Abstract Rationale Mucus plugging is a feature of moderate-to-severe asthma, associated with adverse clinical outcomes including airway obstruction, exacerbations and impaired lung function. Mucus scores provide an estimate of mucus burden by visually assessing the presence of plugs in individual lung segments; however, mucus scores do not capture quantitative characteristics such as volume, mass or the area of airway obstruction. This study investigated the effect of tezepelumab on mucus plugging in CASCADE (NCT03688074), a phase 2, randomized, placebo-controlled trial in patients with moderate-to-severe, uncontrolled asthma, using an extended set of quantitative mucus metrics. Methods CASCADE was an exploratory, double-blind trial of adults (18-75 years old) with moderate-to-severe asthma, randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 28 weeks. Standardized, high-resolution computed tomography scans were obtained at baseline and end of treatment, and mucus plugs across 18 lung segments were scored by a blinded expert radiologist. Secondary analyses included a generation-weighted mucus scoring method. Quantitative metrics comprised the number, mass, volume, length and density of plugs, as well as mucus-obstructed diameters and areas. Changes in mucus metrics from baseline to end-of-treatment were compared between groups overall and, to align with studies of other biologics, in a subgroup of participants with elevated type 2 (T2) inflammatory biomarkers (T2-high, defined by a blood eosinophil count ≥300 cells/μL and fractional exhaled nitric oxide ≥25 ppb) at baseline. Results Of 116 randomized patients, 82 completed both baseline and end-of-treatment computed tomography assessments (placebo, n = 45 T2-high, n = 7; tezepelumab, n = 37 T2-high, n = 5). Across all mucus metrics, greater reductions were observed in the tezepelumab group than in placebo, especially among patients with elevated T2 biomarkers (Table). For example, in T2-high tezepelumab recipients, mean reductions in mucus plug volume (−0.73 mL) and mass (−0.64 g) versus placebo were more than threefold the reductions observed in the overall population (−0.24 mL and −0.20 g, respectively). Similarly, the difference in mean segmental mucus score reduction between tezepelumab and placebo was substantially larger in the T2-high subgroup (−6.8) than in the overall population (−1.7). Conclusions Tezepelumab consistently reduced airway mucus plugging and obstruction compared with placebo across multiple complementary metrics among adults with moderate-to-severe, uncontrolled asthma. These effects were particularly pronounced in patients with elevated T2 biomarkers, though the sample size was small. The use of diverse quantitative imaging endpoints enabled a more comprehensive assessment of the treatment effects of tezepelumab in this population. This abstract is funded by: AstraZeneca & Amgen
Gispert et al. (Fri,) studied this question.