Abstract Rationale Conventional airway assessments are limited in their ability to detect structural changes. Functional Respiratory Imaging (FRI) is a computed tomography (CT)-based technique that uses 3D airway modeling and computational fluid dynamics for non-invasive measurement of airway volume and resistance with greater sensitivity than standard spirometry. Recent studies have demonstrated that tezepelumab reduces mucus plugs and improves lung function in patients with moderate-to-severe uncontrolled asthma, with greatest effects in patients with elevated type 2 inflammatory biomarkers at baseline (T2-high). This analysis evaluated the effect of tezepelumab on airway resistance using FRI measures collected in the phase 2 CASCADE (NCT03688074) study. Methods CASCADE was an exploratory, double-blind, placebo-controlled trial in adults (18-75 years) with moderate-to-severe uncontrolled asthma, randomized 1:1 to tezepelumab 210 mg or placebo every 4 weeks for 28 weeks. High-resolution CT scans were performed at baseline and end-of-treatment. CT data were postprocessed to segment the airway tree and generate 3D models for computational fluid dynamics. FRI yielded measurements of distal inspiratory airway resistance (IRAW) and volume-corrected specific internal airway resistance (SIRAW). Changes in IRAW and SIRAW were compared between treatment groups overall and for four subgroups defined by baseline blood eosinophil count (BEC; ≥300 or 300 cells/μL) and fractional exhaled nitric oxide (FeNO; ≥25 or 25 ppb) thresholds: T2-high (both BEC and FeNO elevated), BEC-high FeNO-low, FeNO-high BEC-low, and T2-low (neither BEC nor FeNO elevated). Normality was assessed using the Shapiro-Wilk test and treatment differences by the Mann-Whitney U test. Results Of the 116 randomized patients, 68 (placebo n = 40; tezepelumab n = 28) had both baseline and end-of-treatment CT scans suitable for FRI analysis. Distributions of SIRAW and IRAW were non-Gaussian per Shapiro-Wilk testing. Tezepelumab produced greater reductions in distal airway resistance compared with placebo in the overall cohort (SIRAW p=0.0139, IRAW p=0.0094), with greatest effects among T2-high (SIRAW p=0.0051, IRAW p=0.0303) and BEC-high FeNO-low (SIRAW p=0.0112, IRAW p=0.0112). The SIRAW reduction in FeNO-high BEC-low patients did not reach nominal significance, and no effects were associated with tezepelumab treatment in T2-low patients (Table). Conclusions Tezepelumab significantly reduced airway resistance compared with placebo in moderate-to-severe uncontrolled asthma, especially in T2-high patients. These findings support the positive effects of tezepelumab in reducing asthma-related T2 inflammation and associated airway resistance. This abstract is funded by: AstraZeneca & Amgen
Vegas-Sanchez-Ferrero et al. (Fri,) studied this question.