Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma

Abstract

Clinical Implications•This analysis of a phase 2a study shows that the addition of dupilumab to mometasone furoate nasal spray improves clinical and patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. •This analysis of a phase 2a study shows that the addition of dupilumab to mometasone furoate nasal spray improves clinical and patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory condition affecting the upper airways, with chronic symptoms such as nasal congestion, partial (hyposmia) or total (anosmia) loss of smell, anterior/posterior rhinorrhea, and mild facial pain.1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists.Rhinol Suppl. 2012; 50: 1-298Crossref Google Scholar As many as 66% of patients with CRSwNP have comorbid asthma and suffer from more severe nasal obstruction, higher levels of lower airway inflammation, and worse asthma control than those without CRS.2Orlandi R.R. Kingdom T.T. Hwang P.H. Smith T.L. Alt J.A. Baroody F.M. et al.International Consensus Statement on Allergy and Rhinology: Rhinosinusitis.Int Forum Allergy Rhinol. 2016; 6: S22-209Crossref PubMed Scopus (607) Google Scholar, 3Bilodeau L. Boulay M.E. Prince P. Boisvert P. Boulet L.P. Comparative clinical and airway inflammatory features of asthmatics with or without polyps.Rhinology. 2010; 48: 420-425Crossref PubMed Scopus (35) Google Scholar Thus, patients with CRSwNP and comorbid asthma have a high disease burden, seriously impacting health-related quality of life (HRQoL).2Orlandi R.R. Kingdom T.T. Hwang P.H. Smith T.L. Alt J.A. Baroody F.M. et al.International Consensus Statement on Allergy and Rhinology: Rhinosinusitis.Int Forum Allergy Rhinol. 2016; 6: S22-209Crossref PubMed Scopus (607) Google Scholar, 3Bilodeau L. Boulay M.E. Prince P. Boisvert P. Boulet L.P. Comparative clinical and airway inflammatory features of asthmatics with or without polyps.Rhinology. 2010; 48: 420-425Crossref PubMed Scopus (35) Google Scholar Markers of type 2-mediated inflammation and antibody production (eg, IL-5, IgE) are associated with both CRSwNP and asthma pathogenesis.2Orlandi R.R. Kingdom T.T. Hwang P.H. Smith T.L. Alt J.A. Baroody F.M. et al.International Consensus Statement on Allergy and Rhinology: Rhinosinusitis.Int Forum Allergy Rhinol. 2016; 6: S22-209Crossref PubMed Scopus (607) Google Scholar Dupilumab, a fully human VelocImmune-derived4Macdonald L.E. Karow M. Stevens S. Auerbach W. Poueymirou W.T. Yasenchak J. et al.Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes.Proc Natl Acad Sci USA. 2014; 111: 5147-5152Crossref PubMed Scopus (182) Google Scholar, 5Murphy A.J. Macdonald L.E. Stevens S. Karow M. Dore A.T. Pobursky K. et al.Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice.Proc Natl Acad Sci USA. 2014; 111: 5153-5158Crossref PubMed Scopus (228) Google Scholar monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13, key drivers of type 2 diseases such as atopic dermatitis, asthma, and allergic rhinitis.6Gandhi N.A. Bennett B.L. Graham N.M. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (284) Google Scholar In a 16-week phase 2a study in adults with CRSwNP refractory to intranasal corticosteroids (INCS), adding dupilumab to mometasone furoate nasal spray (MFNS) reduced nasal polyp burden versus MFNS alone and significantly improved nasal congestion and airflow, sense of smell, HRQoL, and other nasal symptoms.7Bachert C. Mannent L. Naclerio R.M. Mullol J. Ferguson B.J. Gevaert P. et al.Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis. A randomized clinical trial.JAMA. 2016; 315: 469-479Crossref PubMed Scopus (494) Google Scholar We present a subgroup analysis of patients with CRSwNP and comorbid asthma from this study, examining the effect of dupilumab on patient-reported outcomes (PROs) for CRSwNP and asthma, and inflammatory biomarkers. This randomized, double-blind, placebo-controlled study included a 4-week run-in and 16-week blinded-treatment period.5Murphy A.J. Macdonald L.E. Stevens S. Karow M. Dore A.T. Pobursky K. et al.Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice.Proc Natl Acad Sci USA. 2014; 111: 5153-5158Crossref PubMed Scopus (228) Google Scholar Patients aged ≥18 to 65 years with bilateral NP and 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 add-on to MFNS for 16 weeks. The effect of dupilumab on various NP outcomes in patients with CRSwNP has previously been published.7Bachert C. Mannent L. Naclerio R.M. Mullol J. Ferguson B.J. Gevaert P. et al.Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis. A randomized clinical trial.JAMA. 2016; 315: 469-479Crossref PubMed Scopus (494) Google Scholar Of 60 patients randomized, 35 (16 dupilumab, 19 placebo) had CRSwNP and comorbid asthma. Baseline demographics and disease characteristics were similar between the study groups (Table E1, available in this article's Online Repository at www.jaci-inpractice.org). Mean (standard deviation) age was 49.4 (9.0) years; 14 patients were men, and 13 patients (37.1%) had aspirin-exacerbated respiratory disease (42.1% placebo, 31.3% dupilumab). At baseline, patients had moderate-to-severe CRSwNP, and inflammatory biomarker levels were generally similar across treatment groups. Among patients with CRSwNP and comorbid asthma, dupilumab-treated patients (vs placebo) showed a significant improvement in endoscopic NP score (P < .001), sense of smell (P < .001), Lund-Mackay computed tomography total score (P < .001), and significant reduction in CRSwNP disease severity (P < .001). Furthermore, a significant improvement in the total 22-item Sino-Nasal Outcome Test score at week 16 was observed in dupilumab-treated patients (vs placebo) (P < .001). Dupilumab versus placebo also produced significant improvements in forced expiratory volume in 1 second % predicted (P = .04) and 5-item Asthma Control Questionnaire (ACQ-5) total score (P < .001) exceeding the minimal clinically important difference (MCID) of 0.5.7Bachert C. Mannent L. Naclerio R.M. Mullol J. Ferguson B.J. Gevaert P. et al.Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis. A randomized clinical trial.JAMA. 2016; 315: 469-479Crossref PubMed Scopus (494) Google Scholar 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).8EuroQol GroupEuroQol—a new facility for the measurement of health-related quality of life.Health Policy. 1990; 16: 199-208Crossref PubMed Scopus (11012) Google Scholar SF-36 comprises 8 domains assessing physical functioning, social functioning, role limitations due to physical and emotional problems, mental health, energy/vitality, bodily pain, and general health perception. 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).9Ware Jr., J.E. Sherbourne C.D. The MOS 36-item Short-Form Health Survey (SF-36): I. Conceptual framework and item selection.Med Care. 1992; 30: 473-483Crossref PubMed Scopus (27317) Google Scholar 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 P value <.05 for the comparison between dupilumab and placebo was considered statistically significant. For each of the individual ACQ-5 scores, a significant difference between treatment groups was observed from baseline to week 16 in favor of dupilumab (Table I). ACQ-5 responder rate (MCID ≥ 0.5) was significantly higher (P = .038) in dupilumab-treated patients (62.5%) versus placebo (15.8%). Dupilumab versus placebo produced significant improvements in health status, measured by EQ-5D VAS (P < .001; Figure 1, A). In dupilumab-treated patients, significant improvements from baseline were observed in 5 SF-36 domains (general health, physical functioning, role-physical, social functioning, and vitality) and PCS (P < .05) (Figure 1, B). For placebo, change from baseline was statistically significant (P < .05) in only 2 domains (role-physical and social functioning) and PCS (Figure 1, B). Dupilumab-treated patients (vs placebo) showed a significantly greater reduction from baseline in serum (P = .002) and nasal (P = .04) secretion levels of total IgE (Table E2, available in this article's Online Repository at www.jaci-inpractice.org).Table IACQ-5 scores at baseline and change from baseline at week 16 in patients with CRSwNP and comorbid asthmaACQ-5†Recall period = 1 wk; score range = 0-6. Lower score indicates better control of asthma.MeasureMean score (SD) at baselineLS mean change (SE) from baseline to week 16LS mean difference for dupilumab vs placebo (95% CI)Placebo/MFNS (n = 19)Dupilumab/MFNS (n = 16)Placebo/MFNS (n = 12)Dupilumab/MFNS (n = 15)Total overall‡Within-group MCID of 0.5.Total1.63 (0.87)1.55 (1.11)−0.10 (0.20)−1.19 (0.19)−1.09 (−1.54, −0.63)∗P < .001 vs placebo.Item 1§Within-patient MCID of 0.6.Woken at night by asthma1.00 (1.10)0.88 (1.45)0.08 (0.24)–0.91 (0.23)–0.99 (–1.55, –0.42)P < .01 vs placebo.Item 2§Within-patient MCID of 0.6.Awake in morning with asthma symptoms2.00 (1.37)1.69 (1.25)0.01 (0.22)–1.46 (0.20)–1.46 (–1.94, –0.99)∗P < .001 vs placebo.Item 3§Within-patient MCID of 0.6.Limited in activities1.38 (1.20)1.25 (1.13)–0.11 (0.23)–0.93 (0.21)–0.83 (–1.34, –0.32)P < .01 vs placebo.Item 4§Within-patient MCID of 0.6.Shortness of breath2.19 (1.33)1.94 (1.24)–0.29 (0.29)–1.33 (0.27)–1.04 (–1.77, –0.31)P < .01 vs placebo.Item 5§Within-patient MCID of 0.6.Wheezing time1.56 (0.63)2.00 (1.90)–0.54 (0.36)–1.50 (0.34)–0.96 (–1.81, –0.12)∗P < .05 vs placebo.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 = 1 wk; score range = 0-6. Lower score indicates better control of asthma.‡ Within-group MCID of 0.5.§ Within-patient MCID of 0.6. Open table in a new tab 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. This subgroup analysis of patients with CRSwNP and comorbid asthma extends the previously reported observations that adding dupilumab to MFNS treatment improves nasal polyp burden, asthma control, lung function, and HRQoL.7Bachert C. Mannent L. Naclerio R.M. Mullol J. Ferguson B.J. Gevaert P. et al.Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis. A randomized clinical trial.JAMA. 2016; 315: 469-479Crossref PubMed Scopus (494) Google Scholar The effects of dupilumab on CRSwNP-specific clinical outcomes and PROs in patients with asthma were similar in magnitude to those reported for the overall population.7Bachert C. Mannent L. Naclerio R.M. Mullol J. Ferguson B.J. Gevaert P. et al.Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis. A randomized clinical trial.JAMA. 2016; 315: 469-479Crossref PubMed Scopus (494) Google Scholar Focusing on PROs, the clinical benefit of dupilumab in patients with CRSwNP and comorbid asthma was observed for CRSwNP disease and symptom severity, and asthma control (assessed by ACQ-5 total and individual item scores) reflecting a reduced impact of asthma on daily activities and an improved HRQoL. Significant improvement from baseline in general health perception, physical functioning, and vitality was only observed with dupilumab treatment and not in the placebo arm. In conclusion, treatment with dupilumab was associated with an improvement of both clinical and patient-reported NP-specific outcomes, and asthma-specific outcomes in patients with CRSwNP and comorbid asthma. Editorial assistance was provided by Bilge Yoruk, PhD, and Ravi Subramanian, PhD, of Excerpta Medica funded by Sanofi Genzyme and Regeneron Pharmaceuticals . Table E1Baseline demographics and disease characteristics of patients with CRSwNP with comorbid asthmaPlacebo/MFNS (n = 19)Dupilumab/MFNS (n = 16)Patient characteristic Age, mean (SD), y47.7 (9.9)51.4 (7.6) Male, n (%)7 (36.8)7 (43.8) Duration of CRSwNP, mean (SD), y11.32 (8.93)8.95 (6.33) Duration of asthma, mean (SD), y20.15 (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∗Higher scores indicate worse status., mean (SD)5.53 (1.02)5.94 (0.85) CT Lund-Mackay total score, range 0-24∗Higher scores indicate worse status., mean (SD)19.95 (5.65)19.07 (4.23) CRSwNP disease severity VAS (0-10 cm)∗Higher scores indicate worse status., mean (SD)6.66 (2.36)6.23 (2.73) Daily congestion/obstruction score (0-3)†Average of the last 7 d before randomization.1.67 (0.74)1.43 (0.73) Daily AM loss of smell score†Average of the last 7 d before randomization. (0-3)†Average of the last 7 d before randomization.2.93 (0.24)2.47 (0.96) SNOT-22 total score (0-110), mean (SD)∗Higher scores indicate worse status.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), % predicted79.76 (14.55)82.19 (17.71)Baseline levels of biomarkers Serum blood eosinophil count, mean (SD), 109/L0.55 (0.83)0.51 (0.25) Serum ECP, mean (SD), ng/mL37.26 (48.33)35.38 (26.27) Nasal secretion ECP, mean (SD), ng/mL16.47 (11.49)41.80 (43.44) Serum total IgE, mean (SD), IU/mL233.06 (300.44)167.13 (153.77) Nasal secretion total IgE, mean (SD), IU/mL7.53 (5.64)20.93 (41.78) Serum TARC, mean (SD), pg/mL506.20 (422.59)506.77 (340.29) Serum periostin, mean (SD), ng/mL72.86 (28.52)80.42 (24.44) Nasal secretion periostin, mean (SD), ng/mL6.92 (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. Open table in a new tab Table E2Inflammatory biomarker levels at baseline and change from baseline at week 16 in patients with CRSwNP and comorbid asthmaBiomarkerPlacebo/MFNS group (n = 19)Dupilumab/MFNS group (n = 16)LS mean difference for dupilumab vs placebo at week 16 (95% CI)∗Based on the mixed-effects model with repeated measures.P valueBaseline mean (SD)Week 16 mean (SD)LS mean change from baseline (SE)Baseline mean (SD)Week 16 mean (SD)LS mean change from baseline (SE)Serum blood eosinophil count, 109/L0.55 (0.83)0.37 (0.19)–0.15 (0.17)0.51 (0.25)0.53 (0.37)–0.06 (0.16)0.09 (–0.34, 0.51).682Serum ECP, ng/mL37.26 (48.33)15.57 (11.92)–14.58 (9.83)35.38 (26.27)41.60 (47.60)6.66 (9.77)21.25 (–3.70, 46.20).094Nasal secretion ECP, ng/mL16.47 (11.49)29.08 (38.72)26.47 (11.31)41.80 (43.44)39.07 (38.19)16.92 (9.98)–9.55 (–35.89, 16.80).472Serum total IgE, IU/mL233.06 (300.44)128.87 (143.70)–38.09 (12.22)167.13 (153.77)102.07 (119.46)–86.59 (12.38)–48.49 (–78.66, –18.33).002Nasal secretion total IgE, IU/mL7.53 (5.64)13.77 (21.46)6.86 (5.03)20.93 (41.78)5.53 (4.05)–5.31 (4.31)–12.17 (–23.76, –0.57).04Serum TARC, pg/mL506.20 (422.59)384.19 (235.65)–125.80 (44.78)506.77 (340.29)288.94 (154.06)–204.62 (48.99)–78.82 (–183.10, 25.45).135Serum periostin, ng/mL72.86 (28.52)53.05 (18.76)–17.09 (7.52)80.42 (24.44)57.83 (22.27)–13.83 (6.53)3.26 (–13.05, 19.57).692Nasal secretion periostin, ng/mL6.92 (5.44)8.37 (6.91)0.64 (2.53)7.27 (5.78)4.26 (5.71)–2.96 (2.16)–3.60 (–7.60, 0.40).076CI, 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. Open table in a new tab 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. 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.