Efficacy and safety of an anti–IL-13 mAb in patients with severe asthma: A randomized trial Erika H. De Boever, PhD,a Claire Ashman, BSc,b Anthony P. Cahn, MB BS,c Nicholas W. Locantore, PhD,d Phil Overend, BSc (Hons),e Isabelle J. Pouliquen, PharmD,f Adrian P. Serone, PhD,g Tracey J. Wright, PhD,b Mair M. Jenkins, MB BS,h Inderpal S. Panesar, MRPharmS,i Sivayogan S. Thiagarajah, MB ChB,j and King of Prussia and Pittsburgh, Pa, Stevenage, Middlesex, Brentford, Birmingham, and High Wycombe, Sally E. Wenzel, MDk United Kingdom, Research Triangle Park, NC, and San Francisco, Calif Background: Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti–IL13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor a1 and a2. Objectives: We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids. Methods: Patients who remained symptomatic (Asthma Control _1.5) after uptitration to 1000 mg/d fluticasone Questionnaire score > propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n 5 99) or placebo (n 5 99). Results: Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586 5 20.31, placebo 5 20.17, P 5 .058) and FEV1 (GSK679586 5 20.01, placebo 5 0.03, P 5.276). Similar analyses From aAlternative Discovery and Development, GlaxoSmithKline, King of Prussia; b Biopharm Research, cRespiratory Discovery Medicine, and eII/Biopharm Clinical Statistics, GlaxoSmithKline, Stevenage; dRespiratory Medicines Development, GlaxoSmithKline, Research Triangle Park; fClinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Middlesex; gGenentech, Research and Early Development, San Francisco; hEmerging Markets R&D, GlaxoSmithKline, Brentford; i ISP Pharma, Birmingham; jGlobal Medical Safety, Janssen Pharmaceuticals, High Wycombe; and kAsthma Institute, University of Pittsburgh Medical Center, Pittsburgh. The design, conduct, analysis, and publication of this research were sponsored by GlaxoSmithKline Research and Development. S.E.W. received compensation from GlaxoSmithKline for participation in a study-related advisory board meeting and help with study design and has also received consultancy fees from GlaxoSmithKline. I.S.P. received compensation from GlaxoSmithKline for study management. S.S.T. is a former employee of GlaxoSmithKline. A.P.S. is a shareholder of GlaxoSmithKline and former full-time employee of the company. P.O. is a shareholder and employee of GlaxoSmithKline currently on sabbatical at LSHTM University of London. Disclosure of potential conflict of interest: I. S. Panesar has received one or more consulting fees or honoraria from ISP Pharma. S. S. Thiagarajah and A. P. Serone were formerly employed by and own stock/stock options in GlaxoSmithKline and are currently employed by and own stock/stock options in Janssen Pharmaceutical Companies of Johnson & Johnson and Genentech, respectively. S. E. Wenzel has been supported by one or more grants from GlaxoSmithKline, has consultancy arrangements with Janssen Pharmaceutical Companies of Johnson & Johnson, has received one or more grants from or has one or more grants pending with Array Biopharma, and owns stock/stock options in Amgen, MedImmune, and Sanofi Aventis. The rest of the authors are employed by and own stock/stock options in GlaxoSmithKline. Received for publication February 7, 2013; revised December 4, 2013; accepted for publication January 2, 2014. Available online February 28, 2014. Corresponding author: Erika H. De Boever, PhD, GlaxoSmithKline UW2291, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail: [email protected]. 0091-6749/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.01.002

in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most adverse events were nonserious and unrelated to treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles). Conclusions: Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids. (J Allergy Clin Immunol 2014;133:989-96.) Key words: IL-13, IL13Ra1, IL13Ra2, efficacy, safety, pharmacokinetics, pharmacodynamics

Severe refractory asthma is characterized by persistent airway obstruction and frequent, often severe exacerbations despite high-dose inhaled corticosteroids (ICSs) given with or without long-acting b-agonists (LABAs) or oral corticosteroids (OCSs).1,2 Although these patients represent only 5% to 10% of the overall asthmatic population, they contribute disproportionately to health care expenditures.3,4 Thus there is a significant need for new therapies offering improvements in asthma control in this group of patients. Clinical phenotypes of asthma associated with distinct cellular profiles have been identified, including a molecular signature consistent with TH2 cytokine–induced gene expression.5-8 IL-13, a TH2 cytokine, is considered a key driver of airway hyperresponsiveness9,10 and other aspects of asthma, such as mucus hypersecretion and airway remodeling.11-13 Persistence of asthma symptoms despite high-dose corticosteroids has been linked to increased IL-13 levels in the lungs,14-17 suggesting that IL-13 expression might drive disease and contribute to corticosteroid resistance in some patients. IL-13 is produced by hematopoietic and nonhematopoietic cells,18,19 most notably activated T lymphocytes (especially TH2 cells), mast cells, basophils, and type 2 innate lymphoid cells, and signals primarily through the type 2 IL-4 receptor (IL-4R, which is composed of IL-13 receptor [IL-13R] a1 and IL-4Ra). The role of the second IL-13 receptor (IL-13Ra2) is unclear, but it might act as a decoy to regulate IL-13 activity, or alternatively, IL-13 signal transduction through IL-13Ra2 might be involved in the pathology of fibrosis.20,21 IL-4 shares functional redundancy with IL-13 because of shared receptor use at the type 2 IL-4R; however, IL-4 can also signal 989

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Abbreviations used ACQ: Asthma Control Questionnaire ADA: Anti-drug antibody AE: Adverse event ECLIA: Electrochemiluminescence immunoassay FENO: Fraction of exhaled nitric oxide FPE: Fluticasone propionate or equivalent ICS: Inhaled corticosteroid IL-4R: IL-4 receptor IL-13R: IL-13 receptor LABA: Long-acting b-agonist LLQ: Lower limit of quantification MSD: MesoScale Discovery OCS: Oral corticosteroid PK: Pharmacokinetics SAE: Serious adverse event

exclusively through the type 1 IL-4R (composed of IL-4Ra and the common g chain).22,23 The relevance of signaling redundancy with respect to the clinical efficacy of IL-13–targeting therapies remains unknown. GSK679586 is a humanized IgG1-type mAb that specifically binds and neutralizes IL-13.22,24 GSK679586 inhibits IL-13 bioactivity in vitro and demonstrated dose-dependent pharmacologic activity in the lungs of patients with mild intermittent asthma.25 The current study evaluated the efficacy and safety of GSK679586 as add-on therapy in patients with severe asthma who remained symptomatic despite maximum recommended doses of ICSs (with or without LABAs and OCSs). Such patients represent a high unmet clinical need with few remaining effective treatment options.

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8 countries from December 2008 to April 2010. The study was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki, and applicable regulatory requirements and with approval by local ethics committees. Written informed consent was obtained from all patients. At the end of the 4-week run-in period, eligible patients were randomized (1:1) to receive 10 mg/kg GSK679586 intravenously or normal saline at day 1, week 4, and week 8. Additionally, the study was stratified by use of concurrent OCSs to control for potential confounding of treatment effects.

Assessments ACQ-7 and pulmonary function testing were performed at screening, before run-in, at baseline, and 2, 4, 8, 12, 16, 20, and 24 weeks after treatment initiation. The primary end point was the change from baseline in ACQ-7 scores26,27 over 12 weeks. Asthma exacerbations were defined as worsening of asthma symptoms requiring an emergency department visit, hospitalization, and/or an increased OCS dose. Changes from baseline in free and total serum IL-13 levels, serum total IgE levels, and blood eosinophil counts were evaluated over the same time period as exploratory end points. IL-13 and IgE levels were measured with sandwich electrochemiluminescence immunoassays (ECLIAs; lower limit of quantification [LLQ], 15.63 pg/mL) on the MesoScale Discovery (MSD) platform (Gaithersburg, Md) and a commercially available sandwich ELISA (AlerCHEK, Portland, Me; LLQ, 12.6 IU/mL), respectively. Sparse pharmacokinetic (PK) sampling was performed through 26 to 36 weeks, and GSK679586 plasma concentrations were measured by using a chemiluminescent immunoassay (LLQ, 100 ng/mL). Individual and population PK parameters28 were estimated by using NONMEM, version V. Safety and tolerability were evaluated from treatment initiation through final follow-up based on adverse events (AEs), clinical laboratory tests, physical examinations, vital signs, and electrocardiograms. Immunogenicity assessments were performed throughout the study, and anti-GSK679586 anti-drug antibodies (ADAs) were detected by using a bridging ECLIA on the MSD platform. Positive ECLIA samples were further analyzed in a cell-based reporter system to determine whether the antibodies had neutralizing activity.

METHODS See the Methods section in this article’s Online Repository at www. jacionline.org for additional methodological details.

Study population Patients aged 18 to 75 years with severe asthma who were symptomatic _1.5) while receiving (Asthma Control Questionnaire [ACQ]-7 score > 500 mg/d or greater fluticasone propionate or equivalent (FPE) and had a prebronchodilator FEV1 of 35% to 80% of predicted normal value with 12% or greater reversibility on b2-agonist inhalation were eligible to enter the _25 mg/d prednisolone or equivalent) were run-in phase. LABAs or OCSs (< allowed. During the 4-week run-in period, the ICS dose was increased to 1000 mg/d FPE, as suggested by current British Thoracic Society Step 4 guidelines. No changes were made to the ICS dose in patients already taking 1000 mg/d FPE or greater or to other asthma maintenance therapy. Only patients who _1.5) while taking > _1000 mg/d FPE remained symptomatic (ACQ-7 score > were eligible to enter the study. Key exclusions were omalizumab therapy within the prior 4 months; methotrexate, troleandomycin, oral gold, cyclosporine, or other experimental anti-inflammatory therapies within 3 months; acute respiratory illness within 4 weeks; acute asthma exacerbation requiring hospitalization or intubation within 3 or 6 months, respectively; a history of chronic pulmonary conditions (other than asthma); or 12 or more pack years of smoking.

Trial design This double-blind, randomized, placebo-controlled, parallel-group study (clinicaltrials.gov identifier NCT00843193) was conducted at 34 sites across

Statistical analysis Eighty patients per treatment group provided an estimated 90% power to detect a clinically meaningful treatment difference of 0.5 for the primary end point (change from baseline in ACQ-7 score over 12 weeks) by using a 2-sample t test and assuming an SD of 0.90 and a 10% dropout rate. Final efficacy analyses used an adjusted type I error rate of an a value of 0.035 for hypothesis testing because 1 planned interim analysis was performed. Changes from baseline in ACQ-7 scores, ACQ-6 scores, and FEV1 (including post hoc subgroup analyses) were analyzed by means of analysis of covariance at 2 weeks and by using a mixed model for repeated measures at other visits and over 12 weeks.29 Covariates included sex, age, baseline OCS use, and predose assessment. SAS version 9.1.3 software (SAS Institute, Cary, NC) was used for all analyses.

RESULTS Of the 237 patients enrolled in the study, 198 remained _1.5) at the completion of the symptomatic (ACQ-7 score > run-in period, and 99 each received treatment (Fig 1). Patients’ demographics and baseline characteristics were generally similar for each treatment group (Table I). The study population was primarily white and sex balanced. In addition to receiving ICSs at a dose of at least 1000 mg/d FPE, most patients were also receiving maintenance therapy with LABAs (91%), and 16% of patients were receiving OCSs. A total of 179 patients completed the study; the primary reasons for early discontinuation were withdrawal of consent and AEs (Fig 1).

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FIG 1. Flow of patients through the study. *One patient randomized to GSK679586 was misallocated placebo infusions; this patient was included in the placebo group for all analyses.

TABLE I. Patients’ demographics and baseline characteristics Placebo (n 5 99)

Age (y), mean (SD) Female sex, no. (%) White, no. (%) Body mass index (kg/m2), mean (SD) Pulmonary function, mean (SD)* FEV1 (L) FEV1 (% reversibility) FEV1 (% predicted) FVC (L) Asthma maintenance therapy, no. (%)  OCS LABA Rescue medication use, mean (SD)* No. of puffs of b-agonist/d Asthma control, mean (SE)* ACQ-7 ACQ-6 _LLQ, no. (%)* Serum free IL-13 > _LLQ, no. (%)* Serum total IL-13 > Blood eosinophil count (3 109/L), mean (SE)* Serum total IgE (IU/L), mean (SE)*

51 49 95 28 1.89 22 58 2.91

GSK679586 (n 5 99)

(12) (49) (96) (4) (0.67) (10) (13) (0.92)

51 51 96 28 1.75 26 55 2.81

(0.57) (15) (12) (0.83)

16 (16) 93 (94)

2.2 (0.3)

2.4 (0.28)

(0.1) (0.1) (2) (15) (0.03) (58)

2.7 2.5 7 15 0.27 282

Adjusted least-squares means

(11) (52) (97) (4)

16 (16) 87 (88)

2.6 2.4 2 15 0.27 353

TABLE II. Effect of GSK679586 and placebo on ACQ-7 scores and FEV1 by study visit and over 12 weeks for the intent-totreat population

(0.1) (0.1) (7) (15) (0.02) (48)

FVC, Forced vital capacity. *Based on measurements obtained after completion of the run-in period.  All patients were also receiving 1000 mg/d FPE or greater.

Efficacy Both treatment groups demonstrated a decrease (improvement) in ACQ-7 scores over 12 weeks of treatment (adjusted least squares mean values of 20.31 and 20.17 for GSK679586 and placebo, respectively). However, the estimated treatment difference of 20.14 (95% CI, 20.28 to 0.00) was not statistically significant

Treatment difference (GSK679586 2 placebo)

GSK679586 Placebo (n 5 99) (n 5 99) Estimate

ACQ-7 score Weeks 4-12* Week 2 Week 4 Week 8 Week 12 FEV1 (L) Weeks 4-12* Week 2 Week 4 Week 8 Week 12

95% CI

P value

20.31 20.21 20.30 20.22 20.35

20.17 20.10 20.11 20.17 20.27

20.14 20.11 20.19 20.05 20.08

20.28 20.27 20.34 20.23 20.31

to to to to to

0.00 0.06 20.03 0.14 0.14

.058 .196 .019 .616 .467

20.01 20.03 0.02 20.03 20.04

0.03 20.02 0.01 0.01 0.06

20.04 20.01 0.01 20.04 20.10

20.12 20.08 20.08 20.12 20.19

to to to to to

0.03 0.06 0.09 0.05 0.00

.276 .769 .899 .423 .054

*Analysis of treatment response over 12 weeks includes data at weeks 4, 8, and 12.

(P 5.058) or clinically meaningful (Table II). There was also no difference in the percentage of ACQ-7 ‘‘responders’’ (>0.5-point improvement over the treatment period) between groups (27% for placebo and 29% for GSK679586, Fig 2). FEV1 also showed minimal changes from baseline over the 12-week treatment period (20.01 L and 0.03 L for GSK679586 and placebo, respectively) or at any study visit (Table II). An analysis of ACQ-6 scores to determine the effect of the lack of effect on FEV1 on the evaluation of asthma control, although borderline significant, also did not demonstrate a clinically meaningful treatment effect over 12 weeks (adjusted least squares mean difference 5 20.16; 95% CI, 20.32

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FIG 2. Bar plot of responders for ACQ-7 scores (A) and FEV1 (B) over 12 weeks without strata information.

points, including changes from baseline in ACQ scores and FEV1 over 16 and 24 weeks; responder analyses based on clinically meaningful decreases in ACQ scores (20.50) or FEV1 (200 mL); changes from baseline in individual ACQ component scores; changes from baseline in forced expiratory flow, midexpiratory phase and forced vital capacity and daily patient-reported b-agonist use; daytime/nighttime asthma symptoms; and weekly variability in peak expiratory flow rate.

FIG 3. Mean change from baseline in serum total IL-13 levels (A), serum total IgE levels (B), and blood eosinophil counts (C) in patients receiving 10 mg/kg GSK679586 or placebo infusions.

to 20.01; P 5 .037). Asthma exacerbations were reported with similar frequency by patients receiving GSK679586 (14 events in 11 patients) and placebo (16 events in 13 patients) during the 12-week treatment period. No evidence of a significant treatment effect was observed on analysis of other asthma control and pulmonary function end

Pharmacodynamic and subgroup analyses Mean total serum IL-13 levels, which were similar between treatment groups at baseline, accumulated after treatment with GSK679586 while remaining essentially unchanged with placebo treatment (Fig 3, A). Overall, 51 (52%) of 99 patients in the GSK679586 group had measurable increases in total IL-13 levels, which were defined as at least 2 total IL-13 measurements more than twice the LLQ of the assay, compared with 4 (4%) of 99 placebo-treated patients. Free serum IL-13 levels were less than the LLQ of the assay at baseline and throughout treatment for the majority of patients in both treatment groups. The lack of a similar detectable increase in free IL-13 levels among GSK679586-treated patients suggests that the increases in total IL-13 represent binding of free IL-13 by GSK679586 to form an antibody-cytokine complex. Total serum IgE levels (Fig 3, B) and blood eosinophil counts (Fig 3, C) remained essentially unchanged after treatment with GSK679586. Throughout the study, mean total IgE levels were generally comparable for GSK679586 and placebo, whereas mean eosinophil counts tended to be slightly higher for GSK679586 than placebo because of a downward trend in eosinophil counts in the placebo group during treatment. Considerable between-patient variability in baseline total IgE levels and blood eosinophil counts was observed in both the GSK679586 group ( Fatigue Headache Hypertension Dizziness Peripheral edema

Placebo (n 5 99)

GSK679586 (n 5 99)

49 (49)

52 (53)

6 5 6 3 2 2 3 1 10

13 10 4 4 5 4 3 4 15

(6) (5) (6) (3) (2) (2) (3) (1) (10)

1 (1) 1 (1) 3 (3) 0 1 (1)

(13) (10) (4) (4) (5) (4) (3) (4) (15)

4 (4) 3 (3) 0 2 (2) 1 (1)

of patients who had a substantial baseline increase in total IgE levels, eosinophil counts, or both. Among patients in the upper tertile, on the basis of screening eosinophil counts (ie, eosinophils >0.30 GI/L), there were no treatment differences of clinical relevance in ACQ-7 scores or FEV1 over 12 weeks or at any study visit (see Table E1 in this article’s Online Repository at www.jacionline.org). No significant treatment differences in ACQ-7 scores and FEV1 were observed at any study visit for the subpopulation of patients who had both IgE levels of greater than 100 IU/mL and eosinophil counts of greater than 0.14 GI/L after completion of the run-in period (see Table E2 in this article’s Online Repository at www.jacionline.org) or high baseline IgE levels (patients in the upper tertile with IgE > _245.26 IU/mL, see Table E3 in this article’s Online Repository at www.jacionline.org).

PK GSK679586 population PK parameter estimates are presented in Table III. After repeat intravenous administration (3 doses), GSK679586 clearance was slow, and the volume of distribution at steady state, inclusive of both the central and peripheral compartments, was close to the plasma volume, indicating limited drug distribution into the tissues. The terminal half-life derived from the population PK parameter estimates was approximately 21 days. No trends were apparent between GSK679586

plasma concentrations and levels of total IgE or free IL-13 or log-transformed cumulative GSK679586 area under the curve and ACQ-7 scores, ACQ-6 scores, or FEV1 weighted mean values over 12 weeks based on visual examination of scatterplots of these variables.

Safety and tolerability GSK679586 was generally well tolerated and had an acceptable safety profile. Most AEs were nonserious, mild or moderate in intensity, and considered by the investigator to be unrelated to treatment. Table IV summarizes AEs reported for 3% or more of patients in the study, both for all events regardless of causality and for events assessed by the investigator as treatment related. Headache and nasopharyngitis were reported more frequently for patients in the GSK679586 group compared with the placebo group; most of these events were considered unrelated to treatment. Fifteen serious adverse events (SAEs) were reported during the study (GSK679586, 8 SAEs in 8 patients; placebo, 7 SAEs in 5 patients). Two of the 15 SAEs (lethargy and supraventricular extrasystoles) were assessed as related to GSK679586; neither event resulted in discontinuation of treatment. Six patients discontinued treatment because of AEs. Two of these were deemed by the blinded investigator to be related to study treatment: 1 subject in the placebo group discontinued treatment because of fatigue, and 1 GSK679586treated subject had mild gastrointestinal disturbance and a parasite-positive stool sample that resulted in discontinuation of study treatment. No clinically meaningful trends were observed in vital signs, clinical laboratory data, or electrocardiographic data. Immunogenicity After study initiation, 2 GSK679586-treated and 4 placebosubjects were screened and confirmed positive for anti-drug antibodies at 1 or more time points during the study. However, subsequent titer determinations from both the treatment and placebo groups were nearly identical, suggesting the development of an ADA response was unlikely. Neutralizing antibodies were not demonstrated within any sample that had been confirmed positive. Also, PK and safety profiles were unaffected. DISCUSSION This is the first report of anti–IL-13 therapy in patients with severe asthma who remain symptomatic despite maximally indicated doses of ICSs with or without LABAs, OCSs, or both. Although well tolerated, GSK679586 did not demonstrate a statistically significant or clinically meaningful improvement in asthma control (ACQ-7 score) or pulmonary function (FEV1) over 12 weeks of treatment relative to placebo. In addition, there was no apparent benefit of GSK679586 on the incidence of severe exacerbations, which were defined as worsening of asthma symptoms requiring OCSs, an emergency department visit, or hospitalization. These results are in contrast to those reported for other anti–IL-13 or anti–IL-13/IL-4–targeting therapies, which have shown an improvement in lung function30-32 (or reduction in exacerbation incidence33,34), although in patients with less severe disease and using a less stringent definition of asthma exacerbations. Interestingly, none

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of these therapies has produced substantial improvement in asthma symptoms. Potential explanations for the lack of efficacy of GSK679586 in this study include the possibility that (1) the potency or dosing regimen of GSK679586 was inadequate to provide clinical benefit; (2) the patients with severe asthma taking high-dose corticosteroids no longer had a significantly uncontrolled IL-13 component to their disease or only a subgroup of these patients had the potential to benefit from IL-13–targeting therapies; (3) blockade of IL-13 signaling alone was insufficient to provide clinical benefit because of functional redundancy with IL-4 or other mediators of asthma in this population; or (4) immunogenicity. Suboptimal drug potency or an inadequate dosing regimen could be postulated for the lack of efficacy observed in this study. The dosing regimen of 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 was selected based on PK and pharmacodynamic data obtained from a repeat ascending dose study in atopic patients with mild asthma who required only intermittent use of short-acting b-agonists.25 In that study dose-dependent reductions were observed in the fraction of exhaled nitric oxide (FENO), which is consistent with those previously reported for ICSs,35 indicating that 2 once-monthly intravenous infusions of GSK679586 produced pharmacologic effects in the lungs of patients with mild asthma. In the current study neither IL-13 levels in the lung nor FENO values were measured to confirm pharmacology in this population. GSK679586 exposures in the current study were similar to those observed in patients with mild asthma and thus would have been within the predicted range for pharmacologic activity and efficacy. This assumes that FENO is a useful marker of lung inflammation in patients with severe refractory asthma and that dose responses and local exposures in patients with severe asthma are similar to those in patients with mild asthma. It is estimated that approximately 15% of an infused mAb would reach a well-perfused organ, such as the lung.36 Given the large intravenous GSK679586 dose (10 mg/kg) used, it would be unlikely that local drug exposures were inadequate to provide sufficient target coverage in the airways. Furthermore, a modest effect on nighttime awakening and wheezing (2 components of the ACQ-7 questionnaire) was observed compared with placebo (20.2 and 20.3 difference, respectively). Although these effects did not meet the predefined threshold for clinical significance, this suggests that GSK679586 was able to penetrate the lung and potentially provides some evidence of pharmacology. However, another explanation could be differences in antibody affinity of the various molecules used in clinical studies, and it is possible that the potency of GSK679586 contributed to the lack of efficacy. Indeed, as has been shown for the anti–respiratory syncytial virus antibody palivizumab, changes in antibody affinity can significantly affect pharmacology in the lung.37 The composition of the study population is a key difference between the current study and other trials of anti–IL-13– or anti–IL-13/IL-4–targeting therapies.30-34 Previous studies were conducted primarily in patients with moderate-to-severe asthma receiving intermediate-to-high doses of ICS. Because high-dose ICSs have been reported to suppress sputum IL-13 to undetectable levels in patients with moderate asthma,14 those patients receiving intermediate doses of ICSs might have benefited clinically from an increase to maximally indicated doses, thus obviating the need for anti–IL-13 therapy. However, our study included only

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patients with severe asthma who remained symptomatic despite receiving at least 1000 mg/d FPE and for whom few effective treatment options are available. It is conceivable that in some of these subjects, the high-dose ICS regimen might have already maximally suppressed IL-13 because only approximately half of the GSK679586-treated patients had measurable levels of total serum IL-13 during treatment. Post hoc analysis of patients with detectable serum IL-13 levels showed no improvement in efficacy in this subset. Thus the remaining symptoms, lung function changes, and perhaps exacerbations might not be driven by IL-13 in this severe population. For the majority of the anti–IL-13– and anti–IL-13/IL-4– targeting approaches evaluated to date, the greatest clinical effect has been observed in selected subgroups of patients with mild and moderate asthma. Pitrakinra, a recombinant IL-4 mutein that blocks the effects of both IL-4 and IL-13, improved the exacerbation incidence in response to medication withdrawal in asthmatic patients with high peripheral blood eosinophil counts (>350 cells/mm3).33 Lebrikizumab, an anti–IL-13 mAb, produced relatively modest improvements in lung function after 12 weeks of treatment (FEV1), but this effect appeared to wane with continued lebrikizumab therapy. Moreover, the treatment benefit was largely limited to a subset of patients with high baseline levels of serum periostin (which was used as a surrogate marker for IL-13 activity) and to those patients with both high baseline serum periostin and FENO values.30 These data suggest that anti–IL-13 and anti–IL-13/IL-4 therapeutics might be most useful in targeted subpopulations with residual TH2 inflammation. It remains to be seen whether such responsive subgroups exist in patients with severe asthma. In the current study of patients with severe asthma, post hoc analyses of ACQ-7 scores and FEV1 did not identify treatment-responsive subgroups based on combinations of eosinophil counts and serum IgE level cut points similar to those used in the lebrikizumab and pitrakinra studies.30,33 However, in contrast to the pitrakinra study (and as seen with treatment with anti–IL-538), stratification by blood eosinophil counts did not identify a group of responders. Because serum periostin and FENO values were not measured in this study and serum IL-13 levels were less than the limit of quantification in most patients at baseline, it cannot be confirmed whether treatment-responsive subgroups of patients with severe asthma exist based on these clinical phenotypes. IL-13/IL-4 signaling is complex, and the mechanism of signal inhibition by some competitor approaches is different compared with GSK679586. For example, molecules such as pitrakinra (an IL-4 mutein), AMG-317, and dupilumab (both anti–IL-4Ra mAbs) compete with endogenous IL-13 and IL-4 to prevent binding and hence signaling through the type 2 IL-4R (and with respect to IL-4 the type 1 IL-4R), whereas GSK679586, tralokinumab, and IMA-026 prevent IL-13 interaction at both IL-13Rs but are unable to block IL-4 signaling (GlaxoSmithKline, unpublished data). Other IL-13–only blocking antibodies, such as anrukinzumab (IMA-638) and lebrikizumab, inhibit IL-13 signaling through the type 2 IL-4R not by blocking IL-13 binding to IL-13Ra1 but by preventing recruitment of the IL-4Ra chain into a functional type 2 IL-4R complex, and additionally, they do not appear to prevent IL-13 binding to IL-13Ra2.33,39 Therefore it is conceivable that differences in the mechanism of IL-13 inhibition and/or a requirement to block IL-4 (to mitigate the potential for functional redundancy) could influence achieving the most optimal clinical outcome. However, because

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tralokinumab and lebrikizumab bind IL-13 at distinct epitopes (and hence block IL-13 signaling in different ways) but demonstrate similar activity in patients with moderate-to-severe asthma,30,31 the mechanism of IL-13 inhibition might not be relevant as long as IL-13 signaling is effectively blocked. Recent data indicate that IL-13 is a negative regulator of TH17 cytokine production.40 TH17 cells, but not TH0, TH1, TH2, or induced regulatory T cells, express IL-13Ra1 receptors: and IL-13 engagement is associated with inhibition of TH17 cell function. Conversely, neutralizing IL-13 ex vivo in human TH17-differentiated cells increased IL-17A protein expression40 and promotes TH17-mediated inflammation.41 Thus IL-13–targeting therapeutics, such as GSK679586, could decrease TH2-mediated inflammation but enhance a TH17-mediated airway inflammation in certain patients. Such an unintended effect of IL-13 blockade could have contributed to the lack of efficacy in this study. Finally, because of the nearly identical assay titers demonstrated between the GSK679586-treated and placebo groups, the development of an ADA response was considered unlikely and thus would not adequately explain the lack of efficacy demonstrated. All confirmed positive samples were also neutralizing antibody negative, which was consistent with the absence of an ADA response affecting efficacy. In conclusion, GSK679586 was well tolerated but did not demonstrate a clinically meaningful improvement in asthma control or pulmonary function in a broad population of patients with severe asthma refractory to high-dose ICSs or in subpopulations of patients with severe asthma with high blood eosinophil counts, serum IgE levels, or both. Further studies are needed to determine whether anti–IL-13 or anti–IL-13/IL-4 therapies can provide clinical benefit in patients with severe asthma or a subpopulation of these patients beyond that observed with high-dose ICSs alone. We thank the following persons for their contributions to the conduct and reporting of this study, their critical review during the development of this manuscript, or both: the study investigators, Patty Wolf, Joanne Thompson, Catherine Wang, Thomas Lee, and other members of the GlaxoSmithKline study team. Manuscript coordination and management was provided by Doug Wicks, MPH, CMPP, of GlaxoSmithKline. Editorial support in the form of development of an outline and first draft of the manuscript, editorial suggestions, assembling tables and figures, copyediting, fact checking, and referencing was provided by Lisa Cass, Cass Consulting, and funded by GlaxoSmithKline.

Clinical implications: If confirmed by other trials, determining the inflammatory asthma phenotype of patients with severe refractory asthma will be a critical component in the selection of appropriate adjunctive therapy.

REFERENCES 1. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44. 2. Wenzel S. Pathology of difficult asthma. Paediatr Respir Rev 2003;4:306-11. 3. Sullivan SD, Rasouliyan L, Russo PA, Kamath T, Chipps BE. for the TENOR Study Group. Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma. Allergy 2007;62:126-33. 4. Breekveldt-Postma NS, Erkens JA, Aalbers R, van de Ven MJT, Lammers JJ, Herings RMC. Extent of uncontrolled disease and associated medical costs in severe asthma—a PHARMO study. Curr Med Res Opin 2008;24:975-83.

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5. Green RH, Brightling CE, Bradding P. The reclassification of asthma based on subphenotypes. Curr Opin Allergy Clin Immunol 2007;7:43-50. 6. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-24. 7. Bradding PB, Green RH. Subclinical phenotypes of asthma. Curr Opin Allergy Clin Immunol 2010;10:54-9. 8. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388-95. 9. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: Central mediator in allergic asthma. Science 1998;282:2258-61. 10. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev 2004;202: 175-90. 11. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999; 103:779-88. 12. Yang G, Volk A, Petley T, Emmell E, Giles-Komar J, Shang X, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine 2004;28:224-32. 13. Fulkerson PC, Fischetti CA, Hassman LM, Nikolaidis NM, Rothenberg ME. Persistent effects induced by IL-13 in the lung. Am J Respir Cell Mol Biol 2006;35:337-46. 14. Saha SK, Berry MA, Parker D, Siddiqui S, Morgan A, May R, et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol 2008;121:685-91. 15. Townley RG, Gendapodi PR, Qutna N, Evans J, Romero FA, Abel P. Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of beta-adrenergic bronchodilators and corticosteroids. Ann Allergy Asthma Immunol 2009;102:190-7. 16. Kraft M, Lewis C, Pham D, Chu HW. IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma. J Allergy Clin Immunol 2001;107:602-6. 17. Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY. A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol 1996;157:2654-9. 18. Allahverdian S, Harada N, Singhera GK, Knight DA, Dorscheid DR. Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF. Am J Respir Cell Mol Biol 2008;38:153-60. 19. Ruız-Gonzalez V, Cancino-Diaz JC, Rodrıguez-Martınez S, Cancino-Diaz ME. Keratinocytes treated with peptidoglycan from Staphylococcus aureus produce vascular endothelial growth factor, and its expression is amplified by the subsequent production of interleukin-13. Int J Dermatol 2009;48:846-54. 20. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13a2 receptor is involved in induction of TGF-b1 production and fibrosis. Nat Med 2006;12:99-106. 21. Strober W, Kitani A, Fichtner-Feigl S, Fuss IJ. The signaling function of the IL13Ra2 receptor in the development of gastrointestinal fibrosis and cancer surveillance. Curr Mol Med 2009;9:740-50. 22. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, et al. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 2008;132:259-72. 23. Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 2003;111:677-90. 24. Lupardus PJ, Birnbaum ME, Garcia KC. Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13 Ra2. Structure 2010;18:332-42. 25. Hodsman P, Ashman C, Cahn T, De Boever E, Locantore N, Serone A, et al. I13105054: a dose-escalating study of the safety and pharmacokinetics of GSK679586 in healthy volunteers and mild asthmatics. Br J Clin Pharmacol 2013;75:118-28. 26. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14: 902-7. 27. Juniper EF, O’Bryne PM, Ferrie PJ, King DR, Roberts JN. Measuring asthma control. Clinic questionnaire or daily diary. Am J Respir Crit Care Med 2000; 162:1330-4. 28. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49:633-59. 29. Littell RC, Milliken GA, Stroup WW, Wolfinger RD, Schabenberger O. SAS for mixed models. 2nd ed. Cary (NC): SAS Institute; 2006. 30. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365: 1088-98.

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31. Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013;41:330-8. 32. Corren J, Busse W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, et al. A randomized, controlled, Phase 2 study of AMG 317, an IL-4Ra antagonist, in patients with asthma. Am J Respir Crit Care Med 2010;181: 788-96. 33. Wenzel S, Ind PW, Otulana BA, Bleecker ER, Kuna P, Yen YP. Inhaled pitrakinra, an IL-4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma [abstract]. Abstract #P3980. Available at: www.ersnet.org. 34. Wenzel SE, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013;368:2455-66. 35. Jatakanon A, Karitonov S, Lim S, Barnes PJ. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999;54:108-14.

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36. Shah DK, Betts AM. Antibody biodistribution coefficients. Inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. mAbs 2013;5:297-305. 37. Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J 2010;12:33-43. 38. Pavord I, Kern S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for Severe Eosinophilic Asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9. 39. Kasaian MT, Raible D, Marquette K, Cook TA, Zhou S, Tan XY, et al. IL-13 antibodies influence IL-13 clearance in humans by modulating scavenger activity of IL-13Ra2. J Immunol 2011;187:561-9. 40. Newcomb DC, Boswell MG, Zhou W, Huckabee MM, Goleniewska K, Sevin CM, et al. Human Th17 cells express a functional IL-13 receptor and IL-13 attenuates IL17A production. J Allergy Clin Immunol 2011;127:1006-13. 41. Newcomb DC, Peebles RS. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013;25:755-60.

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METHODS Study population In addition to the study eligibility criteria outlined in the primary article, all patients had a diagnosis of asthma for 6 or more months according to Global Initiative for Asthma guidelines. Patients were excluded from the study if there was a strong family history of TH1 cytokine–related inflammatory disorders, evidence of lung infection on chest radiography, lower respiratory tract infection within 6 weeks of the study, or more than 3 such infections requiring antibiotic treatment within 3 months of the study.

Trial design A computer-generated randomization schedule was generated by Discovery Biometrics (GlaxoSmithKline, King of Prussia, Pa) by using validated in-house software and was stratified by OCS use at baseline with a 1:1 allocation. Patient randomization numbers and container treatment assignment list numbers were assigned through an in-house interactive voice-response system after a patient’s eligibility was confirmed at the completion of the run-in period. Masked GSK679586 and normal saline infusions were prepared by an independent unblinded pharmacist in equivalent final solution volumes (40-60 mL, depending on subject weight) to blind the subject, investigator, and all other outcome assessors to treatment allocation.

Assessments Self-administered components of the ACQ-7 (items 1-6) and self-reporting of daily asthma symptoms were completed by the subject before clinical consultation and measurement of morning peak expiratory flow rate, respectively. Pulmonary function testing was performed by using spirometry, according to the American Thoracic Society/European Respiratory Society recommendations,E1 and all measurements (FEV1, forced vital capacity, and forced expiratory flow, midexpiratory phase) were derived by using a central spirometry vendor (CompleWare, Iowa City, Iowa). Samples for measurement of free and total serum IL-13 levels, serum IgE levels, and blood eosinophil counts were collected at baseline and periodically through 24 weeks after treatment initiation. Free and total IL-13 levels were measured by using sandwich ECLIAs on the MSD platform. The total IL-13 ECLIA detected both free IL-13 and IL-13 bound to GSK679586, whereas the free IL-13 ECLIA was shown to detect only unbound IL-13. IL-13 concentrations were calculated by regression analysis against a recombinant IL-13 calibrator curve in pooled human serum. Total IgE levels were measured with a commercially available sandwich ELISA (AlerCHEKE), and IgE concentrations were determined by using interpolation from a 4-parameter logistic standard curve and adjusted based on sample dilutions. Eosinophil counts were measured as part of the standard white blood cell differential. Immunogenicity assessments were performed at screening, baseline, and 2, 4, 8, 12, 16, 20, and 24 weeks after initiation of treatment and at the final PK/ immunogenicity follow-up visit. Anti-GSK679586 antibodies (ADAs) were detected by using a bridging ECLIA on the MSD platform. Samples that screened positive for ADAs were reanalyzed in the presence of excess unlabeled GSK679586 in a confirmatory assay. Confirmed positive samples were further analyzed for ADA titer and neutralizing antibodies. Anti-GSK679586 neutralizing antibodies were detected by using a cell-based reporter system in which inhibition of IL-13–mediated reporter expression through the addition of exogenous GSK679586 is reduced in the presence of neutralizing antibody in the human serum samples. Sparse PK sampling was used in which samples were collected in all patients before and at the end of the first infusion, 1 hour after onset of the second and third infusions, 12 weeks after treatment initiation, and at a final follow-up visit 26 to 36 weeks after treatment initiation (depending on when the GSK679586 plasma concentration was estimated not to interfere with

anti-GSK679586 antibody measurements), and additional samples were collected either between 0.25 and 0.75 hours after onset of the first infusion, before the second infusion, and 20 weeks after treatment initiation (group 1, patients with odd randomization numbers) or 4 days after the first infusion, before and 4 days after the third infusion, and 24 weeks after treatment initiation (group 2, patients with even randomization numbers). PK samples were collected into EDTA tubes, gently inverted, and immediately placed on water ice. Plasma was separated by means of refrigerated (48C) centrifugation at 3000 rpm for 10 to 15 minutes within 30 minutes of sample collection, and aliquots were stored at 2208C until shipped for analysis. Plasma samples were analyzed by the Department of Worldwide Bioanalysis, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, by using a chemiluminescent immunoassay validated over the range of 100 to 2500 ng/mL for 100 mL of human plasma diluted 10-fold in assay buffer. Within- and between-run coefficients of variation for the assay were 17.8% or less and 13.2% or less, respectively, and the percentage bias ranged from 218.1% to 7.5%. A 2-compartment model with first-order elimination was selected based on prior knowledge of GSK679586 PK. This model, using the ADVAN 3 subroutine in NONMEM version V, was parameterized in terms of macro constants with estimation of intersubject variance (eta) of clearance and volume of the central compartment, and residual error was modeled by using an exponential component. The first-order conditional estimation method with interaction was used. Covariates were investigated, but none were found to be statistically significant and retained in the final model. On completion of model building, individual PK parameter estimates were obtained by using a post hoc Bayesian approach. Area under the curve for the dosing interval (0-t), maximum plasma concentration (Cmax), and time to maximum plasma concentration (tmax) were estimated by using the integration method with ADVAN 6.

Statistical analysis An interim futility analysis was performed by an independent unblinded statistician. Determination of futility or study continuation was based on considerations of conditional powerE2 based on treatment differences in ACQ-7 scores and FEV1. An interim population PK analysis was also conducted to assess the effect of anti-GSK679586 antibody on GSK679586 plasma concentrations and determine the appropriate time point for the final follow-up visit. In the final analyses of ACQ-7 scores, ACQ-6 scores, and FEV1, change from baseline over 12 weeks was analyzed by using the mixed model for repeated measures,E3 including data at 4, 8, and 12 weeks after the first dose and fitted with fixed effects for treatment, visit, treatment by visit, sex, baseline OCS use, baseline result (ACQ-7 score, ACQ-6 score, or FEV1) and age, patient as a random effect, and visit as the repeated-measures term. An unstructured covariance matrix was used to model the error structure. Change from baseline in ACQ-7 scores, ACQ-6 scores, and FEV1 at 2 weeks after the first dose was analyzed by using an analysis of covariance model, controlling for treatment, sex, baseline OCS use, baseline ACQ-7 score, and age. A treatment-visit interaction was found to be statistically significant at the 10% level and was retained in the model for FEV1. Other efficacy end points, biomarkers, and model-predicted PK parameters were summarized, graphically assessed by treatment and time, or both. Tolerability data were summarized by treatment. No inferential statistical analyses were performed. REFERENCES E1. Miller MR, Hankinson J, Odencrantz J, Brusasco V, Burgos F, Casaburi R, et al. Standardization of spirometry. Eur Respir J 2005;26:319-38. E2. Lan KKG, Wittes J. The B-value: a tool for monitoring data. Biometrics 1988;44: 579-85. E3. Littell RC, Milliken GA, Stroup WW, Wolfinger RD, Schabenberger O. SAS for mixed models. 2nd ed. Cary (NC): SAS Institute; 2006.

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TABLE E1. Effect of GSK679586 and placebo on ACQ-7 scores and FEV1 by study visit and over 12 weeks for the subpopulation of patients with eosinophil counts of greater than 0.30 3109/L at the screening visit Adjusted least-squares means

Treatment difference (GSK679586 2 placebo)

GSK679586 Placebo (n 5 32) (n 5 37) Estimate

ACQ-7 score Week 2 Week 4 Week 8 Week 12 Weeks 4-12* FEV1 (L) Week 2 Week 4 Week 8 Week 12 Weeks 4-12*

95% CI

P value

20.33 20.40 20.26 20.58 20.41

20.11 20.06 20.25 20.29 20.21

20.22 20.33 20.01 20.29 20.20

20.49 20.62 20.31 20.66 20.47

to to to to to

0.05 20.04 0.29 0.09 0.07

.107 .024 .958 .132 .139

0.04 0.11 0.05 0.06 0.07

0.08 0.14 0.15 0.16 0.15

20.04 20.03 20.11 20.10 20.08

20.15 20.17 20.25 20.25 20.20

to to to to to

0.07 0.11 0.03 0.04 0.04

.472 .659 .129 .157 .193

*Analysis of treatment response over 12 weeks includes data at weeks 4, 8, and 12.

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TABLE E2. Effect of GSK679586 and placebo on ACQ-7 scores and FEV1 by study visit for the subpopulation of patients with both IgE levels of greater than 100 IU/mL and eosinophil counts of greater than 0.14 3 109/L at the end of the run-in period Adjusted-least squares means

ACQ-7 score Week 4 Week 8 Week 12 FEV1 Week 4 Week 8 Week 12

GSK679586 (n 5 41)

Placebo (n 5 41)

20.14 0.05 20.10

20.14 20.11 20.31

0.03 20.01 20.04

0.13 0.08 0.12

Treatment difference (GSK679586 2 placebo) 95% CI

P value

0.00 0.17 0.21

20.23 to 0.23 20.14 to 0.48 20.18 to 0.59

.9982 .2855 .2853

20.10 20.09 20.16

20.22 to 0.02 20.23 to 0.05 20.31 to 0.00

.0964 .1889 .0521

Estimate

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TABLE E3. Effect of GSK679586 and placebo on ACQ-7 scores by study visit for the subpopulation of patients with baseline IgE levels of 245.26 IU/mL or greater Adjusted least-squares means

Treatment difference (GSK679586 2 placebo)

GSK679586 Placebo (n 5 31) (n 5 34) Estimate

ACQ-7 score Week 4 Week 8 Week 12 Weeks 4-12

20.30 20.06 20.28 20.22

20.03 20.08 20.10 20.06

20.27 0.02 20.17 20.15

95% CI

20.56 20.30 20.59 20.42

to to to to

0.03 0.33 0.24 0.11

P value

.0762 .9167 .4070 .2445