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

Patients with severe, uncontrolled asthma are at risk of recurrent asthma exacerbations and hospitalizations despite standard-of-care treatment with inhaled corticosteroids (ICS) and long-acting β₂ agonists (LABAs) [1‐3], and consequently experience poor health-related quality of life (HRQoL) [4]. Additional treatment options for these patients include biologic therapies. 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 [5‐8], and are less effective in patients with lower blood eosinophil counts [9‐12]. Furthermore, improvements in physiology and symptom scores are inconsistent [5‐8]. Thus, there remains an unmet need for effective therapies, particularly for patients without eosinophilic or allergic phenotypes and those who do not respond to current biologic treatments. 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.

Tezepelumab is a human monoclonal antibody (IgG2λ) that binds specifically to thymic stromal lymphopoietin (TSLP), blocking it from interacting with its heterodimeric receptor (Fig. 1) [13‐15]. TSLP is an epithelial-derived cytokine implicated in the initiation and persistence of airway inflammation in response to airborne triggers of asthma such as viruses, allergens, pollutants and other airborne irritants that interact with the airway epithelium; it is a key regulator of downstream inflammatory pathways in the airway, both T2 mediated and non-T2 mediated, as well as of other related processes such as epithelial barrier function [16‐18]. TSLP has been shown to act in conjunction with other epithelial-derived cytokines, such as IL-25 and IL-33, to promote T2 inflammatory responses [19].

In the phase 2b PATHWAY study, tezepelumab reduced asthma exacerbations by up to 71% compared with placebo in patients with severe, uncontrolled asthma, and improved lung function, asthma control and patient HRQoL [14]. Exacerbation reduction was irrespective of baseline allergic or eosinophilic status, or levels of T2 inflammatory biomarkers [14, 15]. Based on the reduction in exacerbations in a broad population of patients with severe asthma in PATHWAY, including those with low blood eosinophil counts, tezepelumab was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2019 for patients with severe asthma without an eosinophilic phenotype who are receiving ICS/LABA and additional asthma controllers with or without OCS [20]. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma are subsequently being investigated in a programme of ongoing phase 3 trials, including NAVIGATOR (ClinicalTrials.gov identifier: NCT03347279), SOURCE (NCT03406078) and DESTINATION (NCT03706079).

This article describes the design and objectives of CASCADE, an ongoing phase 2 study that is running concurrently with the phase 3 tezepelumab trials noted above. CASCADE aims to explore the mechanism of action of tezepelumab in improving clinical outcomes in patients with moderate-to-severe, uncontrolled asthma across a range of baseline blood eosinophil counts, who are expected to span the spectrum of T2 inflammation. The study will investigate the effects of tezepelumab on airway inflammation and airway remodelling in this patient population, using primarily bronchoscopy-based assessments.

In the phase 2b PATHWAY study, treatment with tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER), irrespective of baseline inflammation status, and improved lung function, asthma control and HRQoL in patients with severe, uncontrolled asthma [14], demonstrating that blocking TSLP can be an effective therapeutic approach in this patient population. The phase 2 CASCADE study is designed to investigate the mechanisms by which tezepelumab exerts an airway anti-inflammatory effect in adults with moderate-to-severe, uncontrolled asthma.

The primary objective of CASCADE is to assess change from baseline in the numbers of multiple airway submucosal inflammatory cells in response to tezepelumab. Previous mechanistic studies of biologic therapies for asthma have focused on counts of airway eosinophils, rather than other inflammatory cell types. Studies of omalizumab have shown that anti-IgE treatment decreases both airway eosinophils and IgE [27‐29], while studies of mepolizumab and benralizumab have demonstrated that anti-IL-5 treatment also reduces airway eosinophils [25, 26, 30‐33]. Anti-IL-13 treatment with tralokinumab was not effective in reducing bronchial, sputum or blood eosinophils [34]. Results from a mechanistic study of anti-IL-4 treatment with dupilumab have not yet been published, although 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 (tissue eosinophils, CD3+ T cells, CD4+ T cells and chymase- or tryptase-positive mast cells) [35]. For CASCADE, eosinophils, neutrophils, T cells and mast cells were selected as the primary cell types of interest as they characterize airway inflammation in both T2-high and T2-low asthma [36‐39]. TSLP has been shown to participate in the activation and/or development of eosinophils [40, 41], neutrophils [42], T cells [43] and mast cells [44‐47]. Thus, blocking TSLP with tezepelumab may impact numbers of these cell types in the bronchial submucosa of patients with moderate-to-severe asthma, via effects on cellular activation, development and migration to inflamed tissues, suggesting potential efficacy in a range of patients, including those with non-eosinophilic phenotypes. Furthermore, as 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, therefore, may benefit a broad population of patients with severe asthma who have differing levels of T2 inflammation.

The effectiveness of tezepelumab in a broad patient population has previously been demonstrated in the PATHWAY study, in which exacerbations were improved in response to treatment with tezepelumab in patients with low and high baseline blood eosinophil counts (< 250 and ≥ 250 cells/μL, respectively) and low and high T2 inflammation [14]. To ensure that CASCADE is conducted in a cohort of patients representative of the spectrum of T2 inflammation, the study enrolled patients with a range of baseline blood eosinophil counts (< 150, 150 to < 300 and ≥ 300 cells/μL). Although blood eosinophil count alone may not be sufficient to characterize T2 inflammation fully, for the purposes of this study, it is considered to be an adequate measure for screening patients. After the study is completed, the three-gene mean (bronchial airway epithelial expression levels of POSTN, CLCA1 and SERPINB2) will be used to determine the level of T2 inflammation in the participating patients. The three-gene mean has been demonstrated to be suitable as a surrogate marker of T2-driven inflammation in patients with mild-to-moderate asthma [22‐24]. This marker has been proposed to correlate with FeNO, blood eosinophils and airway hyper-responsiveness [23], and with clinical markers of T2 inflammation in patients with mild through to severe asthma [50]. We therefore assume that because these tissue-based and clinical markers of inflammation increase in more severe disease, so too will the three-gene mean, which should therefore perform similarly in a population of patients with moderate-to-severe asthma in terms of identifying inflammatory phenotypes and potentially predicting response to therapy. The range of inflammatory phenotypes enrolled in CASCADE is a unique feature of this study compared with previous mechanistic studies of currently approved biologics in asthma, which have been conducted in patients with specific phenotypes [25‐33]. Also unique to this mechanistic study compared with previous studies of biologics in asthma is the analysis of tezepelumab PK and inflammatory biomarkers in BAL fluid. Additional exploratory outcomes (e.g. effect on blood eosinophil counts and levels of IgE and FeNO) will be included in CASCADE to investigate and understand further the potential effects of tezepelumab in patients with moderate-to-severe, uncontrolled asthma.

Key learnings from previous mechanistic studies of biologics in asthma were applied to the design of CASCADE, such as ensuring that the study will be of sufficient duration to enable effective evaluation of aspects of airway remodelling. A treatment period of 28 weeks was selected for CASCADE, compared with 12 weeks in previous mechanistic studies such as the MESOS study of tralokinumab, during which airway remodelling was not observed [51]. RBM thickness and airway epithelial integrity were selected as measures of airway remodelling in patients with asthma [52‐54] in CASCADE. Given that TSLP may potentially be involved in epithelial homeostasis [55], wound healing [56] and airway smooth muscle proliferation [57], it is expected that RBM thickness and epithelial integrity may be affected by treatment with tezepelumab. Other measures of airway remodelling in CASCADE will include histology and computed tomography to estimate large-airway morphology and resistance, and impulse oscillometry to assess small-airway obstruction. Airway remodelling as a result of biologic treatment has previously been explored in studies of omalizumab, in which changes in RBM thickness were assessed microscopically [58, 59].

CASCADE will use the same dosing regimen (210 mg Q4W) as the ongoing phase 3 trials of tezepelumab in patients with severe asthma. Selection of the 210 mg Q4W dosing regimen was based on efficacy data and exposure–response analyses from the phase 2b PATHWAY study [14, 60]. AAER data from PATHWAY indicated that tezepelumab 210 mg Q4W was more effective than the 70 mg Q4W dosage, whereas the dosage of 280 mg every 2 weeks did not provide additional benefit [14]. Furthermore, based on the primary efficacy endpoint of AAER and the pharmacodynamic endpoint of FeNO, an exposure response to tezepelumab was identified [60]. Tezepelumab was well tolerated at all doses used in PATHWAY (70, 210 and 280 mg) and safety profiles were comparable between the tezepelumab and placebo groups, with no evidence of a dose relationship to treatment-emergent adverse events in the study population [14].

Owing to the COVID-19 pandemic that began after CASCADE was underway, steps were taken to ensure the safety of study participants, to allow adherence to study treatment and to allow study-specific procedures to take place [61]. The protocol was amended to permit at-home dosing of study drug by a healthcare professional and to allow extension of the treatment period by up to 6 months. This ensures that participants can continue to receive study drug until circumstances allow them to visit the study site for end of treatment endpoint assessments. Specifically, bronchoscopies for research purposes are not permitted during the COVID-19 pandemic in the countries in which the study is being conducted. Furthermore, final follow-up visits can be replaced by a virtual or telephone visit. It was important to implement virtual visits and at-home dosing rapidly, because doing so reduced the risk of exposing study participants to SARS-CoV-2. These changes were discussed with local regulatory authorities, ethics committees and institutional review boards before the study protocol was formally amended.

At the onset of the COVID-19 pandemic, enrolment for CASCADE was complete; therefore, recruitment for the study was not affected. However, owing to the extension of the treatment period to allow end of treatment bronchoscopies to take place, database lock is delayed until ongoing patients with delayed bronchoscopies have completed them.

Patients with severe, uncontrolled asthma are a population with a significant unmet need for new treatments that have wide-ranging effects on airway inflammation and provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. CASCADE will evaluate the effect of tezepelumab on airway inflammatory cells and airway remodelling in a broad population of patients with moderate-to-severe, uncontrolled asthma and differing levels of T2 inflammation. CASCADE aims to determine the mechanisms by which tezepelumab improves clinical outcomes in patients with moderate-to-severe asthma and to further demonstrate its potential to reduce airway inflammation in patients with eosinophilic or non-eosinophilic asthma.