https://orcid.org/0000-0001-6709-9795
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Abstract
Purpose
Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR.
Methods
Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc).
Results
Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (–12.57 points [–19.40, –5.73]) and 52 weeks (–10.58 points [–17.75, –3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status.
Conclusion
Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.
Graphical Abstract
Plain Language Summary
Asthma is a long-term condition caused by ongoing inflammation of the lower airways. The main symptoms are difficulty breathing, coughing, wheezing and shortness of breath. Approximately 41% of patients with severe asthma also have chronic rhinosinusitis with nasal polyps, a condition that affects the upper airways and sinuses. Nasal polyps are painless soft growths inside your nose that can keep growing if not treated. Symptoms include nasal congestion with mucus, facial pain and a reduced sense of smell or taste. People with both severe asthma and nasal polyps often have severe symptoms.
Thymic stromal lymphopoietin (TSLP) is a signaling molecule released by cells lining the airways in response to airborne triggers, such as smoke, pollen and viruses. TSLP activates several pathways that cause inflammation in the airways, leading to asthma symptoms. Tezepelumab is a biologic treatment that targets the very start of these inflammatory pathways by blocking TSLP.
The 1-year-long clinical trial called “NAVIGATOR” reported that tezepelumab reduced asthma attacks and improved lung function and asthma symptom control compared with placebo in patients with severe asthma that was not controlled with their current medicines. This analysis of data from NAVIGATOR looked at patients with both severe asthma and nasal polyps, showing that tezepelumab treatment improved sino-nasal symptoms compared with placebo. Tezepelumab also reduced asthma attacks and improved asthma symptoms, regardless of a patient’s medical history of nasal polyps. The effects of tezepelumab in patients with severe nasal polyps are being investigated in another clinical trial called “WAYPOINT”.
Data Sharing Statement
This study is registered at ClinicalTrials.gov with the identifier NCT03347279 (registration date: 20 November 2017). Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Ethics Approval and Consent to Participate
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice guidelines and applicable regulatory requirements. All patients or their guardians provided written informed consent before participation in the study.
Acknowledgments
The authors thank Christopher S Ambrose, MD, Gene Colice, MD, and Bill Cook, PhD, of AstraZeneca, Gaithersburg, MD, USA, for their contributions to the NAVIGATOR study. Andrew Menzies-Gow has a new and additional affiliation of Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK. Medical writing support for this manuscript was provided by Elizabeth Gandhi, PhD, of PharmaGenesis Cambridge, Cambridge, UK, with funding from AstraZeneca and Amgen Inc. The findings reported in this manuscript have been previously presented (in part) at the European Respiratory Society International Congress, September 5–8, 2021, virtual meeting (Menzies-Gow A, et al. Eur Respir J. 2021;58:PA876) and at the American Academy of Allergy Asthma and Immunology Annual Meeting February 25–28, 2022, Phoenix, AZ, USA (Carr T, et al. J Allergy Clin Immunol. 2022;149:Suppl AB152).
Author Contributions
All authors made significant contributions to the work reported, whether to the study conception, design and execution; data acquisition, analysis and interpretation; or all these areas. All authors contributed to drafting, revising or critically reviewing the article; gave final approval of the version to be published; agreed on the journal to which the article was submitted; and agreed to be accountable for all aspects of the work.
Disclosure
Tanya M Laidlaw has served on scientific advisory boards for Amgen, GSK, Regeneron and Sanofi. Andrew Menzies-Gow is an employee of AstraZeneca and may own stock or stock options in AstraZeneca; has attended advisory board meetings for AstraZeneca, GSK, Novartis, Regeneron, Sanofi and Teva Pharmaceuticals; has received speaker fees from AstraZeneca, Novartis, Sanofi and Teva Pharmaceuticals; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva Pharmaceuticals; and has consultancy agreements with AstraZeneca and Sanofi. Joseph K Han has received consultancy fees from AstraZeneca, Genentech, Gossamer Bio, GSK, Novartis, Regeneron and Sanofi-Genzyme. Elliot Israel has served as a consultant to and received personal fees from 4D Pharma, AB Science, the Allergy and Asthma Network, Amgen, AstraZeneca, Avillion, Biometry, Cowen, Equillium, Genentech, GSK, Merck, National Heart, Lung and Blood Institute, Novartis, Pneuma Respiratory, PPS Health, Regeneron Pharmaceuticals, Sanofi, Sienna Biopharmaceuticals, Teva Pharmaceuticalsand Westchester Medical Center; has received non-financial support from Circassia, Teva Pharmaceuticals and Vorso Corp; and has received clinical research grants from AstraZeneca, Avillion, Genentech, Gossamer Bio, National Institutes of Health (NIH), Novartis, Patient-Centered Outcomes Research Institute and Sanofi; royalties or licenses from UpToDate – Wolters Kluwer; stock options from Nesos Corp; study drug for NIH PrecISE trial for CSL Behring, Laurel Pharmaceuticals, Om Pharmaceuticals, Nestlé and Sun Pharmaceuticals; study drug for NIH IDEA for Sanofi-Regeneron. Jason K Lee has received research support from ALK, AstraZeneca Bausch Health, Genentech, GSK, Meda, Medexus, Miravo, Novartis, Regeneron, Roche, Sanofi-Genzyme and Takeda; has received fees for speakers’ bureau from Aralez, AstraZeneca, GSK, Medexus, Merck, Mylan, Novartis and Sanofi-Genzyme; and has received consultancy fees from and is an advisory committee member of AstraZeneca, GSK, Medexus, Novartis, Regeneron and Sanofi-Genzyme. Tobias Welte has received fees for lectures and/or advisory board meetings from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, MSD, Novartis, Roche, Pfizer and Sanofi Aventis; grants from the German Ministry of Research and Education, AstraZeneca and GSK. Jonathan Corren has received grants and personal fees from AstraZeneca, Genentech, RAPT, Regeneron and Vectura; and has received grants from Optinose, Pulmatrix, Sanofi and Teva Pharmaceuticals. Scott Caveney and Jean-Pierre Llanos are employees of Amgen and own stock in Amgen. Nicole Martin, Neil Martin, Ayman Megally, Bhavini Parikh and Sylvia Vong are employees of AstraZeneca and may own stock or stock options in AstraZeneca. The authors report no other conflicts of interest in this work.