Original Article Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose Christian Domingo, MDa, Jorge F. Maspero, MDb, Mario Castro, MD, MPHc, Nicola A. Hanania, MD, MSd, Linda B. Ford, MDe, David M.G. Halpin, MBBS, DPhil, FRCPf, David J. Jackson, MRCP, MS, PhDg,h, Nadia Daizadeh, PhDi, Michel Djandji, MDi, Colin P. Mitchell, PhDi, Nora Crikelairj, Juby A. Jacob-Nara, MD, MPH, DHSck, Yamo Deniz, MDj, Paul J. Rowe, MDk, and Benjamin Ortiz, MDj Barcelona, Spain; Buenos Aires, Argentina; Kansas City, Kan; Houston, Texas; Bellevue, Neb; Exeter and London, United Kingdom; Cambridge, Mass; Tarrytown, NY; and Bridgewater, NJ What is already known about this topic? Oral corticosteroids (OCS) are occasionally used to manage severe asthma, but their long-term use is associated with considerable adverse side effects. There is an important clinical need for novel OCS-sparing treatment strategies. What does this article add to our knowledge? This analysis showed dupilumab significantly reduced the OCS dose, improved the likelihood of no longer requiring OCS, and improved clinical outcomes in patients with OCS-dependent severe asthma receiving a lower or higher OCS dose at baseline. How does this study impact current management guidelines? The Global Initiative for Asthma (GINA) does not recommend maintenance OCS to manage severe asthma if other options are available. Dupilumab provides an effective OCS-sparing treatment with a demonstrated safety profile for patients taking lower or higher OCS at baseline. BACKGROUND: Dupilumab, a fully human monoclonal versus placebo reduced oral corticosteroid (OCS) dose and antibody, blocks the shared receptor component for improved clinical outcomes in patients with OCS-dependent interleukin-4/-13, key and central drivers of type 2 inflamma- severe asthma. Dupilumab efficacy in patients with varying tion in multiple diseases. In the phase 3 LIBERTY ASTHMA disease burden (defined by baseline OCS dose) has not been VENTURE (VENTURE) study (NCT02528214), dupilumab assessed. a Pulmonary Service, Parc Taulí Corporation, Sabadell, Autonomous University of Sanofi, and Teva; and reports royalties from Elsevier. N. A. Hanania reports Barcelona (UAB), Barcelona, Spain research support from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; b Fundación CIDEA, Buenos Aires, Argentina and is a consultant for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, c Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi. L. B. Ford reports grant School of Medicine, Kansas City, Kan support through institution from 3M, Aimmune Therapeutics, AstraZeneca, DBV d Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Technologies, Genentech, GlaxoSmithKline, Glenmark, Hoffmann-La Roche, Houston, Texas Novartis, Pearl Pharmaceuticals, Sanofi, and Teva; and is a national consultant for e Asthma & Allergy Center, Bellevue, Neb Sanofi. D. M. G. Halpin is an advisory board member and has received speaker f University of Exeter Medical School, College of Medicine and Health, University of fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Exeter, Exeter, UK GlaxoSmithKline, Novartis, Pfizer, Sandoz, and Sanofi. D. J. Jackson reports g King’s College London, London, UK advisory board fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, h Guy’s and St. Thomas’ NHS Foundation Trust, London, UK Novartis, Sanofi, and Teva. N. Daizadeh is a former employee of Sanofi and may i Sanofi, Cambridge, Mass hold stock and/or stock options in the company. M. Djandji, C. P. Mitchell, J. A. j Regeneron Pharmaceuticals, Inc., Tarrytown, NY Jacob-Nara, and P. J. Rowe are employees of Sanofi and may hold stock and/or k Sanofi, Bridgewater, NJ stock options in the company. N. Crikelair and Y. Deniz are employees and Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials. shareholders of Regeneron Pharmaceuticals, Inc. B. Ortiz is a former employee gov Identifier: NCT02528214. Medical writing/editorial assistance was funded and shareholder of Regeneron Pharmaceuticals, Inc. by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc., according to the Good Received for publication September 23, 2021; revised February 22, 2022; accepted Publication Practice guideline. for publication March 7, 2022. Conflicts of interest: C. Domingo reports travel and speaker fees from ALK, Allergy Available online April 8, 2022. Therapeutics, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer Corresponding author: Christian Domingo, MD, S. Pneumologia, Planta Primera, Pharma, GlaxoSmithKline, HAL Allergy, ImmunoTek, Menarini, Novartis, Edifici Tauli Nou, Corporació Sanitària Parc Taulí, Parc Tauli 1, 08208 Sabadell, Pfizer, Sanofi-Aventis, Stallergenes Greer, Takeda, and Teva. J. F. Maspero is a Barcelona, Spain. E-mail: cdomingo@tauli.cat. consultant for AstraZeneca and Sanofi; has received speaker fees from 2213-2198 GlaxoSmithKline, Menarini, Novartis, and Uriach; and has received research Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy grants from Novartis. M. Castro reports research support from American Lung of Allergy, Asthma & Immunology. This is an open access article under the CC Association, AstraZeneca, GlaxoSmithKline, National Institutes of Health (NIH), BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Novartis, PCORI, Pulmatrix, Sanofi-Aventis, and Shionogi; is a consultant for https://doi.org/10.1016/j.jaip.2022.03.020 Genentech, Novartis, Sanofi-Aventis, and Teva; reports speaker fees from AstraZeneca, Genentech, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., 1835 1836 DOMINGO ET AL J ALLERGY CLIN IMMUNOL PRACT JULY 2022 glaucoma, depression, and anxiety.6,8 In addition, the long-term Abbreviations used use of systemic corticosteroids in adults is associated with greater ANCOVA- Analysis of covariance health care costs and health care resource utilization.9,10 CI- Confidence interval Long-term use of systemic corticosteroids and cumulative FEV1- Forced expiratory volume in 1 second exposure to OCS owing to repeated acute bursts are associated LS- Least squares with greater health care resource utilization and costs9,10 as a OCS- Oral corticosteroids OR- Odds ratio result of the increase in the incidence of adverse events. Novel TEAE- Treatment-emergent adverse event OCS-sparing treatment strategies are, therefore, important to VENTURE- LIBERTY ASTHMA VENTURE help improve patient outcomes.11 Several biologics blocking type 2 inflammatory pathways have demonstrated OCS-sparing effect and are approved to treat OBJECTIVE: This post hoc analysis of VENTURE evaluated OCS-dependent severe asthma,12 including dupilumab.13,14 dupilumab efficacy across subgroups defined by baseline OCS Dupilumab is a fully human VelocImmune-derived15,16 mono- dose. clonal antibody that blocks the shared receptor component for METHODS: The OCS dose, proportion no longer needing OCS interleukin-4 and interleukin-13, key and central drivers of type at week 24, annualized severe exacerbation rate, and least squares 2 inflammation in multiple diseases.17,18 In the phase 3 mean change from baseline in pre- and post-bronchodilator LIBERTY ASTHMA VENTURE (VENTURE) study forced expiratory volume in 1 second at week 24 were evaluated (NCT02528214), add-on dupilumab versus placebo significantly in VENTURE patients with OCS-dependent severe asthma reduced maintenance OCS dose over 24 weeks by 70.1% versus receiving dupilumab 300 mg every 2 weeks versus placebo, 41.9%.19 Despite the decreased use of OCS in this population, categorized by a baseline OCS dose of less than 10 mg/d or 10 or dupilumab reduced the severe asthma exacerbation rate by 59% more mg/d. and improved pre-bronchodilator forced expiratory volume in 1 RESULTS: Dupilumab reduced daily OCS dose from baseline at second (FEV1) by 0.22 L compared with placebo; these findings week 24 in both dose groups. In dupilumab-/placebo-treated occurred independently of baseline eosinophil levels.19 patients with a baseline OCS dose of less than 10 mg/d and 10 or Whereas VENTURE demonstrated the OCS-sparing effect of more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 dupilumab in patients with severe asthma with chronic OCS, the (P < .01/P < .05), respectively. Dupilumab significantly reduced study enrolled patients with a wide range of OCS doses at the annualized severe exacerbation rate by 71% and 48% baseline (5e35 mg/d; median 10 mg/d). It was unknown (P < .01/P < .05). At week 24, dupilumab improved pre- and whether the efficacy of dupilumab was consistent across patients post-bronchodilator forced expiratory volume in 1 second in with varying OCS doses at baseline—that is, if the clinical patients in both dose groups. benefit of dupilumab differed in patients receiving lower doses CONCLUSIONS: In patients with OCS-dependent severe compared with those receiving higher doses of OCS. Therefore, asthma receiving lower or higher baseline OCS doses, dupilumab this post hoc analysis of VENTURE aimed to evaluate the efficacy significantly reduced the OCS dose and improved the likelihood of dupilumab in reducing OCS dose and improving clinical of no longer requiring OCS while also reducing exacerbations outcomes in patients with OCS-dependent severe asthma and improving lung function. Ó 2022 The Authors. Published receiving daily OCS doses less than 10 mg or 10 or more by Elsevier Inc. on behalf of the American Academy of Allergy, (prednisone or prednisolone or equivalent) at baseline. Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- METHODS nc-nd/4.0/). (J Allergy Clin Immunol Pract 2022;10:1835-43) VENTURE study design Key words: Asthma; Dupilumab; Exacerbation; Lung function; The LIBERTY ASTHMA VENTURE study was a phase 3, Chronic oral corticosteroids; Interleukin-4; Interleukin-13 randomized, double-blind, placebo-controlled trial that assessed the efficacy and safety of dupilumab in patients with OCS-dependent severe asthma. A complete description of the VENTURE study INTRODUCTION design has been previously published.19 In short, OCS dose was Patients with severe asthma represent approximately 3% to optimized during screening over 3 to 10 weeks and adjusted to 10% of the total asthma patient population.1-3 Severe asthma is a establish the lowest dose required to manage patients’ asthma predominantly type 2edriven disease,4,5 and prior to the era of symptoms. Patients were randomized 1:1 to receive subcutaneous biologics targeting type 2 inflammation, oral corticosteroids dupilumab 300 mg every 2 weeks or matched placebo as an add-on (OCS) were the only therapeutic option for patients with asthma to their adjusted OCS dose for 24 weeks. The treatment period uncontrolled with inhaled therapy alone.6 It is estimated that consisted of a 4-week induction phase during which patients were 30% to 46% of patients with severe asthma used to receive randomized to investigational treatment coadministered with the long-term OCS.6,7 However, national registry data from several optimal OCS dose established during screening; a 16-week OCS countries still highlight high proportions of patients continuing reduction phase (week 4e20), during which the OCS dose was to be managed with OCS.3,5 In a retrospective, nationwide study down-titrated every 4 weeks following a predetermined schedule if in Spain, 31.2% of patients with severe asthma were OCS- the patient did not meet any predefined criteria prohibiting dose dependent3 and 51.7% of patients with severe asthma in the reduction; and a 4-week maintenance phase in which patients U.K. Severe Asthma Registry were on maintenance OCS.5 remained on the OCS dose established at week 20.19 Despite the efficacy of OCS in severe asthma, their use is VENTURE was conducted in accordance with the Declaration of associated with side effects, including weight gain, metabolic Helsinki and International Conference on Harmonisation Good syndrome, type 2 diabetes, bone density loss and fractures, Clinical Practice guidelines and was approved by local institutional J ALLERGY CLIN IMMUNOL PRACT DOMINGO ET AL 1837 VOLUME 10, NUMBER 7 review boards and ethics committees. All patients provided written (<150, 150 cells/mL), visit, treatment-by-visit interaction, baseline informed consent before participating in the trial. pre- or post-bronchodilator FEV1, and baseline-by-visit interaction as covariates. Subgroup, subgroup-by-treatment, and subgroup-by- Patients treatment-by-visit interactions were included as additional Patients aged 12 years or older who had physician-diagnosed covariates in the model used to derive interaction P values. asthma for 1 or more years based on the Global Initiative for Between-treatment differences in the proportion of patients no Asthma (GINA) 2014 definition20 and who were receiving longer requiring OCS at week 24 were expressed as odds ratios treatment with regular systemic corticosteroids in the previous (ORs). The ORs for the proportion of patients no longer requiring 6 months (5e35 mg/d of prednisone or prednisolone or equivalent) OCS at week 24 were calculated by combining results from participated in VENTURE.19 In this post hoc analysis, patients were analyzing multiple imputed data using a logistic regression model by divided into subgroups defined by baseline optimized OCS dose less Rubin’s rule, with treatment group, optimized OCS dose at baseline, than 10 mg/d and 10 or more mg/d. The rationale for this threshold study center region, and baseline eosinophils (<150 vs 150 cells/ was based on the median baseline optimized OCS dose of 10 mg/d mL) as covariates. The overall significance of the subpopulation-by- in VENTURE. The subgroup of patients who were not able to treatment interaction was calculated using a logistic regression discontinue OCS at week 24 was also analyzed. model, with treatment group, optimized OCS dose at baseline, study Post hoc analysis outcomes center region, baseline eosinophils (<150 vs 150 cells/mL), The mean OCS dose at baseline, week 12, and week 24, and subpopulation, and subpopulation-by-treatment interaction as reduction from baseline in OCS dose at these times, as well as the covariates. proportion of patients who were able to be fully tapered off OCS by week 24, were analyzed in patients receiving less than 10 mg/d and RESULTS 10 or more mg/d OCS at baseline. Mean OCS dose at baseline, Patients week 12, and week 24 was also assessed in patients who did not A total of 210 patients were randomized in LIBERTY discontinue OCS at week 24. Clinical efficacy outcomes included ASTHMA VENTURE, 103 to dupilumab and 107 to placebo. the annualized rate of severe asthma exacerbations during the At baseline, 82 patients were receiving a daily OCS dose of less 24-week treatment period and the change from baseline in pre- and than 10 mg (dupilumab n ¼ 46; placebo n ¼ 36), and 128 post-bronchodilator FEV1 (L) over time up to week 24, which were patients were receiving a daily OCS dose of 10 or more mg analyzed in all 3 subgroups. (dupilumab n ¼ 57; placebo n ¼ 71). Baseline patient de- mographics and clinical characteristics were generally consistent Post hoc statistical analysis between the dupilumab and the placebo groups (Table I). Mean All analyses were post hoc and performed on the overall intention- (SD) patient age was 52.9  12.6 years and 50.3  12.6 years to-treat population separated into subpopulations of patients based in patients receiving an OCS dose of less than 10 mg/d and 10 or on their baseline OCS dose (ie, <10 and 10 mg/d) or ability to more mg/d at baseline, respectively. The majority of patients stop OCS at week 24. Changes in OCS dose were calculated as least (59%e61%) were female. Pre- and post-bronchodilator FEV1 squares (LS) mean reduction from baseline. The LS mean differences and 5-item Asthma Control Questionnaire scores were compa- between the dupilumab and the placebo groups were calculated for rable between treatment groups and subpopulations. Differences both baseline OCS dose subpopulations (<10 and 10 mg/d) by between the groups receiving an OCS dose of less than combining results from analyzing multiple imputed data using an 10 mg/d and 10 or more mg/d included a greater exacerbation analysis of covariance (ANCOVA) model by Rubin’s rule. The history and higher fractional exhaled nitric oxide levels in the ANCOVA model included treatment group, optimized OCS dose at latter group, which are consistent with more severe disease. The baseline, study center region, and baseline eosinophil level subgroup mean (SD) number of severe asthma exacerbations in the past (<150 vs 150 cells/mL) as covariates. The overall significance of year in the dupilumab and placebo groups was 1.89  1.86 and the subpopulation-by-treatment interaction was calculated using an 1.67  1.22, respectively, in the group receiving an OCS dose of ANCOVA model with treatment group, optimized OCS dose at less than 10 mg/d, and 2.11  2.25 and 2.42  2.58, respec- baseline, study center region, baseline eosinophil level subgroup tively, in the group receiving an OCS dose of 10 or more mg/d. (<150 vs 150 cells/mL), subpopulation, and subpopulation-by- The mean optimized baseline OCS dose in the dupilumab and treatment interaction as covariates. placebo groups was 6.14  1.26 mg/d and 6.18  1.40 mg/d, The adjusted annualized rate of severe exacerbations was respectively, in the group receiving an OCS dose of less than calculated using a negative binomial model with the total number of 10 mg/d, and 14.47  5.52 mg/d and 14.58  5.93 mg/d, events onset from randomization up to visit 11 (week 24) or last respectively, in the group receiving an OCS dose of 10 or contact date (whichever came earlier) as the response variable, and more mg/d. the treatment group, region, number of events within 1 year prior to the study, baseline eosinophils (<150, 150 cells/mL), subgroup, Reduction in OCS dose over time and treatment-by-subgroup interaction as covariates. The unadjusted Compared with placebo, dupilumab reduced the mean OCS annualized rate of severe exacerbations was calculated for patients dose over time in both subpopulations (P value for interaction at who did not reduce OCS dose to 0 mg/d at week 24. week 12 ¼ .59; P value for interaction at week 24 ¼ .54) Changes in pre- and post-bronchodilator FEV1 were calculated as (Figure 1). In the subgroup receiving an OCS dose of less than 10 LS mean change from baseline by visit. The LS mean and LS mean mg/d, the mean daily OCS dose was 6.1 mg at baseline and 1.3 difference in dupilumab versus placebo were derived from a mixed- mg (78% reduction) and 1.2 mg (80% reduction) at weeks 12 effect model with repeated measures, with the change from baseline and 24, respectively, in patients receiving dupilumab. For patients in pre- or post-bronchodilator FEV1 as the response variable, and the receiving placebo, the mean daily OCS dose was 6.2 mg at treatment group, age, sex, height, region, baseline eosinophils baseline and 3.2 mg (47% reduction) and 3.5 mg (44% 1838 DOMINGO ET AL J ALLERGY CLIN IMMUNOL PRACT JULY 2022 TABLE I. Baseline demographics and clinical characteristics Baseline OCS dose < 10 mg/d Baseline OCS dose ‡ 10 mg/d Characteristic Placebo (n [ 36) Dupilumab (n [ 46) Placebo (n [ 71) Dupilumab (n [ 57) Age (y), mean (SD) 49.8 (13.6) 55.4 (11.2) 51.2 (12.5) 49.1 (12.8) Male, n (%) 14 (38.9) 19 (41.3) 28 (39.4) 22 (38.6) BMI (kg/m2), mean (SD) 29.1 (6.1) 28.0 (5.4) 30.1 (6.0) 29.6 (6.3) Age at asthma onset (y), mean (SD) 31.5 (17.6) 34.0 (21.3) 31.6 (15.9) 28.9 (16.5) Time since asthma diagnosis (y), 18.27 (13.25) 21.42 (17.89) 19.63 (12.90) 20.22 (11.91) mean (SD) Number of severe asthma 1.67 (1.22) 1.89 (1.86) 2.42 (2.58) 2.11 (2.25) exacerbations experienced in the past year, mean (SD) Preoptimized daily OCS dose (mg/d), 7.03 (2.31) 7.76 (3.21) 14.26 (5.86) 15.04 (6.50) mean (SD) Optimized daily OCS dose (mg/d), 6.18 (1.40) 6.14 (1.26) 14.58 (5.93) 14.47 (5.52) mean (SD) Preoptimized daily OCS dose (mg/d), 5.00 7.50 10.00 12.50 median Optimized daily OCS dose (mg/d), 6.25 5.00 12.50 12.50 median Ongoing atopic condition,* n (%) 25 (69.4) 31 (67.4) 52 (73.2) 43 (75.4) Atopic dermatitis, n (%) 3 (8.3) 3 (6.5) 5 (7.0) 5 (8.8) Chronic rhinosinusitis, n (%) 11 (30.6) 10 (21.7) 17 (23.9) 12 (21.1) Nasal polyposis, n (%) 9 (25.0) 11 (23.9) 12 (16.9) 12 (21.1) Former smoker, n (%) 7 (19.4) 14 (30.4) 10 (14.1) 10 (17.5) Pre-bronchodilator FEV1 (L), 1.62 (0.60) 1.49 (0.57) 1.63 (0.62) 1.57 (0.49) mean (SD) Post-bronchodilator FEV1 (L), 1.93 (0.80) 1.79 (0.60) 1.87 (0.70) 1.86 (0.60) mean (SD) FEV1 reversibility (%), mean (SD) 21.24 (31.69) 22.49 (29.83) 17.03 (17.45) 19.07 (17.31) ACQ-5 score (scale 0e6), mean (SD) 2.57 (1.04) 2.27 (1.28) 2.59 (1.12) 2.53 (1.21) Blood eosinophils (Giga/L), 0.27 (0.15e0.47) 0.33 (0.16e0.51) 0.22 (0.11e0.41) 0.26 (0.17e0.52) median (IQR) Total IgE, median (IU/mL), (IQR) 143.00 (74.00e397.00) 179.00 (96.00e389.00) 135.00 (36.00e307.00) 201.00 (84.00e611.00) FeNO (ppb), median (IQR) 23.00 (15.00e52.00) 27.00 (14.00e46.00) 30.00 (18.00e58.00) 35.50 (16.50e51.00) ACQ-5, 5-Item Asthma Control Questionnaire; BMI, body mass index; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IQR, interquartile range; ppb, parts per billion. *A patient is considered to have an ongoing atopic medical condition if he or she has any of the following ongoing conditions: atopic dermatitis, allergic conjunctivitis, allergic rhinitis, eosinophilic esophagitis, food allergy, or hives; or has baseline total IgE  100 IU/mL and  1 aeroantigen-specific IgE (0.35 IU/mL) at baseline. reduction) at weeks 12 and 24, respectively. The LS mean dif- or more mg/d OCS at study baseline, dupilumab significantly ference in reduction from baseline between dupilumab and pla- reduced the adjusted annualized rate of severe exacerbations cebo was 1.8 mg at week 12 (95% CI 0.65e2.85; P ¼.0017) and compared with placebo by 71% (relative risk 0.29; 95% CI 2.1 mg at week 24 (95% CI 0.84e3.32; P ¼ .001) (Figure 1, A). 0.13e0.64; P ¼ .003) and 48% (relative risk 0.52; 95% CI In the subgroup receiving an OCS dose of 10 or more mg/d, the 0.31e0.86; P ¼ .01), respectively (Figure 2). mean daily OCS dose was 14.5 mg at baseline and 6.3 mg (58% Dupilumab improved pre- and post-bronchodilator FEV1 at reduction) at week 12 and 4.7 mg (69% reduction) at week 24 in week 24 compared with placebo, and improvements from patients receiving dupilumab. For patients treated with placebo, baseline FEV1 were sustained and comparable between both the mean daily OCS dose was 14.6 mg at baseline and, at weeks subgroups (P value for interaction: pre-bronchodilator 12 and 24, respectively, 7.3 mg (51% reduction) and 7.8 mg FEV1 ¼ .54; post-bronchodilator FEV1 ¼ .85) (Figure 3). In (46% reduction). The LS mean difference in reduction from the subpopulation of patients who received a baseline OCS dose baseline between dupilumab and placebo was 1.2 mg at week 12 of less than 10 mg/d, LS mean (standard error) change from (95% CI e0.61 to 3.01; P ¼ 0.19) and 3.3 mg at week 24 (95% baseline at week 24 in pre-bronchodilator FEV1 was 0.26 L CI 0.96e5.54; P ¼ .005) (Figure 1, B). (0.07) in the dupilumab group, and 0.11 L (0.08) in the placebo group (LS mean difference between dupilumab and placebo: Clinical outcomes 0.15 L; 95% CI 0.04 to 0.33; P ¼ .13) (Figure 3, A). Dupilumab reduced the adjusted annualized rate of severe Dupilumab improved pre-bronchodilator FEV1 from baseline at asthma exacerbations compared with placebo, irrespective of the week 24 in the subgroup of patients who received an OCS dose baseline OCS dose (P value for interaction ¼ .19) (Figure 2). In of 10 or more mg/d to a similar magnitude as the low-dose the subgroups of patients who received less than 10 mg/d and 10 subgroup (0.23 L [0.07]), while pre-bronchodilator FEV1 J ALLERGY CLIN IMMUNOL PRACT DOMINGO ET AL 1839 VOLUME 10, NUMBER 7 Placebo Dupilumab 300 mg q2w 16.0 16.0 14.6 14.5 14.0 14.0 Mean OCS dose (mg/d) Mean OCS dose (mg/d) 12.0 12.0 10.0 10.0 7.8 8.0 8.0 7.3 6.2 6.1 6.3 6.0 6.0 4.7 4.0 3.2 3.5 4.0 2.0 1.3 1.2 2.0 n = 36 n = 46 n = 36 n = 45 n = 36 n = 45 n = 71 n = 57 n = 71 n = 56 n = 70 n = 56 0 0 Baseline Wk 12 Wk 24 Baseline Wk 12 Wk 24 FIGURE 1. Mean OCS dose at baseline, wk 12, and wk 24 in patients receiving (A) OCS dose < 10 mg/d and (B) OCS dose 10 mg/d at baseline. q2w, Every 2 wk. Placebo Dupilumab 300 mg q2w 1.8 1.62 (1.07–2.46) 71% 1.52 48% exacerbation rate, estimate (95% CI) 1.6 (1.14–2.03) Adjusted annualized severe 1.4 1.2 1.0 * 0.8 0.78 † (0.50–1.23) 0.47 0.6 (0.23–0.94) 0.4 0.2 n = 36 n = 46 n = 71 n = 57 0 Baseline OCS dose Baseline OCS dose < 10 mg/d ≥ 10 mg/d FIGURE 2. Adjusted annualized rate of severe exacerbations. q2w, Every 2 wk. *P < .05; †P < .01; vs placebo. decreased by 0.03 L (0.06) in placebo-treated patients (LS mean at the start of the trial (P value for interaction ¼ .36) (Figure 4). difference between dupilumab and placebo, 0.26 L; 95% CI In patients who received less than 10 mg/d OCS at study 0.09e0.43; P ¼ .003) (Figure 3, B). baseline, 72.3% treated with dupilumab versus 41.7% treated In patients with an OCS dose of less than 10 mg/d at baseline, with placebo no longer required OCS by week 24 (OR dupi- post-bronchodilator FEV1 at week 24 improved by 0.15 L (0.06) lumab vs placebo 3.75; 95% CI 1.40e10.01; P ¼ .008) from baseline in patients treated with dupilumab and decreased (Figure 4). In patients with an OCS dose of 10 or more mg/d at by 0.05 L (0.06) in patients treated with placebo (LS mean study baseline, 37.0% receiving dupilumab versus 22.5% difference between dupilumab and placebo 0.20 L; 95% CI receiving placebo no longer required OCS by week 24 (OR 0.05e0.35; P ¼ .01) (Figure 3, C). Similar results were observed dupilumab vs placebo 2.32; 95% CI 1.00e5.38; P ¼ .05) in the subgroup of patients receiving 10 or more mg/d OCS at (Figure 4). baseline. At week 24, post-bronchodilator FEV1 improved by 0.13 L (0.06) from baseline in patients receiving dupilumab and Outcomes in patients who did not eliminate OCS by decreased by 0.05 L (0.05) in patients receiving placebo (LS week 24 mean difference between dupilumab and placebo 0.18 L; 95% Baseline patient demographics and clinical characteristics of CI 0.02e0.34; P ¼ .03) (Figure 3, D). patients who required OCS at week 24 were generally consistent between treatment arms (Table II). The mean daily OCS dose at Proportion of patients who no longer required OCS baseline and week 24 was 13.4 mg and 6.7 mg (44% reduction), at week 24 respectively, in patients treated with dupilumab, and 12.8 mg A greater proportion of patients treated with dupilumab were and 8.9 mg (23% reduction), respectively, in patients treated able to eliminate OCS by week 24, irrespective of the OCS dose with placebo (Figure 5). 1840 DOMINGO ET AL J ALLERGY CLIN IMMUNOL PRACT JULY 2022 Placebo Dupilumab 300 mg q2w 0.4 0.4 * * † * † † † Change from baseline in pre-bronchodilator Change from baseline in pre-bronchodilator FEV1, LS mean (± SE) 0.3 0.3 FEV1, LS mean (± SE) 0.2 0.2 0.1 0.1 0 0 –0.1 –0.1 –0.2 –0.2 0 2 4 6 8 12 16 20 24 0 2 4 6 8 12 16 20 24 Wk Wk No. of patients No. of patients Placebo 36 35 35 36 36 36 35 36 34 Placebo 71 69 69 70 71 69 71 71 70 A Dupilumab 300 mg q2w 46 45 44 45 44 45 44 45 44 B Dupilumab 300 mg q2w 57 56 54 56 56 54 54 55 53 0.4 * 0.4 * * Change from baseline in post-bronchodilator Change from baseline in post-bronchodilator 0.3 0.3 FEV1, LS mean (± SE) FEV1, LS mean (± SE) 0.2 0.2 0.1 0.1 0 0 –0.1 –0.1 –0.2 –0.2 0 12 24 0 12 24 Wk Wk No. of patients No. of patients Placebo 34 33 31 Placebo 71 68 69 Dupilumab 300 mg q2w 45 42 42 Dupilumab 300 mg q2w 57 53 50 FIGURE 3. LS mean change from baseline in pre-bronchodilator FEV1 in patients receiving (A) OCS < 10 mg/d and (B) OCS  10 mg/d and in post-bronchodilator FEV1 in patients receiving (C) OCS < 10 mg/d and (D) OCS  10 mg/d. q2w, Every 2 wk; SE, standard error. *P < .05; †P < .01; vs placebo. Placebo Dupilumab 300 mg q2w OR vs placebo (95% CI) OR vs placebo (95% CI) 3.75 (1.40–10.01) 2.32 (1.00–5.38) 100.0 † * 90.0 Proportion of patients no longer 80.0 72.3 requiring OCS at wk 24 (%) 70.0 60.0 50.0 41.7 40.0 37.0 30.0 22.5 20.0 10.0 0 Baseline OCS dose Baseline OCS dose < 10 mg/d ≥ 10 mg/d FIGURE 4. Proportion of patients who no longer required OCS at wk 24. q2w, Every 2 wk. *P < .05; †P < .01; vs placebo. Dupilumab- versus placebo-treated patients who did not (0.05) in the placebo group (LS mean difference between completely discontinue OCS at week 24 also experienced dupilumab and placebo 0.21 L; 95% CI 0.05e0.36; P ¼ .01) improvements in clinical outcomes. The unadjusted annualized (Figure 6, A). Similarly, post-bronchodilator FEV1 improved by rate of severe asthma exacerbations was numerically lower in the 0.12 L (0.06) from baseline in the dupilumab group and dupilumab (1.27) versus placebo (2.10) groups. At week 24, pre- decreased by 0.06 L (0.05) in the placebo group (LS mean bronchodilator FEV1 significantly improved by 0.20 L (0.06) difference between dupilumab and placebo 0.18 L; 95% CI from baseline in the dupilumab group and decreased by 0.01 L 0.03-0.34; P ¼ .02) (Figure 6, B). J ALLERGY CLIN IMMUNOL PRACT DOMINGO ET AL 1841 VOLUME 10, NUMBER 7 TABLE II. Baseline demographics and clinical characteristics of patients who did not reduce their OCS dose to 0 mg/d at wk 24 ITT Characteristic Placebo (n [ 75) Dupilumab (n [ 47) Age (y), mean (SD) 50.8 (12.7) 49.7 (11.7) Male, n (%) 25 (33.3) 16 (34.0) BMI (kg/m2), mean (SD) 29.79 (5.82) 29.48 (6.37) Age at asthma onset (y), mean (SD) 29.9 (16.1) 27.9 (17.4) Time since asthma diagnosis (y), mean (SD) 20.94 (13.30) 21.84 (14.76) Number of severe asthma exacerbations experienced in the past year, mean (SD) 2.47 (2.32) 2.34 (2.40) Preoptimized daily OCS dose (mg/d), mean (SD) 12.71 (6.17) 14.28 (7.20) Optimized daily OCS dose (mg/d), mean (SD) 12.77 (6.75) 13.35 (6.72) Preoptimized daily OCS dose (mg/d), median 10.00 12.50 Optimized daily OCS dose (mg/d), median 10.00 12.50 Ongoing atopic condition,* n (%) 52 (69.3) 31 (66.0) Atopic dermatitis, n (%) 6 (8.0) 3 (6.4) Chronic rhinosinusitis, n (%) 20 (26.7) 13 (27.7) Nasal polyposis, n (%) 14 (18.7) 11 (23.4) Former smoker, n (%) 11 (14.7) 14 (29.8) Pre-bronchodilator FEV1 (L), mean (SD) 1.52 (0.56) 1.49 (0.55) Post-bronchodilator FEV1 (L), mean (SD) 1.75 (0.69) 1.75 (0.65) FEV1 reversibility (%), mean (SD) 16.88 (17.18) 17.57 (14.92) ACQ-5 score (scale 0e6), mean (SD) 2.59 (1.06) 2.35 (1.24) Blood eosinophils (Giga/L), median (IQR) 0.23 (0.11e0.47) 0.24 (0.16e0.54) Total IgE (IU/mL), median (IQR) 135.00 (40.00e302.00) 169.00 (50.00e498.00) FeNO (ppb), median (IQR) 32.00 (18.00e56.00) 32.50 (14.00e53.00) ACQ-5, 5-Item Asthma Control Questionnaire; BMI, body mass index; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IQR, interquartile range; ITT, intention-to-treat; ppb, parts per billion. *A patient is considered to have an ongoing atopic medical condition if he or she has any of the following ongoing conditions: atopic dermatitis, allergic conjunctivitis, allergic rhinitis, eosinophilic esophagitis, food allergy, or hives; or has baseline total IgE  100 IU/mL and  1 aeroantigen-specific IgE (0.35 IU/mL) at baseline. Placebo Dupilumab 300 mg q2w DISCUSSION 16.0 In the LIBERTY ASTHMA VENTURE study, subcutane- 14.0 13.4 ous dupilumab 300 mg every 2 weeks reduced OCS dose and 12.8 improved clinical outcomes in patients aged 12 years or older 12.0 with OCS-dependent severe asthma.19 In this post hoc analysis Mean OCS dose (mg/d) 10.0 of VENTURE, which assessed whether subpopulations of pa- 8.9 8.0 7.6 7.6 tients with OCS-dependent severe asthma responded differ- 6.7 6.0 ently to dupilumab based on their OCS dose at baseline, dupilumab demonstrated consistent efficacy in patients 4.0 receiving a lower or higher OCS dose at baseline. Dupilumab 2.0 significantly reduced the mean OCS dose over time from a 0 n = 75 n = 47 n = 75 n = 47 n = 75 n = 47 mean daily dose at baseline of 6.1 mg to 1.2 mg at week 24 in Baseline Wk 12 Wk 24 patients receiving a baseline OCS dose of less than 10 mg/d, and from 14.5 mg to 4.7 mg in patients receiving a baseline FIGURE 5. Mean OCS dose at baseline, wk 12, and wk 24 in OCS dose of 10 or more mg/d. Dupilumab also significantly patients who did not reduce OCS dose to 0 mg/d at wk 24. q2w, improved the odds of no longer requiring OCS at week 24 Every 2 wk. versus placebo (72.3% vs 41.7% and 37.0% vs 22.5% of pa- tients receiving a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, respectively). Safety While reducing OCS dose, dupilumab improved clinical out- Dupilumab was generally well tolerated in VENTURE. In the comes across patients receiving a lower or higher OCS dose at overall safety population, the incidence of treatment-emergent baseline, regardless of their ability to completely stop using OCS at adverse events was similar across treatment groups, and the week 24. Dupilumab significantly reduced the adjusted annualized most common treatment-emergent adverse events reported in the rate of severe asthma exacerbations by 71% and 48% versus pla- dupilumab versus placebo groups, respectively, were transient cebo in patients receiving a baseline OCS dose of less than blood eosinophilia (14% vs 1%) and injection-site reactions (9% 10 mg/d and 10 or more mg/d, respectively. Consistent with the vs 4%). The reported adverse events of eosinophilia were overall population, a numerical reduction in severe exacerbation laboratory findings without clinical consequence, and associated rate was observed in dupilumab-treated patients who did not adverse events were not reported. discontinue OCS at week 24. Dupilumab also improved lung 1842 DOMINGO ET AL J ALLERGY CLIN IMMUNOL PRACT JULY 2022 Placebo Dupilumab 300 mg q2w 0.4 * † * * * † * 0.4 * Change from baseline in post-bronchodilator Change from baseline in pre-bronchodilator 0.3 0.3 FEV1 (L), LS mean (± SE) FEV1 (L), LS mean (± SE) 0.2 0.2 0.1 0.1 0 0 –0.1 –0.1 –0.2 –0.2 0 2 4 6 8 12 16 20 24 0 12 24 Wk Wk No. of patients No. of patients Placebo 75 73 73 74 75 73 74 75 74 Placebo 74 71 72 Dupilumab 300 mg q2w 47 47 43 47 47 45 45 46 44 Dupilumab 300 mg q2w 47 43 40 FIGURE 6. LS mean change from baseline in (A) pre-bronchodilator FEV1 and (B) post-bronchodilator FEV1 in patients who did not reduce OCS dose to 0 mg/d at wk 24. q2w, Every 2 wk; SE, standard error. *P < .05; †P < .01; vs placebo. function in the subgroups of patients defined by baseline OCS systematically accompanied by the statistically significant dose and in those who did not reduce daily OCS dose to 0 mg at improvement in lung function24-26,28,29 demonstrated by week 24. Pre-bronchodilator and post-bronchodilator FEV1 were dupilumab in both VENTURE30 and the post hoc analysis improved over time with dupilumab treatment consistently in presented here. patients who received an OCS dose of less than 10 mg/d or 10 or The limitations of this study are inherent to its design, as all more mg/d at baseline, despite the high placebo response for pre- the analyses were post hoc. It is possible that the 1:1 dupilu- bronchodilator FEV1 in patients with a baseline OCS dose of less mab:placebo randomization in the VENTURE primary study than 10 mg/d. A decline in post-bronchodilator FEV1 values over may not be maintained in this post hoc analysis. The limited time was observed in patients treated with placebo. Dupilumab 24-week study duration and titration protocol of VENTURE did therefore appears to preserve and improve lung function despite a not allow for down-titration of the OCS dose to 0 mg in patients reduction in OCS dose. receiving an optimized OCS dose of 35 mg/d at baseline. Although, in some cases, the effect of dupilumab was greater in Furthermore, it is possible that some patients could not reduce the subgroup of patients receiving less than 10 mg/d OCS at OCS to 0 mg/d owing to adrenal insufficiency. baseline, this trend was not consistent across clinical outcomes, In conclusion, this post hoc analysis shows that dupilumab and no significant interaction effects were observed for any significantly reduced the OCS dose, improved the likelihood of outcome assessed. Therefore, efficacy of dupilumab in OCS dose no longer requiring OCS, and improved clinical outcomes in reduction and clinical outcome improvement is independent of patients with OCS-dependent severe asthma receiving a lower or baseline OCS dose category. higher OCS dose at baseline. OCS-sparing treatment strategies are increasingly important in improving patient outcomes,11,12,21 due to the well-known toxicity and morbidity burden associated with long-term OCS use,6,8,12,22 in addition to the greater health care costs Acknowledgments and health care resource utilization connected with their This research was sponsored by Sanofi and Regeneron use.9,10,22 GINA 2020 recommended that, whereas add-on Pharmaceuticals, Inc. ClinicalTrials.gov Identifier: maintenance OCS of 7.5 or more mg/d prednisone equiva- NCT02528214. 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