Clinical Communications

Dupilumab improves patient-reported nasal obstruction, higher levels of lower airway inflammation,
outcomes in patients with chronic and worse asthma control than those without CRS.2,3 Thus,
rhinosinusitis with nasal polyps and patients with CRSwNP and comorbid asthma have a high disease
comorbid asthma burden, seriously impacting health-related quality of life
(HRQoL).2,3 Markers of type 2-mediated inflammation and
Claus Bachert, MD, PhDa,b, Peter W. Hellings, MD, PhDc,
antibody production (eg, IL-5, IgE) are associated with both
Joaquim Mullol, MD, PhDd, Robert M. Naclerio, MDe, CRSwNP and asthma pathogenesis.2
Jingdong Chao, PhDf, Nikhil Amin, MDf, Dupilumab, a fully human VelocImmune-derived4,5 mono-
Annette Grabher, MD, MPHg, Brian N. Swanson, PhDg, clonal antibody, blocks the shared receptor component for IL-4
Jennifer D. Hamilton, PhDg, Sophie Guillonneau, MSch, and IL-13, thus inhibiting signaling of both IL-4 and IL-13, key
Christine Tanioui, Donghui Zhang, PhDg, drivers of type 2 diseases such as atopic dermatitis, asthma, and
allergic rhinitis.6 In a 16-week phase 2a study in adults with
Gianluca Pirozzi, MD, PhDg,
CRSwNP refractory to intranasal corticosteroids (INCS), adding
Neil M.H. Graham, MB, BS, MD, MPHf, dupilumab to mometasone furoate nasal spray (MFNS) reduced
Heribert Staudinger, MD, PhDg, Leda P. Mannent, MDh, nasal polyp burden versus MFNS alone and significantly improved
and Asif Khan, MB, BS, MPHh nasal congestion and airflow, sense of smell, HRQoL, and other
nasal symptoms.7 We present a subgroup analysis of patients with
Clinical Implications CRSwNP and comorbid asthma from this study, examining the
effect of dupilumab on patient-reported outcomes (PROs) for

This analysis of a phase 2a study shows that the addition CRSwNP and asthma, and inflammatory biomarkers.
of dupilumab to mometasone furoate nasal spray This randomized, double-blind, placebo-controlled study
improves clinical and patient-reported outcomes in included a 4-week run-in and 16-week blinded-treatment
patients with chronic rhinosinusitis with nasal polyps and period.5 Patients aged 18 to 65 years with bilateral NP and
comorbid asthma. chronic symptoms of rhinosinusitis despite INCS treatment 2
months, and 2 rhinosinusitis symptoms (nasal obstruction,
nasal discharge, facial pain/pressure, reduction/loss of smell),
were randomized 1:1 to dupilumab 300 mg weekly or placebo, as
TO THE EDITOR: add-on to MFNS for 16 weeks.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a The effect of dupilumab on various NP outcomes in patients
common inflammatory condition affecting the upper airways, with CRSwNP has previously been published.7 Of 60 patients
with chronic symptoms such as nasal congestion, partial (hypo- randomized, 35 (16 dupilumab, 19 placebo) had CRSwNP and
smia) or total (anosmia) loss of smell, anterior/posterior rhinor- comorbid asthma. Baseline demographics and disease character-
rhea, and mild facial pain.1 As many as 66% of patients with istics were similar between the study groups (Table E1, available
CRSwNP have comorbid asthma and suffer from more severe in this article’s Online Repository at www.jaci-inpractice.org).

TABLE I. ACQ-5 scores at baseline and change from baseline at week 16 in patients with CRSwNP and comorbid asthma
Mean score (SD) at baseline LS mean change (SE) from baseline to week 16
LS mean difference
Placebo/MFNS Dupilumab/MFNS Placebo/MFNS Dupilumab/MFNS for dupilumab vs placebo
†
ACQ-5 Measure (n [ 19) (n [ 16) (n [ 12) (n [ 15) (95% CI)

Total Total 1.63 (0.87) 1.55 (1.11) 0.10 (0.20) 1.19 (0.19) 1.09 (1.54, 0.63)***
overallz
Item 1x Woken at night by asthma 1.00 (1.10) 0.88 (1.45) 0.08 (0.24) e0.91 (0.23) e0.99 (e1.55, e0.42)**
Item 2x Awake in morning with 2.00 (1.37) 1.69 (1.25) 0.01 (0.22) e1.46 (0.20) e1.46 (e1.94, e0.99)***
asthma symptoms
Item 3x Limited in activities 1.38 (1.20) 1.25 (1.13) e0.11 (0.23) e0.93 (0.21) e0.83 (e1.34, e0.32)**
Item 4x Shortness of breath 2.19 (1.33) 1.94 (1.24) e0.29 (0.29) e1.33 (0.27) e1.04 (e1.77, e0.31)**
Item 5x Wheezing time 1.56 (0.63) 2.00 (1.90) e0.54 (0.36) e1.50 (0.34) e0.96 (e1.81, e0.12)*
LS means (and corresponding P values) are based on the mixed-effects model with repeated measures.
ACQ-5, 5-Item Asthma Control Questionnaire; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; LS, least squares; MCID, minimal clinically
important difference; MFNS, mometasone fuorate nasal spray; SD, standard deviation; SE, standard error.
*P < .05 vs placebo.
**P < .01 vs placebo.
***P < .001 vs placebo.
†Recall period ¼ 1 wk; score range ¼ 0-6. Lower score indicates better control of asthma.
zWithin-group MCID of 0.5.
xWithin-patient MCID of 0.6.

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improvements in forced expiratory volume in 1 second % pre-

dicted (P ¼ .04) and 5-item Asthma Control Questionnaire
(ACQ-5) total score (P < .001) exceeding the minimal clinically
important difference (MCID) of 0.5.7
In this study, we further assessed the effect of dupilumab on
HRQoL in patients with CRSwNP with comorbid asthma using
the 5-dimension EuroQoL questionnaire (EQ-5D) visual analog
scale (VAS) and 36-item Short-Form Health Survey (SF-36).
EQ-5D VAS provides a simple measure of the patient’s self-rated
health on a vertical virtual analog scale, with scores 0 to 100 mm
(worst-best imaginable health state).8 SF-36 comprises 8 do-
mains assessing physical functioning, social functioning, role
limitations due to physical and emotional problems, mental
health, energy/vitality, bodily pain, and general health percep-
tion. Two summary scores, the physical (PCS) and mental health
component summary, are calculated by the aggregation of the 8
SF-36 subscales, to evaluate the physical and mental health,
respectively (higher scores indicating better HRQoL).9 The
effects of dupilumab on the individual ACQ-5 scores (woken at
night by asthma, awake in morning with asthma symptoms,
limited in activities, shortness of breath, wheezing time), as well
as inflammatory biomarkers (eosinophils, eosinophil cationic
protein, thymus and activation-regulated chemokine, IgE, and
periostin), were also assessed.
Changes in clinical outcomes and PROs from baseline to week
16 in patients with CRSwNP and comorbid asthma were
reported as least-squares mean values and analyzed using a
mixed-effects model with a repeated-measures approach. An
unstructured correlation matrix was used to analyze within-
patient errors; there was no imputation for missing data. A
FIGURE 1. Change in generic HRQoL outcomes: least-squares P value <.05 for the comparison between dupilumab and
mean change from baseline in EQ-5D self-rated health VAS placebo was considered statistically significant.
(mm) score at week 16 (A), and in SF-36 individual domain scores For each of the individual ACQ-5 scores, a significant differ-
at week 16 (B). LS means (and corresponding P values) are based ence between treatment groups was observed from baseline to
on the mixed-effects model with repeated measures. Blue aster- week 16 in favor of dupilumab (Table I). ACQ-5 responder rate
isks indicate statistically significant improvement from baseline (MCID  0.5) was significantly higher (P ¼ .038) in dupilumab-
within dupilumab-treated patients (P < .05). Gray asterisks indi- treated patients (62.5%) versus placebo (15.8%). Dupilumab
cate statistically significant improvement from baseline within versus placebo produced significant improvements in health sta-
placebo-treated patients (P < .05). BP, Bodily pain; EQ-5D, 5- tus, measured by EQ-5D VAS (P < .001; Figure 1, A). In
dimension EuroQoL questionnaire; GH, general health; HRQoL, dupilumab-treated patients, significant improvements from
health-related quality of life; MCS, mental component summary; baseline were observed in 5 SF-36 domains (general health,
MFNS, mometasone furoate nasal spray; MH, mental health; physical functioning, role-physical, social functioning, and
PCS, physical component summary; PF, physical functioning; RE, vitality) and PCS (P < .05) (Figure 1, B). For placebo, change
role-emotional; RP, role-physical; SE, standard error; SF, social from baseline was statistically significant (P < .05) in only 2 do-
functioning; SF-36, 36-item Short-Form Health Survey; VAS, vi- mains (role-physical and social functioning) and PCS (Figure 1,
sual analog scale; VT, vitality. B). Dupilumab-treated patients (vs placebo) showed a significantly
greater reduction from baseline in serum (P ¼ .002) and nasal
Mean (standard deviation) age was 49.4 (9.0) years; 14 patients (P ¼ .04) secretion levels of total IgE (Table E2, available in this
were men, and 13 patients (37.1%) had aspirin-exacerbated article’s Online Repository at www.jaci-inpractice.org).
respiratory disease (42.1% placebo, 31.3% dupilumab). At This subgroup analysis of patients with CRSwNP and co-
baseline, patients had moderate-to-severe CRSwNP, and in- morbid asthma extends the previously reported observations that
flammatory biomarker levels were generally similar across treat- adding dupilumab to MFNS treatment improves nasal polyp
ment groups. Among patients with CRSwNP and comorbid burden, asthma control, lung function, and HRQoL.7 The ef-
asthma, dupilumab-treated patients (vs placebo) showed a sig- fects of dupilumab on CRSwNP-specific clinical outcomes and
nificant improvement in endoscopic NP score (P < .001), sense PROs in patients with asthma were similar in magnitude to those
of smell (P < .001), Lund-Mackay computed tomography total reported for the overall population.7 Focusing on PROs, the
score (P < .001), and significant reduction in CRSwNP disease clinical benefit of dupilumab in patients with CRSwNP and
severity (P < .001). Furthermore, a significant improvement in comorbid asthma was observed for CRSwNP disease and
the total 22-item Sino-Nasal Outcome Test score at week 16 was symptom severity, and asthma control (assessed by ACQ-5 total
observed in dupilumab-treated patients (vs placebo) (P < .001). and individual item scores) reflecting a reduced impact of asthma
Dupilumab versus placebo also produced significant on daily activities and an improved HRQoL. Significant
J ALLERGY CLIN IMMUNOL PRACT CLINICAL COMMUNICATIONS 2449
VOLUME 7, NUMBER 7

improvement from baseline in general health perception, physical D. Zhang, G. Pirozzi, H. Staudinger, L. P. Mannent, and A. Khan are employees
of Sanofi and may hold stock and/or stock options in the company. B. N. Swanson
functioning, and vitality was only observed with dupilumab
is the former Sanofi employee and may hold stock or stock options in the com-
treatment and not in the placebo arm. pany. C. Taniou is the employee of Altran Technologies.
In conclusion, treatment with dupilumab was associated with Received for publication January 11, 2019; revised March 6, 2019; accepted for
an improvement of both clinical and patient-reported NP-spe- publication March 15, 2019.
cific outcomes, and asthma-specific outcomes in patients with Available online March 27, 2019.
Corresponding author: Claus Bachert, MD, PhD, Upper Airway Research Labora-
CRSwNP and comorbid asthma. tory, Department of Otorhinolaryngology, Ghent University Hospital, C. Hey-
manslaan 10, B-9000 Ghent, Belgium. E-mail: [email protected].
2213-2198
Acknowledgments Ó 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy
Editorial assistance was provided by Bilge Yoruk, PhD, and of Allergy, Asthma & Immunology. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Ravi Subramanian, PhD, of Excerpta Medica funded by Sanofi
https://doi.org/10.1016/j.jaip.2019.03.023
Genzyme and Regeneron Pharmaceuticals.
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Upper Airway Research Laboratory, Department of Otorhinolaryngology, Ghent 1. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS
University Hospital, Ghent, Belgium 2012: European position paper on rhinosinusitis and nasal polyps 2012. A
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CLINTEC, Karolinska Institute, Stockholm, Sweden summary for otorhinolaryngologists. Rhinol Suppl 2012;50:1-298.
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Laboratory of Experimental Immunology, Department of Otorhinolaryngology— 2. Orlandi RR, Kingdom TT, Hwang PH, Smith TL, Alt JA, Baroody FM, et al.
Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int
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IDIBAPS, Hospital Clínic Barcelona, University of Barcelona, CIBERES, Barce- Forum Allergy Rhinol 2016;6(Suppl 1):S22-209.
lona, Catalonia, Spain 3. Bilodeau L, Boulay ME, Prince P, Boisvert P, Boulet LP. Comparative clinical
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Johns Hopkins Hospital, Baltimore, Md and airway inflammatory features of asthmatics with or without polyps. Rhi-
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Sanofi, Bridgewater, NJ 4. Macdonald LE, Karow M, Stevens S, Auerbach W, Poueymirou WT,
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Sanofi, Chilly-Mazarin, France Yasenchak J, et al. Precise and in situ genetic humanization of 6 Mb of mouse
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Altran Technologies, Vélizy-Villacoublay, France immunoglobulin genes. Proc Natl Acad Sci USA 2014;111:5147-52.
The research was sponsored by Sanofi and Regeneron Pharmaceuticals. 5. Murphy AJ, Macdonald LE, Stevens S, Karow M, Dore AT, Pobursky K, et al.
Dupilumab is in clinical development for the treatment of chronic rhinosinusitis with Mice with megabase humanization of their immunoglobulin genes generate an-
nasal polyps and currently has no marketing authorization for this indication. tibodies as efficiently as normal mice. Proc Natl Acad Sci USA 2014;111:5153-8.
Conflicts of interest: C. Bachert is the principal investigator of the study, and serves 6. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD.
on the advisory boards of ActoBiotics, ALK, ASIT Biotech, AstraZeneca, Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug
Novartis, Sanofi, and Stallergenes. P. W. Hellings serves on the advisory board of Discov 2016;15:35-50.
Regeneron Pharmaceuticals, Inc. J. Mullol is the member of national and inter- 7. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al.
national scientific advisory boards (consulting) of and receives fees for lectures Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic
and grants for research projects from ALK-Abelló, Allakos, FAES, Genentech, sinusitis and nasal polyposis. A randomized clinical trial. JAMA 2016;315:
Glenmark, GSK, Mylan, Menarini, MSD, Novartis, Regeneron Pharmaceuticals, 469-79.
Sanofi Genzyme, UCB, and Uriach. R. M. Naclerio serves on the advisory board 8. EuroQol Group. EuroQol—a new facility for the measurement of health-related
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2449.e1 CLINICAL COMMUNICATIONS J ALLERGY CLIN IMMUNOL PRACT
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TABLE E1. Baseline demographics and disease characteristics of patients with CRSwNP with comorbid asthma
Placebo/MFNS (n [ 19) Dupilumab/MFNS (n [ 16)

Patient characteristic
Age, mean (SD), y 47.7 (9.9) 51.4 (7.6)
Male, n (%) 7 (36.8) 7 (43.8)
Duration of CRSwNP, mean (SD), y 11.32 (8.93) 8.95 (6.33)
Duration of asthma, mean (SD), y 20.15 (17.40) 15.46 (12.13)
Patients with aspirin-sensitive asthma, n (%) 8 (42.1) 5 (31.3)
Baseline measures of CRSwNP
Nasal polyps endoscopic score, range 0-8*, mean (SD) 5.53 (1.02) 5.94 (0.85)
CT Lund-Mackay total score, range 0-24*, mean (SD) 19.95 (5.65) 19.07 (4.23)
CRSwNP disease severity VAS (0-10 cm)*, mean (SD) 6.66 (2.36) 6.23 (2.73)
Daily congestion/obstruction score (0-3)† 1.67 (0.74) 1.43 (0.73)
Daily AM loss of smell score† (0-3)† 2.93 (0.24) 2.47 (0.96)
SNOT-22 total score (0-110), mean (SD)* 43.63 (20.66) 40.63 (16.26)
Baseline measures of asthma
ACQ-5 total score, mean (SD) 1.63 (0.87) 1.55 (1.11)
Baseline FEV1, mean (SD), % predicted 79.76 (14.55) 82.19 (17.71)
Baseline levels of biomarkers
Serum blood eosinophil count, mean (SD), 109/L 0.55 (0.83) 0.51 (0.25)
Serum ECP, mean (SD), ng/mL 37.26 (48.33) 35.38 (26.27)
Nasal secretion ECP, mean (SD), ng/mL 16.47 (11.49) 41.80 (43.44)
Serum total IgE, mean (SD), IU/mL 233.06 (300.44) 167.13 (153.77)
Nasal secretion total IgE, mean (SD), IU/mL 7.53 (5.64) 20.93 (41.78)
Serum TARC, mean (SD), pg/mL 506.20 (422.59) 506.77 (340.29)
Serum periostin, mean (SD), ng/mL 72.86 (28.52) 80.42 (24.44)
Nasal secretion periostin, mean (SD), ng/mL 6.92 (5.44) 7.27 (5.78)

ACQ-5, 5-item Asthma Control Questionnaire; AM, morning; CRSwNP, chronic rhinosinusitis with nasal polyps; CT, computed tomography; ECP, eosinophil cationic protein;
FEV1, forced expiratory volume in 1 s; MFNS, mometasone fuorate nasal spray; SD, standard deviation; SNOT-22, 22-item Sino-Nasal Outcome Test; TARC, thymus and
activation-regulated chemokine; VAS, visual analog scale.
*Higher scores indicate worse status.
†Average of the last 7 d before randomization.
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TABLE E2. Inflammatory biomarker levels at baseline and change from baseline at week 16 in patients with CRSwNP and comorbid asthma
Placebo/MFNS group (n [ 19) Dupilumab/MFNS group (n [ 16)
LS mean difference for
Baseline Week LS mean change Week LS mean change dupilumab vs placebo
Biomarker mean (SD) 16 mean (SD) from baseline (SE) Baseline mean (SD) 16 mean (SD) from baseline (SE) at week 16 (95% CI)* P value

Serum blood eosinophil count, 10 /L 9

0.55 (0.83) 0.37 (0.19) e0.15 (0.17) 0.51 (0.25) 0.53 (0.37) e0.06 (0.16) 0.09 (e0.34, 0.51) .682
Serum ECP, ng/mL 37.26 (48.33) 15.57 (11.92) e14.58 (9.83) 35.38 (26.27) 41.60 (47.60) 6.66 (9.77) 21.25 (e3.70, 46.20) .094
Nasal secretion ECP, ng/mL 16.47 (11.49) 29.08 (38.72) 26.47 (11.31) 41.80 (43.44) 39.07 (38.19) 16.92 (9.98) e9.55 (e35.89, 16.80) .472
Serum total IgE, IU/mL 233.06 (300.44) 128.87 (143.70) e38.09 (12.22) 167.13 (153.77) 102.07 (119.46) e86.59 (12.38) e48.49 (e78.66, e18.33) .002
Nasal secretion total IgE, IU/mL 7.53 (5.64) 13.77 (21.46) 6.86 (5.03) 20.93 (41.78) 5.53 (4.05) e5.31 (4.31) e12.17 (e23.76, e0.57) .04
Serum TARC, pg/mL 506.20 (422.59) 384.19 (235.65) e125.80 (44.78) 506.77 (340.29) 288.94 (154.06) e204.62 (48.99) e78.82 (e183.10, 25.45) .135
Serum periostin, ng/mL 72.86 (28.52) 53.05 (18.76) e17.09 (7.52) 80.42 (24.44) 57.83 (22.27) e13.83 (6.53) 3.26 (e13.05, 19.57) .692
Nasal secretion periostin, ng/mL 6.92 (5.44) 8.37 (6.91) 0.64 (2.53) 7.27 (5.78) 4.26 (5.71) e2.96 (2.16) e3.60 (e7.60, 0.40) .076
CI, Confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; ECP, eosinophil cationic protein; LS, least squares; MFNS, mometasone fuorate nasal spray; SD, standard deviation; SE, standard error; TARC, thymus and
activation-regulated chemokine.
*Based on the mixed-effects model with repeated measures.

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