CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma

Claire Emson, Sarah Diver, Latifa Chachi, Ayman Megally, Cherrie Small, John Downie, Jane R Parnes, Karin Bowen, Gene Colice, Chris E Brightling, Claire Emson, Sarah Diver, Latifa Chachi, Ayman Megally, Cherrie Small, John Downie, Jane R Parnes, Karin Bowen, Gene Colice, Chris E Brightling

Abstract

Background: Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study.

Methods: CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18-75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants' type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit.

Discussion: CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation.

Trial registration: NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Keywords: Asthma; T2 inflammation; TSLP; Tezepelumab.

Conflict of interest statement

CEB has received grants and consultancy fees from AstraZeneca. CE, GC, AM, CS and KB are employees of AstraZeneca and own stock and stock options in AstraZeneca. JD and JRP are employees of Amgen Inc. and own stock and stock options in Amgen Inc. SD and LC declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mechanism of action by which tezepelumab improves clinical outcomes in patients with asthma. TSLP is released from the airway epithelium in response to insults such as virus, allergens and pollutants, triggering an inflammatory cascade. Tezepelumab blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various inflammatory cytokines and cell types. The primary and secondary objectives of CASCADE comprise assessment of the effects of tezepelumab on the cell types labelled with an asterisk. IgE, immunoglobulin E; IL, interleukin; ILC2, group 2 innate lymphoid cell; Th, T helper cell; TSLP, thymic stromal lymphopoietin
Fig. 2
Fig. 2
Study design. *For participants who cannot visit the study site at week 28 owing to the COVID-19 pandemic, treatment can be extended to up to 52 weeks until they are able to visit the study site. Q4W, every 4 weeks. SC, subcutaneous

References

    1. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, 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.
    1. Zeiger RS, Schatz M, Chen W, Li Q, Khatry DB, Tran TN. Adherent uncontrolled adult persistent asthma: characteristics and asthma outcomes. J Allergy Clin Immunol Pract. 2015;3:986–990. doi: 10.1016/j.jaip.2015.06.016.
    1. Global strategy for asthma management and prevention. Updated 2019. []. Accessed 21 Sept 2020.
    1. Chastek B, Korrer S, Nagar SP, Albers F, Yancey S, Ortega H, Forshag M, Dalal AA. Economic burden of illness among patients with severe asthma in a managed care setting. J Manag Care Spec Pharm. 2016;22:848–861.
    1. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.
    1. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
    1. 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.
    1. Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, Bachuwa G, Chandran A. Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma. 2018;56:1–10.
    1. Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, Olsson RF, Martin UJ, Goldman M, Bora study investigators. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019;7:46–59.
    1. Swedin L, Saarne T, Rehnberg M, Glader P, Niedzielska M, Johansson G, Hazon P, Catley MC. Patient stratification and the unmet need in asthma. Pharmacol Ther. 2017;169:13–34. doi: 10.1016/j.pharmthera.2016.06.016.
    1. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, Ford L, Sher L, FitzGerald JM, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486–2496. doi: 10.1056/NEJMoa1804092.
    1. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, Lal P, Arron JR, Harris JM, Busse W. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804–811. doi: 10.1164/rccm.201208-1414OC.
    1. Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, FitzGerald JM, Boedigheimer M, Davis BE, Dias C, 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.
    1. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, van der Merwe R. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936–946. doi: 10.1056/NEJMoa1704064.
    1. Corren J, Garcia Gil E, Parnes J, Pham T, Griffiths J. Tezepelumab treatment effect on annualized rate of exacerbations by baseline biomarkers in uncontrolled severe asthma patients: phase 2b PATHWAY study. J Allergy Clin Immunol. 2019;199:A2621.
    1. Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol. 2010;11:289–293. doi: 10.1038/ni.1852.
    1. Zhang Y, Zhou B. Functions of thymic stromal lymphopoietin in immunity and disease. Immunol Res. 2012;52:211–223. doi: 10.1007/s12026-012-8264-z.
    1. Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019;20:1603–1609. doi: 10.1038/s41590-019-0524-9.
    1. Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets. 2020;1–16.
    1. Tezepelumab granted Breakthrough Therapy Designation by US FDA []. Accessed 21 Sept 2020.
    1. Global strategy for asthma management and prevention. Updated 2018. []. Accessed 21 Sept 2020.
    1. Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, Fedorowicz G, Modrusan Z, Fahy JV, Woodruff PG, Arron JR. Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Immunol. 2011;186:1861–1869. doi: 10.4049/jimmunol.1002568.
    1. Bhakta NR, Solberg OD, Nguyen CP, Nguyen CN, Arron JR, Fahy JV, Woodruff PG. A qPCR-based metric of Th2 airway inflammation in asthma. Clin Transl Allergy. 2013;3:24. doi: 10.1186/2045-7022-3-24.
    1. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388–395. doi: 10.1164/rccm.200903-0392OC.
    1. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–984. doi: 10.1056/NEJMoa0808991.
    1. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086–1096. doi: 10.1016/j.jaci.2013.05.020.
    1. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170:583–593. doi: 10.1164/rccm.200312-1651OC.
    1. Riccio AM, Dal Negro RW, Micheletto C, De Ferrari L, Folli C, Chiappori A, Canonica GW. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol. 2012;25:475–484. doi: 10.1177/039463201202500217.
    1. van Rensen EL, Evertse CE, van Schadewijk WA, van Wijngaarden S, Ayre G, Mauad T, Hiemstra PS, Sterk PJ, Rabe KF. Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy. 2009;64:72–80. doi: 10.1111/j.1398-9995.2008.01881.x.
    1. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, Barnes N, Robinson D, Kay AB. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003;112:1029–1036. doi: 10.1172/JCI17974.
    1. Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003;167:199–204. doi: 10.1164/rccm.200208-789OC.
    1. Menzies-Gow A, Flood-Page P, Sehmi R, Burman J, Hamid Q, Robinson DS, Kay AB, Denburg J. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol. 2003;111:714–719. doi: 10.1067/mai.2003.1382.
    1. Kelly EA, Esnault S, Liu LY, Evans MD, Johansson MW, Mathur S, Mosher DF, Denlinger LC, Jarjour NN. Mepolizumab attenuates airway eosinophil numbers, but not their functional phenotype, in asthma. Am J Respir Crit Care Med. 2017;196:1385–1395. doi: 10.1164/rccm.201611-2234OC.
    1. Russell RJ, Chachi L, FitzGerald JM, Backer V, Olivenstein R, Titlestad IL, Ulrik CS, Harrison T, Singh D, Chaudhuri R, et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir Med. 2018;6:499–510. doi: 10.1016/S2213-2600(18)30201-7.
    1. Evaluation of dupilumab’s effects on airway inflammation in patients with asthma (EXPEDITION) []. Accessed 21 Sept 2020.
    1. Greer AM, Matthay MA, Kukreja J, Bhakta NR, Nguyen CP, Wolters PJ, Woodruff PG, Fahy JV, Shin JS. Accumulation of BDCA1(+) dendritic cells in interstitial fibrotic lung diseases and Th2-high asthma. PLoS One. 2014;9:e99084. doi: 10.1371/journal.pone.0099084.
    1. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160:1532–1539. doi: 10.1164/ajrccm.160.5.9806170.
    1. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis. 1993;147:697–704. doi: 10.1164/ajrccm/147.3.697.
    1. Costa JJ, Weller PF, Galli SJ. The cells of the allergic response: mast cells, basophils, and eosinophils. JAMA. 1997;278:1815–1822. doi: 10.1001/jama.1997.03550220021005.
    1. Wong CK, Hu S, Cheung PF, Lam CW. Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am J Respir Cell Mol Biol. 2010;43:305–315. doi: 10.1165/rcmb.2009-0168OC.
    1. Cook EB, Stahl JL, Schwantes EA, Fox KE, Mathur SK. IL-3 and TNFalpha increase thymic stromal lymphopoietin receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation. Clin Mol Allergy. 2012;10:8. doi: 10.1186/1476-7961-10-8.
    1. Li Y, Wang W, Lv Z, Li Y, Chen Y, Huang K, Corrigan CJ, Ying S. Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J Immunol. 2018;200:2253–2262. doi: 10.4049/jimmunol.1701455.
    1. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–680. doi: 10.1038/ni805.
    1. Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G. 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.
    1. Torii Y, Ito T, Amakawa R, Sugimoto H, Amuro H, Tanijiri T, Katashiba Y, Ogata M, Yokoi T, Fukuhara S. Imidazoquinoline acts as immune adjuvant for functional alteration of thymic stromal lymphopoietin-mediated allergic T cell response. J Immunol. 2008;181:5340–5349. doi: 10.4049/jimmunol.181.8.5340.
    1. Tanaka J, Watanabe N, Kido M, Saga K, Akamatsu T, Nishio A, Chiba T. Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions. Clin Exp Allergy. 2009;39:89–100. doi: 10.1111/j.1365-2222.2008.03151.x.
    1. Rochman I, Watanabe N, Arima K, Liu YJ, Leonard WJ. Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. J Immunol. 2007;178:6720–6724. doi: 10.4049/jimmunol.178.11.6720.
    1. Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011;41:1862–1871. doi: 10.1002/eji.201041195.
    1. 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.
    1. Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7:301ra129. doi: 10.1126/scitranslmed.aab3142.
    1. Brightling C, Wang M, Braddock M, Nordenmark L, Gottlow M, Colice G. MESOS: considerations in designing a mechanistic study for a biologic used to treat asthma. Clin Invest (Lond) 2015;5:713–722. doi: 10.4155/cli.15.36.
    1. James AL, Maxwell PS, Pearce-Pinto G, Elliot JG, Carroll NG. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002;166:1590–1595. doi: 10.1164/rccm.2108069.
    1. Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J. 2010;17:e85–e93. doi: 10.1155/2010/318029.
    1. Naylor B. The shedding of the mucosa of the bronchial tree in asthma. Thorax. 1962;17:69–72. doi: 10.1136/thx.17.1.69.
    1. Hanabuchi S, Watanabe N, Liu YJ. TSLP and immune homeostasis. Allergol Int. 2012;61:19–25. doi: 10.2332/allergolint.11-RAI-0394.
    1. Datta A, Alexander R, Sulikowski MG, Nicholson AG, Maher TM, Scotton CJ, Chambers RC. Evidence for a functional thymic stromal lymphopoietin signaling axis in fibrotic lung disease. J Immunol. 2013;191:4867–4879. doi: 10.4049/jimmunol.1300588.
    1. Redhu NS, Shan L, Movassagh H, Gounni AS. Thymic stromal lymphopoietin induces migration in human airway smooth muscle cells. Sci Rep. 2013;3:2301. doi: 10.1038/srep02301.
    1. Mauri P, Riccio AM, Rossi R, Di Silvestre D, Benazzi L, De Ferrari L, Dal Negro RW, Holgate ST, Canonica GW. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett. 2014;162:2–10. doi: 10.1016/j.imlet.2014.08.010.
    1. Riccio AM, Mauri P, De Ferrari L, Rossi R, Di Silvestre D, Benazzi L, Chiappori A, Dal Negro RW, Micheletto C, Canonica GW. Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months. Clin Transl Allergy. 2017;7:6. doi: 10.1186/s13601-017-0143-1.
    1. 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.
    1. Fleming TR, Labriola D, Wittes J. Conducting clinical research during the COVID-19 pandemic: protecting scientific integrity. JAMA. 2020;324:33–4.

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