Allergy Assessment of dupilumab in children with moderate-to- severe type 2 asthma with or without evidence of allergic asthma Journal: Allergy Manuscript ID ALL-2022-00989.R2 Wiley - Manuscript type: Original Article Fo Date Submitted by the 06-Mar-2023 Author: rP Complete List of Authors: Papadopoulos, Nikolaos; University of Athens, 2nd Pediatric Clinic Szefler, Stanley ; University of Colorado Anschutz Medical Campus Department of Pediatrics Bacharier, Leonard; Monroe Carell Junior Children's Hospital at ee Vanderbilt Maspero, Jorge; Fundación CIDEA domingo, christian; Consorcio Corporacion Sanitaria Parc Tauli rR Fiocchi, Alessandro; Ospedale Pediatrico Bambino Gesu Lee, Jason; Evidence Based Medical Educator and Toronto Allergy and Asthma Clinic, Evidence Based Medical Educator and Toronto Allergy and Asthma Clinic ev Daizadeh, Nadia; Sanofi J, David Lederer; Regeneron Pharmaceuticals Inc Hardin, Megan; Sanofi Gall, Rebecca; Regeneron Pharmaceuticals Inc iew Djandji, Michel; Sanofi Siddiqui, Shahid; Regeneron Pharmaceuticals Inc Jacob-Nara, Juby A.; Sanofi Deniz, Yamo; Regeneron Pharmaceuticals Inc Rowe, Paul; Sanofi Original Article Topics: Asthma and Lower Airway Disease News and Views Topics: IgE, allergens and epitopes, asthma, asthma treatment, biologics, Keywords: pediatrics Background: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in Abstract: patients aged 6–11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). Methods: Annualized rate of severe exacerbations (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV 1), percent-predicted pre- Page 1 of 88 Allergy 1 2 3 4 BD FEV 1 (ppFEV 1), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. Results: 350 children (261 with and 89 5 without evidence of allergic asthma) were included. Dupilumab vs 6 placebo significantly reduced AER in patients with (0.24 vs 0.62, relative 7 risk reduction[RRR]: 62% [95% CI, 39–76], p<.0001) and without (0.39 8 vs 0.80, RRR: 51% [95% CI, 0–76], p<.05) evidence of allergic asthma. 9 Significant improvements in ppFEV 1, pre-bronchodilator FEV 1, and 10 ACQ-7 scores were observed in dupilumab vs placebo throughout the 11 treatment period in patients with evidence of allergic asthma. In patients 12 without evidence of allergic asthma, numerical improvements in pre- 13 bronchodilator FEV 1 and asthma control were observed by Week 52. Conclusion: Dupilumab vs placebo reduced asthma exacerbations in 14 children with type 2 asthma irrespective of evidence of allergic asthma; 15 similar trends were observed in changes in lung function. Significant 16 improvement in asthma control was observed in patients with evidence 17 of allergic asthma, but not in those without. 18 19 Fo 20 21 22 23 rP 24 25 26 ee 27 28 29 rR 30 31 32 ev 33 34 35 36 iew 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 2 of 88 1 2 3 4 5 6 7 8 9 Point-by-point response template 10 Date: 03/06/2023 11 12 Manuscript Number: ALL-2022-00989 13 Title of Article: Assessment of dupilumab in children with moderate-to-severe type 2 asthma 14 with or without evidence of allergic asthma 15 Name of the Corresponding Author: Nikolaos G. Papadopoulos 16 17 Email Address of the Corresponding Author: ngp@allergy.gr 18 19 Dear Dr. Akdis, dear Cezmi, Fo 20 In VOYAGE, dupilumab improved clinical efficacy in children with type 2 asthma (baseline levels 21 of eosinophils ≥150 cells/µL or FeNO ≥20 ppb). In our manuscript, we present a post-hoc 22 23 analysis evaluating the efficacy of dupilumab in patients with type 2 asthma, with and without rP 24 evidence of allergic asthma. Our results support the use of dupilumab to treat patients 25 regardless of allergic status, with patients with allergic asthma demonstrating a stronger 26 response to treatment. ee 27 28 We thank the reviewers for their careful and critical review of our manuscript, and for 29 recommending it for publication. We have incorporated their requested minor revision in the rR 30 graphical abstract accordingly. 31 32 Major changes and additions to the revised manuscript (please list): ev 33 34 1. A * has been added to the graphical abstract to refer to P < 0.05, as it was originally missing 35 36 Specific Responses: iew 37 38 Response to Reviewer #1: 39 40 Comment 1: The authors addressed adequatelly the questions, revision requests and concerns. 41 It is appropriate for publication, if a minor revision is made at the graphical abstract (one 42 43 asterisk is missing in front of p<0.05). 44 45 Reply 1: We thank the reviewer for their positive recommendation, and for flagging the typo 46 in the graphical abstract. This has now been revised accordingly. 47 48 Response to Reviewer #2: 49 50 Comment 1: Im satistified with the answers of the authors and the paper is acceptable as it is 51 52 Reply 1: We thank the reviewer for their positive recommendation. 53 54 Sincerely, 55 56 Nikolaos Papadopoulos (corresponding author) 57 58 59 60 Page 3 of 88 Allergy 1 2 3 Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or 4 5 6 without evidence of allergic asthma 7 8 Short title: Dupilumab in children with T2 asthma and allergy 9 10 11 12 13 Nikolaos G Papadopoulos, MD, PhD1, Stanley J Szefler MD2, Leonard B Bacharier, MD3, Jorge F 14 15 Maspero, MD4, Christian Domingo, MD5, Alessandro Fiocchi MD6, Jason K Lee, MD7, Nadia Daizadeh, 16 17 PhD8, David J Lederer, MD9, Megan Hardin, MD8, Rebecca Gall, MD9, Michel Djandji, MD8, Shahid 18 19 Siddiqui, MD9, Juby A Jacob-Nara, MD, MPH, DHSc10, Yamo Deniz, MD9, Paul J Rowe, MD, ATSF10 20 21 Fo 22 23 1The 2nd Pediatric Clinic, University of Athens, Greece; 2The University of Colorado School of 24 rP 25 26 Medicine and Children’s Hospital Colorado, Department of Pediatrics, The Breathing Institute, 27 28 Aurora, CO, USA; 3The Monroe Carell Jr Children’s Hospital at Vanderbilt University Medical Center, ee 29 30 31 Nashville, TN, USA; 4The Fundación CIDEA, Buenos Aires, Argentina; 5The Corporació Sanitària Parc rR 32 33 Taulí, Sabadell, Autonomous University of Barcelona, Barcelona, Spain; 6The Bambino Gesù 34 35 Children's Hospital, IRCCS, Rome, Italy, 7Evidence Based Medical Educator and Toronto Allergy and ev 36 37 Asthma Clinic, Toronto, ON, Canada, 8Sanofi, Cambridge, MA, USA; 9Regeneron Pharmaceuticals, 38 iew 39 Inc., Tarrytown, NY, USA; 10Sanofi, Bridgewater, NJ, USA. 40 41 42 43 44 Corresponding author: Nikolaos G Papadopoulos 45 46 Address: University of Athens, 41 Fidippidou street, Athens, Attica 11527, Greece 47 48 Phone: +30 210 7776964 49 50 51 Email: ngp@allergy.gr 52 53 54 55 Support statement: Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov 56 57 identifier: NCT02948959 58 59 60 Allergy Page 4 of 88 1 2 3 Manuscript Stats 4 5 6  Target journal: Allergy 7  Abstract: 250/250 8 9  Main text: 3635/3500 10 11  Figures and/or tables: 1 Table and 4 Figures/6 total max. 12  References: 18/no limit given 13 14  Supplementary materials: 2 Figures 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 5 of 88 Allergy 1 2 3 Highlights: 4 5 6  In type 2 patients, dupilumab vs placebo significantly reduced exacerbation rates 7 irrespective of allergic status 8 9  Significant improvements vs placebo in lung function and asthma control were observed 10 11 throughout the treatment period in patients with evidence of allergic asthma 12  In the small population of patients without evidence of allergic asthma, numerical 13 14 improvements in lung function and asthma control were observed 15 16 17 18 19 20 Graphical abstract: 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 6 of 88 1 2 3 Disclosure of potential conflict of interest: 4 5 6 Papadopoulos NG: AstraZeneca, Boehringer Ingelheim, GSK, HAL Allergy, Menarini, Mylan, Novartis, 7 8 Nutricia, OM Pharma, Regeneron Pharmaceuticals, Inc., Sanofi – speaker, advisory board member. 9 10 Szefler SJ: AstraZeneca, GSK, Moderna, OM Pharma, Propeller Health, Regeneron Pharmaceuticals, 11 12 Inc., Sanofi – consultant fees paid to the university. 13 14 Bacharier LB: AstraZeneca, GSK, Regeneron Pharmaceuticals, Inc., Sanofi – speaker fees; Cystic 15 16 17 Fibrosis Foundation, Vertex, AstraZeneca, DBV Technologies – data and safety monitoring board; 18 19 NIH, Sanofi – research support. 20 21 Maspero JF: AstraZeneca, Sanofi – consultant; GSK, Menarini, Novartis, Uriach – speaker fees; Fo 22 23 Novartis – research grants. 24 rP 25 26 Domingo C: ALK, Allergy Therapeutics, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, 27 28 Ferrer Pharma, GSK, HAL Allergy, Inmunotek, Menarini, Novartis, Pfizer, sanofi-aventis, Stallergenes ee 29 30 Greer, Takeda, Teva – travel and speaker fees. 31 rR 32 Fiocchi AG: Danone SA, Hipp GmbH, Abbott SA, Novartis, Ferrero – speaker, advisory board member. 33 34 35 Sanofi, Novartis, Ferrero – research grants. ev 36 37 Lee JK: AstraZeneca, GSK, Novartis, Regeneron, Genetech, Sanofi, ALK, Medexus, Miravo, Bausch 38 iew 39 Health, Takeda, CSL – speaking fees. Research funding and clinical trials from AstraZeneca, GSK, 40 41 Takeda, Regeneron, Novartis, Genentech, Sanofi. 42 43 44 Daizadeh N: Sanofi – former employee, may hold stock and/or stock options in the company. 45 46 Hardin M, Jacob-Nara JA, Djandji M, Rowe PJ: Sanofi − employees, may hold stock and/or stock 47 48 options in the company. 49 50 Lederer DJ, Deniz Y, Gall R, Siddiqui S: Regeneron Pharmaceuticals, Inc. − employees and share 51 52 53 54 55 56 57 58 59 60 Page 7 of 88 Allergy 1 2 3 ABSTRACT 4 5 6 Background: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 7 8 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks 9 10 the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of 11 12 VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6–11 years with type 2 13 14 15 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30IU/mL and ≥1 16 17 perennial aeroallergen-specific IgE ≥0.35kU/L). 18 19 Methods: Annualized rate of severe exacerbations (AER) and changes in pre-bronchodilator (Pre-BD) 20 21 forced expiratory volume in one second (FEV1), percent-predicted pre-BD FEV1 (ppFEV1), and Asthma Fo 22 23 24 Control Score (ACQ)-7 were assessed during the treatment period. rP 25 26 Results: 350 children (261 with and 89 without evidence of allergic asthma) were included. 27 28 Dupilumab vs placebo significantly reduced AER in patients with (0.24 vs 0.62, relative risk ee 29 30 reduction[RRR]: 62% [95% CI, 39–76], p<.0001) and without (0.39 vs 0.80, RRR: 51% [95% CI, 0–76], 31 rR 32 33 p<.05) evidence of allergic asthma. Significant improvements in ppFEV1, pre-bronchodilator FEV1, 34 35 and ACQ-7 scores were observed in dupilumab vs placebo throughout the treatment period in ev 36 37 patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical 38 iew 39 improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. 40 41 42 Conclusion: Dupilumab vs placebo reduced asthma exacerbations in children with type 2 asthma 43 44 irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. 45 46 Significant improvement in asthma control was observed in patients with evidence of allergic 47 48 asthma, but not in those without. 49 50 51 52 53 Keywords 54 55 Asthma; allergic; exacerbation; percentage predicted FEV1, dupilumab 56 57 58 59 60 Allergy Page 8 of 88 1 2 3 Abbreviations 4 5 6 ACQ-7-IA, Asthma Control Questionnaire 7-item version Interviewer-Administered 7 8 AER, adjusted annualized severe exacerbation rates 9 10 FeNO, fractional exhaled nitric oxide FeNO 11 12 FEV1, forced expiratory volume in 1 second 13 14 GINA, Global Initiative for Asthma 15 16 17 ICS, inhaled corticosteroids 18 19 IgE, immunoglobulin E 20 21 IL, interleukin Fo 22 23 ITT, intention to treat 24 rP 25 26 MMRM, mixed-effect model with repeated measures 27 28 ppb, parts per billion ee 29 30 ppFEV1, percentage of predicted forced expiratory volume in 1 second 31 rR 32 q2w, every 2 weeks 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 9 of 88 Allergy 1 2 3 BACKGROUND 4 5 6 Type 2 inflammation is the most common type of inflammation seen in asthma in children1,2 and is 7 8 reflected by elevated levels of peripheral or sputum eosinophils, fractional exhaled nitric oxide 9 10 (FeNO), and/or IgE, and includes asthma characterized as eosinophilic and/or allergic.3-5 Allergic 11 12 asthma, traditionally considered to be driven by an IgE-mediated process, is a subtype of type 2 13 14 15 inflammation.6 16 17 Dupilumab, a fully human monoclonal antibody,7,8 blocks the shared receptor component for 18 19 interleukin (IL)-4 and IL-13, type 2 inflammatory cytokines implicated in numerous allergic diseases 20 21 ranging from asthma to atopic dermatitis,9 thus inhibiting their signaling. It is approved in the USA Fo 22 23 24 for patients aged ≥ 6 years with moderate-to-severe asthma with an eosinophilic phenotype10 and in rP 25 26 the EU in patients aged ≥ 6 years with severe asthma with type 2 inflammation.11 27 28 The phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959) was a 52-week, randomized, double- ee 29 30 blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of dupilumab in 31 rR 32 33 children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma.12 Dupilumab treatment 34 35 vs placebo significantly reduced severe asthma exacerbations and rapidly improved lung function in ev 36 37 children with type 2 asthma. These improvements were sustained throughout the 52-week 38 iew 39 treatment period and dupilumab was generally well-tolerated in this age group.12 40 41 42 In adult and adolescent patients with uncontrolled, moderate-to-severe asthma, dupilumab reduced 43 44 severe asthma exacerbations and improved lung function and asthma control in patients with and 45 46 without evidence of allergic asthma.13 The potential impact of a patient’s allergic status on 47 48 dupilumab efficacy has not been evaluated in children. The aim of this post hoc analysis, therefore, 49 50 was to explore the efficacy of dupilumab among patients with type 2 inflammatory asthma in 51 52 53 VOYAGE, who did and did not have evidence of allergic asthma. 54 55 56 57 58 59 60 Allergy Page 10 of 88 1 2 3 METHODS 4 5 6 Study design and oversight 7 8 Full details of the LIBERTY ASTHMA VOYAGE study have been previously published.12 In brief, 9 10 VOYAGE, a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multinational 11 12 study, assessed efficacy and safety of dupilumab in children aged 6 to 11 years with uncontrolled, 13 14 15 moderate-to-severe asthma. Data were collected by the Investigators and analyzed by the sponsors 16 17 according to a predefined statistical analysis plan. The study was conducted in accordance with the 18 19 Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice 20 21 guideline, and applicable regulatory requirements. An independent data and safety monitoring Fo 22 23 24 committee conducted blinded monitoring of patient safety data. The local institutional review board rP 25 26 or ethics committee at each study center oversaw trial conduct and documentation. Parents or 27 28 guardians of patients provided written informed consent before their participation in the trial. ee 29 30 Pediatric patients provided assent according to the Ethics Committee approved standard practice for 31 rR 32 33 pediatric patients at each participating center. 34 35 ev 36 37 Patients and interventions 38 iew 39 Children aged 6 to 11 years were eligible to participate in VOYAGE if they had physician-diagnosed 40 41 42 moderate-to-severe asthma based on the GINA 2015 guidelines.14 Full details of inclusion and 43 44 exclusion criteria have been described previously.12 Per protocol, enrolment of patients with 45 46 baseline blood eosinophils <150 cells/µl was limited to 20% of the total population. Eligible patients 47 48 were randomized to receive subcutaneous dupilumab or volume-matched placebo at the same dose 49 50 every 2 weeks (q2w) for 52 weeks in a weight-tiered fashion: those with a bodyweight of ≤30 kg at 51 52 53 randomization received dupilumab 100 mg or matched placebo while those with a bodyweight >30 54 55 kg received dupilumab 200 mg or matching placebo. The study period comprises from enrolment of 56 57 the first participant on April 21, 2017, to study completion on August 26, 2020. 58 59 60 Page 11 of 88 Allergy 1 2 3 Patients included in this sub-analysis of VOYAGE were those with type 2 asthma, defined as baseline 4 5 6 blood eosinophils ≥150 cells/µl or FeNO ≥20 ppb, patients with baseline eosinophils ≥150 cells/µl, 7 8 and patients with FeNO ≥20 ppb at baseline. These patients were further stratified according to 9 10 whether they met or did not met the criteria for evidence of allergic asthma at baseline, using 11 12 functional definitions that are narrower than definitions that would be used to identify patients with 13 14 allergic asthma in clinical practice. Evidence of allergic asthma was defined as a total serum IgE ≥30 15 16 17 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline as described previously.13 18 19 Sensitization to the following perennial aeroallergens was assessed: Dermatophagoides farinae, 20 21 Dermatophagoides pteronyssinus, Alternaria tenuis/alternata, Cladosporium herbarum, cat and dog Fo 22 23 danders, German cockroach, and Aspergillus fumigatus. 24 rP 25 26 27 28 Endpoints ee 29 30 The primary endpoint was the annualized severe exacerbation rate during the 52-week treatment 31 rR 32 period. Severe exacerbations were defined as a deterioration of asthma requiring: i) the use of 33 34 35 systemic corticosteroids for ≥3 days, or ii) hospitalization or emergency room visit because of ev 36 37 asthma, requiring systemic corticosteroids. Secondary endpoints analyzed were the change from 38 iew 39 baseline over time in both pre-bronchodilator percent predicted forced expiratory volume in 1 40 41 second (ppFEV1., key secondary endpoint) and absolute pre-bronchodilator FEV1, and change from 42 43 44 baseline in asthma control over time, as assessed using the Asthma Control Questionnaire 7-item 45 46 version Interviewer-Administered (ACQ-7-IA). The effect of treatment on specific IgE to perennial 47 48 aeroallergens over the 52-week treatment period was also examined in patients who had 49 50 sensitization to one or more aeroallergens at baseline (≥0.35 kU/L). 51 52 53 54 55 56 57 58 59 60 Allergy Page 12 of 88 1 2 3 Statistical analysis 4 5 6 Data were analyzed on an intention-to-treat (ITT) basis according to the assigned intervention, 7 8 irrespective of whether an intervention was received.12 Data for both weight-tiered doses of 9 10 dupilumab (100 or 200 mg q2w) or matched placebo were pooled for analysis. 11 12 Annualized severe exacerbation rates were analyzed using a negative binomial model, which 13 14 included the total number of events observed from randomization up to week 52 or last study 15 16 17 contact date (whichever comes earlier) as the response variable, and included treatment group, age, 18 19 baseline weight group (≤30 kg, >30 kg), region (pooled country), baseline eosinophil strata (<300 20 21 cells/µL, ≥300 cells/µL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline inhaled corticosteroid dose Fo 22 23 (ICS) level (medium- or high-dose), and number of severe exacerbations within 1 year prior to the 24 rP 25 26 study as covariates, and log-transformed standardized observation duration as an offset variable. 27 28 Change from baseline in ppFEV1 and absolute pre-bronchodilator FEV1 were analyzed using a mixed- ee 29 30 effect model with repeated measures (MMRM) approach, which used, as appropriate, change from 31 rR 32 baseline in ppFEV1 or pre-bronchodilator FEV1 up to Week 52 as the response variable, and included 33 34 35 pooled treatment groups, baseline weight groups, region, ethnicity, baseline eosinophil strata, ev 36 37 baseline FeNO level, baseline ICS dose level, visit, treatment by visit interaction, baseline value of the 38 iew 39 respective endpoint (percentage predicted or absolute FEV1), and baseline-by-visit interaction as 40 41 covariates. The change from baseline in pre-bronchodilator FEV1 up to week 52 was derived using 42 43 44 MMRM model with all the covariates mentioned above along with age, sex, and baseline height. 45 46 Change from baseline in ACQ-7-IA score over time was derived from an MMRM model with change 47 48 from baseline in ACQ-7-IA score up to Week 52 as the response variable and pooled treatment 49 50 groups, age, baseline weight group, region, baseline eosinophil strata, baseline FeNO level, baseline 51 52 53 ICS dose level, visit, treatment-by-visit interaction, baseline ACQ-7-IA score, and baseline-by-visit 54 55 interaction as covariates. 56 57 Change from baseline in total IgE and specific IgE over time were analyzed using the Wilcoxon rank- 58 59 sum test for patients in the safety population. 60 Page 13 of 88 Allergy 1 2 3 4 5 6 7 8 RESULTS 9 10 Study patients 11 12 350 patients randomized in VOYAGE (86% of the overall VOYAGE ITT population) had type 2 asthma 13 14 15 at baseline, defined as baseline eosinophil count of ≥150 cells/µl or FeNO ≥20ppb, and were 16 17 included in this analysis. Of these, 261 (75%) met the criteria used to define evidence of allergic 18 19 asthma: placebo n=81, dupilumab n=180. The remaining 89 (25%) patients (placebo n=33, 20 21 dupilumab n=56) did not meet these criteria (IgE <30 IU/mL or no positive specific IgE among the Fo 22 23 24 aeroallergens tested). In the subgroup of patients with blood eosinophils ≥150 cells/µl, 251 met the rP 25 26 criteria for allergic asthma (placebo n=79, dupilumab n=172), whereas the remaining 80 (placebo 27 28 n=29, dupilumab n=51) did not. In the subgroup of patients with FeNO ≥20ppb, 176 met the criteria ee 29 30 for allergic asthma (placebo n=53, dupilumab n=123), whereas the remaining 27 (placebo n=9, 31 rR 32 33 dupilumab n=18) did not. 34 35 The baseline characteristics of patients with type 2 inflammation with and without evidence of ev 36 37 allergic asthma are provided in Table 1. Baseline characteristics were similar across treatment arms 38 iew 39 and subgroups. Patients with evidence of allergic asthma at baseline had higher median levels of 40 41 42 total serum IgE than those without evidence of allergic asthma (with evidence of allergic asthma: 43 44 569 [placebo] and 680 [dupilumab] IU/mL; without evidence of allergic asthma: 69.5 [placebo] and 45 46 113.5 [dupilumab] IU/mL). 47 48 49 50 Annualized rate of severe asthma exacerbations 51 52 53 Overall, dupilumab reduced annualized severe exacerbation rates relative to placebo in patients 54 55 with and without evidence of allergic asthma. In the subgroup of patients with type 2 asthma and 56 57 evidence of allergic asthma, the adjusted annualized severe asthma exacerbation event rate was 58 59 0.24 (95% confidence interval [CI], 0.16 to 0.36) in the dupilumab group vs 0.62 (95% CI, 0.40 to 60 Allergy Page 14 of 88 1 2 3 0.94) in the placebo group (relative risk reduction [RRR] vs. placebo of 62% (95% CI, 39% to 76%; 4 5 6 p<.0001) (Figure 1). In the subgroup of patients with type 2 asthma with no evidence of allergic 7 8 asthma, the adjusted annualized severe asthma exacerbation event rates were 0.39 (95% CI, 0.23 to 9 10 0.68) vs 0.80 (95% CI, 0.47 to 1.37) for dupilumab and placebo groups, respectively (RRR vs. placebo 11 12 of 51% (95% CI, 0 to 76; p=.0494). There was no statistical evidence that the treatment effect of 13 14 dupilumab on exacerbations varied by allergic asthma status (pinteraction=0.6011). 15 16 17 Similar results were seen in the subgroup of patients with ≥150 eosinophils/µL, irrespective of 18 19 allergic phenotype, and in patients with ≥20 ppb FeNO and allergic asthma at baseline (Figure S1). 20 21 Patient numbers were very low in the subgroup of patients with ≥20 ppb FeNO without evidence of Fo 22 23 allergic asthma (n=9 [placebo] and n=18 [dupilumab]), therefore statistical comparisons were not 24 rP 25 26 possible in this subgroup, but trends were similar. 27 28 ee 29 30 Lung function 31 rR 32 Percentage of predicted pre-bronchodilator FEV1 33 34 35 In the sub-group of patients with type 2 asthma and evidence of allergic asthma, dupilumab ev 36 37 significantly improved pre-bronchodilator ppFEV1 from baseline compared with matched placebo 38 iew 39 (Figure 2). Significant improvements vs placebo were observed as early as the first assessment at 40 41 Week 2, and these persisted throughout the 52-week treatment period, with an LS mean difference 42 43 44 vs placebo of 5.71 (95% CI, 2.02 to 9.39, p=.003), and 9.27 (95% CI, 5.16 to 13.37, p<.0001), at Weeks 45 46 12 and 52, respectively. In the sub-group of type 2 patients without evidence of allergic asthma, 47 48 numerical improvements in ppFEV1 compared to placebo were observed, with an LS mean difference 49 50 vs placebo of 4.53 (95% CI, -1.30 to 10.35, p=.126), and 3.93 (95% CI, -2.41 to 10.26, p=.221), at 51 52 53 Weeks 12 and 52, respectively (Figure 2). Significant improvements compared to placebo were 54 55 observed at Week 4, 6, and 48 (p<.05) but at all other time points the improvements were numerical 56 57 and not significant. 58 59 60 Page 15 of 88 Allergy 1 2 3 Similar results were seen in the subgroups of patients with ≥150 eosinophils/µL and patients with 4 5 6 ≥20 ppb FeNO at baseline, except in those with elevated FeNO without evidence of allergic asthma, 7 8 where no differences were found between dupilumab and placebo (Figure S2). 9 10 The p-values for interaction between treatment arm assignment and allergic asthma status were 11 12 0.605at Week 12 and 0.132 at Week 52 for the change from baseline in ppFEV1 endpoint. 13 14 15 16 17 18 19 Absolute pre-bronchodilator FEV1 20 21 In the sub-group of patients with type 2 asthma and evidence of allergic asthma, dupilumab Fo 22 23 significantly improved the absolute pre-bronchodilator FEV1 from baseline compared with matched 24 rP 25 26 placebo, with improvements observed as early as Week 2 and sustained over the treatment period 27 28 (Figure 3). At Week 2, the LS mean difference in pre-bronchodilator FEV1 improvement over baseline ee 29 30 vs placebo was 0.10L (95% CI, 0.03 to 0.17, p=.003), which further increased to 0.12L (95% CI, 0.04 to 31 rR 32 0.19, p=.002) at Week 12 and 0.20L (95% CI, 0.12 to 0.29, p<.0001) at Week 52. Similar to the 33 34 35 findings for the ppFEV1 endpoint, in patients without allergic asthma, the magnitude of ev 36 37 improvements in absolute pre-bronchodilator FEV1 relative to placebo was lower than in patients 38 iew 39 with allergic asthma, with an LS mean difference of −0.002L (95% CI, −0.10 to 0.10, p=.98) at Week 2 40 41 and numerical improvements over baseline of 0.07L (95% CI, −0.04 to 0.18, p=.184) at Week 12, and 42 43 44 0.07L (95% CI, −0.06 to 0.21, p=.266) at Week 52. 45 46 The p-values for interaction between treatment arm assignment and allergic asthma status were 47 48 0.35 at Week 12 and 0.06 at Week 52 for the change from baseline in absolute FEV1 endpoint. 49 50 51 52 53 Asthma control (ACQ-7-IA scores) 54 55 Dupilumab significantly improved ACQ-7-IA scores compared with placebo in patients with evidence 56 57 of allergic asthma. Improvements were rapid, with significant improvements vs placebo evident as 58 59 early as the first assessment at Week 2, and these improvements were sustained throughout the 60 Allergy Page 16 of 88 1 2 3 study remaining significant vs placebo at all timepoints (Figure 4). At Week 24, the LS mean 4 5 6 difference vs placebo was −0.41 (95% CI, −0.61 to −0.22, p<.0001). In the subgroup of type 2 patients 7 8 without evidence of allergic asthma, little difference between treatments was observed throughout 9 10 the treatment period (Figure 4), with an LS mean difference vs placebo of −0.12 (95% CI, −0.47 to 11 12 −0.24, p=.522) at Week 24. 13 14 The p-values for interaction between treatment arm assignment and allergic asthma status were 15 16 17 0.11 at Week 24 and 0.14 at Week 52 for the change from baseline in ACQ-7-IA endpoint. 18 19 20 21 Total IgE Fo 22 23 Dupilumab reduced levels of total IgE over time in patients with type 2 inflammatory asthma, 24 rP 25 26 irrespective of their allergic status (Figure S3 of this article’s Online Repository). In patients with 27 28 evidence of an allergic asthma phenotype, median concentrations of total serum IgE were reduced ee 29 30 by 78.8% by Week 52, vs a 0.9% increase in patients on placebo (p<.0001). In patients without 31 rR 32 evidence of an allergic asthma phenotype, even though baseline concentrations were much lower, 33 34 35 dupilumab still reduced median IgE levels by 77.8% over the 52-week treatment duration, vs a 7.8% ev 36 37 increase in patients on placebo (p<.0001) (Figure S3). 38 iew 39 The p-values for interaction between treatment arm assignment and allergic asthma status were 40 41 0.70 at Week 24 and 0.13 at Week 52 for the percent change from baseline in total IgE levels over 42 43 44 time endpoint. 45 46 47 48 Perennial aeroallergen-specific IgE 49 50 The effect of treatment on allergen-specific IgE levels in patients who were positive (≥0.35 kU/L) at 51 52 53 baseline for one or more of the perennial aeroallergens examined is presented in Figure S4 of this 54 55 article’s Online Repository. In dupilumab-treated patients, substantial reductions from baseline over 56 57 the 52-week treatment period were observed in allergen-specific IgE levels to Dermatophagoides 58 59 farinae, Dermatophagoides pteronyssinus, and German cockroach both in patients with mono- 60 Page 17 of 88 Allergy 1 2 3 allergen sensitization to the respective aeroallergen and in those with multi-allergen sensitization 4 5 6 (ie, patients with allergen-specific IgE ≥0.35 kU/L for more than one aeroallergen). Similar reductions 7 8 over time were observed in multi-allergen-sensitized patients treated with dupilumab who were 9 10 allergic to dog and cat dander and Alternaria tenuis/alternata. However, no differences between 11 12 dupilumab and placebo were observed in patients who were mono-sensitized to Cladosporium 13 14 herbarum and Alternaria tenuis/alternata. Dupilumab treatment did not affect serum IgE levels to 15 16 17 Cladosporium herbarum/hormodendrum or Aspergillus fumigatus whether in mono- or multi- 18 19 allergen sensitized patients. No change was observed with placebo treatment on specific IgE levels 20 21 to any of the 8 perennial aeroallergens assessed. Fo 22 23 24 rP 25 26 Safety 27 28 In the primary analysis,12 dupilumab was well tolerated with an acceptable safety profile. In this ee 29 30 analysis, the incidence of treatment emergent adverse events was balanced across treatment groups 31 rR 32 (Table S1). 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 18 of 88 1 2 3 DISCUSSION 4 5 6 In this post hoc analysis of LIBERTY ASTHMA VOYAGE, conducted in children aged 6 to 11 years with 7 8 moderate-to-severe asthma, dupilumab significantly reduced the rate of severe exacerbations and 9 10 improved lung function (ppFEV1 and absolute FEV1) and asthma control (ACQ-7-IA scores) in patients 11 12 with type 2 asthma (baseline blood eosinophils ≥150 cells/µL or ≥20 ppb FeNO) and evidence of 13 14 15 allergic asthma, with similar trends observed in patients without evidence of allergic asthma. As 16 17 reported previously, similar treatment effects were observed in QUEST in adult and adolescent 18 19 patient populations with type 2 asthma irrespective of their allergic status at baseline.13 The 20 21 improvements in lung function and asthma control in the subgroup with evidence of allergic asthma Fo 22 23 24 were rapid, observed by Week 2, and were sustained throughout the treatment period. Dupilumab rP 25 26 vs placebo also improved lung function in patients with type 2 without evidence of allergic asthma, 27 28 although these differences were not significant at most time points. These findings are consistent ee 29 30 with the efficacy profile seen in QUEST patients with uncontrolled, moderate-to-severe asthma 31 rR 32 33 where clinical efficacy with regard to exacerbation rates, lung function, and asthma control was 34 35 observed irrespective of evidence of allergic status: dupilumab vs placebo significantly reduced ev 36 37 exacerbation rates and improved lung function and asthma control for both patients with and 38 iew 39 without evidence of allergic asthma, at most time points.13 40 41 42 The results for annualized exacerbation rates support the efficacy of dupilumab in children with type 43 44 2 asthma irrespective of evidence of allergic asthma, highlighting that suppression of IL-4 and IL-13 45 46 leads to clinically meaningful improvements in type 2 inflammatory asthma irrespective of the 47 48 patient’s allergic status. Given that 75% of children with type 2 asthma included in this analysis also 49 50 had evidence of allergic asthma, determining the efficacy of dupilumab in this patient population is 51 52 53 important, particularly since allergens are known to trigger asthma attacks in 60 to 90% of children.15 54 55 In the small population that did not have evidence of allergic asthma despite having evidence of type 56 57 2 inflammation, numerical improvements in lung function, were observed. Differences vs placebo in 58 59 FEV1 and ACQ-7-IA scores were not significant at most time points, however, small patient numbers 60 Page 19 of 88 Allergy 1 2 3 in this post-hoc analysis may provide inadequate statistical power. Additionally, in the subgroup 4 5 6 without evidence of allergic asthma, dupilumab improved absolute pre-BD FEV1 over baseline by 330 7 8 mL at Week 52; Santanello et al. have previously reported that patients perceive improvements in 9 10 pre-BD FEV1 >230 mL as an indication of treatment success.16 11 12 The steady and sustained decrease in total IgE over the 52-week treatment period observed in 13 14 dupilumab-treated patients with evidence of allergic asthma, is consistent with the mechanism of 15 16 17 action of dupilumab with reductions even greater than in QUEST,17 and was also reported in the 18 19 overall VOYAGE population.12 In contrast, IgE levels in placebo patients without evidence of allergic 20 21 asthma, who already had lower levels at baseline compared with the population with evidence of Fo 22 23 allergic asthma, remained stable or even rose slightly relative to baseline. Dupilumab treatment also 24 rP 25 26 reduced allergen-specific serum IgE levels against 6 of the 8 perennial aeroallergens tested. Why 27 28 dupilumab did not affect specific IgE levels in two of the three fungal allergens tested (Cladosporium ee 29 30 herbarum/hormodendrum and Aspergillus fumigatus) but was effective at reducing IgE directed 31 rR 32 against Alternaria tenuis/alternata is presently unclear. In addition, reductions for IgE against three 33 34 35 allergens were only observed in patients with multi-allergen sensitizations, who had higher baseline ev 36 37 concentrations of total serum IgE compared with those who had only one (mono) sensitization or 38 iew 39 non-sensitized patients. Since polysensitization to ≥2 food and/or aeroallergens is a known risk 40 41 factor for the development of asthma,18 it may be the case that patients who exhibited multi- 42 43 44 allergen sensitization may have been more responsive to suppression of type 2 inflammation. 45 46 A limitation of this study was the post hoc nature of the analyses, as the study was not primarily 47 48 designed or powered to investigate differences between type 2 patients with or without evidence of 49 50 allergic asthma. As only 25% of type 2 patients had no evidence of allergic asthma, and the study 51 52 53 design included a 2:1 dupilumab: placebo treatment allocation, the proportion of patients without 54 55 evidence of allergic asthma receiving placebo was less than 10% of the total population evaluated. 56 57 Therefore, although findings in the population with evidence of allergic asthma are robust, the 58 59 60 Allergy Page 20 of 88 1 2 3 inconsistent statistical significance observed across efficacy variables in the non-allergic population 4 5 6 should be interpreted with caution. 7 8 Secondly, the racial distribution of patients included in the study also potentially limits extrapolation 9 10 across populations. The vast majority of patients were white (>85% in each analysis group), and 11 12 therefore results may differ in more racial diverse populations. 13 14 Another limitation was how allergic status was identified. The allergic status was identified post-hoc 15 16 17 to a defined set of common aeroallergens, percutaneous allergy skin testing was not performed and 18 19 allergic reactions to the panel of aeroallergens were based solely on specific IgE levels at a baseline 20 21 of ≥0.35 kU/L. Furthermore, as no pollen or spore counts or home allergen levels were performed Fo 22 23 during the study to assess the amount of allergen present in individual participants’ homes and/or 24 rP 25 26 geographic areas, it is not possible to ascertain the degree to which each patient was exposed to 27 28 these allergens. ee 29 30 A further limitation is the definition of allergic asthma used in this study, as it allows that the 31 rR 32 subgroup of patients without evidence of allergic asthma may have had either IgE ≥30 IU/mL or ≥1 33 34 35 positive specific allergen. Also, some patients without evidence of allergic asthma may have been ev 36 37 sensitized to allergens not included in the panel. Further studies to investigate the efficacy of 38 iew 39 dupilumab treatment more specifically in children with moderate-to-severe type 2 asthma with or 40 41 without evidence of allergic asthma might be needed to help physicians optimally tailor treatment in 42 43 44 this patient population. 45 46 47 48 The majority of children aged 6 to 11 years with moderate-to-severe asthma from VOYAGE 49 50 presented characteristics of type 2 inflammation at baseline (elevated blood eosinophils or FeNO). 51 52 53 Among the VOYAGE patients with type 2 asthma, the majority also exhibited evidence of allergic 54 55 asthma. Dupilumab vs matched placebo significantly reduced severe exacerbation rates irrespective 56 57 of evidence of allergic asthma at baseline. Improvements in lung function parameters were also 58 59 observed but to a lower degree in patients without evidence of allergic asthma. 60 Page 21 of 88 Allergy 1 2 3 Taken together, these data support the role of dupilumab in treating pediatric patients aged 6 to 11 4 5 6 years with moderate-to-severe asthma, regardless of evidence of allergic asthma. However, the 7 8 patient cohort without evidence of allergic asthma was small as mentioned earlier, thus the data 9 10 should be interpreted with caution. Patients with evidence of allergic asthma demonstrated clinically 11 12 meaningful responses to dupilumab treatment, supporting the role of IL-4 and IL-13, and thus type 2 13 14 inflammation, as key drivers of certain patients with allergic asthma. The position of dupilumab 15 16 17 among other biologics in severe allergic pediatric asthma remains to be determined by comparative 18 19 studies, aimed at identifying the most appropriate biomarkers of responsiveness.19,20 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 22 of 88 1 2 3 REFERENCES 4 5 6 1. Licari A, Manti S, Castagnoli R, Leonardi S, Marseglia GL. Measuring inflammation in paediatric 7 8 severe asthma: biomarkers in clinical practice. Breathe (Sheff). 2020 Mar;16(1):190301. 9 10 2. Zoratti EM, Krouse RZ, Babineau DC, et al. Asthma phenotypes in inner-city children. J Allergy 11 12 Clin Immunol. 2016 Oct;138(4):1016-1029. 13 14 15 3. Canonica GW, Blasi F, Crimi N, et al. Defining type 2 asthma and patients eligible for dupilumab 16 17 in Italy: a biomarker-based analysis. Clin Mol Allergy. 2021 May 21;19(1):5. 18 19 4. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 20 21 2015;15(1):57-65 Fo 22 23 24 5. Wenzel SE. Emergence of Biomolecular Pathways to Define Novel Asthma Phenotypes. Type-2 rP 25 26 Immunity and Beyond. Am J Respir Cell Mol Biol. 2016 Jul;55(1):1-4. 27 28 6. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2022. ee 29 30 Accessed October 24, 2022. www.ginasthma.org 31 rR 32 33 7. Macdonald LE, Karow M, Stevens S, et al. Precise and In Situ Genetic Humanization of 6 Mb of 34 35 Mouse Immunoglobulin Genes. Proc Natl Acad Sci U S A. 2014;111:5147-5152. ev 36 37 8. Murphy AJ, Macdonald LE, Stevens S, et al. Mice With Megabase Humanization Of Their 38 iew 39 Immunoglobulin Genes Generate Antibodies As Efficiently As Normal Mice. Proc Natl Acad Sci U 40 41 42 S A. 2014;111:5153-8. 43 44 9. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal 45 46 drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50. 47 48 10. DUPIXENT® (dupilumab). Highlights of Prescribing Information . US Food and Drug 49 50 Administration. Accessed October 24, 2022. 51 52 53 https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf 54 55 11. DUPIXENT® (dupilumab). Summary of Product Characteristics. European Medicines Agency . 56 57 Accessed October 24, 2022. https://www.ema.europa.eu/en/documents/product- 58 59 information/dupixent-epar-product-information_en.pdf 60 Page 23 of 88 Allergy 1 2 3 12. Bacharier LB, Maspero JF, Katelaris CH, et al. Dupilumab in Children with Uncontrolled 4 5 6 Moderate-to-Severe Asthma. N Engl J Med. 2021 November 2021; 385:2230-2240; 7 8 13. Corren J, Castro M, O'Riordan T, et al. Dupilumab Efficacy in Patients with Uncontrolled, 9 10 Moderate-to-Severe Allergic Asthma. J Allergy Clin Immunol Pract. 2020 Feb;8(2):516-526. 11 12 14. Global strategy for asthma management and prevention. Updated 2015. Accessed October 24, 13 14 2022. https://ginasthma.org/wp-content/uploads/2016/01/GINA_Pocket_2015.pdf. Accessed 15 16 17 October 2021. 18 19 15. Do DC, Zhao Y, Gao P. Cockroach allergen exposure and risk of asthma. Allergy. 2016 20 21 Apr;71(4):463-474. Fo 22 23 16. Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes 24 rP 25 26 for asthma measures in a clinical trial? Eur Respir J. 1999 Jul;14(1):23-27. 27 28 17. Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe ee 29 30 Uncontrolled Asthma. N Engl J Med 2018; 378:2486-2496. 31 rR 32 18. Biagini Myers JM, Schauberger E, He H, et al. A Pediatric Asthma Risk Score to better predict 33 34 35 asthma development in young children. J Allergy Clin Immunol. 2019 May;143(5):1803-1810.e2. ev 36 37 19. Charriot J, Maravic M, Huguet M, Vachier I, Suehs C, Bourdin A. "Real-life" management of 38 iew 39 patients with severe asthma in the biologics era: Can we do better? World Allergy Organ J. 2021 40 41 Mar 18;14(4):100528. 42 43 44 20. Yu L, Zhang H, Pan J, Ye L. Pediatric usage of Omalizumab: A promising one. World Allergy Organ 45 46 J. 2021 Dec 11;14(12):100614. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 24 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Data sharing statement 18 19 20 Qualified researchers may request access to patient-level data and related study documents 21 Fo 22 including the clinical study report, study protocol with any amendments, blank case report form, 23 24 statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study rP 25 26 27 documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s 28 ee 29 data sharing criteria, eligible studies, and process for requesting access can be found at: 30 31 http://www.vivli.org/. rR 32 33 34 35 ev 36 Acknowledgments 37 38 iew 39 This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov 40 41 Identifier: NCT02948959. Medical writing/editorial assistance was provided by Natalia Crespo, of 42 43 44 Excerpta Medica, and was funded by Sanofi and Regeneron Pharmaceuticals, Inc., according to the 45 46 Good Publication Practice guideline. 47 48 49 50 51 52 Author contributions: 53 54 LBB, JFM, AF acquired data. DJL, MH, RG, MD, SS, JAJ-N, YD, PJR contributed to the conception and 55 56 57 design of the study. ND did statistical analyses. All authors participated in the interpretation of the 58 59 data, provided critical feedback and final approval for submission, and took responsibility for the 60 Page 25 of 88 Allergy 1 2 3 accuracy, completeness, and protocol adherence of data and analyses. All investigators had 4 5 6 confidentiality agreements with the sponsors. 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 26 of 88 1 2 3 TABLES AND FIGURES 4 5 6 Table 1. Baseline characteristics of VOYAGE patients with type 2 asthma with or without evidence of allergic asthma a b 7 8 Type 2 with evidence of allergic asthma Type 2 without evidence of allergic asthma 9 10 11 Fo Placebo Dupilumab Placebo Dupilumab 12 13 Characteristic rP 14 n=81 n=180 n=33 n=56 15 ee 16 17 Median age (min-max), years 9 (6–11) 9 (6–11) 8 (6–11) 9 (6–11) 18 rR 19 20 Male sex, n (%) 59 (72.8) 118 (65.6) 19 (57.6) 34 (60.7) ev 21 22 Race iew 23 24 25 White 69 (85.2) 155 (86.1) 33 (100) 53 (94.6) 26 27 28 Black/of African descent 5 (6.2) 9 (5.0) 0 (0) 0 (0) 29 30 31 Asian 0 (0) 2 (1.1) 0 (0) 0 (0) 32 33 34 American Indian or Alaska Native 0 (0) 1 (0.6) 0 (0) 0 (0) 35 36 37 Native Hawaiian or Other Pacific Islander 0 (0) 0 (0) 0 (0) 0 (0) 38 39 40 41 42 43 44 45 46 Page 27 of 88 Allergy 1 2 3 4 Other 7 (8.6) 13 (7.2) 0 (0) 3 (5.4) 5 6 Ethnicity 7 8 9 Hispanic or Latino 37 (45.7) 76 (42.2) 14 (42.4) 28 (50.0) 10 11 Fo 12 Not Hispanic or Latino 44 (54.3) 104 (57.8) 19 (57.6) 28 (50.0) 13 rP 14 15 BMI, mean (SD), kg/m2 18.70 (3.36) 18.66 (3.62) 19.81 (5.05) 18.41 (3.17) ee 16 17 18 Age at asthma onset, mean (SD), years 3.8 (2.7) 3.2 (2.5) 3.8 (2.4) 3.3 (2.5) rR 19 20 ev 21 Number of exacerbations in the past year, 22 2.10 (1.26) 2.64 (2.79) 2.36 (2.12) 2.52 (1.73) iew 23 mean (SD) 24 25 26 Pre-bronchodilator FEV1, mean (SD), L 1.54 (0.46) 1.48 (0.39) 1.49 (0.45) 1.47 (0.38) 27 28 29 Pre-bronchodilator ppFEV1, mean (SD), % 78.62 (14.97) 76.67 (14.56) 77.73 (13.51) 80.84 (13.42) 30 31 ACQ-7-IA score, mean (SD) 2.10 (0.73) 2.17 (0.74) 2.15 (0.85) 2.06 (0.57) 32 33 34 Blood eosinophil count, median (Q1–Q3), cells/µL 490.0 (320.0–710.0) 575.0 (360.0–800.0) 360.0 (210.0–470.0) 290.0 (185.0–605.0) 35 36 37 FeNO, ppb, median (Q1–Q3) 25.0 (16.0–39.0) 29.5 (17.0–47.0) 14.5 (9.0–20.0) 13.00 (8.0–23.0) 38 39 40 41 42 43 44 45 46 Allergy Page 28 of 88 1 2 3 4 Total IgE, IU/mL, median (Q1–Q3) 569.0 (270.0–1013.0) 680.0 (348.0–1462.5) 69.5 (26.5–312.5) 113.5 (32.0–286.0) 5 6 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 7 8 with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. Abbreviations: ACQ-7-IA, Asthma Control Questionnaire 7-item version 9 10 11Interviewer-Administered; BMI, body mass index; FeNO, fractional exhaled nitric oxide; ppb, parts per billion; ppFEV1, percentage of predicted forced expiratory volume in 1 second; Fo 12 13SD, standard deviation. rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Page 29 of 88 Allergy 1 2 3 Figure 1. Effect of dupilumab on annualized severe exacerbation rates in pediatric patients with type 2 asthmaa with or without evidence of allergic asthmab 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 35*P<.05; ***P<.001 vs placebo. 36 37aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 38 39with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 40 41 42 43 44 45 46 Allergy Page 30 of 88 1 2 3 Figure 2. Change from baseline over time in pre-bronchodilator ppFEV in patients with type 2 asthmaa with or without evidence of allergic asthmab 1 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31*P<.05, **P<.01, ***P<.001 vs placebo. 32 33 Type 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. The allergic asthma phenotype is defined as patients a b 34 35with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline 36 37 38 39 40 41 42 43 44 45 46 Page 31 of 88 Allergy 1 2 3 Figure 3. Change from baseline over time in absolute pre-bronchodilator FEV in patients with type 2 asthmaa with or without evidence of allergic asthmab 1 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30*P<.05, **P<.01, ***P<.001 vs placebo. 31 32 Type 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. The allergic asthma phenotype is defined as patients a b 33 34with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline 35 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 32 of 88 1 2 3 Figure 4. Change from baseline over time in ACQ-7-IA score in patients with type 2 asthmaa with or without evidence of allergic asthmab 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30*P<.05, **P<.01, ***P<.001 vs placebo. 31 32aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 33 34 with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 35 36 37 38 39 40 41 42 43 44 45 46 Page 33 of 88 Allergy 1 2 3 Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or 4 5 6 without evidence of allergic asthma 7 8 Short title: Dupilumab in children with T2 asthma and allergy 9 10 11 12 13 Nikolaos G Papadopoulos, MD, PhD1, Stanley J Szefler MD2, Leonard B Bacharier, MD3, Jorge F 14 15 Maspero, MD4, Christian Domingo, MD5, Alessandro Fiocchi MD6, Jason K Lee, MD7, Nadia Daizadeh, 16 17 PhD8, David J Lederer, MD9, Megan Hardin, MD8, Rebecca Gall, MD9, Michel Djandji, MD8, Shahid 18 19 Siddiqui, MD9, Juby A Jacob-Nara, MD, MPH, DHSc10, Yamo Deniz, MD9, Paul J Rowe, MD, ATSF10 20 21 Fo 22 23 1The 2nd Pediatric Clinic, University of Athens, Greece; 2The University of Colorado School of 24 rP 25 26 Medicine and Children’s Hospital Colorado, Department of Pediatrics, The Breathing Institute, 27 28 Aurora, CO, USA; 3The Monroe Carell Jr Children’s Hospital at Vanderbilt University Medical Center, ee 29 30 31 Nashville, TN, USA; 4The Fundación CIDEA, Buenos Aires, Argentina; 5The Corporació Sanitària Parc rR 32 33 Taulí, Sabadell, Autonomous University of Barcelona, Barcelona, Spain; 6The Bambino Gesù 34 35 Children's Hospital, IRCCS, Rome, Italy, 7Evidence Based Medical Educator and Toronto Allergy and ev 36 37 Asthma Clinic, Toronto, ON, Canada, 8Sanofi, Cambridge, MA, USA; 9Regeneron Pharmaceuticals, 38 iew 39 Inc., Tarrytown, NY, USA; 10Sanofi, Bridgewater, NJ, USA. 40 41 42 43 44 Corresponding author: Nikolaos G Papadopoulos 45 46 Address: University of Athens, 41 Fidippidou street, Athens, Attica 11527, Greece 47 48 Phone: +30 210 7776964 49 50 51 Email: ngp@allergy.gr 52 53 54 55 Support statement: Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov 56 57 identifier: NCT02948959 58 59 60 Allergy Page 34 of 88 1 2 3 Manuscript Stats 4 5 6  Target journal: Allergy 7  Abstract: 250/250 8 9  Main text: 3635/3500 10 11  Figures and/or tables: 1 Table and 4 Figures/6 total max. 12  References: 18/no limit given 13 14  Supplementary materials: 2 Figures 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 35 of 88 Allergy 1 2 3 Highlights: 4 5 6  In type 2 patients, dupilumab vs placebo significantly reduced exacerbation rates 7 irrespective of allergic status 8 9  Significant improvements vs placebo in lung function and asthma control were observed 10 11 throughout the treatment period in patients with evidence of allergic asthma 12  In the small population of patients without evidence of allergic asthma, numerical 13 14 improvements in lung function and asthma control were observed 15 16 17 18 19 20 Graphical abstract: 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 36 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 37 of 88 Allergy 1 2 3 Disclosure of potential conflict of interest: 4 5 6 Papadopoulos NG: AstraZeneca, Boehringer Ingelheim, GSK, HAL Allergy, Menarini, Mylan, Novartis, 7 8 Nutricia, OM Pharma, Regeneron Pharmaceuticals, Inc., Sanofi – speaker, advisory board member. 9 10 Szefler SJ: AstraZeneca, GSK, Moderna, OM Pharma, Propeller Health, Regeneron Pharmaceuticals, 11 12 Inc., Sanofi – consultant fees paid to the university. 13 14 Bacharier LB: AstraZeneca, GSK, Regeneron Pharmaceuticals, Inc., Sanofi – speaker fees; Cystic 15 16 17 Fibrosis Foundation, Vertex, AstraZeneca, DBV Technologies – data and safety monitoring board; 18 19 NIH, Sanofi – research support. 20 21 Maspero JF: AstraZeneca, Sanofi – consultant; GSK, Menarini, Novartis, Uriach – speaker fees; Fo 22 23 Novartis – research grants. 24 rP 25 26 Domingo C: ALK, Allergy Therapeutics, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, 27 28 Ferrer Pharma, GSK, HAL Allergy, Inmunotek, Menarini, Novartis, Pfizer, sanofi-aventis, Stallergenes ee 29 30 Greer, Takeda, Teva – travel and speaker fees. 31 rR 32 Fiocchi AG: Danone SA, Hipp GmbH, Abbott SA, Novartis, Ferrero – speaker, advisory board member. 33 34 35 Sanofi, Novartis, Ferrero – research grants. ev 36 37 Lee JK: AstraZeneca, GSK, Novartis, Regeneron, Genetech, Sanofi, ALK, Medexus, Miravo, Bausch 38 iew 39 Health, Takeda, CSL – speaking fees. Research funding and clinical trials from AstraZeneca, GSK, 40 41 Takeda, Regeneron, Novartis, Genentech, Sanofi. 42 43 44 Daizadeh N: Sanofi – former employee, may hold stock and/or stock options in the company. 45 46 Hardin M, Jacob-Nara JA, Djandji M, Rowe PJ: Sanofi − employees, may hold stock and/or stock 47 48 options in the company. 49 50 Lederer DJ, Deniz Y, Gall R, Siddiqui S: Regeneron Pharmaceuticals, Inc. − employees and share 51 52 53 54 55 56 57 58 59 60 Allergy Page 38 of 88 1 2 3 ABSTRACT 4 5 6 Background: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 7 8 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks 9 10 the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of 11 12 VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6–11 years with type 2 13 14 15 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30IU/mL and ≥1 16 17 perennial aeroallergen-specific IgE ≥0.35kU/L). 18 19 Methods: Annualized rate of severe exacerbations (AER) and changes in pre-bronchodilator (Pre-BD) 20 21 forced expiratory volume in one second (FEV1), percent-predicted pre-BD FEV1 (ppFEV1), and Asthma Fo 22 23 24 Control Score (ACQ)-7 were assessed during the treatment period. rP 25 26 Results: 350 children (261 with and 89 without evidence of allergic asthma) were included. 27 28 Dupilumab vs placebo significantly reduced AER in patients with (0.24 vs 0.62, relative risk ee 29 30 reduction[RRR]: 62% [95% CI, 39–76], p<.0001) and without (0.39 vs 0.80, RRR: 51% [95% CI, 0–76], 31 rR 32 33 p<.05) evidence of allergic asthma. Significant improvements in ppFEV1, pre-bronchodilator FEV1, 34 35 and ACQ-7 scores were observed in dupilumab vs placebo throughout the treatment period in ev 36 37 patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical 38 iew 39 improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. 40 41 42 Conclusion: Dupilumab vs placebo reduced asthma exacerbations in children with type 2 asthma 43 44 irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. 45 46 Significant improvement in asthma control was observed in patients with evidence of allergic 47 48 asthma, but not in those without. 49 50 51 52 53 Keywords 54 55 Asthma; allergic; exacerbation; percentage predicted FEV1, dupilumab 56 57 58 59 60 Page 39 of 88 Allergy 1 2 3 Abbreviations 4 5 6 ACQ-7-IA, Asthma Control Questionnaire 7-item version Interviewer-Administered 7 8 AER, adjusted annualized severe exacerbation rates 9 10 FeNO, fractional exhaled nitric oxide FeNO 11 12 FEV1, forced expiratory volume in 1 second 13 14 GINA, Global Initiative for Asthma 15 16 17 ICS, inhaled corticosteroids 18 19 IgE, immunoglobulin E 20 21 IL, interleukin Fo 22 23 ITT, intention to treat 24 rP 25 26 MMRM, mixed-effect model with repeated measures 27 28 ppb, parts per billion ee 29 30 ppFEV1, percentage of predicted forced expiratory volume in 1 second 31 rR 32 q2w, every 2 weeks 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 40 of 88 1 2 3 BACKGROUND 4 5 6 Type 2 inflammation is the most common type of inflammation seen in asthma in children1,2 and is 7 8 reflected by elevated levels of peripheral or sputum eosinophils, fractional exhaled nitric oxide 9 10 (FeNO), and/or IgE, and includes asthma characterized as eosinophilic and/or allergic.3-5 Allergic 11 12 asthma, traditionally considered to be driven by an IgE-mediated process, is a subtype of type 2 13 14 15 inflammation.6 16 17 Dupilumab, a fully human monoclonal antibody,7,8 blocks the shared receptor component for 18 19 interleukin (IL)-4 and IL-13, type 2 inflammatory cytokines implicated in numerous allergic diseases 20 21 ranging from asthma to atopic dermatitis,9 thus inhibiting their signaling. It is approved in the USA Fo 22 23 24 for patients aged ≥ 6 years with moderate-to-severe asthma with an eosinophilic phenotype10 and in rP 25 26 the EU in patients aged ≥ 6 years with severe asthma with type 2 inflammation.11 27 28 The phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959) was a 52-week, randomized, double- ee 29 30 blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of dupilumab in 31 rR 32 33 children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma.12 Dupilumab treatment 34 35 vs placebo significantly reduced severe asthma exacerbations and rapidly improved lung function in ev 36 37 children with type 2 asthma. These improvements were sustained throughout the 52-week 38 iew 39 treatment period and dupilumab was generally well-tolerated in this age group.12 40 41 42 In adult and adolescent patients with uncontrolled, moderate-to-severe asthma, dupilumab reduced 43 44 severe asthma exacerbations and improved lung function and asthma control in patients with and 45 46 without evidence of allergic asthma.13 The potential impact of a patient’s allergic status on 47 48 dupilumab efficacy has not been evaluated in children. The aim of this post hoc analysis, therefore, 49 50 was to explore the efficacy of dupilumab among patients with type 2 inflammatory asthma in 51 52 53 VOYAGE, who did and did not have evidence of allergic asthma. 54 55 56 57 58 59 60 Page 41 of 88 Allergy 1 2 3 METHODS 4 5 6 Study design and oversight 7 8 Full details of the LIBERTY ASTHMA VOYAGE study have been previously published.12 In brief, 9 10 VOYAGE, a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multinational 11 12 study, assessed efficacy and safety of dupilumab in children aged 6 to 11 years with uncontrolled, 13 14 15 moderate-to-severe asthma. Data were collected by the Investigators and analyzed by the sponsors 16 17 according to a predefined statistical analysis plan. The study was conducted in accordance with the 18 19 Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice 20 21 guideline, and applicable regulatory requirements. An independent data and safety monitoring Fo 22 23 24 committee conducted blinded monitoring of patient safety data. The local institutional review board rP 25 26 or ethics committee at each study center oversaw trial conduct and documentation. Parents or 27 28 guardians of patients provided written informed consent before their participation in the trial. ee 29 30 Pediatric patients provided assent according to the Ethics Committee approved standard practice for 31 rR 32 33 pediatric patients at each participating center. 34 35 ev 36 37 Patients and interventions 38 iew 39 Children aged 6 to 11 years were eligible to participate in VOYAGE if they had physician-diagnosed 40 41 42 moderate-to-severe asthma based on the GINA 2015 guidelines.14 Full details of inclusion and 43 44 exclusion criteria have been described previously.12 Per protocol, enrolment of patients with 45 46 baseline blood eosinophils <150 cells/µl was limited to 20% of the total population. Eligible patients 47 48 were randomized to receive subcutaneous dupilumab or volume-matched placebo at the same dose 49 50 every 2 weeks (q2w) for 52 weeks in a weight-tiered fashion: those with a bodyweight of ≤30 kg at 51 52 53 randomization received dupilumab 100 mg or matched placebo while those with a bodyweight >30 54 55 kg received dupilumab 200 mg or matching placebo. The study period comprises from enrolment of 56 57 the first participant on April 21, 2017, to study completion on August 26, 2020. 58 59 60 Allergy Page 42 of 88 1 2 3 Patients included in this sub-analysis of VOYAGE were those with type 2 asthma, defined as baseline 4 5 6 blood eosinophils ≥150 cells/µl or FeNO ≥20 ppb, patients with baseline eosinophils ≥150 cells/µl, 7 8 and patients with FeNO ≥20 ppb at baseline. These patients were further stratified according to 9 10 whether they met or did not met the criteria for evidence of allergic asthma at baseline, using 11 12 functional definitions that are narrower than definitions that would be used to identify patients with 13 14 allergic asthma in clinical practice. Evidence of allergic asthma was defined as a total serum IgE ≥30 15 16 17 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline as described previously.13 18 19 Sensitization to the following perennial aeroallergens was assessed: Dermatophagoides farinae, 20 21 Dermatophagoides pteronyssinus, Alternaria tenuis/alternata, Cladosporium herbarum, cat and dog Fo 22 23 danders, German cockroach, and Aspergillus fumigatus. 24 rP 25 26 27 28 Endpoints ee 29 30 The primary endpoint was the annualized severe exacerbation rate during the 52-week treatment 31 rR 32 period. Severe exacerbations were defined as a deterioration of asthma requiring: i) the use of 33 34 35 systemic corticosteroids for ≥3 days, or ii) hospitalization or emergency room visit because of ev 36 37 asthma, requiring systemic corticosteroids. Secondary endpoints analyzed were the change from 38 iew 39 baseline over time in both pre-bronchodilator percent predicted forced expiratory volume in 1 40 41 second (ppFEV1., key secondary endpoint) and absolute pre-bronchodilator FEV1, and change from 42 43 44 baseline in asthma control over time, as assessed using the Asthma Control Questionnaire 7-item 45 46 version Interviewer-Administered (ACQ-7-IA). The effect of treatment on specific IgE to perennial 47 48 aeroallergens over the 52-week treatment period was also examined in patients who had 49 50 sensitization to one or more aeroallergens at baseline (≥0.35 kU/L). 51 52 53 54 55 56 57 58 59 60 Page 43 of 88 Allergy 1 2 3 Statistical analysis 4 5 6 Data were analyzed on an intention-to-treat (ITT) basis according to the assigned intervention, 7 8 irrespective of whether an intervention was received.12 Data for both weight-tiered doses of 9 10 dupilumab (100 or 200 mg q2w) or matched placebo were pooled for analysis. 11 12 Annualized severe exacerbation rates were analyzed using a negative binomial model, which 13 14 included the total number of events observed from randomization up to week 52 or last study 15 16 17 contact date (whichever comes earlier) as the response variable, and included treatment group, age, 18 19 baseline weight group (≤30 kg, >30 kg), region (pooled country), baseline eosinophil strata (<300 20 21 cells/µL, ≥300 cells/µL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline inhaled corticosteroid dose Fo 22 23 (ICS) level (medium- or high-dose), and number of severe exacerbations within 1 year prior to the 24 rP 25 26 study as covariates, and log-transformed standardized observation duration as an offset variable. 27 28 Change from baseline in ppFEV1 and absolute pre-bronchodilator FEV1 were analyzed using a mixed- ee 29 30 effect model with repeated measures (MMRM) approach, which used, as appropriate, change from 31 rR 32 baseline in ppFEV1 or pre-bronchodilator FEV1 up to Week 52 as the response variable, and included 33 34 35 pooled treatment groups, baseline weight groups, region, ethnicity, baseline eosinophil strata, ev 36 37 baseline FeNO level, baseline ICS dose level, visit, treatment by visit interaction, baseline value of the 38 iew 39 respective endpoint (percentage predicted or absolute FEV1), and baseline-by-visit interaction as 40 41 covariates. The change from baseline in pre-bronchodilator FEV1 up to week 52 was derived using 42 43 44 MMRM model with all the covariates mentioned above along with age, sex, and baseline height. 45 46 Change from baseline in ACQ-7-IA score over time was derived from an MMRM model with change 47 48 from baseline in ACQ-7-IA score up to Week 52 as the response variable and pooled treatment 49 50 groups, age, baseline weight group, region, baseline eosinophil strata, baseline FeNO level, baseline 51 52 53 ICS dose level, visit, treatment-by-visit interaction, baseline ACQ-7-IA score, and baseline-by-visit 54 55 interaction as covariates. 56 57 Change from baseline in total IgE and specific IgE over time were analyzed using the Wilcoxon rank- 58 59 sum test for patients in the safety population. 60 Allergy Page 44 of 88 1 2 3 4 5 6 7 8 RESULTS 9 10 Study patients 11 12 350 patients randomized in VOYAGE (86% of the overall VOYAGE ITT population) had type 2 asthma 13 14 15 at baseline, defined as baseline eosinophil count of ≥150 cells/µl or FeNO ≥20ppb, and were 16 17 included in this analysis. Of these, 261 (75%) met the criteria used to define evidence of allergic 18 19 asthma: placebo n=81, dupilumab n=180. The remaining 89 (25%) patients (placebo n=33, 20 21 dupilumab n=56) did not meet these criteria (IgE <30 IU/mL or no positive specific IgE among the Fo 22 23 24 aeroallergens tested). In the subgroup of patients with blood eosinophils ≥150 cells/µl, 251 met the rP 25 26 criteria for allergic asthma (placebo n=79, dupilumab n=172), whereas the remaining 80 (placebo 27 28 n=29, dupilumab n=51) did not. In the subgroup of patients with FeNO ≥20ppb, 176 met the criteria ee 29 30 for allergic asthma (placebo n=53, dupilumab n=123), whereas the remaining 27 (placebo n=9, 31 rR 32 33 dupilumab n=18) did not. 34 35 The baseline characteristics of patients with type 2 inflammation with and without evidence of ev 36 37 allergic asthma are provided in Table 1. Baseline characteristics were similar across treatment arms 38 iew 39 and subgroups. Patients with evidence of allergic asthma at baseline had higher median levels of 40 41 42 total serum IgE than those without evidence of allergic asthma (with evidence of allergic asthma: 43 44 569 [placebo] and 680 [dupilumab] IU/mL; without evidence of allergic asthma: 69.5 [placebo] and 45 46 113.5 [dupilumab] IU/mL). 47 48 49 50 Annualized rate of severe asthma exacerbations 51 52 53 Overall, dupilumab reduced annualized severe exacerbation rates relative to placebo in patients 54 55 with and without evidence of allergic asthma. In the subgroup of patients with type 2 asthma and 56 57 evidence of allergic asthma, the adjusted annualized severe asthma exacerbation event rate was 58 59 0.24 (95% confidence interval [CI], 0.16 to 0.36) in the dupilumab group vs 0.62 (95% CI, 0.40 to 60 Page 45 of 88 Allergy 1 2 3 0.94) in the placebo group (relative risk reduction [RRR] vs. placebo of 62% (95% CI, 39% to 76%; 4 5 6 p<.0001) (Figure 1). In the subgroup of patients with type 2 asthma with no evidence of allergic 7 8 asthma, the adjusted annualized severe asthma exacerbation event rates were 0.39 (95% CI, 0.23 to 9 10 0.68) vs 0.80 (95% CI, 0.47 to 1.37) for dupilumab and placebo groups, respectively (RRR vs. placebo 11 12 of 51% (95% CI, 0 to 76; p=.0494). There was no statistical evidence that the treatment effect of 13 14 dupilumab on exacerbations varied by allergic asthma status (pinteraction=0.6011). 15 16 17 Similar results were seen in the subgroup of patients with ≥150 eosinophils/µL, irrespective of 18 19 allergic phenotype, and in patients with ≥20 ppb FeNO and allergic asthma at baseline (Figure S1). 20 21 Patient numbers were very low in the subgroup of patients with ≥20 ppb FeNO without evidence of Fo 22 23 allergic asthma (n=9 [placebo] and n=18 [dupilumab]), therefore statistical comparisons were not 24 rP 25 26 possible in this subgroup, but trends were similar. 27 28 ee 29 30 Lung function 31 rR 32 Percentage of predicted pre-bronchodilator FEV1 33 34 35 In the sub-group of patients with type 2 asthma and evidence of allergic asthma, dupilumab ev 36 37 significantly improved pre-bronchodilator ppFEV1 from baseline compared with matched placebo 38 iew 39 (Figure 2). Significant improvements vs placebo were observed as early as the first assessment at 40 41 Week 2, and these persisted throughout the 52-week treatment period, with an LS mean difference 42 43 44 vs placebo of 5.71 (95% CI, 2.02 to 9.39, p=.003), and 9.27 (95% CI, 5.16 to 13.37, p<.0001), at Weeks 45 46 12 and 52, respectively. In the sub-group of type 2 patients without evidence of allergic asthma, 47 48 numerical improvements in ppFEV1 compared to placebo were observed, with an LS mean difference 49 50 vs placebo of 4.53 (95% CI, -1.30 to 10.35, p=.126), and 3.93 (95% CI, -2.41 to 10.26, p=.221), at 51 52 53 Weeks 12 and 52, respectively (Figure 2). Significant improvements compared to placebo were 54 55 observed at Week 4, 6, and 48 (p<.05) but at all other time points the improvements were numerical 56 57 and not significant. 58 59 60 Allergy Page 46 of 88 1 2 3 Similar results were seen in the subgroups of patients with ≥150 eosinophils/µL and patients with 4 5 6 ≥20 ppb FeNO at baseline, except in those with elevated FeNO without evidence of allergic asthma, 7 8 where no differences were found between dupilumab and placebo (Figure S2). 9 10 The p-values for interaction between treatment arm assignment and allergic asthma status were 11 12 0.605at Week 12 and 0.132 at Week 52 for the change from baseline in ppFEV1 endpoint. 13 14 15 16 17 18 19 Absolute pre-bronchodilator FEV1 20 21 In the sub-group of patients with type 2 asthma and evidence of allergic asthma, dupilumab Fo 22 23 significantly improved the absolute pre-bronchodilator FEV1 from baseline compared with matched 24 rP 25 26 placebo, with improvements observed as early as Week 2 and sustained over the treatment period 27 28 (Figure 3). At Week 2, the LS mean difference in pre-bronchodilator FEV1 improvement over baseline ee 29 30 vs placebo was 0.10L (95% CI, 0.03 to 0.17, p=.003), which further increased to 0.12L (95% CI, 0.04 to 31 rR 32 0.19, p=.002) at Week 12 and 0.20L (95% CI, 0.12 to 0.29, p<.0001) at Week 52. Similar to the 33 34 35 findings for the ppFEV1 endpoint, in patients without allergic asthma, the magnitude of ev 36 37 improvements in absolute pre-bronchodilator FEV1 relative to placebo was lower than in patients 38 iew 39 with allergic asthma, with an LS mean difference of −0.002L (95% CI, −0.10 to 0.10, p=.98) at Week 2 40 41 and numerical improvements over baseline of 0.07L (95% CI, −0.04 to 0.18, p=.184) at Week 12, and 42 43 44 0.07L (95% CI, −0.06 to 0.21, p=.266) at Week 52. 45 46 The p-values for interaction between treatment arm assignment and allergic asthma status were 47 48 0.35 at Week 12 and 0.06 at Week 52 for the change from baseline in absolute FEV1 endpoint. 49 50 51 52 53 Asthma control (ACQ-7-IA scores) 54 55 Dupilumab significantly improved ACQ-7-IA scores compared with placebo in patients with evidence 56 57 of allergic asthma. Improvements were rapid, with significant improvements vs placebo evident as 58 59 early as the first assessment at Week 2, and these improvements were sustained throughout the 60 Page 47 of 88 Allergy 1 2 3 study remaining significant vs placebo at all timepoints (Figure 4). At Week 24, the LS mean 4 5 6 difference vs placebo was −0.41 (95% CI, −0.61 to −0.22, p<.0001). In the subgroup of type 2 patients 7 8 without evidence of allergic asthma, little difference between treatments was observed throughout 9 10 the treatment period (Figure 4), with an LS mean difference vs placebo of −0.12 (95% CI, −0.47 to 11 12 −0.24, p=.522) at Week 24. 13 14 The p-values for interaction between treatment arm assignment and allergic asthma status were 15 16 17 0.11 at Week 24 and 0.14 at Week 52 for the change from baseline in ACQ-7-IA endpoint. 18 19 20 21 Total IgE Fo 22 23 Dupilumab reduced levels of total IgE over time in patients with type 2 inflammatory asthma, 24 rP 25 26 irrespective of their allergic status (Figure S3 of this article’s Online Repository). In patients with 27 28 evidence of an allergic asthma phenotype, median concentrations of total serum IgE were reduced ee 29 30 by 78.8% by Week 52, vs a 0.9% increase in patients on placebo (p<.0001). In patients without 31 rR 32 evidence of an allergic asthma phenotype, even though baseline concentrations were much lower, 33 34 35 dupilumab still reduced median IgE levels by 77.8% over the 52-week treatment duration, vs a 7.8% ev 36 37 increase in patients on placebo (p<.0001) (Figure S3). 38 iew 39 The p-values for interaction between treatment arm assignment and allergic asthma status were 40 41 0.70 at Week 24 and 0.13 at Week 52 for the percent change from baseline in total IgE levels over 42 43 44 time endpoint. 45 46 47 48 Perennial aeroallergen-specific IgE 49 50 The effect of treatment on allergen-specific IgE levels in patients who were positive (≥0.35 kU/L) at 51 52 53 baseline for one or more of the perennial aeroallergens examined is presented in Figure S4 of this 54 55 article’s Online Repository. In dupilumab-treated patients, substantial reductions from baseline over 56 57 the 52-week treatment period were observed in allergen-specific IgE levels to Dermatophagoides 58 59 farinae, Dermatophagoides pteronyssinus, and German cockroach both in patients with mono- 60 Allergy Page 48 of 88 1 2 3 allergen sensitization to the respective aeroallergen and in those with multi-allergen sensitization 4 5 6 (ie, patients with allergen-specific IgE ≥0.35 kU/L for more than one aeroallergen). Similar reductions 7 8 over time were observed in multi-allergen-sensitized patients treated with dupilumab who were 9 10 allergic to dog and cat dander and Alternaria tenuis/alternata. However, no differences between 11 12 dupilumab and placebo were observed in patients who were mono-sensitized to Cladosporium 13 14 herbarum and Alternaria tenuis/alternata. Dupilumab treatment did not affect serum IgE levels to 15 16 17 Cladosporium herbarum/hormodendrum or Aspergillus fumigatus whether in mono- or multi- 18 19 allergen sensitized patients. No change was observed with placebo treatment on specific IgE levels 20 21 to any of the 8 perennial aeroallergens assessed. Fo 22 23 24 rP 25 26 Safety 27 28 In the primary analysis,12 dupilumab was well tolerated with an acceptable safety profile. In this ee 29 30 analysis, the incidence of treatment emergent adverse events was balanced across treatment groups 31 rR 32 (Table S1). 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 49 of 88 Allergy 1 2 3 DISCUSSION 4 5 6 In this post hoc analysis of LIBERTY ASTHMA VOYAGE, conducted in children aged 6 to 11 years with 7 8 moderate-to-severe asthma, dupilumab significantly reduced the rate of severe exacerbations and 9 10 improved lung function (ppFEV1 and absolute FEV1) and asthma control (ACQ-7-IA scores) in patients 11 12 with type 2 asthma (baseline blood eosinophils ≥150 cells/µL or ≥20 ppb FeNO) and evidence of 13 14 15 allergic asthma, with similar trends observed in patients without evidence of allergic asthma. As 16 17 reported previously, similar treatment effects were observed in QUEST in adult and adolescent 18 19 patient populations with type 2 asthma irrespective of their allergic status at baseline.13 The 20 21 improvements in lung function and asthma control in the subgroup with evidence of allergic asthma Fo 22 23 24 were rapid, observed by Week 2, and were sustained throughout the treatment period. Dupilumab rP 25 26 vs placebo also improved lung function in patients with type 2 without evidence of allergic asthma, 27 28 although these differences were not significant at most time points. These findings are consistent ee 29 30 with the efficacy profile seen in QUEST patients with uncontrolled, moderate-to-severe asthma 31 rR 32 33 where clinical efficacy with regard to exacerbation rates, lung function, and asthma control was 34 35 observed irrespective of evidence of allergic status: dupilumab vs placebo significantly reduced ev 36 37 exacerbation rates and improved lung function and asthma control for both patients with and 38 iew 39 without evidence of allergic asthma, at most time points.13 40 41 42 The results for annualized exacerbation rates support the efficacy of dupilumab in children with type 43 44 2 asthma irrespective of evidence of allergic asthma, highlighting that suppression of IL-4 and IL-13 45 46 leads to clinically meaningful improvements in type 2 inflammatory asthma irrespective of the 47 48 patient’s allergic status. Given that 75% of children with type 2 asthma included in this analysis also 49 50 had evidence of allergic asthma, determining the efficacy of dupilumab in this patient population is 51 52 53 important, particularly since allergens are known to trigger asthma attacks in 60 to 90% of children.15 54 55 In the small population that did not have evidence of allergic asthma despite having evidence of type 56 57 2 inflammation, numerical improvements in lung function, were observed. Differences vs placebo in 58 59 FEV1 and ACQ-7-IA scores were not significant at most time points, however, small patient numbers 60 Allergy Page 50 of 88 1 2 3 in this post-hoc analysis may provide inadequate statistical power. Additionally, in the subgroup 4 5 6 without evidence of allergic asthma, dupilumab improved absolute pre-BD FEV1 over baseline by 330 7 8 mL at Week 52; Santanello et al. have previously reported that patients perceive improvements in 9 10 pre-BD FEV1 >230 mL as an indication of treatment success.16 11 12 The steady and sustained decrease in total IgE over the 52-week treatment period observed in 13 14 dupilumab-treated patients with evidence of allergic asthma, is consistent with the mechanism of 15 16 17 action of dupilumab with reductions even greater than in QUEST,17 and was also reported in the 18 19 overall VOYAGE population.12 In contrast, IgE levels in placebo patients without evidence of allergic 20 21 asthma, who already had lower levels at baseline compared with the population with evidence of Fo 22 23 allergic asthma, remained stable or even rose slightly relative to baseline. Dupilumab treatment also 24 rP 25 26 reduced allergen-specific serum IgE levels against 6 of the 8 perennial aeroallergens tested. Why 27 28 dupilumab did not affect specific IgE levels in two of the three fungal allergens tested (Cladosporium ee 29 30 herbarum/hormodendrum and Aspergillus fumigatus) but was effective at reducing IgE directed 31 rR 32 against Alternaria tenuis/alternata is presently unclear. In addition, reductions for IgE against three 33 34 35 allergens were only observed in patients with multi-allergen sensitizations, who had higher baseline ev 36 37 concentrations of total serum IgE compared with those who had only one (mono) sensitization or 38 iew 39 non-sensitized patients. Since polysensitization to ≥2 food and/or aeroallergens is a known risk 40 41 factor for the development of asthma,18 it may be the case that patients who exhibited multi- 42 43 44 allergen sensitization may have been more responsive to suppression of type 2 inflammation. 45 46 A limitation of this study was the post hoc nature of the analyses, as the study was not primarily 47 48 designed or powered to investigate differences between type 2 patients with or without evidence of 49 50 allergic asthma. As only 25% of type 2 patients had no evidence of allergic asthma, and the study 51 52 53 design included a 2:1 dupilumab: placebo treatment allocation, the proportion of patients without 54 55 evidence of allergic asthma receiving placebo was less than 10% of the total population evaluated. 56 57 Therefore, although findings in the population with evidence of allergic asthma are robust, the 58 59 60 Page 51 of 88 Allergy 1 2 3 inconsistent statistical significance observed across efficacy variables in the non-allergic population 4 5 6 should be interpreted with caution. 7 8 Secondly, the racial distribution of patients included in the study also potentially limits extrapolation 9 10 across populations. The vast majority of patients were white (>85% in each analysis group), and 11 12 therefore results may differ in more racial diverse populations. 13 14 Another limitation was how allergic status was identified. The allergic status was identified post-hoc 15 16 17 to a defined set of common aeroallergens, percutaneous allergy skin testing was not performed and 18 19 allergic reactions to the panel of aeroallergens were based solely on specific IgE levels at a baseline 20 21 of ≥0.35 kU/L. Furthermore, as no pollen or spore counts or home allergen levels were performed Fo 22 23 during the study to assess the amount of allergen present in individual participants’ homes and/or 24 rP 25 26 geographic areas, it is not possible to ascertain the degree to which each patient was exposed to 27 28 these allergens. ee 29 30 A further limitation is the definition of allergic asthma used in this study, as it allows that the 31 rR 32 subgroup of patients without evidence of allergic asthma may have had either IgE ≥30 IU/mL or ≥1 33 34 35 positive specific allergen. Also, some patients without evidence of allergic asthma may have been ev 36 37 sensitized to allergens not included in the panel. Further studies to investigate the efficacy of 38 iew 39 dupilumab treatment more specifically in children with moderate-to-severe type 2 asthma with or 40 41 without evidence of allergic asthma might be needed to help physicians optimally tailor treatment in 42 43 44 this patient population. 45 46 47 48 The majority of children aged 6 to 11 years with moderate-to-severe asthma from VOYAGE 49 50 presented characteristics of type 2 inflammation at baseline (elevated blood eosinophils or FeNO). 51 52 53 Among the VOYAGE patients with type 2 asthma, the majority also exhibited evidence of allergic 54 55 asthma. Dupilumab vs matched placebo significantly reduced severe exacerbation rates irrespective 56 57 of evidence of allergic asthma at baseline. Improvements in lung function parameters were also 58 59 observed but to a lower degree in patients without evidence of allergic asthma. 60 Allergy Page 52 of 88 1 2 3 Taken together, these data support the role of dupilumab in treating pediatric patients aged 6 to 11 4 5 6 years with moderate-to-severe asthma, regardless of evidence of allergic asthma. However, the 7 8 patient cohort without evidence of allergic asthma was small as mentioned earlier, thus the data 9 10 should be interpreted with caution. Patients with evidence of allergic asthma demonstrated clinically 11 12 meaningful responses to dupilumab treatment, supporting the role of IL-4 and IL-13, and thus type 2 13 14 inflammation, as key drivers of certain patients with allergic asthma. The position of dupilumab 15 16 17 among other biologics in severe allergic pediatric asthma remains to be determined by comparative 18 19 studies, aimed at identifying the most appropriate biomarkers of responsiveness.19,20 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 53 of 88 Allergy 1 2 3 REFERENCES 4 5 6 1. Licari A, Manti S, Castagnoli R, Leonardi S, Marseglia GL. Measuring inflammation in paediatric 7 8 severe asthma: biomarkers in clinical practice. Breathe (Sheff). 2020 Mar;16(1):190301. 9 10 2. Zoratti EM, Krouse RZ, Babineau DC, et al. Asthma phenotypes in inner-city children. J Allergy 11 12 Clin Immunol. 2016 Oct;138(4):1016-1029. 13 14 15 3. Canonica GW, Blasi F, Crimi N, et al. Defining type 2 asthma and patients eligible for dupilumab 16 17 in Italy: a biomarker-based analysis. Clin Mol Allergy. 2021 May 21;19(1):5. 18 19 4. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 20 21 2015;15(1):57-65 Fo 22 23 24 5. Wenzel SE. Emergence of Biomolecular Pathways to Define Novel Asthma Phenotypes. Type-2 rP 25 26 Immunity and Beyond. Am J Respir Cell Mol Biol. 2016 Jul;55(1):1-4. 27 28 6. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2022. ee 29 30 Accessed October 24, 2022. www.ginasthma.org 31 rR 32 33 7. Macdonald LE, Karow M, Stevens S, et al. Precise and In Situ Genetic Humanization of 6 Mb of 34 35 Mouse Immunoglobulin Genes. Proc Natl Acad Sci U S A. 2014;111:5147-5152. ev 36 37 8. Murphy AJ, Macdonald LE, Stevens S, et al. Mice With Megabase Humanization Of Their 38 iew 39 Immunoglobulin Genes Generate Antibodies As Efficiently As Normal Mice. Proc Natl Acad Sci U 40 41 42 S A. 2014;111:5153-8. 43 44 9. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal 45 46 drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50. 47 48 10. DUPIXENT® (dupilumab). Highlights of Prescribing Information . US Food and Drug 49 50 Administration. Accessed October 24, 2022. 51 52 53 https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf 54 55 11. DUPIXENT® (dupilumab). Summary of Product Characteristics. European Medicines Agency . 56 57 Accessed October 24, 2022. https://www.ema.europa.eu/en/documents/product- 58 59 information/dupixent-epar-product-information_en.pdf 60 Allergy Page 54 of 88 1 2 3 12. Bacharier LB, Maspero JF, Katelaris CH, et al. Dupilumab in Children with Uncontrolled 4 5 6 Moderate-to-Severe Asthma. N Engl J Med. 2021 November 2021; 385:2230-2240; 7 8 13. Corren J, Castro M, O'Riordan T, et al. Dupilumab Efficacy in Patients with Uncontrolled, 9 10 Moderate-to-Severe Allergic Asthma. J Allergy Clin Immunol Pract. 2020 Feb;8(2):516-526. 11 12 14. Global strategy for asthma management and prevention. Updated 2015. Accessed October 24, 13 14 2022. https://ginasthma.org/wp-content/uploads/2016/01/GINA_Pocket_2015.pdf. Accessed 15 16 17 October 2021. 18 19 15. Do DC, Zhao Y, Gao P. Cockroach allergen exposure and risk of asthma. Allergy. 2016 20 21 Apr;71(4):463-474. Fo 22 23 16. Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes 24 rP 25 26 for asthma measures in a clinical trial? Eur Respir J. 1999 Jul;14(1):23-27. 27 28 17. Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe ee 29 30 Uncontrolled Asthma. N Engl J Med 2018; 378:2486-2496. 31 rR 32 18. Biagini Myers JM, Schauberger E, He H, et al. A Pediatric Asthma Risk Score to better predict 33 34 35 asthma development in young children. J Allergy Clin Immunol. 2019 May;143(5):1803-1810.e2. ev 36 37 19. Charriot J, Maravic M, Huguet M, Vachier I, Suehs C, Bourdin A. "Real-life" management of 38 iew 39 patients with severe asthma in the biologics era: Can we do better? World Allergy Organ J. 2021 40 41 Mar 18;14(4):100528. 42 43 44 20. Yu L, Zhang H, Pan J, Ye L. Pediatric usage of Omalizumab: A promising one. World Allergy Organ 45 46 J. 2021 Dec 11;14(12):100614. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 55 of 88 Allergy 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Data sharing statement 18 19 20 Qualified researchers may request access to patient-level data and related study documents 21 Fo 22 including the clinical study report, study protocol with any amendments, blank case report form, 23 24 statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study rP 25 26 27 documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s 28 ee 29 data sharing criteria, eligible studies, and process for requesting access can be found at: 30 31 http://www.vivli.org/. rR 32 33 34 35 ev 36 Acknowledgments 37 38 iew 39 This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov 40 41 Identifier: NCT02948959. Medical writing/editorial assistance was provided by Natalia Crespo, of 42 43 44 Excerpta Medica, and was funded by Sanofi and Regeneron Pharmaceuticals, Inc., according to the 45 46 Good Publication Practice guideline. 47 48 49 50 51 52 Author contributions: 53 54 LBB, JFM, AF acquired data. DJL, MH, RG, MD, SS, JAJ-N, YD, PJR contributed to the conception and 55 56 57 design of the study. ND did statistical analyses. All authors participated in the interpretation of the 58 59 data, provided critical feedback and final approval for submission, and took responsibility for the 60 Allergy Page 56 of 88 1 2 3 accuracy, completeness, and protocol adherence of data and analyses. All investigators had 4 5 6 confidentiality agreements with the sponsors. 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 57 of 88 Allergy 1 2 3 TABLES AND FIGURES 4 5 6 Table 1. Baseline characteristics of VOYAGE patients with type 2 asthma with or without evidence of allergic asthma a b 7 8 Type 2 with evidence of allergic asthma Type 2 without evidence of allergic asthma 9 10 11 Fo Placebo Dupilumab Placebo Dupilumab 12 13 Characteristic rP 14 n=81 n=180 n=33 n=56 15 ee 16 17 Median age (min-max), years 9 (6–11) 9 (6–11) 8 (6–11) 9 (6–11) 18 rR 19 20 Male sex, n (%) 59 (72.8) 118 (65.6) 19 (57.6) 34 (60.7) ev 21 22 Race iew 23 24 25 White 69 (85.2) 155 (86.1) 33 (100) 53 (94.6) 26 27 28 Black/of African descent 5 (6.2) 9 (5.0) 0 (0) 0 (0) 29 30 31 Asian 0 (0) 2 (1.1) 0 (0) 0 (0) 32 33 34 American Indian or Alaska Native 0 (0) 1 (0.6) 0 (0) 0 (0) 35 36 37 Native Hawaiian or Other Pacific Islander 0 (0) 0 (0) 0 (0) 0 (0) 38 39 40 41 42 43 44 45 46 Allergy Page 58 of 88 1 2 3 4 Other 7 (8.6) 13 (7.2) 0 (0) 3 (5.4) 5 6 Ethnicity 7 8 9 Hispanic or Latino 37 (45.7) 76 (42.2) 14 (42.4) 28 (50.0) 10 11 Fo 12 Not Hispanic or Latino 44 (54.3) 104 (57.8) 19 (57.6) 28 (50.0) 13 rP 14 15 BMI, mean (SD), kg/m2 18.70 (3.36) 18.66 (3.62) 19.81 (5.05) 18.41 (3.17) ee 16 17 18 Age at asthma onset, mean (SD), years 3.8 (2.7) 3.2 (2.5) 3.8 (2.4) 3.3 (2.5) rR 19 20 ev 21 Number of exacerbations in the past year, 22 2.10 (1.26) 2.64 (2.79) 2.36 (2.12) 2.52 (1.73) iew 23 mean (SD) 24 25 26 Pre-bronchodilator FEV1, mean (SD), L 1.54 (0.46) 1.48 (0.39) 1.49 (0.45) 1.47 (0.38) 27 28 29 Pre-bronchodilator ppFEV1, mean (SD), % 78.62 (14.97) 76.67 (14.56) 77.73 (13.51) 80.84 (13.42) 30 31 ACQ-7-IA score, mean (SD) 2.10 (0.73) 2.17 (0.74) 2.15 (0.85) 2.06 (0.57) 32 33 34 Blood eosinophil count, median (Q1–Q3), cells/µL 490.0 (320.0–710.0) 575.0 (360.0–800.0) 360.0 (210.0–470.0) 290.0 (185.0–605.0) 35 36 37 FeNO, ppb, median (Q1–Q3) 25.0 (16.0–39.0) 29.5 (17.0–47.0) 14.5 (9.0–20.0) 13.00 (8.0–23.0) 38 39 40 41 42 43 44 45 46 Page 59 of 88 Allergy 1 2 3 4 Total IgE, IU/mL, median (Q1–Q3) 569.0 (270.0–1013.0) 680.0 (348.0–1462.5) 69.5 (26.5–312.5) 113.5 (32.0–286.0) 5 6 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 7 8 with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. Abbreviations: ACQ-7-IA, Asthma Control Questionnaire 7-item version 9 10 11Interviewer-Administered; BMI, body mass index; FeNO, fractional exhaled nitric oxide; ppb, parts per billion; ppFEV1, percentage of predicted forced expiratory volume in 1 second; Fo 12 13SD, standard deviation. rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 60 of 88 1 2 3 Figure 1. Effect of dupilumab on annualized severe exacerbation rates in pediatric patients with type 2 asthmaa with or without evidence of allergic asthmab 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 35*P<.05; ***P<.001 vs placebo. 36 37aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 38 39with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 40 41 42 43 44 45 46 Page 61 of 88 Allergy 1 2 3 Figure 2. Change from baseline over time in pre-bronchodilator ppFEV in patients with type 2 asthmaa with or without evidence of allergic asthmab 1 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31*P<.05, **P<.01, ***P<.001 vs placebo. 32 33 Type 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. The allergic asthma phenotype is defined as patients a b 34 35with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 62 of 88 1 2 3 Figure 3. Change from baseline over time in absolute pre-bronchodilator FEV in patients with type 2 asthmaa with or without evidence of allergic asthmab 1 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30*P<.05, **P<.01, ***P<.001 vs placebo. 31 32 Type 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. The allergic asthma phenotype is defined as patients a b 33 34with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline 35 36 37 38 39 40 41 42 43 44 45 46 Page 63 of 88 Allergy 1 2 3 Figure 4. Change from baseline over time in ACQ-7-IA score in patients with type 2 asthmaa with or without evidence of allergic asthmab 4 5 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30*P<.05, **P<.01, ***P<.001 vs placebo. 31 32aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients 33 34 with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 35 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 64 of 88 1 For With evidence of allergic asthma Without evidence of allergic asthma 2 Pee 1.4 3 Adjusted annualized severe exacerbation 4 1.2 –62% –51% 5 r Re 6 rate estimate (95% CI) 1.0 7 vie 8 0.8 9 * w 10 0.6 11 12 0.4 *** 13 14 0.2 15 n = 81 n = 180 n = 33 n = 56 16 0 17 Placebo Dupilumab Placebo Dupilumab 18 19 Page 65 of 88 Allergy Placebo Dupilumab 1 2 Blood eosinophils ≥ 150 cells/µL FeNO ≥ 20 ppb Fo 3 4 rP 5 6 –61% –61% –63% eer 7 8 9 1.8 Re 10 Adjusted annualized severe exacerbation 11 1.6 12 vie 1.4 13 rate estimate (95% CI) 14 1.2 w 15 16 1.0 0.88b 17 0.8 18 ** 19 0.6 0.51b 20 0.4 *** *** 21 22 0.2 23 n = 79 n = 172 n = 29 n = 51 n = 53 n = 123 n=9 n = 18 0 24 Evidence of No evidence of Evidence of No evidence of 25 allergic asthma allergic asthma allergic asthma allergic asthma 26 27 Allergy Page 66 of 88 Placebo Dupilumab 1 With evidence of allergic asthma 2 3 ** *** *** *** ** ** *** *** *** ** * ** *** * ** *** 4 16 5 14 6 Change from baseline in percent predicted FEV1, LS mean (SE) 7 12 8 9 10 10 11 8 12 6 13 14 4 Fo 15 16 2 17 rP 0 18 0 4 8 12 16 20 24 28 32 36 40 44 48 52 19 Week 20 ee 21 Number of patients 22 Placebo 81 77 79 79 79 80 80 79 77 79 75 74 76 74 23 Dupilumab 180 172 173 175 175 173 176 171 171 166 166 165 163 163 rR 24 25 26 Without evidence of allergic asthma 27 ev 28 * * * 16 29 Change from baseline in percent 30 iew predicted FEV1, LS mean (SE) 14 31 32 12 33 10 34 35 8 36 37 6 38 4 39 40 2 41 42 0 43 0 4 8 12 16 20 24 28 32 36 40 44 48 52 44 Week 45 Number of patients 46 47 Placebo 33 32 33 32 31 32 33 33 33 32 32 33 33 32 48 Dupilumab 56 53 53 53 52 51 52 53 51 51 51 49 49 35 49 50 51 Page 67 of 88 Allergy Placebo Dupilumab 1 With evidence of allergic asthma 2 3 ** *** *** *** ** ** ** *** *** ** * * *** * * *** 4 16 5 6 14 7 12 LS mean change ± SEa 8 9 10 10 11 ≥ 150 eosinophils/µL 8 12 13 6 14 Fo 4 15 16 2 17 rP 18 0 19 BL 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 20 ee Week 21 Number of patients 22 Placebo 79 73 75 77 77 77 77 77 78 78 77 75 77 73 72 74 72 23 rR Dupilumab 172 169 164 166 165 167 167 167 165 168 163 163 158 158 157 155 156 24 25 26 ev 27 ** *** *** *** *** *** *** *** *** ** * ** *** * ** *** 16 28 ie 29 12 30 31 w LS mean change ± SEa 32 8 33 34 ≥20 ppb FeNO 4 35 36 0 37 38 39 –4 40 41 –8 42 BL 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 43 Week 44 Number of patients 45 Placebo 53 48 49 51 51 51 51 52 52 52 51 50 51 50 48 50 48 46 47 Dupilumab 123 121 118 120 119 122 122 121 120 122 119 119 118 116 115 114 116 48 49 Allergy Page 68 of 88 Placebo Dupilumab 1 Without evidence of allergic asthma 2 3 * 4 16 5 14 6 7 12 LS mean change ± SEa 8 9 10 10 8 11 ≥ 150 eosinophils/µL 12 6 13 14 4 Fo 15 2 16 17 rP 0 18 BL 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 19 20 Week ee 21 Number of patients 22 Placebo 29 29 28 29 29 29 28 27 28 29 29 29 28 28 29 29 28 23 rR Dupilumab 51 50 48 47 49 47 49 48 47 48 49 47 48 47 45 45 48 24 25 26 ev 27 16 28 ie 29 12 30 LS mean change ± SEa 31 w 8 32 33 34 4 ≥20 ppb FeNO 35 36 0 37 38 –4 39 40 –8 41 42 BL 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 43 Week 44 Number of patients 45 Placebo 9 9 9 9 9 9 8 9 9 9 9 9 8 9 9 9 8 46 Dupilumab 18 18 18 17 17 17 17 17 17 17 17 16 16 16 15 14 17 47 48 49 Page 69 of 88 Allergy 1 Placebo Dupilumab 2 3 With evidence of allergic asthma 4 5 ** *** *** *** *** ** ** *** *** ** * ** *** ** ** *** 6 0.50 7 Change from baseline in pre-BD FEV1, 0.45 8 0.40 9 10 0.35 11 LS mean (SE) 0.30 12 0.25 13 14 0.20 15 0.15 Fo 16 0.10 17 18 0.05 r 19 0 20 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Pe 21 Week 22 23 Number of patients er 24 Placebo 81 77 79 79 79 80 80 79 77 79 75 74 76 74 25 Dupilumab 180 172 173 175 175 173 176 171 171 166 166 165 163 163 26 Re 27 Without evidence of allergic asthma 28 29 * * vie 30 0.50 31 Change from baseline in pre-BD FEV1, 0.45 32 33 0.40 w 34 0.35 35 LS mean (SE) 0.30 36 37 0.25 38 0.20 39 0.15 40 41 0.10 42 0.05 43 0 44 0 4 8 12 16 20 24 28 32 36 40 44 48 52 45 Week 46 47 Number of patients 48 Placebo 33 32 33 32 31 32 33 33 33 32 32 33 33 32 49 Dupilumab 56 53 53 53 52 51 52 53 51 51 51 49 49 52 50 51 52 53 Allergy Page 70 of 88 Placebo Dupilumab 1 2 With evidence of allergic asthma 3 4 *** *** 60 5 6 Median percent change with Q1-Q3 7 30 8 9 10 0 11 12 –30 13 14 Fo 15 –60 16 17 rP 18 –90 19 BL 24 52 20 Week ee 21 Number of patients 22 Placebo 80 78 75 23 Dupilumab 180 177 167 rR 24 25 26 27 ev Without evidence of allergic asthma 28 *** *** 29 60 30 iew Median percent change with Q1-Q3 31 32 30 33 34 0 35 36 37 –30 38 39 40 –60 41 42 43 –90 BL 24 52 44 45 Week 46 Number of patients 47 Placebo 32 31 32 48 Dupilumab 50 48 49 49 50 51 Page 71 of 88 Allergy Placebo Dupilumab 1 2 With evidence of allergic asthma 3 4 ** *** ** ** *** *** ** ** *** *** ** *** *** *** *** *** 0 5 6 7 Change in ACQ-7-IA score, 8 –0.5 9 LS mean (± SE) 10 11 –1.0 12 13 14 15 –1.5 16 Fo 17 18 –2.0 19 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 rP 20 Week 21 22 Number of patients ee 23 Placebo 81 77 78 80 80 80 80 79 80 80 79 77 78 74 76 77 77 24 Dupilumab 180 178 173 176 174 174 176 175 172 176 172 172 167 169 165 168 170 25 rR 26 27 Without evidence of allergic asthma 28 ev 29 * 30 0 31 iew 32 Change in ACQ-7-IA score, 33 –0.5 34 LS mean (± SE) 35 36 –1.0 37 38 39 40 –1.5 41 42 43 –2.0 44 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 45 Week 46 47 Number of patients 48 Placebo 33 33 32 33 33 33 33 31 32 32 33 33 33 32 33 33 33 49 Dupilumab 56 54 53 53 53 52 53 52 51 52 53 51 51 31 50 51 52 50 51 52 53 54 Allergy Page 72 of 88 PBO mono-allergen DPL mono-allergen PBO multi-allergen DPL multi-allergen 1 sensitization sensitization sensitization sensitization 2 A. fumigatus Cat Dander 3 100 100 80 80 4 Percentage change fom baseline Percentage change fom baseline in specific IgE (IU/mL), median in specific IgE (IU/mL), median 60 60 5 40 40 6 20 20 7 0 0 –20 –20 8 –40 –40 9 –60 –60 10 –80 –80 11 –100 BL 24 52 –100 BL 24 52 12 Week Week 13 Number of patients Number of patients 14 PBO mono-allergen DPL mono-allergen 18 35 16 33 17 32 PBO mono-allergen DPL mono-allergen 18 33 15 31 16 30 15 PBO multi-allergen 61 53 54 PBO multi-allergen 60 50 54 16 DPL multi-allergen 142 128 127 DPL multi-allergen 139 125 123 17 D. farinae D. pteronyssinus 18 100 100 19 80 80 Percentage change fom baseline Percentage change fom baseline in specific IgE (IU/mL), median in specific IgE (IU/mL), median 20 60 40 60 40 21 Fo 20 20 22 0 0 23 –20 –20 24 –40 –40 rP –60 –60 25 –80 –80 26 –100 –100 27 BL 24 Week 52 BL 24 Week 52 28 ee Number of patients Number of patients 29 PBO mono-allergen 11 11 10 PBO mono-allergen 8 7 8 30 DPL mono-allergen PBO multi-allergen 14 33 13 32 12 30 DPL mono-allergen PBO multi-allergen 22 28 22 25 21 26 31 DPL multi-allergen 84 82 79 DPL multi-allergen 58 56 52 rR 32 Dog Dander German Cockroach 33 100 100 34 80 80 Percentage change fom baseline Percentage change fom baseline in specific IgE (IU/mL), median in specific IgE (IU/mL), median 35 60 60 ev 40 40 36 20 20 37 0 0 38 iew –20 –20 39 –40 –40 –60 –60 40 –80 –80 41 –100 –100 42 BL 24 Week 52 BL 24 Week 52 43 Number of patients Number of patients 44 PBO mono-allergen 18 15 16 PBO mono-allergen 18 15 16 45 DPL mono-allergen PBO multi-allergen 34 60 32 52 30 53 DPL mono-allergen PBO multi-allergen 34 60 32 51 30 53 46 DPL multi-allergen 141 126 126 DPL multi-allergen 139 126 124 47 A. tenuis/alternata C. herbarum/hormodendrum 48 100 100 49 80 80 Percentage change fom baseline Percentage change fom baseline 50 in specific IgE (IU/mL), median in specific IgE (IU/mL), median 60 60 51 40 40 20 20 52 0 0 53 –20 –20 54 –40 –40 55 –60 –60 –80 –80 56 –100 –100 57 BL 24 52 BL 24 52 58 Week Week Number of patients Number of patients 59 PBO mono-allergen 19 17 18 PBO mono-allergen 18 15 16 60 DPL mono-allergen 34 32 31 DPL mono-allergen 35 33 31 PBO multi-allergen 61 55 56 PBO multi-allergen 61 54 55 DPL multi-allergen 142 133 128 DPL multi-allergen 142 127 127 Page 73 of 88 Allergy 1 2 3 Table 1. Baseline characteristics of VOYAGE patients with type 2 asthmaa with or without evidence of 4 5 6 allergic asthmab 7 8 Type 2 with evidence of allergic Type 2 without evidence of allergic 9 asthma asthma 10 11 Placebo Dupilumab Placebo Dupilumab 12 Characteristic n=81 n=180 n=33 n=56 13 14 Median age (min-max), years 9 (6–11) 9 (6–11) 8 (6–11) 9 (6–11) 15 16 Male sex, n (%) 59 (72.8) 118 (65.6) 19 (57.6) 34 (60.7) 17 18 Race 19 White 69 (85.2) 155 (86.1) 33 (100) 53 (94.6) Fo 20 21 Black/of African descent 5 (6.2) 9 (5.0) 0 (0) 0 (0) 22 23 Asian 0 (0) 2 (1.1) 0 (0) 0 (0) rP 24 25 American Indian or Alaska 0 (0) 1 (0.6) 0 (0) 0 (0) 26 Native ee 27 Native Hawaiian or Other 28 0 (0) 0 (0) 0 (0) 0 (0) Pacific Islander 29 rR 30 Other 7 (8.6) 13 (7.2) 0 (0) 3 (5.4) 31 32 Ethnicity ev 33 34 Hispanic or Latino 37 (45.7) 76 (42.2) 14 (42.4) 28 (50.0) 35 Not Hispanic or Latino 44 (54.3) 104 (57.8) 19 (57.6) 28 (50.0) 36 iew 37 BMI, mean (SD), kg/m2 18.70 (3.36) 18.66 (3.62) 19.81 (5.05) 18.41 (3.17) 38 39 Age at asthma onset, mean 3.8 (2.7) 3.2 (2.5) 3.8 (2.4) 3.3 (2.5) 40 (SD), years 41 42 Number of exacerbations in 43 the past year, 2.10 (1.26) 2.64 (2.79) 2.36 (2.12) 2.52 (1.73) 44 mean (SD) 45 46 Pre-bronchodilator FEV1, 1.54 (0.46) 1.48 (0.39) 1.49 (0.45) 1.47 (0.38) 47 mean (SD), L 48 Pre-bronchodilator ppFEV1, 49 78.62 (14.97) 76.67 (14.56) 77.73 (13.51) 80.84 (13.42) 50 mean (SD), % 51 ACQ-7-IA score, mean (SD) 2.10 (0.73) 2.17 (0.74) 2.15 (0.85) 2.06 (0.57) 52 53 Blood eosinophil count, 490.0 (320.0– 575.0 (360.0– 360.0 (210.0– 290.0 (185.0– 54 median (Q1–Q3), cells/µL 710.0) 800.0) 470.0) 605.0) 55 56 57 58 59 60 Allergy Page 74 of 88 1 2 3 4 25.0 (16.0– 29.5 (17.0– 13.00 (8.0– FeNO, ppb, median (Q1–Q3) 14.5 (9.0–20.0) 5 39.0) 47.0) 23.0) 6 Total IgE, IU/mL, median (Q1– 569.0 (270.0– 680.0 (348.0– 69.5 (26.5– 113.5 (32.0– 7 8 Q3) 1013.0) 1462.5) 312.5) 286.0) 9 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or 10 FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is defined as patients with asthma and 11 serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 12 13 Abbreviations: ACQ-7-IA, Asthma Control Questionnaire 7-item version Interviewer-Administered; BMI, 14 body mass index; FeNO, fractional exhaled nitric oxide; ppb, parts per billion; ppFEV1, percentage of 15 predicted forced expiratory volume in 1 second; SD, standard deviation. 16 17 18 19 Fo 20 21 22 23 rP 24 25 26 ee 27 28 29 rR 30 31 32 ev 33 34 35 36 iew 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 75 of 88 Allergy 1 2 3 Table S1. Summary of safety over the 52-week treatment period in patients with type 2 4 5 asthmaa with or without evidence of allergic asthmab . 6 7 8 Without evidence of allergic 9 With evidence of allergic asthma asthma 10 11 12 Placebo Dupilumab Placebo Dupilumab Event, no. patients (%) 13 (N = 80) (N = 180) (N = 33) (N = 54) 14 15 Any TEAE 65 (81.3) 153 (85.0) 24 (72.7) 41 (75.9) 16 17 Any treatment- 18 6 (7.5) 11 (6.1) 0 2 (3.7) 19 emergent SAE Fo 20 Any TEAE leading to 21 0 0 0 0 death 22 23 Any TEAE leading to rP 24 permanent treatment 2 (2.5) 3 (1.7) 0 2 (3.7) 25 discontinuation 26 ee 27 Eosinophiliac 1 (1.3) 13 (7.2) 0 3 (1.9) 28 29 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥150 cells/µL or FeNO rR 30 ≥20 ppb at baseline. bThe allergic asthma phenotype is defined as patients with asthma and serum total 31 32 IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. cPrimary System Organ Class Preferred Term. ev 33 34 35 36 iew 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 76 of 88 1 2 3 4 5 6 7 8 ONLINE REPOSITORY MATERIALS 9 10 11 12 13 14 15 16 17 Dupilumab is effective in children with moderate-to-severe type 2 asthma 18 19 with or without evidence of allergic asthma 20 21 Fo 22 23 24 rP 25 26 Nikolaos G Papadopoulos, MD, PhD, Stanley J Szefler, MD, Leonard B Bacharier, MD, Jorge F 27 28 Maspero, MD, Christian Domingo, MD, Alessandro Fiocchi MD, Jason K Lee, MD, Nadia Daizadeh, ee 29 30 PhD, David J Lederer, MD, Megan Hardin, MD, Rebecca Gall, MD, Michel Djandji, MD, Shahid 31 rR 32 33 Siddiqui, MD, Juby A Jacob-Nara, MD, MPH, DHSc, Yamo Deniz, MD, Paul J Rowe, MD, ATSF 34 35 ev 36 37 This appendix has been provided by the authors to give readers additional information about 38 iew 39 their work. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 77 of 88 Allergy Papadopoulos NG, et al - VOYAGE allergic mscpt |2 1 2 3 Contents 4 Table S1. Summary of safety over the 52-week treatment period in patients with type 2 asthmaa 5 6 with or without evidence of allergic asthmab ....................................................................................3 7 Figure S1. Annualized rate of severe asthma exacerbations over the 52-week treatment period in 8 9 patients with elevated eosinophils and FeNO at baseline, with or without evidence of allergic 10 asthmaa...............................................................................................................................................4 11 Figure S2. Percentage of predicted pre-bronchodilator FEV1 during the 52-week treatment period 12 13 in patients with elevated eosinophils and FeNO at baseline, with or without evidence of allergic 14 asthmaa...............................................................................................................................................5 15 Figure S3. Effect of dupilumab on serum total IgE levels during the 52-week treatment period in 16 17 patients with type 2 asthmaa with or without evidence of allergic asthmab......................................6 18 Figure S4. Effect of dupilumab on allergen-specific serum IgE levels during the 52-week treatment 19 period in patients with type 2 asthmaa and with baseline allergen-specific serum IgE levels ≥0.35 20 21 kU/mL. Aspergillus fumigatus (A), cat dander (B), Dermatophagoides farinae (C), Fo 22 Dermatophagoides pteronyssinus (D), dog dander (E), German cockroach (F), Alternaria 23 tenuis/alternata (G), and Cladosporium herbarum/hormodendrum (H)...........................................7 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 78 of 88 Papadopoulos NG, et al - VOYAGE allergic mscpt |3 1 2 3 Table S1. Summary of safety over the 52-week treatment period in patients with type 2 asthmaa with or without evidence of allergic asthmab . 4 5 6 7 With evidence of allergic asthma Without evidence of allergic asthma 8 9 10 Placebo Dupilumab Placebo Dupilumab 11 Event, no. patients (%) (N = 80) (N = 180) (N = 33) (N = 54) Fo 12 13 rP 14 Any TEAE 65 (81.3) 153 (85.0) 24 (72.7) 41 (75.9) 15 ee 16 Any treatment-emergent SAE 6 (7.5) 11 (6.1) 0 2 (3.7) 17 18 rR Any TEAE leading to death 0 0 0 0 19 20 ev 21 Any TEAE leading to permanent 2 (2.5) 3 (1.7) 0 2 (3.7) 22 treatment discontinuation iew 23 24 Eosinophiliac 1 (1.3) 13 (7.2) 0 3 (1.9) 25 aType 26 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥150 cells/µL or FeNO ≥20 ppb at baseline. bThe allergic asthma phenotype is 27 defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. cPrimary System Organ Class 28 Preferred Term. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Page 79 of 88 Allergy Papadopoulos NG, et al - VOYAGE allergic mscpt |4 1 2 3 Figure S1. Annualized rate of severe asthma exacerbations over the 52-week treatment period in patients with elevated eosinophils and FeNO at 4 5 baseline, with or without evidence of allergic asthmaa. 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 *P<.05, **P<.01, ***P<.001 vs placebo. 35 aThe allergic asthma phenotype is defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 36 37 bUnadjusted annualized severe asthma exacerbation rate = The total number of events that occurred during the 52-week treatment period divided by the total 38 number of patient-years followed in the 52-week treatment period. Adjusted annualized event rate are not presented as the sample size is too small to provide 39 40 valid estimates. 41 42 −63% 43 44 45 46 Allergy Page 80 of 88 Papadopoulos NG, et al - VOYAGE allergic mscpt |5 1 2 3 Figure S2. Percentage of predicted pre-bronchodilator FEV1 during the 52-week treatment period in patients with elevated eosinophils and FeNO at 4 5 baseline, with or without evidence of allergic asthmaa. 6 7 8 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 *P<.05, **P<.01, ***P<.001 vs placebo. 39 aThe allergic asthma phenotype is defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 40 41 42 43 44 45 46 Page 81 of 88 Allergy Papadopoulos NG, et al - VOYAGE allergic mscpt |6 1 2 3 Figure S3. Effect of dupilumab on serum total IgE levels during the 52-week treatment period in patients with type 2 asthmaa with or without 4 5 evidence of allergic asthmab. 6 7 8 9 10 11 Fo 12 13 rP 14 *** *** *** *** 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 ***P<.001 vs placebo. Calculated based on Wilcoxon rank sum test. 33 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is 34 35 defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 82 of 88 Papadopoulos NG, et al - VOYAGE allergic mscpt |7 1 2 3 Figure S4. Effect of dupilumab on allergen-specific serum IgE levels during the 52-week treatment 4 5 period in patients with type 2 asthmaa and with baseline allergen-specific serum IgE levels ≥0.35 6 kU/mL. Aspergillus fumigatus (A), cat dander (B), Dermatophagoides farinae (C), 7 8 Dermatophagoides pteronyssinus (D), dog dander (E), German cockroach (F), Alternaria 9 tenuis/alternata (G), and Cladosporium herbarum/hormodendrum (H). 10 11 12 13 14 15 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 aType2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 59 60 20 ppb at baseline. CI, Confidence interval; q2w, every 2 weeks. Page 83 of 88 Allergy 1 2 3 4 5 6 7 8 9 10 11 12 13 ONLINE REPOSITORY MATERIALS 14 15 16 17 18 19 20 Dupilumab is effective in children with moderate-to-severe type 2 asthma 21 Fo 22 with or without evidence of allergic asthma 23 24 rP 25 26 27 Nikolaos G Papadopoulos, MD, PhD, Stanley J Szefler, MD, Leonard B Bacharier, MD, Jorge F 28 ee 29 Maspero, MD, Christian Domingo, MD, Alessandro Fiocchi MD, Jason K Lee, MD, Nadia Daizadeh, 30 31 PhD, David J Lederer, MD, Megan Hardin, MD, Rebecca Gall, MD, Michel Djandji, MD, Shahid rR 32 Siddiqui, MD, Juby A Jacob-Nara, MD, MPH, DHSc, Yamo Deniz, MD, Paul J Rowe, MD, ATSF 33 34 35 ev 36 This appendix has been provided by the authors to give readers additional information about 37 their work. 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Allergy Page 84 of 88 1 2 3 4 5 6 7 8 Papadopoulos NG, et al - VOYAGE allergic mscpt |2 9 10 Contents 11 Table S1. Summary of safety over the 52-week treatment period in patients with type 2 asthmaa 12 with or without evidence of allergic asthmab ....................................................................................3 13 Figure S1. Annualized rate of severe asthma exacerbations over the 52-week treatment period in 14 patients with elevated eosinophils and FeNO at baseline, with or without evidence of allergic 15 asthmaa...............................................................................................................................................4 16 Figure S2. Percentage of predicted pre-bronchodilator FEV1 during the 52-week treatment period 17 in patients with elevated eosinophils and FeNO at baseline, with or without evidence of allergic 18 asthmaa...............................................................................................................................................5 19 Figure S3. Effect of dupilumab on serum total IgE levels during the 52-week treatment period in 20 patients with type 2 asthmaa with or without evidence of allergic asthmab......................................6 21 Fo Figure S4. Effect of dupilumab on allergen-specific serum IgE levels during the 52-week treatment 22 period in patients with type 2 asthmaa and with baseline allergen-specific serum IgE levels ≥0.35 23 kU/mL. Aspergillus fumigatus (A), cat dander (B), Dermatophagoides farinae (C), 24 Dermatophagoides pteronyssinus (D), dog dander (E), German cockroach (F), Alternaria rP 25 tenuis/alternata (G), and Cladosporium herbarum/hormodendrum (H)...........................................7 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 85 of 88 Allergy 1 2 3 4 Papadopoulos NG, et al - VOYAGE allergic mscpt |3 5 6 7 Table S1. Summary of safety over the 52-week treatment period in patients with type 2 asthmaa with or without evidence of allergic asthmab . 8 9 With evidence of allergic asthma Without evidence of allergic asthma 10 11 Fo 12 Placebo Dupilumab Placebo Dupilumab 13 Event, no. patients (%) (N = 80) (N = 180) (N = 33) (N = 54) rP 14 15 Any TEAE 65 (81.3) 153 (85.0) 24 (72.7) 41 (75.9) ee 16 17 Any treatment-emergent SAE 6 (7.5) 11 (6.1) 0 2 (3.7) 18 rR 19 Any TEAE leading to death 0 0 0 0 20 ev 21 Any TEAE leading to permanent 2 (2.5) 3 (1.7) 0 2 (3.7) treatment discontinuation 22 iew 23 Eosinophiliac 1 (1.3) 13 (7.2) 0 3 (1.9) 24 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥150 cells/µL or FeNO ≥20 ppb at baseline. bThe allergic asthma phenotype is 25 26 defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. cPrimary System Organ Class 27 Preferred Term. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 86 of 88 1 2 3 4 Papadopoulos NG, et al - VOYAGE allergic mscpt |4 5 6 7 Figure S1. Annualized rate of severe asthma exacerbations over the 52-week treatment period in patients with elevated eosinophils and FeNO at Commented [EM1]: Figure updated to show 95% CI as error bars instead of numbers, as requested by reviewer 8 baseline, with or without evidence of allergic asthmaa. 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 *P<.05, **P<.01, ***P<.001 vs placebo. 32 33 aThe allergic asthma phenotype is defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 34 bUnadjusted annualized severe asthma exacerbation rate = The total number of events that occurred during the 52-week treatment period divided by the total 35 number of patient-years followed in the 52-week treatment period. Adjusted annualized event rate are not presented as the sample size is too small to provide 36 valid estimates. 37 −63% 38 39 40 41 42 1.01 43 (0.58–1.76) 44 45 46 Page 87 of 88 Allergy 1 2 3 4 Papadopoulos NG, et al - VOYAGE allergic mscpt |5 5 6 7 Figure S2. Percentage of predicted pre-bronchodilator FEV1 during the 52-week treatment period in patients with elevated eosinophils and FeNO at 8 baseline, with or without evidence of allergic asthmaa. 9 10 11 Fo 12 13 rP 14 15 ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 31 32 33 34 *P<.05, **P<.01, ***P<.001 vs placebo. 35 aThe allergic asthma phenotype is defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 36 37 38 39 40 41 42 43 44 45 46 Allergy Page 88 of 88 1 2 3 4 Papadopoulos NG, et al - VOYAGE allergic mscpt |6 5 6 7 Figure S3. Effect of dupilumab on serum total IgE levels during the 52-week treatment period in patients with type 2 asthmaa with or without 8 evidence of allergic asthmab. 9 10 11 Fo 12 13 rP 14 15 *** *** *** *** ee 16 17 18 rR 19 20 ev 21 22 iew 23 24 25 26 27 28 29 30 ***P<.001 vs placebo. Calculated based on Wilcoxon rank sum test. 31 aType 2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb at baseline. bThe allergic asthma phenotype is 32 defined as patients with asthma and serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L at baseline. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Page 89 of 88 Allergy 1 2 3 4 5 6 7 8 Papadopoulos NG, et al - VOYAGE allergic mscpt |7 9 10 11 Figure S4. Effect of dupilumab on allergen-specific serum IgE levels during the 52-week treatment 12 period in patients with type 2 asthmaa and with baseline allergen-specific serum IgE levels ≥0.35 13 kU/mL. Aspergillus fumigatus (A), cat dander (B), Dermatophagoides farinae (C), 14 Dermatophagoides pteronyssinus (D), dog dander (E), German cockroach (F), Alternaria 15 tenuis/alternata (G), and Cladosporium herbarum/hormodendrum (H). 16 17 18 19 20 21 Fo 22 23 24 rP 25 26 27 28 ee 29 30 31 rR 32 33 34 35 ev 36 37 38 iew 39 40 41 42 43 44 45 46 47 48 49 50 51 aType2 asthma is defined as patients with asthma with baseline blood eosinophils ≥ 150 cells/µL or FeNO ≥ 52 20 ppb at baseline. CI, Confidence interval; q2w, every 2 weeks. 53 54 55 56 57 58 59 60