Tezepelumab for Severe Asthma: One Drug Targeting Multiple Disease Pathways and Patient Types

Abstract

Asthma is a heterogeneous inflammatory disease of the airways, affecting many children, adolescents, and adults worldwide. Up to 10% of people with asthma have severe disease, associated with a higher risk of hospitalizations, greater healthcare costs, and poorer outcomes. Patients with severe asthma generally require high-dose inhaled corticosteroids and additional controller medications to achieve disease control; however, many patients remain uncontrolled despite this intensive treatment. The treatment of severe uncontrolled asthma has improved with greater understanding of asthma pathways and phenotypes as well as the advent of targeted biologic therapies. Tezepelumab, a monoclonal antibody, blocks thymic stromal lymphopoietin, an epithelial cytokine that has multifaceted effects on the initiation and persistence of asthma inflammation and pathophysiology. Unlike other biologic treatments, tezepelumab has demonstrated efficacy across severe asthma phenotypes, with the magnitude of effects varying by phenotype. Here we describe the anti-inflammatory effects and efficacy of tezepelumab across the most relevant phenotypes of severe asthma. Across clinical studies, tezepelumab reduced annualized asthma exacerbation rates versus placebo by 63–71% in eosinophilic severe asthma, by 58–68% in allergic severe asthma, by 67–71% in allergic and eosinophilic severe asthma, by 34–49% in type 2-low asthma, and by 31–41% in oral corticosteroid-dependent asthma. Furthermore, in all these asthma phenotypes, tezepelumab demonstrated higher efficacy in reducing exacerbations requiring hospitalizations or emergency department visits versus placebo. In patients with severe uncontrolled asthma, who commonly have multiple drivers of inflammation and disease, tezepelumab may modulate airway inflammation more extensively, as other available biologics block only specific downstream components of the inflammatory cascade.

Plain Language Summary

Asthma is characterized by an immune response leading to airway inflammation. People with severe asthma may react to different triggers and develop different types of airway inflammation. In patients with asthma, a protein called thymic stromal lymphopoietin (TSLP) plays an important role in the immune response that leads to the signs and symptoms of asthma. TSLP is released by the airway lining in response to different asthma triggers, driving an immune chain reaction, leading to airway narrowing and tightening, increased airway inflammation, worsening asthma symptoms, and asthma attack. Tezepelumab is a monoclonal antibody (a type of protein) that prevents TSLP from attaching to its receptor, thereby blocking its activity, reducing airway inflammation and asthma symptoms. Tezepelumab is an add-on medicine for the treatment of people aged 12 years or older with severe asthma that is not controlled with their current medicines.

In this article, we discuss how tezepelumab may work in different types of asthma, for example allergic asthma, eosinophilic asthma, and T2-low asthma. We also describe how effective tezepelumab is in these different asthma types, through the reduction of asthma attacks and improvement in lung function, symptom control, and quality of life, leading to fewer emergency department visits and hospitalizations for asthma.

Keywords:

• exacerbations
• eosinophilic
• allergic
• type 2
• oral corticosteroid-dependent
• airway hyperresponsiveness

Abbreviations

AAER, annualized asthma exacerbation rate; ACQ-6, asthma control questionnaire; AE, adverse event; AHR, airway hyperresponsiveness; AQLQ(S)+12, asthma quality of life questionnaire; ASMC, airway smooth muscle cell; BAL, bronchoalveolar lavage; BEC, blood eosinophil count; CI, confidence interval; ED, emergency department; FDA, US Food and Drug Administration; FEIA+, fluorescence enzyme immunoassay positive; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in one second; HRQoL, health-related quality of life; Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cell; ILC2, innate lymphoid cell type 2; LS, least squares; NAC, nasal allergen challenge; NP, nasal polyp; OCS, oral corticosteroid; OR, odds ratio; Q4W, every 4 weeks; SAE, serious adverse event; SCIT, subcutaneous allergen immunotherapy; SGRQ, St George’s Respiratory Questionnaire; T2, type 2; Th2, type 2 T helper; TNSS, total nasal symptom score; TSLP, thymic stromal lymphopoietin; US, United States.

Acknowledgments

The authors thank Sarah Amir and Emma East from Lucid Group, Marlow, Buckinghamshire, UK, for providing medical writing and editorial support, which was funded by AstraZeneca in accordance with Good Publication Practice 2022 (GPP22) guidelines.

Author Contributions

All authors made a significant contribution to the work reported, through the conception, study design, execution, acquisition of data, and/or analysis and interpretation; took part in drafting, revising and/or critically reviewing the article; gave final approval of the version to be published; agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Disclosure

RP Jr received consulting/advisory board fees from AstraZeneca, Genentech, Praesidia Biotherapies Inc., RIFM, and TEVA; fees for speaking from AstraZeneca, Merck & Co, and Sanofi; and research grants from ACTIV-1, AgoMab, AstraZeneca, Janssen, Medimmune, RIFM, TEVA, and Vault Health. NL received consulting fees from Amgen, AstraZeneca, Avillion, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for non-speaker bureau presentations from GSK and Astra Zeneca; and travel support from Astra Zeneca, Sanofi and GSK; her institution received research support from Amgen, AstraZeneca, Avillion, Evidera, Gossamer Bio, Genentech, GSK, Janssen, Regeneron, Sanofi, Novartis and Teva. She is an honorary faculty member of Observational and Pragmatic Research Institute (OPRI) but does not receive compensation for this role. JC received grants and personal fees from AstraZeneca, Genentech and Vectura, and has received grants from Optinose, Regeneron, Novartis, Pulmatrix, Sanofi and Teva Pharmaceuticals. CA is an employee of AstraZeneca and holds stock and stock options. The authors report no other conflicts of interest in this work.

Additional information

Funding

Funding for this article was provided by AstraZeneca.