How does Tezspire (tezepelumab) work to treat asthma exacerbations?

Mechanism of Viral-Triggered Asthma Exacerbations and Tezspire's Role in Treatment

Tezspire (tezepelumab) is highly effective for treating asthma exacerbations by blocking thymic stromal lymphopoietin (TSLP), an epithelial cytokine that initiates the inflammatory cascade triggered by viruses and other stimuli, making it effective across both type 2 and non-type 2 asthma phenotypes.

Viral-Triggered Asthma Exacerbations

Pathophysiology

• Viral respiratory infections are major triggers for asthma exacerbations, characterized by progressively worsening shortness of breath, cough, wheezing, and chest tightness 1
• These exacerbations involve acute or subacute episodes with decreased expiratory airflow, where objective measures of lung function (spirometry or PEF) are more reliable indicators of severity than symptoms 1
• Viruses trigger epithelial damage, leading to release of epithelial-derived cytokines like TSLP, which initiates and sustains both allergic and eosinophilic inflammation in asthma 2

Clinical Impact

• Severe exacerbations can be life-threatening and occur in patients at any level of asthma severity—intermittent, mild, moderate, or severe persistent asthma 1
• Risk factors for severe exacerbations include previous severe exacerbations, frequent healthcare utilization, high SABA use, and difficulty perceiving airway obstruction 1

Tezspire (Tezepelumab) Mechanism of Action

Primary Mechanism

• Tezepelumab is a human monoclonal antibody (IgG2λ) that specifically binds to and blocks TSLP, an epithelial cytokine that initiates the inflammatory cascade in asthma 2
• By targeting TSLP, tezepelumab acts upstream in the inflammatory pathway, blocking multiple downstream inflammatory processes simultaneously 3, 2

Broad Anti-inflammatory Effects

• Tezepelumab demonstrates a broad anti-inflammatory effect by blocking multiple pathways:
  • Inhibits IL-4, IL-13, and IL-5 pathways 3
  • Reduces serum total IgE levels 3
  • Decreases fractional exhaled nitric oxide (FeNO) 3
  • Reduces both blood and submucosal eosinophils without affecting neutrophil levels 3
  • Reduces bronchial hyperresponsiveness and mucus plugs 3

Clinical Efficacy of Tezspire

Exacerbation Reduction

• Compared to placebo, tezepelumab reduces the annualized asthma exacerbation rate over 52 weeks by:
  • 62% in patients with allergic asthma 2
  • 71% in patients with eosinophilic asthma (baseline blood eosinophil count ≥300 cells/μL) 2
  • 71% in patients with both allergic and eosinophilic phenotypes 2
  • 56-61% in patients with and without persistent airflow obstruction 4

Lung Function Improvement

• Tezepelumab significantly improves pre-bronchodilator FEV1 compared to placebo:
  • In patients with persistent airflow obstruction: 0.24L vs 0.07L improvement (difference: 0.17L) 4
  • In patients without persistent airflow obstruction: 0.20L vs 0.12L improvement (difference: 0.08L) 4
• 12.1% of patients with persistent airflow obstruction at baseline no longer had obstruction after 52 weeks of tezepelumab treatment (vs 6.6% with placebo) 4

Long-term Benefits

• Tezepelumab demonstrates sustained efficacy and safety over 104 weeks of treatment 5
• Long-term treatment results in continued reduction in asthma exacerbations with a favorable safety profile 5

Clinical Application of Tezspire

Indication

• Tezspire is approved as an add-on maintenance therapy for people ages 12 years and older with severe asthma symptoms not controlled by current medication 6
• It is administered subcutaneously by a healthcare provider once monthly (210 mg) 3, 6

Patient Selection

• Tezepelumab is effective across known asthma phenotypes, making it suitable for:
  • Type 2 asthma (allergic and/or eosinophilic) 1
  • Non-type 2 asthma after ruling out other chronic obstructive airway diseases 1
  • Patients with persistent airflow obstruction, which can be difficult to treat 4

Advantages Over Other Biologics

• Unlike other biologics that target specific downstream components of type 2 inflammation (anti-IgE, anti-IL5/IL5R, anti-IL4R), tezepelumab acts upstream by blocking TSLP 2
• This upstream action provides efficacy across both allergic and eosinophilic phenotypes, as well as in patients without elevated type 2 biomarkers 2

Practical Considerations

• Tezepelumab should be administered subcutaneously in the abdomen, thigh, or upper arm using an auto-injector or pre-filled syringe 1
• First two injections should be given in a hospital setting for training and monitoring for potential side effects 1
• Clinical response may take weeks to months to become apparent 1

By targeting TSLP, Tezspire effectively interrupts the inflammatory cascade triggered by viruses and other stimuli, providing broad protection against asthma exacerbations across different asthma phenotypes.