How does Tezspire (tezepelumab) work in treating asthma exacerbations triggered by viruses?

Virus-Triggered Asthma Exacerbations and Tezspire (Tezepelumab) Efficacy

Tezepelumab (Tezspire) effectively treats asthma exacerbations triggered by viruses by blocking thymic stromal lymphopoietin (TSLP), reducing airway inflammation, and stabilizing the bronchial epithelial immune response without compromising antiviral host resistance. 1

Mechanism of Viral-Triggered Asthma Exacerbations

• Respiratory viral infections, particularly rhinovirus, are the predominant triggers for acute worsening of asthma symptoms, responsible for approximately 80-85% of exacerbations in children and 50% in adults 2, 3
• Viral infections cause neutrophilic inflammation of both upper and lower airways, making them difficult to distinguish from bacterial infections 3
• Experimental models show rhinovirus increases eosinophilic inflammation and airway hyperresponsiveness in allergic individuals 2
• Viruses trigger inflammatory cascades in the airways, leading to increased mucus production, bronchial hyperresponsiveness, and airflow obstruction 3
• Patients with asthma experience more severe and prolonged symptoms from viral infections compared to non-asthmatic individuals 3

Tezepelumab's Mechanism of Action

• Tezepelumab is a first-in-class human monoclonal antibody (IgG2λ) that specifically binds to and blocks TSLP, an epithelial-derived cytokine 4, 5
• TSLP is released from airway epithelial cells in response to multiple triggers associated with asthma exacerbations, including viruses, allergens, and pollutants 4
• By targeting TSLP, tezepelumab acts upstream in the inflammatory cascade, affecting multiple downstream inflammatory pathways rather than single components 4, 5
• This upstream blockade provides a broader effect on airway inflammation compared to biologics that target individual downstream elements 4

Tezepelumab's Effect on Viral-Triggered Inflammation

• Recent research demonstrates that tezepelumab reduces IL-33 expression in bronchial epithelial cells and IL-33 protein levels in bronchoalveolar lavage fluid 1
• When bronchial epithelial cells from tezepelumab-treated patients were challenged with viral mimics (poly(I:C)) or rhinovirus:
  • IL-33 gene and protein levels decreased significantly 1
  • Production of IL-4, IL-13, and IL-17A was reduced 1
  • Importantly, IFNβ and IFNλ expression and viral load remained unchanged, indicating preserved antiviral host resistance 1
• This suggests tezepelumab stabilizes the bronchial epithelial immune response to respiratory viruses without compromising viral defense mechanisms 1

Clinical Efficacy of Tezepelumab

• In the phase 2b PATHWAY and phase 3 NAVIGATOR studies, tezepelumab reduced asthma exacerbations by up to 71% compared with placebo in patients with severe, uncontrolled asthma 4, 5
• Tezepelumab demonstrated efficacy across all asthma phenotypes, including:
  • 62% reduction in exacerbations in patients with allergic asthma (perennial aeroallergen sensitization) 5
  • 71% reduction in patients with blood eosinophil counts ≥300 cells/μL 5
  • 71% reduction in patients with both allergic asthma and elevated blood eosinophils 5
• Tezepelumab also improved pre-bronchodilator FEV1, asthma symptom control, and quality of life 6
• The medication demonstrated broad anti-inflammatory effects by blocking IL-4, IL-13, and IL-5 pathways, reducing serum IgE levels, FeNO, and blood and submucosal eosinophils 6

Administration and Safety

• Tezepelumab (Tezspire) is administered as a 210 mg subcutaneous injection once monthly 6, 7
• The medication was well-tolerated in clinical trials with a safety profile similar to placebo 7
• Most common adverse events included worsening asthma, common cold, headache, and airway inflammation 7

Clinical Implications

• Tezepelumab represents a significant advancement for patients with severe asthma who experience viral-triggered exacerbations 3, 1
• Unlike other biologics that are limited to specific phenotypes (eosinophilic or allergic), tezepelumab works across the spectrum of inflammatory phenotypes 4, 5
• This makes it particularly valuable for patients who don't fit neatly into established phenotypes or who have low blood eosinophil counts 4
• The ability to reduce viral-triggered exacerbations while preserving antiviral immunity addresses a critical unmet need in severe asthma management 1

Pitfalls and Considerations

• Response to tezepelumab is generally higher in patients with elevated blood eosinophils and FeNO levels, though benefits are seen across phenotypes 6
• Regular monitoring for adverse effects is essential, including potential hypersensitivity reactions 3
• Earlier introduction of biological therapies like tezepelumab in the treatment algorithm for patients with recurrent virus-triggered exacerbations may prevent long-term adverse effects of corticosteroids 3