Brusselle, Guy

Riemann, Sebastian

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Reply to Lipworth and Chan

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Disconnect for Tezepelumab on Exacerbations,Symptoms, and Quality of Life in Type 2 Low AsthmaBrian Lipworth and Rory ChanScottish Centre for Respiratory Research, School of Medicine,University of Dundee, Ninewells Hospital, Dundee, United KingdomTo the Editor:Patients with type 2 (T2) low severe uncontrolled asthma representan unmet clinical need in terms of available treatment options. In thisregard, we were somewhat encouraged by the pooled post hoc analysisof the primary endpoint in phase II/III studies with tezepelumabshowing evidence of a 37% mean (95% confidence interval, 0–60%)reduction in exacerbations in a subgroup of patients with T2 lowasthmas defined by blood eosinophil counts,150 cells/μl andfractional exhaled nitric oxide,25ppb (1, 2).However, in such patients with T2 low asthma, there appearedto be a disconnect in regard to a lack of efficacy with tezepelumabfor secondary outcomes, including symptom control and qualityof life, a key point that was overlooked in an accompanyingeditorial (2).Here, for patients with eosinophil counts,150 cells/μl, themean (95% confidence interval) differences for tezepelumab versusplacebo were20.11 (20.34 to 0.11) for the asthma controlquestionnaire and20.13 (20.30 to 0.05) for the asthma quality-of-life questionnaire and, for those with fractional exhaled nitric oxide,25ppb, the respective differences were 0.13 (20.12 to 0.37) and0.08 (20.11 to 0.27), none of which were statistically significant orclinically relevant. Furthermore, in the same biomarker subgroups,the mean differences in prebronchodilator FEV1 were also notsignificant, at 0.00 (20.09 to 0.08) and 0.06 (20.01 to 0.12),respectively.We, therefore, believe prospective mechanistic studies are nowindicated to look at the effects of tezepelumab in patients with T2 lowasthma, perhaps including airway hyperresponsiveness and small-airway function, to see if this might help explain the observedimprovements in exacerbations but not symptoms.Author disclosures are available with the text of this letter atwww.atsjournals.org.Correspondence and requests for reprints should be addressed toBrian Lipworth, M.D., Scottish Centre for Respiratory Research, School ofMedicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.Email: b.j.lipworth@dundee.ac.uk.References1. Corren J, Menzies-Gow A, Chupp G, Israel E, Korn S, Cook B, et al.Efficacy of tezepelumab in severe, uncontrolled asthma: pooledanalysis of PATHWAY and NAVIGATOR studies. Am J Respir Crit CareMed 2023;208:13–24.2. Brusselle G, Riemann S. Is efficacy of tezepelumab independent of severeasthma phenotype? Am J Respir Crit Care Med 2023;208:1–3.Copyright © 2023 by the American Thoracic SocietyReply to Lipworth and ChanGuy Brusselle1,2,3 and Sebastian Riemann11Department of Respiratory Medicine, Ghent University Hospital, Ghent,Belgium; and 2Department of Epidemiology and 3Department ofRespiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam,The NetherlandsORCID IDs: 0000-0001-7021-8505 (G.B.); 0000-0003-1184-7234 (S.R.).From the Authors:Lipworth and Chan highlight an important issue in their letterregarding the post hoc pooled analysis of the PATHWAY (Study toEvaluate the Efficacy and Safety of Tezepelumab in Adult Subjectswith Inadequately Controlled, Severe Asthma) and NAVIGATOR(Study to Evaluate Tezepelumab in Adults and Adolescents withSevere Uncontrolled Asthma) studies: in patients with type 2 lowasthma, there is a disconnect between improvements in exacerbations(37% reduction) with tezepelumab and the lack of a significantbenefit on symptoms and quality of life (QoL) compared withplacebo (1). Because of space limitations, we did not discuss thisdiscordance in our editorial (2). However, discordant effects ofbiological therapies on exacerbations versus symptoms or QoL arenot unique to tezepelumab or type 2 low asthma but have beenThis article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Supported by a grant from AstraZeneca for clinical studies withtezepelumab as part of the WAYPINT trial in patients with chronicrhinosinusitis with nasal polyposis and in the BISA trial withbenralizumab in patients with severe eosinophlic asthma, as well aspayment for giving talks (B.L.). Also, supported by Sanofi/Regeneronfor a clinical study (DISA) in severe asthma with dupilumab and alsothe SINUS 24 study with dupilumab in patients with chronicrhinosinusitis and nasal polyposis, as well as payment for talks (B.L.).Originally Published in Press as DOI: 10.1164/rccm.202304-0746LEon June 6, 2023This article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202305-0792LEon June 6, 2023Correspondence 211CORRESPONDENCE described in other randomized controlled trials, including theDREAM (Dose Ranging Efficacy And safety withMepolizumab insevere asthma) study investigating mepolizumab in severeeosinophilic asthma (3).How can we explain this disconnect? First, the cellular andmolecular mechanisms driving exacerbations versus day-to-daysymptoms and QoL might differ (4). Second, in randomizedcontrolled trials of uncontrolled asthma, there is an importantimprovement in symptoms and QoL in the placebo arm due toa combination of the placebo effect, the Hawthorne effect, andthe natural history of the disease. Therefore, even thoughimprovements in asthma QoL scores from baseline to week 52were observed with tezepelumab in the PATHWAY andNAVIGATOR studies, and were most pronounced in type 2high asthma, the improvement compared with placebo did notreach the minimal clinically important difference. Thiscontrasts with real-life effectiveness studies that comparedclinical outcomes in real-world settings before and duringtreatment (i.e., pre- vs. posttreatment). Intriguingly, the placeboeffect has been shown to have a stronger effect on subjectiveoutcomes such as symptoms and QoL than on objectiveoutcomes such as exacerbations and lung function (5). Inconclusion, when investigating the discordance betweenimprovements in exacerbations as opposed to patient-reportedoutcomes in severe asthma treated with tezepelumab or othermonoclonal antibodies, the mechanisms of diseasepathophysiology as well as the principles of study design needto be taken into account. Author disclosures are available with the text of this letter atwww.atsjournals.org.Correspondence and requests for reprints should be addressed to GuyBrusselle, M.D., Ph.D., Department of Respiratory Medicine, GhentUniversity Hospital, C. Heymanslaan 10, B-9000 Ghent, Belgium.Email: guy.brusselle@uzgent.be.References1. Corren J, Menzies-Gow A, Chupp G, Israel E, Korn S, Cook B, et al.Efficacy of tezepelumab in severe, uncontrolled asthma: pooledanalysis of PATHWAY and NAVIGATOR Studies. Am J Respir CritCare Med 2023;208:13–24.2. Brusselle G, Riemann S. Is efficacy of tezepelumab independent of severeasthma phenotype? Am J Respir Crit Care Med 2023;208:1–3.3. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON,et al. Mepolizumab for severe eosinophilic asthma (DREAM): amulticentre, double-blind, placebo-controlled trial. Lancet 2012;380:651–659.4. Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, et al.After asthma: redefining airways diseases. Lancet 2018;391:350–400.5. Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, et al.Active albuterol or placebo, sham acupuncture, or no intervention inasthma. N Engl J Med 2011;365:119–126.Copyright © 2023 by the American Thoracic SocietyReply to Lipworth and ChanChristopher S. Ambrose1, Elliot Israel5, Karin Bowen2,Jean-Pierre Llanos6, Neil Martin9,10, Bill Cook1, Åsa Hellqvist11,Stephanie Korn12,13, Andrew Menzies-Gow9,14, Stephanie L. Roseti3,Nestor A. Molfino7, Janet M. Griffiths4, and Jane R. Parnes8;on behalf of all authors of Efficacy of Tezepelumab in Severe,Uncontrolled Asthma: Pooled Analysis of the PATHWAY andNAVIGATOR Clinical Trials1Respiratory and Immunology, BioPharmaceuticals Medical, 2Biometrics,Late-Stage Development, 3Late-stage Development, 4TranslationalScience and Experimental Medicine, Research and Early Development,Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca,Gaithersburg, Maryland; 5Pulmonary and Critical Care Medicine, Allergy& Immunology, Brigham andWomen’s Hospital, Harvard Medical School,Boston, Massachusetts; 6Global Medical Affairs, 7Global Development,and 8Translational Medicine, Amgen, Thousand Oaks, California;9Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca,Cambridge, United Kingdom; 10University of Leicester, Leicester,United Kingdom; 11Biometrics, Late Respiratory and Immunology,BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;12IKF Pneumologie Mainz, Mainz, Germany; 13Thoraxklinik Heidelberg,Heidelberg, Germany; and 14Royal Brompton and Harefield Hospitals,London, United KingdomORCID IDs: 0000-0003-4175-7336 (C.S.A.); 0000-0002-7785-6881(J.-P.L.).From the Authors:We thank Drs. Lipworth and Chan for their interest in our articlepublished in a recent issue of the Journal, which describes a pooledanalysis of the PATHWAY (ClinicalTrials.gov ID: NCT 02054130)and NAVIGATOR (ClinicalTrials.gov ID: NCT 03347279) clinicaltrials, which reported the efficacy and safety of tezepelumab inpatients with severe, uncontrolled asthma (1).Pooling data from the PATHWAY and NAVIGATOR trialsincreased statistical precision, allowing more accurate assessment ofthe efficacy of tezepelumab across multiple clinically relevant patientsubgroups, including patients with type 2 (T2)-low asthma. Thegreatest efficacy with tezepelumab was observed in patients with highlevels of T2 inflammatory biomarkers: in this subgroup, tezepelumabtreatment reduced the annualized asthma exacerbation rate (AAER)by 76–78%, and resulted in clinically meaningful improvements inlung function, asthma symptoms, and health-related quality of life(HRQoL) versus placebo. At the other end of the inflammatoryspectrum, as noted by Lipworth and Chan, tezepelumab alsodemonstrated clinically meaningful reductions in AAERs,including exacerbations associated with hospitalizations oremergency department visits, in patients with low levels of T2inflammatory biomarkers. Currently, tezepelumab is the onlyThis article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Supported by AstraZeneca and Amgen Inc.Originally Published in Press as DOI: 10.1164/rccm.202305-0843LEon June 6, 2023212 American Journal of Respiratory and Critical Care Medicine Volume 208 Number 2 | July 15 2023CORRESPONDENCE 

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