Abstract Rationale Tezepelumab is a monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an upstream cytokine and driver of type 2 (T2) inflammation. In the phase 3 NAVIGATOR study (NCT03347279) of patients with severe, uncontrolled asthma, tezepelumab reduced the annualized asthma exacerbation rate (AAER) over 52 weeks and improved lung function compared with placebo. Here, we evaluated the effects of tezepelumab treatment on global gene expression in blood from NAVIGATOR participants and characterized the ability of a systemic gene signature to predict clinical response. Methods RNA sequencing was performed on whole blood samples obtained at baseline and week 52 from 549 NAVIGATOR participants (placebo, n = 278; tezepelumab 210 mg every 4 weeks, n = 271). Differential gene expression, gene set enrichment, weighted correlation network and overrepresentation analyses were performed. Logistic regression was performed to identify genes predictive of response. Module eigengenes (MEs) were used to summarize genes with similar expression patterns. Clinical response analyses assessed AAER and pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1). Results At week 52, tezepelumab significantly altered the expression of 101 genes (100 downregulated, 1 upregulated) (adjusted p 0.05, fold change 1.5) compared with placebo. Key biological pathways modulated by tezepelumab were associated with reduced eosinophil activation and migration; accordingly, the most highly dysregulated genes were significantly correlated with blood eosinophil levels, and the most pronounced transcriptional changes were observed in participants with blood eosinophil counts 300 cells/µL. In addition to eosinophil chemotaxis-related genes, genes in ME8 linked to pathways such as lipid metabolism were predictive of both AAER and pre-BD FEV1 response to tezepelumab, whereas those in ME8 associated with pathways including T-cell immune response were predictive of only pre-BD FEV1. Genes in ME8, ME4, ME1, and ME6 linked to pathways including non-eosinophilic inflammation, transcriptional regulation, and cell signaling (Wnt, adrenergic, and toll-like receptors) were predictive of AAER (Figure). Conclusions In patients with severe, uncontrolled asthma, tezepelumab demonstrated significant systemic effects on blood gene expression reflecting reduced blood eosinophilic inflammation, which was predictive of clinical response in terms of asthma exacerbations and lung function. The identification of multiple gene modules predictive of exacerbation response highlights the complexity of the biological triggers that drive asthma exacerbations and their potentially broad impact on systemic gene expression. This abstract is funded by: AstraZeneca & Amgen
Sherrill et al. (Fri,) studied this question.