NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma
Andrew Menzies-Gow, Gene Colice, Janet M Griffiths, Gun Almqvist, Sandhia Ponnarambil, Primal Kaur, Gennaro Ruberto, Karin Bowen, Åsa Hellqvist, May Mo, Esther Garcia Gil, Andrew Menzies-Gow, Gene Colice, Janet M Griffiths, Gun Almqvist, Sandhia Ponnarambil, Primal Kaur, Gennaro Ruberto, Karin Bowen, Åsa Hellqvist, May Mo, Esther Garcia Gil
Abstract
Background: Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study.
Methods: NAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids (N = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/μL) and low (< 300 cells/μL) blood eosinophil counts. The study comprises a 5-6-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients will receive their prescribed controller medications without change throughout the study. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints include the effect of tezepelumab on lung function, asthma control and health-related quality of life.
Discussion: NAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR (N = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life.
Trial registration: NCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.
Keywords: Clinical trial; Severe asthma; Tezepelumab; Thymic stromal lymphopoietin.
Conflict of interest statement
AMG has: attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi and Teva; received speaker fees from AstraZeneca, Novartis, Roche and Teva; participated in research with AstraZeneca, for which his institution has been remunerated; attended international conferences with Teva; and consultancy agreements with AstraZeneca, Sanofi and Vectura. GC, JMG, GA, SP, GR, KB, ÅH and EGG are employees of AstraZeneca. PK and MM are employees of Amgen Inc.
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References
- Global Asthma Report 2018. . Accessed 5 Mar 2020.
- Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–373. doi: 10.1183/09031936.00202013.
- Chen S, Golam S, Myers J, Bly C, Smolen H, Xu X. Systematic literature review of the clinical, humanistic, and economic burden associated with asthma uncontrolled by GINA steps 4 or 5 treatment. Curr Med Res Opin. 2018;34:2075–2088. doi: 10.1080/03007995.2018.1505352.
- Chastek B, Korrer S, Nagar SP, Albers F, Yancey S, Ortega H, et al. Economic burden of illness among patients with severe asthma in a managed care setting. J Manag Care Spec Pharm. 2016;22:848–861.
- Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J. 2002;19:61–67. doi: 10.1183/09031936.02.00232001.
- Chen H, Gould MK, Blanc PD, Miller DP, Kamath TV, Lee JH, et al. Asthma control, severity, and quality of life: quantifying the effect of uncontrolled disease. J Allergy Clin Immunol. 2007;120:396–402. doi: 10.1016/j.jaci.2007.04.040.
- McDonald VM, Hiles SA, Jones KA, Clark VL, Yorke J. Health-related quality of life burden in severe asthma. Med J Aust. 2018;209:S28–S33. doi: 10.5694/mja18.00207.
- McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199:433–445. doi: 10.1164/rccm.201810-1944CI.
- Genentech. Xolair (omalizumab) prescribing information, 2019. . Accessed 5 Mar 2020.
- AstraZeneca. Faserna (benralizumab) prescribing information, 2019. . Accessed 5 Mar 2020.
- Sanofi/Regeneron. Dupixent (dupilumab) prescribing information, 2019. . Accessed 5 Mar 2020.
- Teva Pharmaceutical Industries. Cinqair (reslizumab) prescribing information, 2019. . Accessed 5 Mar 2020.
- GlaxoSmithKline. Nucala (Mepolizumab) prescribing information, 2019. . Accessed 5 Mar 2020.
- Sanofi-Aventis. Dupilumab summary of product characteristics, 2019.. Accessed 5 Mar 2020.
- Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;13:CD003559.
- Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.
- Xiong XF, Zhu M, Wu HX, Fan LL, Cheng DY. Efficacy and safety of dupilumab for the treatment of uncontrolled asthma: a meta-analysis of randomized clinical trials. Respir Res. 2019;20:108. doi: 10.1186/s12931-019-1065-3.
- Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, et al. Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma. 2019;56:1110–19.
- Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007;204:253–258. doi: 10.1084/jem.20062211.
- Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol. 2012;129:104–111. doi: 10.1016/j.jaci.2011.08.031.
- Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–680. doi: 10.1038/ni805.
- Ying S, O'Connor B, Ratoff J, Meng Q, Fang C, Cousins D, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181:2790–2798. doi: 10.4049/jimmunol.181.4.2790.
- Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005;174:8183–8190. doi: 10.4049/jimmunol.174.12.8183.
- Fujisawa T, Fujisawa R, Kato Y, Nakayama T, Morita A, Katsumata H, et al. Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis. J Allergy Clin Immunol. 2002;110:139–146. doi: 10.1067/mai.2002.126079.
- Hijnen D, De Bruin-Weller M, Oosting B, Lebre C, De Jong E, Bruijnzeel-Koomen C, et al. Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J Allergy Clin Immunol. 2004;113:334–40.
- Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal lymphopoietin (TSLP) Adv Pharmacol. 2013;66:129–155. doi: 10.1016/B978-0-12-404717-4.00004-4.
- Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019;20:1603–1609. doi: 10.1038/s41590-019-0524-9.
- Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936–946. doi: 10.1056/NEJMoa1704064.
- Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370:2102–2110. doi: 10.1056/NEJMoa1402895.
- Pham T-H, Ren P, Parnes JR, Griffiths JM. Tezepelumab reduces multiple key inflammatory biomarkers in patients with severe, uncontrolled asthma in the phase 2b PATHWAY study. Am J Respir Crit Care Med. 2019;199:A2677.
- Upham JW, Jurak LM. How do biologicals and other novel therapies effect clinically used biomarkers in severe asthma? Clin Exp Allergy. 2020. 10.1111/cea.13694 Online ahead of print.
- AstraZeneca. Tezepelumab granted Breakthrough Therapy Designation by US FDA. 2018.. Accessed 5 Mar 2020.
- Globe G, Martin M, Schatz M, Wiklund I, Lin J, von Maltzahn R, et al. Symptoms and markers of symptom severity in asthma – content validity of the asthma symptom diary. Health Qual Life Outcomes. 2015;13:21. doi: 10.1186/s12955-015-0217-5.
- Globe G, Wiklund I, Lin J, Chen WH, Martin M, Mattera MS, et al. Psychometric properties of the asthma symptom diary (ASD), a diary for use in clinical trials of persistent asthma. J Allergy Clin Immunol Pract. 2016;4:60–66. doi: 10.1016/j.jaip.2015.07.008.
- Globe G, Wiklund I, Mattera M, Zhang H, Revicki DA. Evaluating minimal important differences and responder definitions for the asthma symptom diary in patients with moderate to severe asthma. J Patient Rep Outcomes. 2019;3:22. doi: 10.1186/s41687-019-0109-2.
- Corren J, Garcia Gil E, Parnes JR, Pham T, Griffiths JM. Tezepelumab treatment effect on annualized rate of exacerbations by baseline biomarkers in uncontrolled severe asthma patients: phase 2b PATHWAY study. Am J Respir Crit Care Med. 2019;199:A2621.
- Parnes JR, Sullivan JT, Chen L, Dias C. Pharmacokinetics, safety, and tolerability of tezepelumab (AMG 157) in healthy and atopic dermatitis adult subjects. Clin Pharmacol Ther. 2019;106:441–449. doi: 10.1002/cpt.1401.
- Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80:1013–1021. doi: 10.1016/j.jaad.2018.11.059.
- Sakamoto K, Matsuki S, Irie S, Uchida N, Hayashi N, Horiuchi M, et al. A phase 1, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Clin Pharmacol Drug Dev. 2020. 10.1002/cpdd.775. Online ahead of print.
- Ly N, Zheng Y, Griffiths JM, van der Merwe R, Agoram B, Roskos L. Exposure-response analysis of tezepelumab in patients with severe asthma to guide phase 3 dose selection. Eur Respir J. 2018;52:PA1688.
- Jones PW. St George's respiratory questionnaire manual. 2009. . Accessed 5 Mar 2020.
- Wu D, Bleier BS, Li L, Zhan X, Zhang L, Lv Q, et al. Clinical phenotypes of nasal polyps and comorbid asthma based on cluster analysis of disease history. J Allergy Clin Immunol Pract. 2018;6:1297–1305. doi: 10.1016/j.jaip.2017.09.020.
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