reports per-sonal fees from AstraZeneca, Chiesi Pharma-ceuticals, GlaxoSmithKline, and NappPharmaceuticals, and nonfinancial supportfrom Boehringer Ingelheim and Teva Pharma-ceuticals, outside the submitted work. MarcHumbert reports personal fees from Actelion,Merck, and United Therapeutics, and grants andpersonal fees from Bayer and GlaxoSmithKline,outside the submitted work. Ian Hirsch is anemployee of AstraZeneca. Paul Newbold is anemployee of AstraZeneca. Esther Garcia Gil is anemployee of AstraZeneca.

Compliance with Ethics Guidelines. Beforeany patients enrolled, an independent ethicscommittee or institutional review board at eachstudy center approved the clinical study proto-col, and the national regulatory authority eitherapproved the clinical study protocol or receiveda notification according to local regulations (seeelectronic supplementary materials). Studieswere conducted in accordance with the Decla-ration of Helsinki, the International Conferenceon Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for HumanUse and Good Clinical Practice guidelines, andthe ethics committee at each participating site.All patients provided written informed consentat enrollment.

Data Availability. Data underlying thefindings described in this manuscript may berequested in accordance with AstraZeneca’sdata-sharing policy described at https://astrazenecagroup-dt.pharmacm.com/DT/Home.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any medium

or format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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