Abstract
BackgroundPatients 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.MethodsCASCADE 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.DiscussionCASCADE 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 registrationNCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.
Highlights
Patients with severe, uncontrolled asthma, 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
Results from a mechanistic study of anti-IL-4 treatment with dupilumab have not yet been published, data posted on ClinicalTrials.gov indicate that it did not meet the primary endpoint of reduction of inflammatory cells in the bronchial submucosa for any of the cell types assessed [35]
As thymic stromal lymphopoietin (TSLP) is an upstream regulator of the inflammatory cascade in asthma and influences multiple inflammatory pathways [43, 44, 48, 49], it is anticipated that blocking TSLP with tezepelumab may have wide-ranging anti-inflammatory effects and, may benefit a broad population of patients with severe asthma who have differing levels of type 2 (T2) inflammation
Summary
Patients with severe, uncontrolled asthma, 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. Current approved biologic therapies for severe asthma target key mediators of type 2 (T2) inflammation in eosinophilic or allergic asthma, including interleukin (IL)-5, IL-4, IL-13 and immunoglobulin (Ig) E, and are prescribed based on indicators of these phenotypes, including dependence on oral corticosteroids (OCS) for disease control [3]. These therapies reduce exacerbations by approximately 50% but do not eliminate them [5,6,7,8], and are less effective in patients with lower blood eosinophil counts [9,10,11,12]. A therapeutic approach that has a broader effect on airway inflammation than existing biologics could effectively treat a wide range of patients with severe asthma
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