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The mechanism of action for TEZSPIRE in asthma has not been definitively established.
TEZSPIRE is a monoclonal antibody (IgG2λ) directed against thymic stromal lymphopoietin (TSLP)1, a key cytokine involved in initiating and perpetuating the inflammatory response in the airways. It plays a central role in activating various immune cells, contributing to the pathophysiology of asthma.1
TEZSPIRE prevents TSLP from binding to its heterodimeric receptor and disrupts this in the inflammatory cascade associated with asthma.1
Blocking TSLP with TEZSPIRE (tezepelumab) reduces a broad spectrum of biomarkers and cytokines associated with airway inflammation.1,2
As an anti-TSLP monoclonal antibody, TEZSPIRE binds to TSLP upon its release by epithelial cells.1,2 TEZSPIRE’s mechanism of action in asthma has not been definitively established.
Adapted from Wechsler ME, et al. Respir Res. 2020.
The diagnosis of asthma depends on objective measurements of variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation.3
Adapted from Nair P, et al. Clin Chest Med. 2012.
TSLP is a cytokine produced in response to pro-inflammatory stimuli, playing a key role in the initiation and persistence of airway inflammation in asthma. Working at the epithelium, TSLP activates both innate and adaptive immune responses.4,5
It triggers both allergic/eosinophilic and non-allergic/eosinophilic inflammation, driving multiple downstream pathways implicated in clinical features of asthma13. By inhibiting TSLP, TEZSPIRE reduces a broad spectrum of biomarkers and cytokines associated with airway inflammation, including blood eosinophils (EOS), airway submucosal EOS, IgE, FeNO, IL-5, and IL-13.4,5,8,10
Through this mechanism of action, TEZSPIRE offers a first-in-class approach aimed at reducing underlying inflammation and improving asthma control.4
The mechanisms by which TEZSPIRE improves clinical asthma outcomes were studied in the CASCADE phase II study. The trial's primary outcome measure was the reduction from baseline to the EOT in airway submucosal EOS. CASCADE found that this reduction was nominally significantly greater in patients treated with TEZSPIRE compared to those who received a placebo, ratio of geometric least squares mean (LSM) 0.15 (95% CI 0.05–0.41, p<0.001).10
This reduction is believed to result from its impact on airway mast cells and smooth muscle cells. Results are descriptive only. The clinical significance of this outcome and its impact on asthma have not been established.
In airway submucosal eosinophils.
There were no significant differences observed between treatment groups for changes in submucosal neutrophils, T cells or mast cells.10
One of the exploratory endpoints in the CASCADE trial was looking at the impact of airway hyperresponsiveness. Results are descriptive only. The clinical significance of this outcome and its impact on asthma have not been established.
PD is the provoking dose of mannitol that is required to cause a 15% decline in FEV1 from baseline. The higher the PD, the lower the airway hyperresponsiveness.
CASCADE (a phase 2, exploratory, mechanistic, 52-week, placebo-controlled trial, n=116) included patients with moderate-to-severe, uncontrolled asthma. All patients received SOC (MD or HD ICS + additional controller).10
Limitations: Patients were recruited to this trial mainly on the basis of treatment requirements and lung function measures, which did not translate into the expected baseline histological features. Because bronchoscopies for research purposes were not permitted during COVID-19 pandemic in countries where the study was conducted, for participants who could not visit the study site at Week 28 owing to the COVID-19 pandemic, treatment was extended to up to 52 weeks until they were able to visit the study site.10
The reduction in airway submucosal eosinophils with tezepelumab in this study was observed despite baseline submucosal eosinophil counts being lower than expected for patients with moderate-to-severe asthma.10
See efficacy data on how TEZSPIRE treats severe asthma phenotypes irrespective of key clinical biomarker levels.1,4,8
TEZSPIRE (tezepelumab) is indicated as an add-on maintenance treatment in adults and adolescents 12 years and older with severe asthma who are inadequately controlled despite high dose inhaled corticosteroids plus another medicinal product for maintenance treatment1
GB-60758 | DOP: November 2024
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