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Original Investigation |

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis A Randomized Clinical Trial

Claus Bachert, MD, PhD1,2; Leda Mannent, MD3; Robert M. Naclerio, MD4; Joaquim Mullol, MD, PhD5; Berrylin J. Ferguson, MD6; Philippe Gevaert, MD, PhD1; Peter Hellings, MD, PhD7; Lixia Jiao, PhD8; Lin Wang, PhD8; Robert R. Evans, PharmD9; Gianluca Pirozzi, MD, PhD8; Neil M. Graham, MD, MPH9; Brian Swanson, PhD8; Jennifer D. Hamilton, PhD9; Allen Radin, MD9; Namita A. Gandhi, PhD9; Neil Stahl, PhD9; George D. Yancopoulos, MD, PhD9; E. Rand Sutherland, MD, MPH10
[+] Author Affiliations
1Upper Airway Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium
2Clintec, Karolinska Institute, Stockholm, Sweden
3Research and Development, Sanofi, Chilly Mazarin, France
4University of Chicago, Chicago, Illinois
5Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
6University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
7Laboratory of Experimental Immunology, Department of Otorhinolaryngology—Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium
8Research and Development, Sanofi, Bridgewater, New Jersey
9Regeneron Pharmaceuticals Inc, Tarrytown, New York
10Immunology and Inflammation Development Franchise, Sanofi Research and Development, Cambridge, Massachusetts
JAMA. 2016;315(5):469-479. doi:10.1001/jama.2015.19330.
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Importance  Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell–mediated diseases.

Objective  To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up.

Interventions  Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks.

Main Outcomes and Measures  Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety.

Results  Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was −0.3 (95% CI, −1.0 to 0.4) with placebo and −1.9 (95% CI, −2.5 to −1.2) with dupilumab (LS mean difference, −1.6 [95% CI, −2.4 to −0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was −8.8 (95% CI, −11.1 to −6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, −18.1 [95% CI, −25.6 to −10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).

Conclusions and Relevance  Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.

Trial Registration  clinicaltrials.gov Identifier: NCT01920893

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Figures

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Figure 1.
Patients Enrolled and Included in the Analysis

MFNS indicates mometasone furoate nasal spray.

aA patient could have more than 1 reason for exclusion.

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Figure 2.
Primary and Secondary End Points for All Patients

The P value comparisons are for week 16. Compared with placebo plus mometasone furoate nasal spray (MFNS), dupilumab plus MFNS significantly improved the endoscopic NPS (maximum score = 8) and morning PNIF. Error bars indicate 95% CIs.

aAssessed as change from baseline averaged over 4 weeks prior to each time point.

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Figure 3.
Quality-of-Life and Symptom-Based Secondary End Points

The P value comparisons are for week 16. Compared with placebo plus mometasone furoate nasal spray (MFNS), dupilumab plus MFNS was associated with a significant improvement in the SNOT-22 total score, sense of smell (assessed by the UPSIT), and self-reported morning posterior rhinorrhea. Error bars indicate 95% CIs.

aAssessed as change from baseline averaged over 4 weeks prior to each time point.

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Figure 4.
End Points in Patients With Comorbid Asthma

The P value comparisons are for week 16. Compared with placebo plus mometasone furoate nasal spray (MFNS), dupilumab plus MFNS was associated with improvements in endoscopic NPS (maximum score = 8), FEV1, FEV1 percent predicted, and ACQ5 score compared with placebo plus MFNS. Error bars indicate 95% CIs.

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Figure 5.
Pharmacodynamic and Type 2 Helper T-cell–Associated Biomarkers

The P value comparisons are for week 16. Compared with placebo plus mometasone furoate nasal spray (MFNS), dupilumab plus MFNS was associated with a significant improvement in pharmacodynamic and type 2 helper T-cell–associated biomarkers. Error bars indicate 95% CIs.

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