TYPE Original Research PUBLISHED 12 April 2023 DOI 10.3389/fimmu.2023.1150162 Remission outcomes in OPEN ACCESS severe eosinophilic asthma EDITED BY Breda Cushen, Beaumont Hospital, Ireland with mepolizumab therapy: REVIEWED BY Preeti Singh Chauhan, Analysis of the REDES study Children’s Hospital of Philadelphia, United States Jose Roberto Lapa E. Silva, Ian Pavord 1, Frances Gardiner 2†, Liam G. Heaney 3, Federal University of Rio de Janeiro, Brazil Patrick Mitchell, Christian Domingo 4, Robert G. Price 5, Alison Pullan 6, Trinity College Dublin, Ireland John Oppenheimer 7, Guy Brusselle 8, Hiroyuki Nagase 9, *CORRESPONDENCE Geoffrey Chupp 10, Emilio Pizzichini 2,11, Peter Howarth peter.h.howarth@gsk.com David Bañas-Conejero 12 and Peter Howarth 2* † Affiliation at the time of the analysis 1 Respiratory Medicine Unit and Oxford Respiratory National Institute for Health Research Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, SPECIALTY SECTION 2 Global Medical, Global Specialty and Primary Care Therapy Area, GSK House, Brentford, This article was submitted to United Kingdom, 3 Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Inflammation, Belfast, Belfast, United Kingdom, 4 Servei de Pneumologia, Corporació Sanitària Parc Taulı´, Sabadell, a section of the journal Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 5 Biostatistics, GSK, Stevenage, Frontiers in Immunology United Kingdom, 6 Plus-Project Partnership Ltd, Knutsford, United Kingdom, 7 Department of Internal RECEIVED 23 January 2023 Medicine, Pulmonary and Allergy, UMDNJ-Rutgers New Jersey Medical School, Newark, NJ, ACCEPTED 16 March 2023 United States, 8 Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium, PUBLISHED 12 April 2023 9 Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan, 10 Yale Center for Asthma and Airways Disease (YCAAD), Yale School of CITATION Medicine, New Haven, CT, United States, 11Department of Clinical Medicine, Federal University of Pavord I, Gardiner F, Heaney LG, Santa Catarina, Santa Catarina, Brazil, 12Specialty Care Medical Department, GSK, Madrid, Spain Domingo C, Price RG, Pullan A, Oppenheimer J, Brusselle G, Nagase H, Chupp G, Pizzichini E, Bañas-Conejero D and Howarth P (2023) Remission outcomes in severe eosinophilic Introduction: Clinical remission as a multicomponent treatment goal in severe asthma with mepolizumab therapy: Analysis of the REDES study. asthma is being explored in clinical practice. This post hoc analysis used data Front. Immunol. 14:1150162. from the REDES study to assess the proportion of patients with severe doi: 10.3389/fimmu.2023.1150162 eosinophilic asthma achieving our multicomponent definitions of clinical COPYRIGHT remission after 1 year of mepolizumab treatment. © 2023 Pavord, Gardiner, Heaney, Domingo, Price, Pullan, Oppenheimer, Brusselle, Nagase, Chupp, Pizzichini, Bañas-Conejero Methods: The real-world, retrospective observational REDES study enrolled and Howarth. This is an open-access article patients with severe eosinophilic asthma who were newly prescribed distributed under the terms of the Creative Commons Attribution License (CC BY). The mepolizumab and with ≥12 months of medical records pre-enrolment. use, distribution or reproduction in other Multicomponent clinical remission was defined as: oral corticosteroid (OCS)- forums is permitted, provided the original free; exacerbation-free; asthma control test (ACT) score ≥20; and with or author(s) and the copyright owner(s) are credited and that the original publication in without post-bronchodilator forced expiratory volume in 1 second ≥80%. this journal is cited, in accordance with Baseline characteristics were also assessed in those who did/did not achieve accepted academic practice. No use, clinical remission. distribution or reproduction is permitted which does not comply with these terms. Results: 37% and 30% of patients with severe eosinophilic asthma met our proposed three- and four-component on-treatment clinical remission definitions; an increase from 2% and 3% at baseline. Most frequently achieved individual components of clinical remission were: OCS-free; ACT score ≥20. For patients fulfilling the multicomponent clinical remission definitions, at baseline we observed higher blood eosinophil counts, better ACT scores and lung function, lower maintenance OCS use, and a slightly lower rate of prior exacerbations versus those who did not. Frontiers in Immunology 01 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 Discussion: Clinical remission is a realistic target in clinical practice for a subset of patients with severe eosinophilic asthma receiving mepolizumab. Further studies are required to elucidate whether features linked to the underlying endotype can help predict treatment outcomes, increase rates of clinical remission, and potentially modify disease progression. KEYWORDS severe asthma, remission, clinical outcomes, real-world, eosinophil biology, mepolizumab 1 Introduction outcomes; namely an era of on-treatment clinical remission (Supplementary Figure 1). We performed a post hoc analysis In 2018, a Lancet Commission paper by Pavord et al. (1) divided using real-world data from the REal worlD Effectiveness and asthma management into three eras, the first focusing on Safety of mepolizumab (REDES) study (7), which included bronchodilator use, the second on inhaled corticosteroids use, patients with severe eosinophilic asthma who were treated with and the third on precision management (including the use of mepolizumab (anti-IL-5 monoclonal antibody) (8) for 1 year, and biologics), and targeted treatment based on a patient’s disease applied our two composite clinical remission definitions (OCS-free; characteristics (Supplementary Figure 1). Within the past 2 exacerbation-free; asthma control test (ACT) score ≥20; and with or decades, the advent of biologics has substantially improved the without post-bronchodilator FEV1 ≥80%). The aim of our analysis treatment paradigm for diseases including severe asthma (2, 3). The was to initiate a dialogue about how biologics might be more way clinical outcomes are measured in severe asthma is evolving imaginatively used, as well as encourage the field to move away from the assessment of single outcomes to composite outcomes, and from single measures of disease control and to consider using for patients with asthma, experts have aimed to reach a consensus composite measures to assess the goal of clinical remission. This on the definition of clinical remission (≥12–<24 months) and could ultimately lead to the earlier proactive use of biologics to alter sustained remission (≥24 months) for those continuing treatment disease progression and enable the emergence of an understanding (Figure 1A) (3–5). The definitions include components that that could herald a fifth era of asthma management, where clinical represent key clinical criteria and patient-reported outcomes to remission off-treatment would become a possibility allowing measure disease activity (3) and allow for the continuation of patients to lead normal lives with total symptom control. background therapy as long as patients are not impacted by side effects. A recent (2022) publication by Menzies-Gow et al. evaluated 2 Materials and methods clinical remission in a subset of patients with severe asthma treated with benralizumab (interleukin-5 [IL-5] receptor a-directed 2.1 Study design and patients monoclonal antibody) using data from three pivotal Phase III clinical trials (6). This post hoc analysis focused only on patients Details of the REDES study design and patient population have with no baseline oral corticosteroid (OCS) use (selected from been published previously (7). Briefly, REDES (GSK ID: 213172) SIROCCO/CALIMA) or those receiving <12.5 mg prednisone/ was a retrospective, real-world, Phase IV, multicentric, prednisolone equivalents/day (ZONDA). The individual observational cohort study enrolling patients with severe components of the composite definition of clinical remission eosinophilic asthma across 24 Spanish hospitals (Supplementary were: no OCS use, no exacerbations, Asthma Control Figure 2). The observational period included 12 months pre- and Questionnaire-6 (ACQ-6) score ≤0.75, and pre-bronchodilator post-mepolizumab treatment. Eligibility criteria for the REDES forced expiratory volume in 1 second (FEV1) increase ≥100 mL. study included: patients ≥18 years of age with a clinical diagnosis The analysis demonstrated that 14.5% and 22.5% of patients of severe uncontrolled eosinophilic asthma; patients who initiated receiving benralizumab achieved remission at 12 (SIROCCO/ mepolizumab ≥12 months before the date of inclusion in the study; CALIMA) or 6 months (ZONDA) compared with 7.7% and 7.5% and had ≥12 months of relevant medical records prior to in the respective placebo groups. All trials required patients to enrolment. The primary endpoint of the REDES study was the remain on background medication with the exception of OCS doses annual rate of clinically significant exacerbations. Secondary in ZONDA. endpoints included pre- and post-bronchodilator spirometric Here we sought to further build on the concept of a new era of tests, and changes in blood eosinophil counts, average OCS daily asthma management, illustrating a potential fourth era, where as a maintenance dose, and symptom control (ACT score) pre- to post- consequence of improved targeted treatment approaches, we mepolizumab treatment. These results have been previously envision patients with asthma experiencing better clinical reported (7). Frontiers in Immunology 02 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 2.2 Definitions of clinical remission 2.4 Statistical analysis In this analysis, we used two definitions of on-treatment clinical For the description of continuous variables, the mean, median, remission. Firstly, a four-component clinical remission definition standard deviation (SD), and interquartile range (IQR) values were that required patients to meet all of the following criteria at Week used, while categorical variables were described using the number 52: i) OCS-free; ii) exacerbation-free (for 52 weeks); iii) an ACT and percentage within categories. All post hoc analyses were score ≥20; and iv) a percent predicted post-bronchodilator FEV1 descriptive in nature and as such no p values were derived. ≥80%. Secondly, a three-component clinical remission definition that included meeting the following criteria at Week 52: i) OCS-free; ii) exacerbation-free (for 52 weeks); and iii) an ACT score 3 Results ≥20 (Figure 1B). 3.1 Proportion of patients achieving clinical remission 2.3 Post hoc endpoints included in this analysis Of the 318 patients included in this analysis, data for the three- and four-component clinical remission definitions were available in Post hoc analyses were performed to determine the proportion 260 (82%) and 144 (45%) patients, respectively. Missing post- of patients meeting the individual components of the clinical bronchodilator FEV1 or ACT scores at Week 52 accounted for remission definitions, to appreciate the individual contribution of the reduced numbers (Figure 2). There were notable differences each component, and those meeting combinations of these between the baseline characteristics for the 174 excluded and the components, including our two definitions of clinical remission at 144 included in the four-component definition; for instance, the Week 52 (three- and four-component clinical remission). group with 144 patients had a slightly lower number of Additionally, a descriptive analysis of differences in the baseline exacerbations in the previous year, higher geometric mean blood demographics and clinical characteristics of patients according to eosinophil counts, higher ACT scores, and received higher median their remission status at Week 52 (i.e., those who met the clinical OCS doses at baseline (Supplementary Table 1). Most baseline remission definitions compared with those who did not) was also characteristics for the 58 excluded from the three-component performed to gain insight into the responsive population. An clinical remission definition and the 260 patients included were exacerbation was defined as the requirement of systemic OCS similar; except that the 260 patients had higher exacerbation rates in treatment for ≥3 days, or a doubling of the dose of maintenance the previous year, higher geometric mean blood eosinophil counts, OCS, or a visit to an emergency department/hospitalization higher ACT scores, and greater prior omalizumab use for treatment. (Supplementary Table 1). A B FIGURE 1 Working definitions of remission in asthma (A) and our composite definitions of on-treatment clinical remission for patients with severe asthma (B) (3–5). ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; FENO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; HCP, healthcare practitioner; OCS, oral corticosteroid; ppb, parts per billion. Frontiers in Immunology 03 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 In the 144 patients analyzed, after 1 year of treatment with of clinical remission; OCS-free (82%) and ACT score ≥20 (73%) mepolizumab, 30% fulfilled the four-component clinical remission were the most frequently achieved (Figure 3B). definition, and 38% fulfilled the three-component definition. This represents an increase (27% and 35%, respectively) from 3% who achieved these criteria at baseline (Figure 3A). Moreover, at baseline 3.2 Characteristics that provide insight on 3–6% met a combination of three components and 3–30% met a who may clinically remit combination of two components of clinical remission. Of those studied 58%, 42%, 15% and 6% of patients met the OCS-free, post- The baseline demographic and clinical characteristics for those bronchodilator FEV1 ≥80%, ACT score ≥20 and exacerbation-free who met the three- and four-component clinical remission components respectively at baseline. After 1 year of treatment with definitions versus those who did not are presented in Tables 1, 2. mepolizumab, 31–50% met the different combinations of three of Results demonstrated that patients who fulfilled both the three- the components of clinical remission, while 36–67% met two of the and four-component definitions had higher geometric mean blood components. At least 50% of patients met any individual eosinophil counts, better ACT scores, and lower maintenance OCS component of clinical remission; OCS-free (81%) and ACT score use compared with those who did not meet each of these definitions. ≥20 (76%) were the most frequently achieved components of For the patients who did not meet the three- or four-component remission (Figure 3A). clinical remission definitions, a slightly higher exacerbation rate in In the larger sub-population (n=260), 37% fulfilled the three- the prior year and worse baseline lung function was seen compared component definition of clinical remission after 1 year of with patients who met either definition. In those fulfilling both mepolizumab treatment, representing an increase (35%) from 2% clinical remission definitions, patients were less likely to have at baseline (Figure 3B). A combination of two of the components of depression, atopic sensitization, or gastroesophageal reflux disease clinical remission was met by 2–7% of patients at baseline, while at baseline, and more likely to have hypersensitivity to non-steroidal 60%, 14% and 6% of patients met OCS-free, ACT score ≥20 and anti-inflammatory drugs and chronic rhinosinusitis with nasal exacerbation-free components respectively at baseline. After 1 year polyps (CRSwNP) than those not achieving each composite of treatment with mepolizumab, 41–65% of patients met a definition. Patients who met the four-component definition were combination of the two different components of clinical more likely to have allergic asthma compared with those who did remission. At least 50% of patients met any individual component not meet this definition; this was in contrast to those meeting the FIGURE 2 Patient attrition and outcome datasets for analysis. ACT, Asthma Control Test; FEV1, forced expiratory volume in 1 second; ITT, intention-to-treat; REDES, REal worlD Effectiveness and Safety of mepolizumab. Frontiers in Immunology 04 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 A B FIGURE 3 Proportion of patients with severe eosinophilic asthma meeting one or multiple elements of the four- (A) and three-component (B) clinical remission definitions at baseline and after 1 year of treatment with mepolizumab. In panel A, 174 patients were excluded owing to missing post- bronchodilator FEV1 values or ACT scores at Week 52. In Panel B, 58 patients were excluded due to missing ACT scores at Week 52. *No exacerbations experienced in the 12 months prior to baseline (Week 0). †No exacerbations experienced up to study Day 365. ‡Patients were not receiving OCS at baseline (Week 0) and remained off OCS at Week 52; §Post-bronchodilator FEV1 percent predicted ≥80% at Week 52. ACT, Asthma Control Test; BD, bronchodilator; FEV1, forced expiratory volume in 1 second; OCS, oral corticosteroid. three-component definition, where allergic asthma was less for those treated with mepolizumab. To our knowledge, this is the frequently observed compared with those not meeting largest study reporting real-world data on remission outcomes for the definition. patients with severe asthma using multicomponent definitions of clinical remission. This is important as it is recognized that approximately 80% of patients with severe eosinophilic asthma 4 Discussion would be excluded from enrolling in randomized controlled trials, owing to the rigorous eligibility criteria, despite being sufficiently Using our proposed multicomponent definitions of clinical severe and biologically suitable for anti-eosinophilic biologics (9). remission, which were aligned with the prior definitions put As such, remission outcomes generated from registration trial data forward based on an expert consensus collected by a Delphi have limited applicability to outcomes in standard clinical care. survey (3, 4), we identified that a subset of patients (37% and Other studies have focused on assessing a patient’s level of 30%) with severe eosinophilic asthma met our proposed three- and treatment response to identify responders and super-responders, four-component definitions of clinical remission following 1 year of such as the RELIght study, a real-world study in which patients with mepolizumab treatment. These results demonstrate that on- severe eosinophilic asthma were treated with mepolizumab (10). A treatment clinical remission is a realistic target in severe asthma recent Delphi consensus defined the criteria for identifying super- Frontiers in Immunology 05 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 TABLE 1 Patient baseline demographics and clinical characteristics in those who did/did not meet the four-component definition of clinical remission following 1 year of mepolizumab treatment. Four-component clinical remission definition* Patients who achieved clinical Patients who did not achieve clinical remission (n=43) remission (n=101) Age, mean (SD), years 58.1 (9.06) 58.8 (14.17) Age at asthma diagnosis, mean (SD), years n=43; 32.2 (16.62) n=99; 34.3 (18.99) Female, n (%) 35 (81) 73 (72) Ethnicity, n (%) Caucasian 39 (91) 93 (92) Hispanic 4 (9) 6 (6) African 0 2 (2) Other 0 0 2 BMI, mean (SD), kg/m n=42; 29.0 (5.15) n=101; 27.8 (5.19) 2 BMI category, n (%), kg/m n=42 n=101 <18.5 0 1 (<1) 18.5–<25.0 11 (26) 28 (28) 25.0–<30.0 14 (33) 46 (46) 30.0–<35.0 13 (31) 17 (17) ≥35.0 4 (10) 9 (9) Smoking status, n (%) Never 26 (60) 60 (59) Ex-smoker (>6 months) 16 (37) 39 (39) Current smoker 0 0 Passive smoker 1 (2) 1 (<1) Not available 0 1 (<1) Exacerbations in the 12 months pre-mepolizumab 4.1 (3.25) 4.2 (3.10) treatment, mean (SD) Baseline blood eosinophil count,† geometric mean (SD 653.85 (0.546) 504.22 (0.779) log), cells/µL Baseline blood eosinophil count category,† n (%), cells/µL <150 1 (2) 7 (7) 150–<300 3 (7) 9 (9) 300–<500 5 (12) 25 (25) 500–<700 10 (23) 23 (23) ≥700 24 (56) 37 (37) Allergic asthma, n (%) 25 (58) 51 (50) Atopic sensitization, n (%) n=43; 14 (33) n=101; 43 (43) Baseline ACT score, mean (SD) n=41; 15.9 (4.88) n=95; 13.7 (4.99) Baseline ACT score category, n (%) n=41 n=95 <20 (uncontrolled) 31 (76) 84 (88) ≥20 (controlled) 10 (24) 11 (12) (Continued) Frontiers in Immunology 06 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 TABLE 1 Continued Four-component clinical remission definition* Patients who achieved clinical Patients who did not achieve clinical remission (n=43) remission (n=101) Baseline post-bronchodilator FEV1%pred, mean (SD) n=41 n=88 86.9 (21.52) 71.2 (23.39) OCS dependent in the 12 months pre-mepolizumab 7 (16) 53 (52) treatment, n (%) Baseline OCS dose, median (IQR), mg/day n=3; 6.3 (5.0, 15.0) n=42; 10.0 (5.0, 15.0) Previous omalizumab treatment, n (%) n=43; 11 (26) n=101; 41 (41) Comorbidities, n (%) Anxiety 12 (28) 21 (21) Atopic dermatitis 0 2 (2) Bronchiectasis 10 (23) 26 (26) Depression 5 (12) 24 (24) EGPA 1 (2) 5 (5) GERD 9 (21) 26 (26) Hypersensitivity to NSAIDs 8 (19) 11 (11) CRSwNP 20 (47) 44 (44) *Definition of clinical remission: exacerbation-free for 52 weeks, OCS-free at Week 52, ACT score ≥20 at Week 52, and predicted post-bronchodilator FEV1 ≥80% at Week 52. 174 patients were excluded owing to missing post-bronchodilator FEV1 values or ACT scores at Week 52. †Where a blood eosinophil count of zero was recorded, a small value (i.e., minimum all non-missing results/2) was added prior to log transformation. ACT, asthma control test; BMI, body mass index; CRSwNP, chronic rhinosinusitis with nasal polyps; EGPA, eosinophilic granulomatosis with polyangiitis; FEV1, forced expiratory volume in 1 second; GERD, gastroesophageal reflux disease; IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; OCS, oral corticosteroid; pred, predicted; SD, standard deviation. TABLE 2 Patient baseline demographics and clinical characteristics in those who did/did not meet the three-component definition of clinical remission following 1 year of mepolizumab treatment. Three-component clinical remission definition† Patients who achieved clinical Patients who did not achieve clinical remission (n=96) remission (n=164) Age, mean (SD), years 56.9 (10.30) 57.0 (14.07) Age at asthma diagnosis, mean (SD), years n=96; 32.2 (16.52) n=155; 35.5 (18.85) Female, n (%) 70 (73) 120 (73) Ethnicity, n (%) Caucasian 88 (92) 147 (90) Hispanic 8 (8) 13 (8) African 0 3 (2) Other 0 1 (<1) BMI, mean (SD), kg/m2 n=95; 28.0 (5.03) n=164; 28.6 (5.69) BMI category, n (%), kg/m2 n=95 n=164 <18.5 0 1 (<1) 18.5–<25.0 31 (33) 41 (25) 25.0–<30.0 33 (35) 69 (42) 30.0–<35.0 23 (24) 35 (21) ≥35.0 8 (8) 18 (11) (Continued) Frontiers in Immunology 07 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 TABLE 2 Continued Three-component clinical remission definition† Patients who achieved clinical Patients who did not achieve clinical remission (n=96) remission (n=164) Smoking status, n (%) Never 63 (66) 100 (61) Ex-smoker (>6 months) 31 (32) 54 (33) Current smoker 0 2 Passive smoker 1 (1) 5 (3) Not available 1 (1) 3 (2) Exacerbations in the 12 months pre-mepolizumab 4.1 (3.34) 4.9 (3.61) treatment, mean (SD) Baseline blood eosinophil count,† geometric mean (SD 675.94 (0.693) 433.24 (1.521) log), cells/µL Baseline blood eosinophil count category,† n (%), cells/µL <150 3 (3) 13 (8) 150–<300 7 (7) 13 (8) 300–<500 15 (16) 48 (29) 500–<700 21 (22) 35 (21) ≥700 50 (52) 55 (34) Allergic asthma, n (%) 55 (57) 103 (63) Atopic sensitization, n (%) n=96; 33 (34) n=163; 75 (46) Baseline ACT score, mean (SD) n=90; 15.2 (5.04) n=154; 13.6 (4.93) Baseline ACT score category, n (%) n=90 n=154 <20 (uncontrolled) 72 (80) 136 (88) ≥20 (controlled) 18 (20) 18 (12) Baseline post-bronchodilator FEV1%pred, mean (SD) n=70 n=102 82.2 (23.29) 73.6 (22.66) OCS dependent in the 12 months pre-mepolizumab 20 (21) 85 (52) treatment, n (%) Baseline OCS dose, median (IQR), mg/day n=13; 5.0 (4.0, 13.3) n=67; 10.0 (5.0, 20.0) Previous omalizumab treatment, n (%) n=96; 34 (35) n=163; 71 (44) Comorbidities, n (%) Anxiety 17 (18) 34 (21) Atopic dermatitis 1 (1) 1 (<1) BronchiectasisP 19 (20) 33 (20) Depression 10 (10) 37 (23) EGPA 2 (2) 7 (4) GERD 15 (16) 43 (26) Hypersensitivity to NSAIDs 18 (19) 19 (12) CRSwNP 54 (56) 67 (41) *Definition of clinical remission: exacerbation-free for 52 weeks, OCS-free at Week 52, and ACT score ≥20 at Week 52. 58 patients were excluded with missing ACT score at Week 52. †Where a blood eosinophil count of zero was recorded, a small value (i.e., minimum all non-missing results/2) was added prior to log transformation. ACT, asthma control test; BMI, body mass index; CRSwNP, chronic rhinosinusitis with nasal polyps; EGPA, eosinophilic granulomatosis with polyangiitis; FEV1, forced expiratory volume in 1 second; GERD, gastroesophageal reflux disease; IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; OCS, oral corticosteroid; pred, predicted; SD, standard deviation. Frontiers in Immunology 08 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 responders as patients who had achieved dramatic improvements in total score <1.5 and post-bronchodilator FEV1 >80%) versus 4.6% at least three or more domains after 1 year of treatment (11). Our (n=9) in the placebo group (14). However, it is well recognized that analysis of real-world outcomes in a biologically relevant, but patients with chronic asthma, particularly severe asthma, have sub- otherwise unrestricted, severe asthma population not only optimal lung function with some showing limited reversibility (9, 15), identifies the proportion of patients achieving clinical remission potentially attributable to structural airway remodeling (16, 17) or based on our composite three- and four-component definitions, but impaired lung growth during infancy and adolescence (18, 19). As also helps to understand the responsiveness of the individual such, in many patients with severe asthma it would be unrealistic to components at this stage of disease severity in patients receiving achieve normal lung function, and it may be more appropriate to mepolizumab treatment. Improvements in asthma control, as evaluate lung function on a case-by-case basis depending on the reflected by the ACT score, and OCS-freedom (no exacerbation disease severity, and aim for stabilization with no further decline. bursts and no maintenance therapy) were the most commonly Indeed, by analogy, a pragmatic approach was taken with rheumatoid achieved individual components of clinical remission. arthritis in which, rather than the structural deformity being expected The real-world REDES study (7) was selected to assess clinical to resolve, the prevention of disease progression and improvement in remission in a real-world severe asthma population, as it had the functionality were the initial targets when assessing the impact of most complete dataset available to us and represented a severe biologic therapy (20). This has further developed, following evidence asthma population that was clinically relevant, with a broad of disease modification, to biologics being used early in the course of spectrum of comorbidities and a significant unmet need as far as the disease to prevent the development of structural damage (21, 22). asthma control was concerned. In REDES, for patients who had If prevention of disease progression was applied to the lung function data available on ACT score (n=279), most patients (85%; n=237) outcome measures in REDES, after 1 year of mepolizumab treatment, had poor asthma control (ACT score <20) at baseline; and of the 63% (n=79/125) of patients would qualify as having no worsening 318 included in the study, the majority of patients (92%; n=292) had from baseline in post-bronchodilator FEV1. Several factors have been experienced a severe OCS-requiring exacerbation in the 12 months linked to an accelerated lung function decline, such as severe prior to treatment and 92% had ≥1 comorbidity (n=292). Moreover, exacerbations, increased blood eosinophil counts, elevated patients had a geometric mean blood eosinophil count of 470 cells/ fractional exhaled nitric oxide (FeNO) levels, and exposure to µL at baseline. These results demonstrate the severity of disease in environmental factors (e.g., tobacco smoking) (23–25). In the this severe eosinophilic asthma population despite receiving REDES study, mepolizumab reduced exacerbations and standard-of-care treatment in line with the Global Initiative for eosinophilic inflammation, two of the recognized adverse factors Asthma (GINA) recommendations up to the initiation of biologic for poorer lung function outcomes (7). Four (1%) patients were therapy (12) and also reflect the nature of severe eosinophilic current smokers with a mean (SD) pack year history of 20 (10.2), asthma managed in routine clinical care. while 33% (n=106) were ex-smokers, and it has been shown that In the sentinel publication by Menzies-Gow et al (4) the authors decline in lung function can still progress in smokers despite smoking initiated a conversation about remission outcomes in severe asthma cessation (26). Further support for the use of mepolizumab to prevent populations and proposed a definition of remission, based on a lung function decline has been demonstrated by a Belgian severe Delphi consensus and by using learnings from other chronic asthma registry publication, which reported that treatment with anti- inflammatory diseases treated with biologics. Their definition of IL-5 biologic therapy as part of standard clinical care attenuated lung remission used optimization and stabilization of lung function as function decline in patients with severe asthma (27). one of the criteria (4). To date, no consensus definition for For this clinical remission analysis, we did not select improvements in FEV1 have been established. In our analysis, we randomized controlled trials to assess clinical remission for have taken the ambitious definition of achieving ≥80% predicted several reasons. Although well-structured for gathering data, post-bronchodilator FEV1 as our reflection of optimization of lung randomized controlled trials typically reflect a narrow patient function, as this is what could be classified as within the normal population compared with the real world owing to the stringent range. A recently published (2023) observational multicenter eligibility criteria. In addition, treatment is also often fixed meaning retrospective study by Maglio et al (13), also used ≥80% predicted it is not possible to assess OCS reduction, unless it is a study post-bronchodilator FEV1, alongside OCS-free, exacerbation-free and focusing on OCS tapering. As such, in a recent analysis of remission ACT score ≥20, aligning with our four-component definition of outcomes from the benralizumab SIROCCO and CALIMA remission. In their study, in 83 patients with severe asthma treated registration studies in severe eosinophilic asthma, patients with mepolizumab for 12 months, they reported the same proportion entering on maintenance OCS were excluded from the analysis. of patients (30%) achieving remission as reported here using our Despite this strongly favoring a positive 1-year outcome for the four-way definition. When comparing the proportion of patients remission criterium of no maintenance OCS, using a four- achieving the individual components of remission, differences were component analysis (no OCS, no exacerbations, ACQ-6 score seen between the two studies. In another post hoc analysis, data from ≤0.75, and pre-bronchodilator FEV1 increase ≥100 mL) they the LIBERTY ASTHMA QUEST study in patients with uncontrolled, reported that 14.5% (n=85/586) of patients treated with moderate-to-severe asthma demonstrated that 20.1% (n=70) of benralizumab fulfilled the remission definition at 12 months, patients who received dupilumab (anti-IL-4 receptor a-directed compared with 7.7% (n=48/620) of patients treated with placebo biologic) achieved a three-component definition of asthma (6). No such restriction was applied to the remission analysis within remission following 1 year of treatment (no exacerbations, ACQ-5 the REDES dataset, in which 31% (n=98/318) were on maintenance Frontiers in Immunology 09 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 OCS therapy at mepolizumab initiation. In relation to the lung clinical appointments. As a result, assessment of the different function criteria, a 100 mL improvement in FEV1 at either 6 or 12 definitions of clinical remission had to be analyzed within months has since been criticized as a criterium for the assessment of reduced outcome datasets (as per Figure 2), where the applicable remission, as the definition originally proposed by the same leading component data were available and collected at Week 52. There author was only to be undertaken at 12 months and did not define a were some notable differences between the baseline characteristics 100 mL improvement as a valid outcome (28). These data for the patients excluded versus included for analysis with the three- underscore the need to better understand whether lung function and four-component definitions. While this may infer a selection fits within a definition of remission in severe asthma or whether it is bias, the potential link with asthma severity was not consistent, and a disease modification validation outcome measure, used to assess therefore we believe our results should be generalizable to the wider the value of remission achieving therapy. We would therefore severe asthma population. This analysis was based on an open-label advocate for the exclusion of lung function parameters from a study without a placebo arm and used pre-treatment (baseline) as a clinical remission definition until further data are generated that comparison. Moreover, the post hoc nature of the analysis means inform the position, and instead suggest utilization of the more care must be taken in data interpretation as the analysis may not be accepted three-component definition discussed here as a starting powered to optimally answer the questions being asked, with a risk point. Alternatively, we would support that prevention of decline in of type I error and overinterpretation. As mentioned previously, this lung function, encompassing stabilization and improvement, is is an exploratory application of a definition for clinical remission, used in lieu of focusing solely on improvements in lung function. which will require revision over time as further data become The determination of demographic or clinical markers that can available. Nonetheless, it does provide valuable insight into the predict whether a patient may or may not achieve clinical remission performance of different components of remission within a real- would be of great benefit. Our analyses suggest that at baseline those world severe asthma population. There is a clear need for a more patients who achieved our measures of clinical remission (three- unified approach to the utilization of lung function outcomes and and four-component definitions) had higher blood eosinophil recognition that while patient-reported outcome measures, such as counts, better ACT scores and lung function, lower maintenance ACT score, are essential components, they also have limitations. For OCS use, and a slightly lower rate of prior exacerbations compared example, some of the scoring components are not specific for with those who did not. Patients meeting the three- and four- asthma and those related to comorbidities not targeted by specific component definitions were more likely to be non-atopic and have asthma interventions will remain. This implies that there may be a CRSwNP versus those who did not achieve remission (although for need for a multi-targeted approach addressing a range of treatable the latter the differences were small in the four-component traits to gain the optimum outcome for each patient. In addition, remission dataset); the higher likelihood of the presence of consideration should be given to the adoption of newer measures CRSwNP may suggest that these subgroups were more likely to that include additional parameters such as future risk of have type-2-driven disease, potentially explaining the better chance exacerbations (e.g., Asthma Impairment and Risk Questionnaire, that they would reach clinical remission on therapy with which is currently being validated) (31). Furthermore, as this study mepolizumab (29). An alternative explanation would be that a was based on data from patients with asthma from a single country, patient’s chance of achieving remission depends on their baseline there may be variations compared with other patient populations disease severity and those not achieving clinical remission relied on that are not reflected within this analysis. Finally, longer-term higher maintenance OCS doses, which may have led to the lower studies (≥2 years) are required to assess whether sustained blood eosinophil counts seen in those not achieving clinical remission while on treatment with mepolizumab is achievable. remission. Patients who achieved clinical remission were also less likely to suffer from depression or gastroesophageal reflux. It has been reported that these comorbidities make it less likely for 5 Conclusions patients to achieve substantial improvements in asthma control as they may, in addition to the underlying asthma, contribute to the The results of this post hoc analysis provide evidence that, in daily level of symptom reporting (30). It is therefore understandable that clinical practice, mepolizumab treatment enables a subset of patients as symptoms, such as breathlessness, are not specific to asthma, they with severe eosinophilic asthma to achieve the proposed composite may limit the likelihood of achieving a remission-defined level of definitions of clinical remission, with more than one-third meeting control. Overall, these data support that initiating treatment at an the three-component definition. Baseline clinical characteristics earlier stage in disease development, in order to prevent the including specific comorbidities that are linked to the underlying development of severe disease (and associated conditions) or endotype and more commonly associated with clinical remission disease worsening, may lead to better long-term outcomes for achievement may help to predict patients who are more likely to patients; and this will require further studies. respond to mepolizumab treatment and reach greater degrees of There were several limitations of this study. First, as to be long-term disease control. The inclusion of clinical remission criteria expected for a real-world study, data gathering was retrospective within future treatment plans, a focus on intervening earlier, and and opportunistic, and as such complete datasets were not available being able to predict the patients who are most likely to achieve on all participants. The most limited outcome data in this study remission will help optimize patient care. These changes will also population was the post-bronchodilator FEV1 and this may be in allow personalized approaches to treatment and ultimately, help us part owing to the 2019 coronavirus disease pandemic disrupting progress into the fourth era of asthma management and beyond. Frontiers in Immunology 10 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 Data availability statement Genentech, GSK, and Boehringer Ingelheim; has received project grant funding from MedImmune, Novartis UK, Roche/Genentech, The original contributions presented in the study are included and GSK; has attended advisory boards/lectures supported by Novartis, in the article/Supplementary Material. Further inquiries can be Roche/Genentech, GSK, Evelo Biosciences, Teva, Theravance, and directed to the corresponding author. Vectura; has received travel funding to attend international respiratory meetings from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva, and GSK; has been involved in asthma clinical trials Ethics statement with GSK, Schering Plough, Synairgen, Novartis, and Roche/ Genentech for which his institution was remunerated; has received The REDES study (GSK ID: 213172), which involved human personal fees for lectures supported by AstraZeneca, Novartis, Roche/ participants was reviewed and approved by Hospital La Genentech, Sanofi, Circassia, GSK, Chiesi and Teva. CD has received Princesa, Madrid. funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Novartis, Stallergenes, and Pfizer. AP is an employee of Plus Project Partnership Author contributions Ltd. JO has served on adjudication committees or data and safety monitoring boards for AstraZeneca, GSK, Novartis, and Sanofi; PH and DB-C were involved in the conception and design of the received consultancy fees from AstraZeneca, GSK, and Sanofi; and work; CD was involved with the acquisition of data; all authors were received grants and personal fees from GSK. GB has received honoraria involved in drafting the work or revising it critically for important for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, intellectual content (i.e., data analysis and interpretation) and all Novartis, Sanofi, and Teva; he is a member of advisory boards for authors agreed to the submission and to be accountable for all Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Merck Sharp aspects of the work. All authors contributed to the article and & Dohme (MSD), Novartis, Sanofi/Regeneron, and Teva. HN has approved the submitted version. received speaker fees from AstraZeneca, GSK, Novartis, and Sanofi and has been an advisory board member for AstraZeneca, GSK and Sanofi. GC has acted as a consultant for AstraZeneca, Genentech, Boehringer Ingelheim, and Teva, attended a speaker’s bureau with AstraZeneca, Acknowledgments Genentech, and Circassia, and received research grants from AstraZeneca and institutional grants from AstraZeneca, Genentech, Editorial support (in the form of writing assistance, including Boehringer Ingelheim, and GSK. He is also a speaker, advisory board preparation of the draft manuscript under the direction and member and a clinical trial site for Amgen, Sanofi-Genzyme, and guidance of the authors, collating and incorporating authors’ Regeneron. PH, RGP, EP and DBC are employees of GSK and own comments for each draft, assembling tables and figures, stocks/shares. FG was an employee of GSK at the time of the analysis grammatical editing and referencing) was provided by Sarah and owns stocks/shares. Farrar, PhD, and Laura Murch, PhD, at Fishawack Indicia Ltd, The authors declare that this study received funding from GSK UK, a part of Fishawack Health, and was funded by GSK. (GSK ID:213172). The funder had the following involvement in the study: input in the study design, data collection/analysis and interpretation. The sponsor did not place any restrictions on Conflict of interest access to data or statements made in the manuscript. Authors had full access to all study data and had final responsibility to IP reports speaker’s honoraria for sponsored meetings from submit the manuscript for publication. AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, and GSK; payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Publisher’s note Teva; honoraria for attending advisory panels with Genentech, Sanofi/ Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, All claims expressed in this article are solely those of the authors Merck, Circassia, Chiesi, and Knopp; payments to support US Food and do not necessarily represent those of their affiliated organizations, and Drug Administration approval meetings from GSK; sponsorship or those of the publisher, the editors and the reviewers. Any product to attend international scientific meetings from Boehringer Ingelheim, that may be evaluated in this article, or claim that may be made by its GSK, AstraZeneca, Teva, and Chiesi; a grant from Chiesi to support a manufacturer, is not guaranteed or endorsed by the publisher. Phase II clinical trial in Oxford. He is co-patent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014–2015, IP Supplementary material was an expert witness for a patent dispute involving Astra Zeneca and Teva. LGH is the Academic Lead for the UK MRC Consortium for The Supplementary Material for this article can be found online at: Stratified Medicine in Severe Asthma – Industrial Pharma partners https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150162/ Amgen, AstraZeneca, MedImmune, Janssen, Novartis, Roche/ full#supplementary-material Frontiers in Immunology 11 frontiersin.org Pavord et al. 10.3389/fimmu.2023.1150162 References 1. Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, et al. After indices. Am J Respir Crit Care Med (2000) 162:1518–23. doi: 10.1164/ asthma: redefining airways diseases. Lancet (2018) 391:350–400. doi: 10.1016/S0140- ajrccm.162.4.9909044 6736(17)30879-6 17. 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