Effect of tezepelumab on airway inflammatory cells, remodeling, and hyperresponsiveness in patients with moderate to severe uncontrolled asthma (CASCADE): a double-blind, randomized, placebo-controlled phase 2 trial

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Background

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), a cytokine derived from epithelial cells. In phase 2b and 3 studies, tezepelumab significantly reduced exacerbations compared to placebo in patients with severe uncontrolled asthma, regardless of baseline levels of type 2 inflammatory biomarkers. We investigated the mechanism action of tezepelumab by evaluating its effects on inflammatory airway cells, airway remodeling and airway hyperresponsiveness.

Methods

CASCADE was an exploratory, double-blind, randomized, placebo-controlled, parallel-group phase 2 study carried out at 27 medical centers in Canada, Denmark, Germany, the United Kingdom and the United States. Adults aged 18 to 75 years with moderate to severe uncontrolled asthma were randomized (1: 1) to receive tezepelumab 210 mg or placebo administered subcutaneously every 4 weeks for an expected period of 28 weeks, extended to 52 weeks if COVID-19 disruptions delayed participants’ end-of-treatment assessments. Randomization was balanced and stratified by the number of blood eosinophils. The primary endpoint was the change between start and end of treatment in the number of submucosal airway inflammatory cells in bronchoscopic biopsy specimens. Eosinophils, neutrophils, CD3+ T cells, CD4+ T cells, tryptase+ mast cells and chymase+ mast cells were assessed separately. This endpoint was also assessed in subgroups based on baseline levels of type 2 inflammatory biomarkers, including blood eosinophil count. Airway remodeling was assessed via the secondary endpoints of change from baseline in reticular basement membrane thickness and epithelial integrity (proportions of bare, damaged and intact epithelium). Exploratory findings included airway hyperresponsiveness to mannitol. All participants who completed at least 20 weeks of study treatment, had an end-of-treatment visit up to 8 weeks after the last dose of study medication, and underwent evaluable bronchoscopies at baseline and at end of treatment were included in the primary efficacy analysis. All participants who received at least one dose of the study drug were included in the safety analyzes. This study is registered with ClinicalTrials.gov, NCT03688074.

Results

Between November 2, 2018 and November 16, 2020, 250 patients were included, of which 116 were randomized (59 to tezepelumab, 57 to placebo). 48 in the tezepelumab group and 51 in the placebo group completed the study and were assessed for the primary endpoint. Treatment with tezepelumab resulted in a nominally significantly greater reduction between start and end of treatment in submucosal airway eosinophils compared to placebo (geometric least squares ratio means 0.15 [95% CI 0·05–0·41]; nominal p + T cells 1 12 [0·86–1·46]; CD4+ T cells 1 18 [0·90–1·55]; tryptase+ mast cells 0.83 [0·61–1·15]; chymase+ mast cells 1 19 [0·67–2·10]; all p> 0 10). In the evaluation of secondary endpoints, there were no significant differences between treatment groups with regard to reticular basement membrane thickness and epithelial integrity. In an exploratory analysis, the reduction in airway hyperresponsiveness to mannitol was significantly greater with tezepelumab compared to placebo (mean least-squares change from baseline interpolated or extrapolated provoking dose of mannitol required to induce ≥ 15% reduction in FEV11 compared to inclusion: tezepelumab 197.4 mg [95% CI 107·9 to 286·9]; placebo 58.6 mg [−30·1
to 147·33]; difference 138.8 [14·2 to 263·3], nominal p = 0.030). Adverse events were reported in 53 (90%) patients in the tezepelumab group and 51 (90%) patients in the placebo group, and there were no safety findings of concern.

Interpretation

The improvements in asthma clinical outcomes seen in previous studies with tezepelumab are likely due, at least in part, to the reduction in inflammation of the eosinophilic airways, as shown here by the reduction in the number of eosinophils from respiratory tract regardless of the baseline blood eosinophil count. Tezepelumab also reduced airway hyperresponsiveness to mannitol, indicating that blocking TSLP may have additional benefits in asthma beyond reducing type 2 airway inflammation.

Funding

AstraZeneca and Amgen.

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