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Randomized Controlled Trial
. 2022 Jan;77(1):186-196.
doi: 10.1111/all.14906. Epub 2021 Jun 4.

Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status

Shigeharu Fujieda  1 , Shoji Matsune  2 , Sachio Takeno  3 , Nobuo Ohta  4 , Mikiya Asako  5 , Claus Bachert  6   7 , Tomoyuki Inoue  8 , Yoshinori Takahashi  8 , Hiroyuki Fujita  8 , Yamo Deniz  9 , Paul Rowe  10 , Benjamin Ortiz  9 , Yongtao Li  10 , Leda P Mannent  11
Affiliations
Randomized Controlled Trial

Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status

Shigeharu Fujieda et al. Allergy. 2022 Jan.

Abstract

Background: The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy.

Methods: Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm.

Results: Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p < 0.001), with improvements maintained or increased at week 52 (p < 0.001). There was no significant interaction between ECRS subgroup (non-/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p > 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups.

Conclusion: Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP.

Keywords: ENT (rhinitis; biologics; eosinophils; inflammation; nasal polyps); sinusitis.

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Conflict of interest statement

Fujieda S: AstraZeneca, GlaxoSmithKline, Kyowa Hakko Kirin, and Sanofi – advisory board member; Kyorin, Mitsubishi Tanabe Pharma, and Taiho Pharma – speaker fees. Matsune S: Sanofi – advisory board member; Kyorin, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Sanofi, Taiho Pharma, and Tanabe Pharma – speaker fees. Takeno S: Sanofi – advisory board member; Sanofi – speaker fees. Ohta N: Mitsubishi Tanabe Pharma, Sanofi, and Taiho Pharma– speaker fees. Asako M: AstraZeneca, Sanofi, and Taiho Pharma – speaker fees. Bachert C: ALK, ASIT Biotech, AstraZeneca, Intrexon Actobiotics, Novartis, Sanofi, Stallergenes Greer – advisory board member. Inoue T, Takahashi Y, Fujita H, Rowe P, Li Y, Mannent LP: Sanofi – employees, may hold stock and/or stock options in the company. Deniz Y, Ortiz B: Regeneron Pharmaceuticals, Inc. – employees and shareholders.

Figures

FIGURE 1
FIGURE 1
Any treatment arm. ECRS, eosinophilic chronic rhinosinusitis; ITT, intention‐to‐treat; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis; MedDRA PT, Medical Dictionary for Regulatory Activities Preferred Term; q2w, every 2 weeks; q4w, every 4 weeks; TEAE, treatment‐emergent adverse event. Figure 1 JESREC algorithm. CT, computed tomography; ECRS, eosinophilic chronic rhinosinusitis; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis; NSAID‐ERD, nonsteroidal antiinflammatory drug‐exacerbated respiratory disease. Figure from: Allergy 75 (2020) 3087–3099 © 2020Asano K, et al. Allergy. Published by John Wiley and Sons Ltd
FIGURE 2
FIGURE 2
Effect of dupilumab 300 mg versus placebo on change from baseline in symptom scores at weeks 24 and 52 by ECRS subgroup: (A) NPS, (B) NC, and (C) LMK‐CT scores. ECRS subgroups were defined according to the JESREC algorithm (Figure 1). Data for dupilumab 300 mg q2w and q2w–q4w treatment arms are pooled. CI, confidence interval; ECRS, eosinophilic chronic rhinosinusitis; ITT, intention‐to‐treat; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis; LMK‐CT, Lund‐Mackay score assessed by CT; LS, least squares; NC, nasal congestion; NPS, nasal polyp score; q2w, every 2 weeks; q4w, every 4 weeks
FIGURE 3
FIGURE 3
Effect of dupilumab 300 mg versus placebo on changes from baseline in secondary efficacy endpoints at weeks 24 and 52 by ECRS subgroup: (A) TSS, (B) UPSIT, (C) SNOT‐22, and (D) CRSwNP severity (VAS) scores. ECRS subgroups were defined according to the JESREC algorithm (Figure 1). Data for dupilumab 300 mg q2w and q2w–q4w treatment arms are pooled. Higher scores indicate greater disease severity, except for UPSIT, where higher scores indicate lower disease severity. CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; ECRS, eosinophilic chronic rhinosinusitis; ITT, intention‐to‐treat; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis; LS, least squares; q2w, every 2 weeks; q4w, every 4 weeks; SNOT‐22, 22‐item Sinonasal Outcome Test; TSS, Total Symptom Score; UPSIT, University of Pennsylvania Smell Identification Test; VAS, visual analog scale
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