Clinical Efficacy among Patients with Chronic Rhinosinusitis with Nasal Polyps and Clinical Features of Obstructive Lung Disease: Post Hoc Analysis of the Phase III SINUS-24 and SINUS-52 Studies

Abstract

Purpose

To provide a descriptive summary of clinical efficacy and health-related quality of life (HRQoL) measures in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and clinical features of obstructive lung disease in the Phase III dupilumab studies SINUS-24 and SINUS-52 (NCT02912468, NCT02898454).

Patients and Methods

Patients met a “broad” definition of having clinical features of obstructive lung disease with any of 3 criteria: (i) pre-bronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) <0.70 and smoking history; (ii) patient-reported medical history of chronic obstructive pulmonary disease (COPD); or (iii) asthma with >10 pack-years’ smoking history. A “narrow” definition including criteria (i) or (ii) was also analyzed. CRSwNP and HRQoL measures were evaluated in all patients and lung function (FEV₁; FEV₁/FVC ratio) was captured and analyzed only in those patients who had a self-reported history of asthma.

Results

Across both studies, 131 patients met the “broad” definition, of whom 90 also had asthma, and 115 patients met the “narrow” definition, of whom 74 had asthma. CRSwNP outcomes and HRQoL were improved with dupilumab vs placebo in both the broad and narrow subgroups. Among the 90 patients who met the broad definition and had asthma, dupilumab improved pre-bronchodilator FEV₁ and FEV₁/FVC ratio at Week 16 (least squares mean differences vs placebo: 0.38 L [95% confidence interval: 0.17, 0.59; p = 0.0004] and 4.8% [1.7%, 7.9%; p = 0.0024], respectively) sustained through Week 24. Similar results were seen in the “narrow” subgroup with asthma.

Conclusion

In a population of patients with CRSwNP and clinical features of obstructive lung disease, dupilumab improved CRSwNP and HRQoL outcomes, and, among those with a history of asthma, also improved lung function. These results support further analyses of dupilumab in patients with evidence of type 2 inflammation and obstructive lung disease such as COPD.

Keywords:

• obstructive lung disease
• chronic obstructive pulmonary disease
• dupilumab
• type 2 inflammation
• interleukin-4
• interleukin-13

Abbreviations

CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRSwNP, chronic rhinosinusitis with nasal polyps; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HRQoL, health-related quality of life; IL, interleukin; INCS, intranasal corticosteroids; LS, least squares; NP, nasal polyps; NPS, nasal polyp score; NSAID-ERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; q2w, every 2 weeks; SC, subcutaneous; SD, standard deviation; SNOT-22, 22-item Sino Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test.

Prior Presentation

Some of the data were previously presented at the 2020 American Thoracic Society (ATS) Virtual Symposium (abstract and poster #223).

Data Sharing Statement

Qualified researchers may request access to patient-level data and related study documents including clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/

Ethics Approval and Informed Consent

The studies were conducted in accordance with the Declaration of Helsinki and the study protocols were approved by Copernicus Group IRB (Protocol # EFC14146, Tracking # SAN4-16-406; Protocol # EFC14280, Tracking # SAN4-16-417). All patients gave written informed consent.

Acknowledgments

Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifier: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52). The authors thank Marcella Ruddy, formerly of Regeneron Pharmaceuticals, Inc., for insight and guidance, Nadia Daizadeh, formerly of Sanofi, for statistical analyses, and Matt Lewis, of Adelphi Communications, for medical writing/editorial assistance funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc., in accordance with Good Publication Practice (GPP3).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Jorge F. Maspero has been a consultant for AstraZeneca, Sanofi, and Teva; reports speaker fees from Boehringer Ingelheim, GlaxoSmithKline, Menarini, Novartis, and Uriach; and reports research grants from Novartis. Claus Bachert has been an advisory board member for ALK, ASIT Biotech, AstraZeneca, Intrexon Actobiotics, Novartis, Sanofi, and Stallergenes Greer. Fernando J. Martinez has been on steering committees for Afferent/Merck, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Nitto, Patara/Respivant, Pearl Pharmaceuticals, ProMedior/Roche, ProMetic, Stromedix/Biogen, and Veracyte; has been an advisory board member for AstraZeneca, Bioscale/Proterrix Bio, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, Genentech, GlaxoSmithKline, Novartis, Pearl Pharmaceuticals, Physicians Education Resource, Sunovion, Teva, and Zambon; has been a consultant for Bridge Biotherapeutics, Bristol Myers Squibb, and twoXR; reports continuing medical education presentation support from the Canadian Respiratory Network, Chiesi, CME Outfitters, Dartmouth University, France Foundation, Inova Fairfax, MD Magazine, Methodist Hospital, Miller Communications, National Association for Continuing Education/Haymarket, New York University, PeerView, Prime Education, Rare Diseases Healthcare Communication, Rockpointe, University of Alabama Birmingham, UpToDate, Vindico, WebMD/MedScape, and Zambon; and has been on the data and safety monitoring board for Boehringer Ingelheim and GlaxoSmithKline. Nicola A. Hanania reports research support from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; and has been a consultant for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi. Benjamin Ortiz and Shahid Siddiqui are employees of and shareholders in Regeneron Pharmaceuticals, Inc. Naimish Patel, Leda P. Mannent, Amy Praestgaard, Megan Hardin, and Nami  Pandit-Abid are employees of and may hold stock and/or stock options in Sanofi. Dr. Benjamin Ortiz is a former employee of Regeneron Pharmaceuticals, Inc. The authors report no other conflicts of interest in this work.

Additional information

Funding

This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.