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

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.

Advances and highlights in asthma in 2021

“…Tezepelumab also decreased AHR (measured by mannitol) and airway inflammation (measured in bronchial biopsies) as compared to placebo 101 . Three additional trials are ongoing to assess the capacity of tezepelumab to reduce oral corticosteroids (OCS) intake 102 and airway inflammation, 103 and to investigate its long‐term safety profile in severe asthmatics 104 . Astegolimab, a mAb targeting ST2 (IL‐33 receptor), decreases exacerbations in adult patients with severe asthma regardless of blood eosinophils 105 .…”

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

“…Finally, CASCADE is a phase 2, double-blind, randomized and placebo-controlled study, focusing on the anti-inflammatory activity of tezepelumab [ 88 ]. Here, 116 patients with uncontrolled, moderate-to-severe asthma, undergoing treatment with 210 mg of tezepelumab administered subcutaneously every 4 weeks for 28 weeks, will be monitored throughout this study period [ 88 ]. Asthmatic subjects will be enrolled regardless of their baseline eosinophilic inflammatory pattern.…”

“…With respect to baseline, the CASCADE trial aims to evaluate the potential inflammatory changes induced by the biological therapy with tezepelumab. In particular, bronchoscopic biopsies will be examined in order to assess the eventual differences occurring between baseline and week 28 with regard to airway submucosal infiltration by eosinophils, neutrophils, T lymphocytes, and mast cells [ 88 ]. Moreover, the possible anti-remodeling action of tezepelumab will be explored by measuring the reticular basement membrane thickening before and after treatment with tezepelumab.…”

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“…The phase 2 placebo-controlled, double-blind, and randomized trial CASCADE recruited patients with inadequately controlled, moderate-to-severe asthma, treated with subcutaneous injections of tezepelumab (210 mg) every 4 weeks for 28 weeks [ 104 ]. Enrolment was independent of baseline eosinophilic inflammatory status.…”

“…In particular, CASCADE main goal was the assessment of the possible anti-inflammatory actions of tezepelumab. In this regard, bronchoscopic biopsy samples were evaluated with the aim of exploring the eventual changes in the inflammatory cellular infiltration of bronchial walls, detectable with respect to baseline at the 28th week of add-on therapy with tezepelumab [ 104 ]. Moreover, the potential effects of this drug on airway remodeling were investigated by measuring the thickness of the reticular basement membrane before and after treatment with tezepelumab.…”