Literature
Clinical Pearls & Morning Reports
Published May 12, 2021
How did tezepelumab compare with placebo regarding the annualized rate of asthma exacerbations in the NAVIGATOR trial?
Approximately 10% of patients with asthma have severe disease and have symptoms and exacerbations despite treatment with maximal standard-of-care controller therapy. Menzies-Gow et al. conducted the NAVIGTOR trial, a phase 3, placebo-controlled trial that evaluated tezepelumab (in addition to background medications) in adults and adolescents with severe, uncontrolled asthma. Read the NEJM Original Article here.
Clinical Pearls
Q: What are some of the targets of current biologic agents used for severe asthma?
A: Severe, uncontrolled asthma contributes disproportionately to the overall burden and cost of asthma. Monoclonal antibodies that target IgE or type 2 (T2) cytokines (interleukin-4, -5, and -13) and their receptors improve disease control for many patients with severe asthma and are included in management guidelines. However, current biologic agents are unsuitable for many patients with severe asthma, particularly those with nonallergic or noneosinophilic phenotypes. Thus, there remains an unmet need for new therapies that are effective in a broader population of patients.
Q: What is tezepelumab?
A: Tezepelumab is a human monoclonal antibody (IgG2λ) that binds specifically to thymic stromal lymphopoietin (TSLP), blocking it from interacting with its heterodimeric receptor. TSLP is an epithelial-cell– derived cytokine implicated in multiple downstream processes involved in asthma pathophysiology. In patients with asthma, TSLP levels are correlated with airway obstruction, disease severity, and glucocorticoid resistance. In addition to driving T2 inflammation of the airway, TSLP has been shown to mediate interactions between airway structural cells and immune cells, which are not exclusively driven by T2 inflammation.
Morning Report Questions
Q: How did tezepelumab compare with placebo regarding the annualized rate of asthma exacerbations in the NAVIGATOR trial?
A: The annualized rate of asthma exacerbations was significantly lower with tezepelumab than with placebo among adults and adolescents with severe, uncontrolled asthma, including those with low blood eosinophil counts (<300 cells per microliter) at baseline. In the overall population, tezepelumab treatment resulted in an annualized rate of asthma exacerbations of 0.93 (95% confidence interval [CI], 0.80 to 1.07), as compared with 2.10 (95% CI, 1.84 to 2.39) in the placebo group (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate of asthma exacerbations was 1.02 (95% CI, 0.84 to 1.23) in the tezepelumab group and 1.73 (95% CI, 1.46 to 2.05) in the placebo group (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001).
Q: How might blocking TSLP reduce inflammation in asthmatic patients with low eosinophilic counts?
A: The role of TSLP as an upstream communicator between airway structural cells and immune cells in response to stimuli (e.g., allergens, viruses, airborne particles, and trauma) suggests allergic and nonallergic mechanisms by which tezepelumab may normalize local inflammation, irrespective of blood eosinophil count. Blocking TSLP is expected to markedly reduce T2 cytokine production by T helper 2 memory cells, innate lymphoid type 2 cells, and mast cells across a spectrum of inflammation. The role of TSLP in mediating T2 and T17 responses through dendritic cells, in addition to cross-talk between mast cells and airway smooth muscle cells, are mechanisms potentially relevant to inflammation in populations with low eosinophil counts.