Targeting TSLP in Asthma

Abstract

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma. Tezepelumab, the TSLP inhibitor farthest along in clinical development, is a human monoclonal antibody (IgG2λ) that binds specifically to TSLP, preventing interactions with its heterodimeric receptor. Results of recently published phase 2 and 3 studies, reviewed in this article, provide evidence of the safety and efficacy of tezepelumab that builds on initial findings. Tezepelumab is safe, well tolerated, and provides clinically meaningful improvements in asthma control, including reduced incidence of exacerbations and hospitalizations in patients with severe asthma. Clinical benefits were associated with reductions in levels of a broad spectrum of cytokines (eg, interleukin [IL]-5, IL-13) and baseline biomarkers (eg, blood eosinophils, immunoglobulin [Ig]E, fractional exhaled nitric oxide [FeNO]) and were observed across a range of severe asthma phenotypes (ie, eosinophilic and non-eosinophilic). These data strengthen the notion that anti-TSLP elicits broad inhibitory effects on pathways that are key to asthma inflammation rather than on narrower inhibition of individual downstream factors. This review presents the rationale for targeting TSLP to treat asthma, as well as the clinical effects of TSLP blockade on asthma outcomes, biomarkers of disease activity, airway inflammation, lung physiology, and patient symptoms.

Keywords: TSLP; anti-TSLP; asthma; exacerbation rates; thymic stromal lymphopoietin.

Figure 1

TSLP Acts Across the Spectrum of Asthma Inflammation. TSLP-driven mechanisms of disease in different asthma endotypes. Epithelial alarmins, including TSLP, are released in response to triggers at the epithelium. The alarmins activate multiple innate and adaptive immune responses that participate in overlapping and distinct pathways. TSLP may also mediate structural cell effects that contribute to airway hyperresponsiveness and remodeling. Figure adapted, with permission, from Gauvreau GM et al. Expert Opin Ther Targets. 2020;24(8):777–792.,

Figure 2

NAVIGATOR: Annualized Rate of Asthma Exacerbations at Week 52, According to Baseline Biomarker Status.

Figure 3

NAVIGATOR: Change from Baseline to Week 52 in Prebronchodilator FEV₁.

Figure 4

Summary Figure: Tezepelumab Demonstrated Efficacy in a Range of Outcomes Across a Broad Population of Patients.,, ^aPATHWAY included three tezepelumab doses; data from the 210-mg dose only are presented; ^bNominal p value; ^cScore difference meets criteria for minimal clinically important difference. ^nsp ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001 compared with placebo group.