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. 2022 Apr;77(4):1231-1244.
doi: 10.1111/all.15067. Epub 2021 Oct 1.

Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials

Joaquim Mullol  1 , Tanya M Laidlaw  2 , Claus Bachert  3   4   5 , Leda P Mannent  6 , G Walter Canonica  7 , Joseph K Han  8 , Jorge F Maspero  9 , Cesar Picado  10 , Nadia Daizadeh  11 , Benjamin Ortiz  12 , Yongtao Li  13 , Marcella Ruddy  14 , Elizabeth Laws  15 , Nikhil Amin  14
Affiliations

Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials

Joaquim Mullol et al. Allergy. 2022 Apr.

Abstract

Background: About one-tenth of patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, is an approved add-on treatment in severe CRSwNP. This post hoc analysis evaluated dupilumab efficacy and safety in patients with CRSwNP with/without NSAID-ERD.

Methods: Data were pooled from the phase 3 SINUS-24 and SINUS-52 studies in adults with uncontrolled severe CRSwNP who received dupilumab 300 mg or placebo every 2 weeks. CRSwNP, nasal airflow, lung function, and asthma control outcomes at Week 24 were evaluated, and treatment-subgroup interactions were assessed for patients with and without NSAID-ERD.

Results: Of 724 patients, 204 (28.2%) had a diagnosis of NSAID-ERD. At Week 24, least squares mean treatment differences demonstrated significant improvements in nasal polyp score, nasal congestion (NC), Lund-Mackay computed tomography, 22-item Sinonasal Outcome Test (SNOT-22), Total Symptom Score (TSS), rhinosinusitis severity visual analog scale, peak nasal inspiratory flow (PNIF), six-item Asthma Control Questionnaire score, and improvement in smell with dupilumab versus placebo (all p < .0001) in patients with NSAID-ERD. Treatment comparisons demonstrated significantly greater improvements with dupilumab in patients with versus without NSAID-ERD for NC (p = .0044), SNOT-22 (p = .0313), TSS (p = .0425), and PNIF (p = .0123).

Conclusions: In patients with uncontrolled severe CRSwNP, dupilumab significantly improved objective measures and patient-reported symptoms to a greater extent in the presence of comorbid NSAID-ERD than without. Dupilumab was well tolerated in patients with/without NSAID-ERD.

Trial registration: ClinicalTrials.gov NCT02912468 NCT02898454.

Keywords: IL-13; IL-4; chronic rhinosinusitis with nasal polyps; dupilumab; non-steroidal anti-inflammatory drug-exacerbated respiratory disease.

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Conflict of interest statement

J. Mullol reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study and grants, personal fees, and other from ALK‐Abelló, AstraZeneca, Genentech, GlaxoSmithKline, Glenmark, Menarini, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mylan‐Meda Pharmaceuticals (Viatris), Novartis, Proctor & Gamble, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB Pharma, and Uriach Group, outside the submitted work.

T.M. Laidlaw reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study and other from AstraZeneca, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi‐Aventis, outside the submitted work.

C. Bachert reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study and personal fees and other from ALK, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Sanofi, and Stallergenes Greer, outside the submitted work.

L.P. Mannent reports personal fees, non‐financial support, and other from Sanofi; and non‐financial support from Regeneron Pharmaceuticals, Inc., during the conduct of the study.

G.W. Canonica reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study and personal fees and other from ALK, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HAL Allergy, Menarini, Mundipharma, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Stallergenes Greer, and Uriach Group, outside the submitted work.

J.K. Han reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study; and other from Sanofi, outside the submitted work.

J.F. Maspero reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study; grants and personal fees from Novartis; and personal fees from AstraZeneca, GlaxoSmithKline, Menarini, Sanofi, Teva, and Uriach Group, outside the submitted work.

C. Picado reports non‐financial support from Regeneron Pharmaceuticals, Inc. and Sanofi, during the conduct of the study; grants, personal fees, and other from Novartis; and personal fees from AstraZeneca, GlaxoSmithKline and Menarini, outside the submitted work.

N. Daizadeh reports personal fees and non‐financial support from Sanofi; and non‐financial support from Regeneron Pharmaceuticals, Inc., during the conduct of the study.

B. Ortiz reports personal fees, non‐financial support, and other from Regeneron Pharmaceuticals, Inc.; and non‐financial support from Sanofi, during the conduct of the study.

Y. Li reports personal fees, non‐financial support, and other from Sanofi; and non‐financial support from Regeneron Pharmaceuticals, Inc., during the conduct of the study.

M. Ruddy reports personal fees, non‐financial support, and other from Regeneron Pharmaceuticals, Inc.; and non‐financial support from Sanofi, during the conduct of the study.

E. Laws reports personal fees, non‐financial support, and other from Sanofi; and non‐financial support from Regeneron Pharmaceuticals, Inc., during the conduct of the study.

N. Amin reports personal fees, non‐financial support, and other from Regeneron Pharmaceuticals, Inc.; and non‐financial support from Sanofi, during the conduct of the study.

Figures

FIGURE 1
FIGURE 1
Changes from baseline to Week 24 in CRSwNP disease control and symptom burden in patients with CRSwNP with and without NSAID‐ERD, as assessed by (A) NPS, (B) patient‐assessed symptom severity score for NC or obstruction, (C) LMK‐CT score, (D) SNOT‐22 score, (E) patient‐reported TSS, (F) VAS for rhinosinusitis, (G) UPSIT score, (H) loss of smell score, and (I) SNOT‐22 smell/taste item score. ***Nominal p < .0001 versus placebo. Abbreviations: BL, baseline; CRSwNP, chronic rhinosinusitis with nasal polyps; LMK‐CT, Lund–Mackay computed tomography; LS, least squares; NPS, nasal polyp score; NSAID‐ERD, non‐steroidal anti‐inflammatory drug‐exacerbated disease; q2w, every 2 weeks; SE, standard error; SNOT‐22, 22‐item Sinonasal Outcome Test; TSS, Total Symptom Score; UPSIT, University of Pennsylvania Smell Identification Test; VAS, visual analog scale.
FIGURE 2
FIGURE 2
Kaplan–Meier analysis of time to first (A) SCS use and (B) NP surgery in patients with CRSwNP with and without NSAID‐ERD. Abbreviations: CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; HR, hazard ratio; NP, nasal polyp; NSAID‐ERD, non‐steroidal anti‐inflammatory drug‐exacerbated disease; q2w, every 2 weeks; SCS, systemic corticosteriods.
FIGURE 3
FIGURE 3
Changes from baseline to Week 24 in airway function and asthma control in patients with CRSwNP with and without NSAID‐ERD, as assessed by (A) PNIF, (B) FEV1, and (C) ACQ‐6 score. Asthma‐specific endpoints (FEV1 and ACQ‐6) were measured only in patients with a recorded history of asthma. **Nominal p =.001, ***nominal p < .0001 versus placebo. Abbreviations: ACQ‐6, six‐item Asthma Control Questionnaire; BL, baseline; CRSwNP, chronic rhinosinusitis with nasal polyps; FEV1, forced expiratory volume in 1 second; LS, least squares; NSAID‐ERD, non‐steroidal anti‐inflammatory drug‐exacerbated disease; PNIF, peak nasal inspiratory flow; q2w, every 2 weeks; SE, standard error.
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