Received: 21 December 2021 | Revised: 10 June 2022 | Accepted: 5 July 2022 DOI: 10.1111/all.15456 ORIGINAL ARTICLE Allergen-Specific Immunotherapy and Biologics Dupilumab reduced impact of severe exacerbations on lung function in patients with moderate-­to-­severe type 2 asthma Alberto Papi1 | Jonathan Corren2 | Mario Castro3 | Christian Domingo4 | Linda Rogers5 | Kenneth R. Chapman6 | Daniel J. Jackson7 | Nadia Daizadeh8 | Nami Pandit-­Abid9 | Rebecca Gall10 | Juby A. Jacob-­Nara9 | Paul J. Rowe9 | Yamo Deniz10 | Benjamin Ortiz10 1 Respiratory Medicine, University of Ferrara and Emergency Department, Abstract University Hospital, Ferrara, Italy Background: Severe asthma exacerbations increase the risk of accelerated lung func- 2 David Geffen School of Medicine at UCLA, Los Angeles, California, USA tion decline. This analysis examined the effect of dupilumab on forced expiratory vol- 3 University of Kansas School of Medicine, ume in 1 s (FEV1) in patients with moderate-­to-­severe asthma and elevated type 2 Kansas City, Kansas, USA biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854). 4 Pulmonary Service, Corporació Sanitària Methods: Changes from baseline in pre-­ and post-­bronchodilator (BD) FEV1 and 5-­ Parc Taulí, Autonomous University of Barcelona, Sabadell, Barcelona, Spain item Asthma Control Questionnaire (ACQ-­5) scores were assessed in patients with 5 Icahn School of Medicine at Mount Sinai, elevated type 2 biomarkers at baseline (type 2–­150/25: eosinophils ≥150 cells/μl and/ New York, New York, USA 6 or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2–­300/25: eosinophils ≥300 University of Toronto, Toronto, Ontario, Canada cells/μl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation dur- 7 University of Wisconsin School of ing the study) or non-­exacerbators. Medicine and Public Health, Madison, Wisconsin, USA Results: In exacerbators and non-­exacerbators, dupilumab increased pre-­BD FEV1 8 Sanofi, Cambridge, Massachusetts, USA by Week 2 vs placebo; differences were maintained to Week 52 (type 2–­150/25: LS 9 Sanofi, Bridgewater Township, New mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10–­0.24) and 0.17 L (0.12–­0.23); Jersey, USA 10 type 2–­300/25: 0.22 L (0.13–­0.30) and 0.21 L (0.15–­0.28)), in exacerbators and non-­ Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA exacerbators, respectively (p < .0001). Similar trends were seen for post-­BD FEV1. Dupilumab vs placebo also showed significantly greater improvements in post-­BD Correspondence Alberto Papi, Respiratory Medicine, FEV1 0–­42 days after first severe exacerbation in type 2–­150/25 (LSMD vs placebo: University of Ferrara, S. Anna University 0.13 L [0.06–­0.20]; p = .006) and type 2–­300/25 (0.14 L [0.06–­0.22]; p = .001) pa- Hospital, Ferrara, Italy. Email: ppa@unife.it tients. ACQ-­5 improvements were greater with dupilumab vs placebo in both groups. Conclusion: Dupilumab treatment led to improvements in lung function independent Funding information Regeneron Pharmaceuticals; Sanofi of exacerbations and appeared to reduce the impact of exacerbations on lung func- tion in patients who experienced a severe exacerbation during the study. KEYWORDS dupilumab, FEV1, severe exacerbations, type 2 biomarkers Abbreviations: ACQ-­5, 5-­item Asthma Control Questionnaire; BD, bronchodilator; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LSMD, least squares mean difference; MMRM, mixed model repeated measures; q2w, every 2 weeks. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. Allergy. 2023;78:233–243.  wileyonlinelibrary.com/journal/all | 233 234 | PAPI et al. GR APHIC AL ABSTR ACT This analysis assessed the effect of dupilumab on FEV1 in QUEST patients with moderate-­to-­severe asthma and elevated type 2 biomarkers. Dupilumab significantly increased FEV1, regardless of number of severe exacerbations; FEV1 recovery was more rapid in dupilumab-­vs placebo-­treated patients. Dupilumab produced rapid and sustained improvement in lung function, including in patients experiencing severe exacerbations. Abbreviations: ACQ-­5, 5-­item Asthma Control Questionnaire; BD, bronchodilator; BL, baseline; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; LS, least squares; q2w, every 2 weeks 1 | I NTRO D U C TI O N uncontrolled, moderate-­to-­severe asthma. Treatment effects were greater in patients with vs without elevated type 2 biomarkers at Patients with asthma are at an increased risk of accelerated loss of lung baseline (blood eosinophils ≥150 cells/μl or FeNO ≥25 ppb).15 1 function compared with healthy individuals. Although age-­related Given the association between severe exacerbations and reduc- decline in lung function is observed in adults without asthma, this is tions in FEV1 and the potential for treatment to attenuate decline often accelerated in patients with asthma, and this may begin early in in lung function, this post hoc analysis aimed to evaluate changes childhood.1,2 A number of other risk factors are associated with loss of in lung function in patients with elevated type 2 biomarkers who lung function, including biological sex, smoking, and exposure to pol- experienced severe exacerbations during treatment with dupilumab 3,4 lutants. Regardless of asthma status, blood and sputum eosinophil or placebo during the QUEST study. counts have been associated with accelerated lung function decline,5 and in patients with asthma, predictors include elevated type 2 inflam- matory biomarkers such as eosinophil counts and fractional exhaled 2 | M E TH O D S nitric oxide (FeNO), low body mass index, and presence of nasal pol- yps.6 In patients with either asthma or chronic obstructive pulmonary 2.1 | Study design disease, the frequency of exacerbations has been linked to a more rapid decline in lung function.7–­9 The use of inhaled corticosteroids Full details of the QUEST study design have been published pre- (ICS) reduces the frequency of exacerbations and degree of lung func- viously.15 In brief, QUEST was a phase 3, randomized, double-­ 7 tion decline, but some patients with severe asthma fail to respond blind, placebo-­controlled study assessing the efficacy and safety adequately to treatment with ICS or ICS plus additional controllers.10 of dupilumab in patients with uncontrolled, moderate-­to-­severe Dupilumab, a fully human monoclonal antibody,11,12 blocks the asthma. The study was conducted in accordance with the Declaration shared receptor component for IL-­4 and IL-­13. These type 2 in- of Helsinki, the principles of Good Clinical Practice, and all local ap- flammatory cytokines are implicated in numerous diseases such as plicable regulations. Patients or their parents/guardians provided asthma and atopic dermatitis.13,14 In the phase 3 LIBERTY ASTHMA informed consent/assent prior to enrollment in the study. Subgroup QUEST study (NCT02414854), add-­on dupilumab 200 mg or 300 mg analysis of primary endpoints by number of asthma exacerbation every 2 weeks (q2w) vs placebo significantly reduced severe asthma events with 1 year prior to study was part of the pre-­specified analy- exacerbations and improved pre-­bronchodilator (BD) forced expira- sis in the study protocol. However, other parts of the analysis were tory volume in 1 s (FEV1) in the overall population of patients with conducted post hoc (e.g., analysis by baseline FeNO subgroups). PAPI et al. | 235 2.2 | Patients change from baseline in pre−/post-­BD FEV1 up to Week 52 as the response variable, and treatment, age, sex, baseline height, region Patients aged ≥12 years with physician-­diagnosed persistent asthma (pooled country), baseline eosinophil strata, baseline ICS dose level, for ≥12 months based on the Global Initiative for Asthma (GINA) rec- visit, treatment-­by-­visit interaction, baseline pre−/post-­BD FEV1, ommendations,16 who were receiving medium-­to-­high dose ICS plus and baseline-­by-­visit interactions as covariates. Additional analysis up to 2 additional controllers (e.g., a long-­acting β2-­agonist or leu- of change from baseline in pre-­and post-­BD FEV1 was performed by kotriene receptor antagonist) were eligible for enrollment. Inclusion smoking status (never smoked or former smoker). Analysis of change criteria included pre-­BD FEV1 ≤ 80% of the predicted normal value in post-­BD FEV1 after onset of the first severe exacerbation event for adults (≤90% for adolescents); FEV1 reversibility ≥12% and using the same MMRM was conducted but with change from study 200 ml; a 5-­item Asthma Control Questionnaire (ACQ-­5) score ≥1.5; baseline in post-­BD FEV1 values on or after the first severe exacer- and ≥1 asthma exacerbation in the past year, defined as a worsen- bation event and prior to second severe exacerbation event as the ing of asthma in the preceding year that resulted in hospitalization, response variable. Duration between first severe exacerbation and emergency medical care, or treatment with systemic glucocorticoids first FEV1 measurement available after onset of first severe exacer- for ≥3 days. Full details of inclusion and exclusion criteria have been bation is presented as median and interquartile ranges. published previously.15 Change from baseline in ACQ-­5 was assessed using a MMRM Patients were randomized 2:2:1:1 to receive add-­on subcuta- design with change from baseline in ACQ-­5 up to week 52 as the neous dupilumab 200 mg or 300 mg or matched placebo q2w for response variable and two pooled treatment groups, age, region 52 weeks. (pooled country), baseline eosinophil strata, baseline ICS dose level, visit, treatment-­by-­visit interaction, baseline ACQ-­5, and baseline-­ by-­visit interaction as covariates. Lower scores indicate greater im- 2.3 | Endpoints provements in asthma control. Outcomes assessed in the current analysis include comparison of the baseline demographics and disease characteristics of exacerba- 3 | R E S U LT S tors and non-­exacerbators, change from baseline over the 52-­week treatment period in pre-­ and post-­BD FEV1, including assessment In total, 1902 patients were included in the QUEST study, of after the first severe exacerbation (and prior to a second severe ex- whom 1519 patients were included in the analysis reported in this acerbation event), and the duration between first severe exacerba- manuscript. All 1519 patients were included in the type 2–­150/25 tion and the first available measurement of pre-­ and post-­BD FEV1 group, and 1219 were also included in the type 2–­300/25 group. following the exacerbation event. Data were censored at onset of Baseline pre-­ and post-­BD FEV1 and reversibility were higher in the potential second exacerbation event. A severe exacerbation dur- non-­exacerbators vs exacerbators in both type 2 subgroups (both ing the study period was defined as a deterioration of asthma that subgroups—­p < .0001 for pre-­BD and post-­BD FEV1; p < .05 for required either the use of systemic corticosteroids for ≥3 days or a reversibility) (Table 1). Across treatment groups, a higher percent- hospitalization or emergency room visit due to asthma and requiring age of exacerbators were on high-­dose ICS at baseline (both sub- systemic corticosteroids. groups—­p < .0001). Similarly, the mean number of severe asthma exacerbations in the previous year was higher in patients in the exac- erbator group (both subgroups—­p ≤ .0001) and a higher percentage 2.4 | Statistical analysis of exacerbator patients had ≥2 exacerbations in the year prior to the study (both subgroups—­p ≤ .0001). No clear differences in baseline Data for the two dupilumab and placebo arms were combined to biomarkers were seen between exacerbators and non-­exacerbators. create one data set for each treatment. Patients with type 2 asthma, As reported previously, exacerbations in the previous year were defined as baseline blood eosinophil count ≥150 cells/μl and/or less common in dupilumab-­treated patients than placebo-­treated FeNO ≥25 ppb (type 2–­150/25) were included in the current analy- patients.15 sis. Analyses were also performed on the subgroup of patients with baseline blood eosinophil count ≥300 cells/μl and/or FeNO ≥25 ppb (type 2–­300/25). Within the type 2–­150/25 and type 2–­300/25 3.1 | Change in pre-­and post-­BD FEV1 groups, patients were stratified by whether or not they experienced a severe exacerbation during the 52-­week study, with exacerbators Non-­exacerbators compared with exacerbators had significantly defined as patients who experienced ≥1 exacerbation and non-­ higher pre-­ and post-­BD FEV1 at baseline (p < .0001), regardless of exacerbators defined as patients who experience no exacerbations biomarker levels at baseline. Significantly greater increases in pre- during the study treatment period. ­BD FEV1 were seen in both exacerbators and non-­exacerbators Change from baseline in pre-­ and post-­BD FEV1 was assessed for dupilumab vs placebo from Week 2 onwards. These differ- using a mixed model repeated measures (MMRM) design, with ences were maintained through to Week 52 and were similar in TA B L E 1 Baseline demographics and patient characteristics 236 | Patients with blood eosinophils ≥150 cells/μl and/or FeNO ≥25 ppb at baseline Patients with blood eosinophils ≥300 cells/μl and/or FeNO ≥25 ppb at baseline a b Exacerbator Non-­exacerbator Exacerbatora Non-­exacerbatorb Combined PBO Combined DPL Combined PBO Combined DPL Combined PBO Combined DPL Combined PBO Combined DPL n 231 280 296 712 189 215 239 576 Age, mean (SD), years 49.0 (14.5) 49.0 (15.4) 47.1 (15.5) 46.7 (15.3) 48.5 (15.1) 48.7 (15.2) 46.6 (15.8) 46.6 (15.2) Female sex, n (%) 155 (67.1) 174 (62.1) 178 (60.1) 421 (59.1) 121 (64.0) 133 (61.9) 145 (60.7) 342 (59.4) Body mass index mean (SD), kg/m2 29.65 (7.39) 29.66 (7.13) 29.20 (6.84) 28.59 (6.16) 28.98 (7.13) 29.42 (7.10) 28.62 (6.46) 28.34 (5.82) Pre-­BD FEV1, mean (SD), L 1.69 (0.54) 1.69 (0.56) 1.82 (0.63) 1.84 (0.63) 1.70 (0.56) 1.67 (0.54) 1.83 (0.64) 1.83 (0.63) Percent predicted pre-­BD FEV1, 56.77 (13.25) 55.97 (13.35) 59.22 (13.66) 59.36 (13.40) 56.50 (13.49) 55.36 (13.46) 59.59 (13.67) 59.05 (13.55) mean (SD), % Post-­BD FEV1, mean (SD), L 2.06 (0.62) 2.02 (0.67) 2.25 (0.77) 2.25 (0.75) 2.07 (0.64) 2.02 (0.64) 2.26 (0.78) 2.24 (0.76) Post-­BD FEV1/FVC,mean (SD), % 65.91 (9.31) 65.07 (11.84) 68.03 (11.56) 67.56 (10.87) 65.30 (9.54) 64.50 (11.90) 68.42 (11.35) 67.31 (10.73) FEV1 reversibility, mean (SD), % 24.27 (15.79) 25.23 (19.40) 27.89 (20.03) 26.95 (22.58) 24.35 (16.20) 25.69 (18.98) 27.97 (20.28) 27.24 (22.87) ICS dose, n (%) High 137 (59.3) 168 (60.0) 144 (48.6) 336 (47.2) 110 (58.2) 132 (61.4) 112 (46.9) 264 (45.8) Medium 92 (39.8) 110 (39.3) 150 (50.7) 368 (51.7) 77 (40.7) 82 (38.1) 126 (52.7) 306 (53.1) With ongoing atopic medical 192 (83.1) 234 (83.6) 252 (85.1) 592 (83.1) 159 (84.1) 179 (83.3) 205 (85.8) 486 (84.4) condition, n (%) Former smoker, n (%) 58 (25.1) 52 (18.6) 46 (15.5) 130 (18.3) 48 (25.4) 40 (18.6) 39 (16.3) 92 (16.0) Number of severe asthma exacerbations experienced in the year before QUEST Mean (SD) 2.62 (2.19) 2.26 (2.35) 1.89 (1.52) 1.99 (2.39) 2.63 (2.17) 2.40 (2.58) 1.95 (1.65) 1.95 (1.57) Median (Q1–­Q3) 2.00 (1.0–­12.0) 2.00 (1.0–­4.0) 1.00 (1.0–­10.0) 1.00 (1.0–­50.0) 2.00 (1.0–­12.0) 2.00 (1.0–­24.0) 1.00 (1.0–­10.0) 1.00 (1.0–­15.0) 1 84 (36.4) 133 (47.5) 158 (53.4) 385 (54.1) 69 (36.5) 96 (44.7) 128 (53.6) 306 (53.1) ≥2 147 (63.6) 147 (52.5) 138 (46.6) 327 (45.9) 120 (63.6) 119 (55.3) 111 (46.4) 270 (46.8) Biomarkers Blood eosinophils, cells/μl n = 231 n = 280 n = 295 n = 712 n = 189 n = 215 n = 238 n = 576 Median (Q1–­Q3) 380.0 310.0 290.0 330.0 430.0 380.0 370.0 390.0 (220.0–­690.0) (190.0–­500.0) (190.0–­480.0) (200.0–­560.0) (310.0–­790.0) (230.0–­590.0) (190.0–­530.0) (235.0–­620.0) Total IgE, IU/ml n = 231 n = 277 n = 291 n = 705 n = 189 n = 212 n = 235 n = 569 Median (Q1–­Q3) 212.0 164.0 210.0 194.0 252.0 191.5 241.0 215.0 (76.0–­515.0) (65.0–­420.0) (73.0–­477.0) (76.0–­542.0) (96.0–­563.0) (81.5–­486.5) (81.0–­496.0) (88.0–­579.0) FeNO, ppb n = 229 n = 276 n = 291 n = 707 n = 188 n = 213 n = 235 n = 571 Median (Q1–­Q3) 34.0 (19.0–­54.0) 27.0 (16.0–­46.0) 30.0 (18.0–­50.0) 30.0 (18.0–­51.0) 38.0 (27.0–­60.5) 33.0 (24.0–­55.0) 34.0 (25.0–­55.0) 37.0 (25.0–­59.0) Abbreviations: BD, bronchodilator; DPL, dupilumab; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; IgE. immunoglobulin E; ICS, inhaled corticosteroid; PBO, placebo; ppb, parts per billion; Q, quarter; SD, standard deviation. a Exacerbators were patients who experienced a severe asthma exacerbation during the QUEST study. b PAPI et al. Non-­exacerbators were patients who did not experience any severe asthma exacerbations during the trial. PAPI et al. | 237 patients included in the type 2–­150/25 and type 2–­300/25 groups. with type 2–­300/25 asthma, by Week 52, LSMD vs placebo was In patients with type 2–­150/25 asthma, by Week 52, least squares 0.17 L (0.09–­0.24) in exacerbators and 0.24 L (0.18–­0.30) in non-­ mean differences (LSMD) (95% CI) for dupilumab vs placebo were exacerbators (both p < .0001; Figure 2B). As observed with pre-­BD 0.17 L (0.10–­0.24) and 0.17 L (0.12–­0.23) in exacerbators and FEV1, absolute post-­BD FEV1 remained lower throughout the study non-­exacerbators, respectively (both p < .0001; Figure 1A). In pa- in exacerbators compared with non-­exacerbators, irrespective of tients with type 2–­300/25 asthma, these differences were 0.22 L baseline biomarkers or treatment group. (0.13–­0.30) and 0.21 L (0.15–­0.28), respectively (both p < .0001; Figure 1B). It should be noted that whereas the LSMDs vs placebo were similar in exacerbators and non-­exacerbators, the absolute 3.2 | Smoking history pre-­BD FEV1 remained lower throughout the study in exacerbators compared with non-­exacerbators in both treatment groups. Similar When stratified by smoking history, significantly greater changes trends were observed in post-­BD FEV1, with significantly greater from baseline in pre-­BD FEV1 were observed for patients from both improvements in the dupilumab vs placebo groups by Week 2, sus- subgroups who had never smoked when treated with dupilumab vs tained through to Week 52, irrespective of exacerbator status. In placebo, independent of exacerbator status (type 2–­150/25 exac- patients with type 2–­150/25 asthma, by Week 52, LSMD (95% CI) erbators –­LSMD [95% CI] vs placebo: 0.19 L [0.11–­0.28], p < .0001; vs placebo was 0.15 L (0.08–­0.22) in exacerbators and 0.19 L (0.14–­ type 2–­150/25 non-­exacerbators: 0.17 L [0.10–­0.23], p < .0001; 0.25) in non-­exacerbators (both p < .0001; Figure 2A). In patients type 2–­3 00/25 exacerbators: 0.26 L [0.16–­0.36], p < .0001; type Combined placebo Combined dupilumab 200/300 mg q2w (A) Patients with blood eosinophils ≥150 cells/µl and/or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations *** ** *** ** *** *** *** ** *** ** ** *** ** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** Change from baseline in pre-BD 0.5 0.5 FEV1 (L), LS mean (± SE) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week Week Number of patients Combined placebo 231 227 222 219 223 217 220 220 215 211 215 211 213 209 207 205 175 296 290 287 288 283 285 290 282 283 276 271 271 272 270 269 266 233 Combined dupilumab 200/300 mg q2w 280 273 272 273 270 265 268 267 268 265 261 256 261 260 259 252 215 712 700 690 690 683 682 691 689 671 677 666 658 664 653 653 639 547 (B) Patients with blood eosinophils ≥300 cells/µl and/or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations *** *** *** *** *** *** *** ** *** *** ** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** Change from baseline in pre-BD 0.5 0.5 FEV1 (L), LS mean (± SE) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week Week Number of patients Combined placebo 189 187 184 180 183 181 182 181 178 173 177 176 175 172 172 169 143 239 233 230 232 228 229 233 227 228 222 219 219 220 219 219 217 188 Combined dupilumab 200/300 mg q2w 215 209 208 209 207 205 205 206 208 203 203 199 201 201 200 194 164 576 567 559 562 556 552 559 558 543 547 538 534 539 531 531 516 443 F I G U R E 1 Change from baseline over time in pre-­BD FEV1 in (A) patients with eosinophil count ≥150 cells/μl and/or FeNO ≥25 ppb at baseline and (B) patients with eosinophil count ≥300 cells/μl and/or FeNO ≥25 ppb at baseline. FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; LS, least squares; ppb, parts per billion; q2w, every 2 weeks; SE, standard error. *p < .05; **p < .01; ***p < .001 vs matched placebo 238 | PAPI et al. Combined placebo Combined dupilumab 200/300 mg q2w (A) Patients with blood eosinophils ≥150 cells/µl and/or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations *** *** *** *** *** *** *** *** *** *** *** *** *** *** Change from baseline in post-BD 0.3 0.3 FEV1 (L), LS mean (± SE) 0.2 0.2 0.1 0.1 0 0 –0.1 –0.1 0 2 4 8 12 24 36 52 0 2 4 8 12 24 36 52 Week Week Number of patients Combined placebo 231 224 220 220 219 215 214 178 296 287 289 281 289 280 272 232 Combined dupilumab 200/300 mg q2w 280 267 272 267 271 266 261 221 712 694 694 685 689 679 666 564 (B) Patients with blood eosinophils ≥300 cells/µl and/or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations *** *** *** *** *** *** *** *** *** *** *** *** *** *** Change from baseline in post-BD 0.3 0.3 FEV1 (L), LS mean (± SE) 0.2 0.2 0.1 0.1 0 0 –0.1 –0.1 0 2 4 8 12 24 36 52 0 2 4 8 12 24 36 52 Week Week Number of patients Combined placebo 189 186 182 180 180 176 177 146 239 231 233 228 232 225 220 186 Combined dupilumab 200/300 mg q2w 215 206 209 204 208 205 201 169 576 562 563 554 557 548 540 455 F I G U R E 2 Change from baseline over time in post-­BD FEV1 during 52 weeks of treatment in (A) patients with eosinophil count ≥150 cells/μl and/or FeNO ≥25 ppb at baseline and (B) patients with eosinophil count ≥300 cells/μl and/or FeNO ≥25 ppb at baseline. *p < . 05; **p < .01; ***p < .001 vs matched placebo. FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; LS, least squares; ppb, parts per billion; q2w, every 2 weeks; SE, standard error 2–­3 00/25 non-­exacerbators: 0.20 L [0.12–­0.27], p < .0001). Greater former smokers, change from baseline in post-­BD FEV1 was similar changes were also seen in non-­exacerbators with a history of smok- between dupilumab and placebo (type 2–­150/25 –­ LSMD [95% CI] ing who received dupilumab vs placebo (type 2–­150/25 –­ LSMD vs placebo: 0.03 L [−0.12 to 0.18], p = .672; type 2–­3 00/25: −0.0002 [95% CI] vs placebo: 0.19 L [95% CI: 0.05–­0.33], p = .08; type 2–­ [−0.17 to 0.17], p = .998). 300/25: 0.25 L [0.09–­0.41], p = .002); however, differences be- tween treatment groups were not significant in exacerbators who were former smokers (type 2–­150/25 –­LSMD [95% CI] vs placebo: 3.3 | Change from baseline in post-­BD FEV1 after 0.13 L [−0.04 to −0.30], p = .143; type 2–­3 00/25: 0.12 L [−0.08 to onset of the first exacerbation −0.32], p = .225). Similar trends were also observed in post-­BD FEV1, with significant differences between treatment groups in Within the exacerbator population, significantly greater improve- both exacerbators (type 2–­150/25 –­ LSMD [95% CI] vs placebo: ments from baseline in post-­BD FEV1 were observed 0–­42 days after 0.19 L [0.12–­0.27], p < .0001; type 2–­3 00/25: 0.22 L [0.13–­0.31], the first severe exacerbation event in dupilumab-­vs placebo-­treated p < .0001) and non-­exacerbators (type 2–­150/25: 0.19 L [0.13–­ patients with either type 2–­150/25 (LSMD [95% CI] vs placebo: 0.25], p < .0001; type 2–­3 00/25: 0.23 L [0.17–­0.30], p < .0001) who 0.13 L [0.06–­0.20], p = .0006) or type 2–­300/25 (0.14 L [0.06–­0.22], had never smoked, and in non-­exacerbators who were former smok- p = .001) asthma (Figure 3). There was also a trend toward greater ers (type 2–­150/25: 0.20 L [0.06–­0.33], p = .004; type 2–­3 00/25: improvements from baseline in post-­BD FEV1 measured at either 0.24 L [0.08–­0.40], p = .003). In the group of exacerbators who were 43–­125 or 126–­210 days after the first severe exacerbation event PAPI et al. | 239 Combined placebo Combined dupilumab 200/300 mg q2w Exacerbator populations Blood eosinophils ≥150 cells/μL Blood eosinophils ≥300 cells/μL and/or FeNO ≥25 ppb and/or FeNO ≥25 ppb LS mean difference 0.13 0.06 0.07 0.14 0.08 0.09 (95% CI) vs placebo (0.06, 0.20) (–0.01, 0.12) (–0.02, 0.15) (0.06, 0.22) (0.002, 0.16) (–0.01, 0.18) *** ** 0.18 0.20 0.16 (0.03) Change from baseline in post-BD 0.14 (0.03) 0.13 FEV1 (L), LS mean (± SE) 0.15 0.12 (0.03) (0.03) 0.10 (0.03) 0.09 0.09 (0.03) 0.10 0.07 0.07 (0.03) (0.04) (0.03) (0.03) 0.05 0 –0.01 –0.03 (0.03) –0.05 (0.03) 0–42 43–125 126–210 0–42 43–125 126–210 Days after first severe exacerbation event BL post-BD FEV1, 1.91 (0.59) 1.99 (0.67) 2.00 (0.53) 2.00 (0.65) 2.12 (0.58) 2.02 (0.74) 1.88 (0.59) 1.97 (0.58) 1.99 (0.53) 2.01 (0.66) 2.11 (0.61) 1.96 (0.67) mean (SD), L F I G U R E 3 Change from baseline in post-­BD FEV1 after onset of the first severe exacerbation event. Two events are considered as different if the start dates are separated by at least 4 weeks. Post-­BD FEV1 measurements on or after the first severe exacerbation event are split into visits based on the days elapsed between the first severe exacerbation event and these measurements: 0–­42 days, 43–­125 days, and 126–­210 days. The exacerbator group includes patients with ≥1 severe exacerbation event during the 52-­week treatment period. Change from baseline in post-­BD FEV1 was derived from MMRM with change from study baseline in post-­BD FEV1 values on or after the first severe exacerbation event and prior to second severe exacerbation event as the response variable, and treatment, age, sex, baseline height, region (pooled country), baseline eosinophil strata, baseline ICS dose level, visit, treatment-­by-­visit interaction, study baseline post-­BD FEV1 value and study baseline-­by-­visit interaction as covariates. BD, bronchodilator; BL, baseline; CI, confidence interval; FeNO: fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LS, least squares; MMRM, mixed model repeated measures; ppb, parts per billion; q2w, every 2 weeks; SD, standard deviation; SE, standard error. **p < .01; ***p < .001 Combined placebo Combined dupilumab 200/300 mg q2w (A) Pre-bronchodilator FEV1 measurements (B) Post-bronchodilator FEV1 measurements Patients with blood Patients with blood Patients with blood Patients with blood eosinophils ≥150 cells/µL eosinophils ≥300 cells/µL eosinophils ≥150 cells/µL eosinophils ≥300 cells/µL 240 and/or FeNO ≥25 ppb 240 and/or FeNO ≥25 ppb 240 and/or FeNO ≥25 ppb 240 and/or FeNO ≥25 ppb 220 220 220 220 200 200 200 200 180 180 180 180 160 160 160 160 Duration (days) Duration (days) 140 140 140 140 120 120 120 120 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 + + + + 20 20 20 20 + + + + 0 0 0 0 F I G U R E 4 Duration (days) between the onset of first severe exacerbation event and the latest (A) pre-­and (B) post-­BD FEV1 (L) measurement on or after the onset of first severe exacerbation. The exacerbator group includes patients with ≥1 severe exacerbation event during the 52-­week treatment period. The duration (days) is calculated as (latest pre-­BD measurement date on or after first severe exacerbation event—­onset date of first severe exacerbation event +1). FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ppb, parts per billion; q2w, every 2 weeks 240 | PAPI et al. in dupilumab-­vs placebo-­treated patients, although these were not by smoking history; however, the difference between treatments in statistically significant (Figure 3). Overall, the median durations be- former smokers who were exacerbators was not significant. A pre- tween first severe exacerbation event and the latest available pre-­ vious study of the effect of smoking in adolescent and early adult and post-­BD FEV1 data were similar in the placebo and dupilumab patients with asthma demonstrated that lung function impairments groups and for patients with type 2–­150/25 and type 2–­300/25 were associated with asthma and smoking early in life and were not asthma (Figure 4A and B). Median duration between first severe fully responsive to bronchodilators, indicating irreversible damage exacerbation and pre-­BD FEV1 data was 8 days (IQR: 1–­15 days) for may have occurred. 22 However, this is unlikely to have been the placebo and 9 days (3–­15) for dupilumab, for both subgroups of pa- case in the patients in the current study, as the absolute changes tients. For type 2–­150/25 patients, median duration between first from baseline in the dupilumab group in pre-­BD FEV1 were similar severe exacerbation and post-­BD FEV1 was 19 days (IQR: 7–­54) in regardless of smoking history. Caution is advised when interpreting the placebo group and 23 days (IQR: 9–­54) in the dupilumab group. this result as the small population sizes in the former-­smoker group Similar durations were observed in type 2–­300/25 patients (18 days confounded clear interpretation of any population-­specific impact. [IQR: 7–­49] and 26 days [IQR: 9–­54] for placebo-­ and dupilumab-­ In patients who experienced exacerbations during the study, a de- treated patients, respectively). cline in lung function was observed in the first 42 days after the first exacerbation in the placebo group, but not in the dupilumab group. Patients who received dupilumab experienced continued improvement 3.4 | Change from baseline in ACQ-­5 scores in lung function, even in the weeks following an exacerbation. The data from the placebo group are in line with the association between ex- In both the type 2–­150/25 and type 2–­300/25 groups, treatment acerbation frequency and accelerated lung function decline observed with dupilumab in non-­exacerbators resulted in significantly greater in previous studies.7–­9 In an analysis of patients with severe asthma improvements in ACQ-­5 scores vs placebo from Week 2, and these enrolled in the DREAM and MENSA phase 3 mepolizumab studies, de- improvements were sustained through Week 52 (LSMD vs placebo cline in lung function was observed in patients with more than 1 exac- p < .0001 at all time points) (Figure 5). In exacerbators in the type erbation and was greater in the placebo group. Across treatments and 2–­150/25 and type 2–­300/25 groups, treatment with dupilumab studies, linear regression analysis suggested that each exacerbation resulted in greater improvements in ACQ-­5 scores vs placebo from event was associated with a 50 ml decline in post-­BD FEV1.6 However, Week 2; however, the LSMD vs placebo was only significant at some these studies included patients on oral corticosteroids, whereas pa- time points (Figure 5). tients dependent on oral corticosteroids were excluded from the QUEST study, precluding direct comparisons of these analyses. During severe exacerbation events, patients have worsening air- 4 | DISCUSSION way inflammation, 23 and this may at least partly explain why dupi- lumab can maintain lung function after an exacerbation. Dupilumab The results presented here indicate that the degree of improvement in blocks the shared receptor component for IL-­4 and IL-­13, which are lung function for dupilumab-­ vs placebo-­treated patients was similar key and central drivers of type 2 inflammation in multiple diseases, for those who suffered breakthrough exacerbations and those who did including asthma.13,24 Reduction of this underlying type 2 inflam- not. However, absolute pre-­and post-­BD FEV1 remained lower in exac- mation may reduce the damage done to the airways by lessening erbators than non-­exacerbators throughout the study. The observed the decline in lung function following an exacerbation as well as by improvements in lung function in both groups indicate that, despite reducing the likelihood of further severe exacerbations. Reduction differences in baseline FEV1, treatment still improves lung function by dupilumab in IL-­13-­driven mucus production, and thus airway in patients who suffer breakthrough exacerbations during treatment. mucus plugging, may also play a role in lessening the decline in lung Compared with non-­exacerbators, exacerbators had more frequent function. The role of dupilumab in reducing underlying inflammation exacerbations during the year prior to study enrollment, indicating that may also explain the greater benefits in patients with type 2–­300/25 they were at higher risk of future exacerbations and more rapid lung asthma compared with those with type 2–­150/25. In a previous anal- function decline, as indicated by a lower FEV1 at baseline. Use of bio- ysis of the QUEST study, the largest clinical benefits with dupilumab logics such as dupilumab in patients with moderate-­to-­severe asthma were observed in patients with the highest levels of elevated type has been shown to both improve lung function and reduce the number 2 biomarkers. 25 It could be hypothesized this is due to more severe of severe exacerbations, thus slowing any further decline in lung func- disease in patients with higher levels of type 2 biomarkers, who tion that may occur during an exacerbation.15,17–­19 As patients with therefore have more potential room for improvement. However, no frequent exacerbations often experience poorer pulmonary function clear differences in the baseline exacerbation rates or FEV1 were ob- and higher symptom burden than non-­exacerbators,20,21 this study in- served between the two type 2 populations studied in this analysis, dicates that optimizing biologic therapy can have substantial benefits suggesting that the degree of elevated type 2 biomarkers was not for patients with a frequent exacerbator phenotype. indicative of the likelihood of exacerbation or decline in lung func- In the current analysis, differences in treatment effects were ob- tion. Thus, this analysis demonstrates that treatment of underlying served between exacerbators and non-­exacerbators when stratified inflammation provides beneficial impacts on the disease course even PAPI et al. | 241 Combined placebo Combined dupilumab (A) Patients with eosinophils ≥150 cells/µl or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations ** * * * * *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** 0 0 ACQ-5 score, LS mean (± SE) –0.2 –0.2 Change from baseline in –0.4 –0.4 –0.6 –0.6 –0.8 –0.8 –1.0 –1.0 –1.2 –1.2 –1.4 –1.4 –1.6 –1.6 –1.8 –1.8 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week Week Number of patients Combined placebo 231 222 216 218 224 216 220 217 214 211 214 209 208 204 204 196 171 296 279 278 281 278 279 287 277 275 273 269 266 270 266 267 261 228 Combined dupilumab 280 272 270 265 264 261 265 266 265 261 260 253 254 253 253 244 208 712 686 678 679 674 674 687 680 666 666 660 648 657 636 636 629 541 (B) Patients with eosinophils ≥300 cells/µl or FeNO ≥25 ppb at baseline Exacerbator populations Non-exacerbator populations ** * * * * * * *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** 0 0 ACQ-5 score, LS mean (± SE) –0.2 –0.2 Change from baseline in –0.4 –0.4 –0.6 –0.6 –0.8 –0.8 –1.0 –1.0 –1.2 –1.2 –1.4 –1.4 –1.6 –1.6 –1.8 –1.8 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week Week Number of patients Combined placebo 189 183 180 180 185 181 183 181 177 174 177 175 171 170 169 163 141 239 224 224 227 225 223 231 223 221 219 217 215 218 216 217 212 183 Combined dupilumab 215 208 207 202 202 200 204 206 205 201 202 197 198 196 195 189 160 576 557 548 554 549 548 559 551 540 539 534 526 534 519 518 511 437 F I G U R E 5 Change from baseline over time in ACQ-­5 score during 52 weeks of treatment in (A) patients with eosinophil count ≥150 cells/μl or FeNO ≥25 ppb at baseline and (B) patients with eosinophil count ≥300 cells/μl or FeNO ≥25 ppb at baseline. ACQ-­5, 5-­item Asthma Control Questionnaire; FeNO, fractional exhaled nitric oxide; LS, least squares; ppb, parts per billion; SE, standard error in patients with lower levels of type 2 biomarkers, as well as in those of detecting lower FEV1 values. However, we found no statistically who continue to experience exacerbations during treatment. or clinically important difference between placebo-­and dupilumab-­ Improvements from baseline in ACQ-­5 scores were greater in treated patients in terms of time from exacerbation to FEV1 mea- patients on dupilumab vs placebo. In both exacerbators and non-­ surement. Therefore, our data point to dupilumab favoring a more exacerbators, improvements were observed as early as Week 2 rapid improvement in lung function after exacerbation events (as and were sustained for the duration of the study, although signif- early as 0–­42 days) compared with placebo (from 43 days onwards). icant differences were only consistent in the larger population of A faster recovery after exacerbations is a priority for many patients. non-­exacerbators. Nevertheless, the FEV1 increase after exacerbations appears not to There are a number of limitations to this study. First, as a post be the only determinant of the overall lung function improvement hoc analysis, the study was not powered to investigate differences seen with dupilumab treatment, as non-­exacerbators also benefit- between treatments in the subgroups of exacerbators and non-­ ted from dupilumab therapy. Third, our study was not designed to exacerbators. Small sample sizes in some subgroups may confound examine the nature of the exacerbations that occurred. For example, interpretation of the data. Second, our post-­exacerbation spirom- it has been reported that patients receiving mepolizumab for severe etry testing was not conducted at pre-­specified intervals relative eosinophilic asthma are heterogenous, with approximately half of to exacerbation events, but at times specified by the overall 52-­ exacerbations being non-­eosinophilic events driven by infection. 26 week protocol. The higher incidence of exacerbation rates seen Fourth, as this was a randomized controlled study, it may be that in placebo-­treated patients might have increased the likelihood of exacerbations were assessed and managed more rapidly than would spirometry occurring sooner after exacerbation events in these pa- have occurred in a real-­world situation. Finally, the study design re- tients vs those treated with dupilumab, leading to higher probability flects previous rather than current GINA recommendations. 242 | PAPI et al. In summary, this analysis shows that treatment with dupilumab Genentech, Novartis, Sanofi; and has received payments for organ- results in significant increases in both pre-­and post-­BD FEV1 in pa- izing educational events from AstraZeneca, Genentech. KRC has tients with elevated type 2 biomarkers, regardless of whether severe received grants and personal fees from AstraZeneca, Boehringer exacerbations occurred. Although lung function in placebo-­treated Ingelheim, CSL Behring, Genentech, Grifols Ltd., Kamada Ltd., Mereo patients declined following severe exacerbation events, dupilumab-­ BioPharma Group, Novartis, Roche, Sanofi; reports grants from treated patients continued to experience improvements in lung Amgen, Baxter, GSK; and has received personal fees from CIHR-­GSK function, suggesting sustained preservation of lung function after Research Chair in Respiratory Health Care Delivery, Merck, UHN. severe exacerbation can be achieved with dupilumab treatment. DJJ is a consultant for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Vifor Pharma; AU T H O R C O N T R I B U T I O N S and reports membership of the data and safety monitoring board AP, JC, MC, CD, LR, KRC, and DJJ contributed to the data collection, for Pfizer. ND is a former employee of Sanofi and may hold stock data analysis, data interpretation, and writing of this manuscript. ND, and/or stock options in the company. NP, JAJ, and PJR are Sanofi NPA, RG, JAJN, PJR, YC, and BO contributed to the study design, employees and may hold stock and/or stock options in the company. data analysis, data interpretation, and writing of this manuscript. RG, YD, and BO are employees and shareholders of Regeneron ND accessed and verified the data and did statistical analyses. All Pharmaceuticals, Inc. authors had full access to all of the data; participated in interpreta- tion of the data, provided critical feedback, and took responsibility ORCID for the accuracy, completeness, and protocol adherence of data and Alberto Papi https://orcid.org/0000-0002-6924-4500 analyses; and took final responsibility to submit for publication. Daniel J. Jackson https://orcid.org/0000-0001-6938-2690 AC K N OW L E D G M E N T S REFERENCES Research sponsored by Sanofi and Regeneron Pharmaceuticals, 1. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-­year fol- Inc. 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