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, Tanya M Laidlaw, Claus Bachert, Leda P Mannent, G Walter Canonica, Joseph K Han, Jorge F Maspero, Cesar Picado, Nadia Daizadeh, Benjamin Ortiz, Yongtao Li, Marcella Ruddy, Elizabeth Laws, Nikhil Amin, Joaquim Mullol, Tanya M Laidlaw, Claus Bachert, Leda P Mannent, G Walter Canonica, Joseph K Han, Jorge F Maspero, Cesar Picado, Nadia Daizadeh, Benjamin Ortiz, Yongtao Li, Marcella Ruddy, Elizabeth Laws, Nikhil Amin

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.

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.

© 2021 Sanofi Genzyme. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

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.

References

    1. Bachert C, Marple B, Schlosser RJ, et al. Adult chronic rhinosinusitis. Nat Rev Dis Primers 2020;6:86.
    1. Fokkens WJ, Lund VJ, Hopkins C, et al. Epos 2020: European position paper on rhinosinusitis and nasal polyps 2020. Rhinology 2020;58:1‐464.
    1. Stevens WW, Schleimer RP, Kern RC. Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract 2016;4:565‐572.
    1. Klonaris D, Doulaptsi M, Karatzanis A, Velegrakis S, Milioni A, Prokopakis E. Assessing quality of life and burden of disease in chronic rhinosinusitis: A review. Rhinology Online 2019;2:6‐13.
    1. Bachert C, Han JK, Wagenmann M, et al. EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management. J Allergy Clin Immunol 2021;147:29‐36.
    1. Boztepe F, Ural A, Paludetti G, De Corso E. Pathophysiology of chronic rhinosinusitis with nasal polyps. In: Cingi C, Bayar Muluk N, eds. All Around The Nose. Springer; 2020: pp 333‐337.
    1. Stevens WW, Ocampo CJ, Berdnikovs S, et al. Cytokines in chronic rhinosinusitis. Role in eosinophilia and aspirin‐exacerbated respiratory disease. Am J Respir Crit Care Med 2015;192:682‐694.
    1. Jonstam K, Swanson BN, Mannent LP, et al. Dupilumab reduces local type 2 pro‐inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy 2019;74:743‐752.
    1. Workman AD, Kohanski MA, Cohen NA. Biomarkers in chronic rhinosinusitis with nasal polyps. Immunol Allergy Clin North Am 2018;38:679‐692.
    1. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin‐exacerbated respiratory disease among asthmatic patients: A meta‐analysis of the literature. J Allergy Clin Immunol 2015;135:676‐681.e671.
    1. White AA, Doherty TA. Role of group 2 innate lymphocytes in aspirin‐exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 2018;32:7‐11.
    1. Steinke JW, Payne SC, Borish L. Eosinophils and mast cells in aspirin‐exacerbated respiratory disease. Immunol Allergy Clin North Am 2016;36:719‐734.
    1. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID‐exacerbated respiratory disease (N‐ERD)‐A EAACI position paper. Allergy 2019;74:28‐39.
    1. Laidlaw TM, Boyce JA. Aspirin‐exacerbated respiratory disease–new prime suspects. N Engl J Med 2016;374:484‐488.
    1. Schneider S, Campion NJ, Villazala‐Merino S, et al. Associations between the quality of life and nasal polyp size in patients suffering from chronic rhinosinusitis without nasal polyps, with nasal polyps or aspirin‐exacerbated respiratory disease. J Clin Med 2020;9(4):925.
    1. Stevens WW, Peters AT, Hirsch AG, et al. Clinical characteristics of patients with chronic rhinosinusitis with nasal polyps, asthma, and aspirin‐exacerbated respiratory disease. J Allergy Clin Immunol Pract 2017;5:1061‐1070.e1063.
    1. Ryan L, Segarra D, Tabor M, Parasher A. Systematic review of outcomes for endoscopic sinus surgery and subsequent aspirin desensitization in aspirin‐exacerbated respiratory disease. World J Otorhinolaryngol Head Neck Surg 2020;6:220‐229.
    1. Williams AN, Simon RA, Woessner KM, Stevenson DD. The relationship between historical aspirin‐induced asthma and severity of asthma induced during oral aspirin challenges. J Allergy Clin Immunol 2007;120:273‐277.
    1. Levy JM, Smith TL. Is aspirin desensitization indicated for the treatment recalcitrant chronic rhinosinusitis with nasal polyposis in aspirin‐exacerbated respiratory disease? Laryngoscope 2017;127:776‐777.
    1. Stevens WW, Jerschow E, Baptist AP, et al. The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin‐exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2021;147:827‐844.
    1. Macdonald LE, Karow M, Stevens S, et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci U S A 2014;111:5147‐5152.
    1. Murphy AJ, Macdonald LE, Stevens S, et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci 2014;111:5153‐5158.
    1. Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL‐4/IL‐13 pathway in atopic diseases. Expert Rev Clin Immunol 2017;13:425‐437.
    1. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS‐24 and LIBERTY NP SINUS‐52): Results from two multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group phase 3 trials. Lancet 2019;394:1638‐1650.
    1. Chong LY, Piromchai P, Sharp S, et al. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev 2020;29(2):CD013513.
    1. DUPIXENT® (dupilumab). Prescribing information, Regeneron Pharmaceuticals. Revised June 2020. Accessed November 24, 2020.
    1. DUPIXENT® (dupilumab). Summary of product characteristics, Regeneron Pharmaceuticals. Revised June 2020. Accessed November 24, 2020.
    1. Kariyawasam HH, James LK, Gane SB. Dupilumab: Clinical efficacy of blocking IL‐4/IL‐13 signalling in chronic rhinosinusitis with nasal polyps. Drug Des Devel Ther 2020;14:1757‐1769.
    1. Choby G, O'Brien EK, Smith A, et al. Elevated urine leukotriene E4 is associated with worse objective markers in nasal polyposis patients. Laryngoscope 2020;131(5):961‐966. doi:10.1002/lary.29137.
    1. Jerschow E, Edin ML, Chi Y, et al. Sinus surgery is associated with a decrease in aspirin‐induced reaction severity in patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol Pract 2019;7:1580‐1588.
    1. Mustafa SS, Vadamalai K, Scott B, Ramsey A. Dupilumab as add‐on therapy for chronic rhinosinusitis with nasal polyposis in aspirin exacerbated respiratory disease. Am J Rhinol Allergy 2021;35(3):399‐407. doi:10.1177/1945892420961969.
    1. Hirano I, Dellon ES, Hamilton JD, et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology 2020;158:111‐122.e110.
    1. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid‐dependent severe asthma. N Engl J Med 2018;378:2475‐2485.
    1. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate‐to‐severe uncontrolled asthma. N Engl J Med 2018;378:2486‐2496.
    1. de Wijs LEM, van der Waa JD, de Jong PHP, Hijnen DJ. Acute arthritis and arthralgia as an adverse drug reaction to dupilumab. Clin Exp Dermatol 2020;45:262‐263.
    1. Willsmore ZN, Woolf RT, Hughes C, et al. Development of inflammatory arthritis and enthesitis in patients on dupilumab: A case series. Br J Dermatol 2019;181:1068‐1070.

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