CONFLICTS OF INTEREST
Maspero JF: AstraZeneca, Sanofi—consultant; GlaxoSmithKline, Menarini, Novartis, Uriach—speaker fees; Novartis—research grants. FitzGerald JM: AstraZeneca, GlaxoSmithKline, Novartis, Teva—advisory board; AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., Sanofi—research funding paid directly to UBC; GlaxoSmithKline—unrestricted grants; AstraZeneca, GlaxoSmithKline, Novartis—speaker honoraria; Vancouver Coastal Health—educational material. Pavord ID: Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva—speakers’ honoraria; AstraZeneca, Teva—organization of educational events; Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GlaxoSmithKline, Knopp Biosciences, Merck, Merck Sharp & Dohme, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, Inc., RespiVert, Sanofi, Schering‐Plough, Teva—advisory boards; AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Napp Pharmaceuticals, Teva—traveling grants; Chiesi—clinical trial support. Rice MS, Rowe P, Hardin M: Sanofi—employees, may hold stock and/or stock options in the company. Maroni J, Amin N, Ruddy M: Regeneron Pharmaceuticals, Inc.—employees and shareholders. Pirozzi G, Teper A: Sanofi—former employees, may hold stock and/or stock options in the company. Graham NMH: Regeneron Pharmaceuticals, Inc.—former employee and shareholder.
AUTHOR CONTRIBUTIONS
J.F. Maspero and J.M. Fitzgerald acquired data and provided interpretation of data (ICMJE Criterion #1), provided critical feedback (ICMJE Criterion #2), gave final approval for submission (ICMJE Criterion #3), and agreed to be accountable for the accuracy and integrity of this work (ICMJE Criterion #4). I.D. Pavord provided interpretation of data (#1), provided critical feedback (#2), gave final approval for submission (#3), and agreed to be accountable for the accuracy and integrity of this work (#4). M.S. Rice, J. Maroni, P. Rowe, G. Pirozzi, N. Amin, M. Ruddy, N.M.H. Graham, A. Teper and M. Hardin contributed to the conception and design of the study and provided interpretation of the data (#1), provided critical feedback (#2), gave final approval for submission (#3), and agreed to be accountable for the accuracy and integrity of this work (#4).
To the Editor,
Asthma prevalence has increased globally among adolescents in recent years, yet this population remains understudied.1 Dupilumab, a fully human VelocImmune®‐derived monoclonal antibody,2, 3 blocks the shared receptor component for interleukin (IL)‐4 and IL‐13, key and central drivers of type 2 inflammation in multiple diseases.4, 5 In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add‐on dupilumab 200/300 mg every 2 weeks vs placebo significantly reduced severe asthma exacerbations and improved pre‐bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate‐to‐severe asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline.6
This post hoc analysis of QUEST assessed the efficacy of dupilumab in adolescent patients aged 12–17 years compared with adults aged ≥18 years. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline and approved by local institutional review boards or ethics committees. All patients provided written informed consent before participating in the trial. Prespecified endpoints were changed from baseline in pre‐bronchodilator FEV1 and annualized severe exacerbation rate (AER). Changes from baseline were assessed post hoc for post‐bronchodilator FEV1, percentage predicted FEV1 (ppFEV1), Asthma Control Questionnaire (ACQ‐5) response, fractional exhaled nitric oxide (FeNO) levels, blood eosinophil counts, and serum total immunoglobulin E (IgE). Subgroups of adolescent and adult patients with elevated type 2 biomarkers (blood eosinophils ≥150 cells/µL or FeNO ≥20 ppb) at baseline were also examined post hoc.
107 adolescents aged 12–17 years (5.6% of total population) and 1795 (94.4%) adults were randomized. Due to the small proportion of adolescents in the overall population, differences in baseline characteristics between patients receiving dupilumab and placebo were observed (Table S1); results should be interpreted within the context of these limitations. Dupilumab significantly improved lung function and exacerbation rates in adults, as previously observed in the overall QUEST population (Figures S1 and S2).6
In the adolescent population, dupilumab (200 and 300 mg) vs matched placebo significantly improved pre‐bronchodilator FEV1 at Week 12 by 0.37L (95% CI, 0.13–0.61; p=.003) and 0.27L (95% CI, 0.02–0.52; p=.037) (Figure 1A). In the 80% of adolescent patients with elevated baseline type 2 biomarker levels treated with dupilumab 200 mg, the magnitude of this improvement was greater (0.43L; 95% CI, 0.17–0.69; p=.002) than in the corresponding intention‐to‐treat (ITT) adolescent subgroup (Figure 1B). At almost all visits during the treatment period, numerically or statistically significant improvements were observed in post‐bronchodilator FEV1 (Figure 1C) and ppFEV1 (Figure 1D) in both dupilumab groups vs placebo in the adolescent population. Improvements in ppFEV1 with dupilumab vs placebo were also observed for adolescents with elevated baseline type 2 biomarkers (Figure 1E).
FIGURE 1.
LS mean change from baseline during the 52‐week treatment period in: pre‐bronchodilator FEV1 (L) in (A) the ITT QUEST adolescent population and (B) the subgroup of adolescents with baseline blood eosinophils ≥150 cells/µL or FeNO ≥20; (C) post‐bronchodilator FEV1 (L) in the ITT QUEST adolescent population; percent predicted pre‐bronchodilator FEV1 (L) in (D) the ITT QUEST adolescent population and (E) the subgroup with baseline blood eosinophils ≥150 cells/µL or FeNO ≥20. FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ITT, intention‐to‐treat; LS, least squares; ppb, parts per billion; q2w, every 2 weeks; SE, standard error. *p < .05, **p < .01, ***p < .001 vs matched (p values based on change from baseline vs placebo)
In adolescents, a 46% numerical reduction in adjusted AER (95% CI, 0.24–1.21) was observed with dupilumab 200 mg vs placebo. Adjusted AER in the dupilumab 300 mg group was 13% (95% CI, 0.48–2.69) higher vs matched placebo (Figure 2A). Similar results were seen in adolescents with elevated baseline type 2 biomarkers (Figure 2B). The increased AER seen in adolescents treated with dupilumab 300 mg is in marked contrast to the AER in adults as well as adolescents exposed to 200 mg q2w, and also contrasts with the improvement in FEV1 observed for adolescents in both the 200 and 300 mg groups. This may be due to the imbalance observed in the number of severe exacerbations in the previous year between the dupilumab 300 mg group and the matched placebo group (mean 1.53 and 2.22, respectively) that would affect the adjusted exacerbation rate. Unadjusted AER was numerically lower with both dupilumab doses vs matched placebo in the overall adolescent population and patients with elevated baseline type 2 biomarkers (Figure 2C,D).
FIGURE 2.
Annualized severe exacerbation rate (AER) during the 52‐week treatment period. Adjusted AER in (A) the ITT QUEST adolescent population and (B) the subgroup of adolescents with baseline blood eosinophils ≥150 cells/µl or FeNO ≥20; unadjusted AER in (C) adolescents and (D) the subgroup with baseline blood eosinophils ≥150 cells/µl or FeNO ≥20 ppb. CI, confidence interval; FeNO, fractional exhaled nitric oxide; ITT, intention‐to‐treat; q2w, every 2 weeks
Dupilumab treatment numerically reduced median FeNO levels and serum total IgE vs placebo in adolescents and adults; median eosinophil concentrations remained constant over time in adolescent patients (Figure S3). Dupilumab treatment numerically improved ACQ‐5 scores vs placebo by Week 52 (Table S2). Health‐related quality‐of‐life improvements (measured by AQLQ scores) mirrored those seen in ACQ‐5 scores (Table S2).
Dupilumab was generally well tolerated, with safety consistent with the known dupilumab safety profile (Table S3).
In conclusion, dupilumab improved lung function and reduced levels of type 2 biomarkers in the subpopulation of adolescents with uncontrolled, moderate‐to‐severe asthma, supporting the use of dupilumab in this population.
Supporting information
Supplementary Material
ACKNOWLEDGMENTS
Critical input on the concept was provided by Heribert Staudinger, MD.
Trial registration: ClinicalTrials.gov Identifier: NCT02414854.
FUNDING INFORMATION
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Medical writing/editorial assistance provided by Grace Manley, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.
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Supplementary Materials
Supplementary Material