Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma

ABSTRACT

Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.

Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,

Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.

KEYWORDS:

• Asthma
• biologics
• inflammation
• tezepelumab
• T2-high asthma
• T2-low asthma
• TSLP

Article highlights

• Thymic Stromal Lymphopoietin (TSLP) is an upstream cytokine constitutively overexpressed in the airways of severe asthmatics.

• Two variants, short form (sfTSLP) and long form (lfTSLP), of TSLP have been identified in allergic inflammatory tissue and immune cells (e.g., macrophages) involved in asthma.

• Tezepelumab is a first-in-class human monoclonal antibody that binds TSLP inhibiting its interaction with TSLP receptor complex.

• The results of a clinical trial demonstrated that tezepelumab compared to placebo reduced asthma exacerbations in adults with moderate-to-severe poorly controlled asthma. Tezepelumab also reduced blood eosinophilic counts, IgE, and FeNO in asthmatic patients

• The long-term safety, tolerability and efficacy of tezepelumab should be confirmed and extended in large, ethnically diverse populations of T2-high and T2-low asthma.

• sfTSLP and lfTSLP should be investigated as possible biomarkers to identify asthmatic patients responsive to tezepelumab.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank the scientists of the CISI Laboratory-WAO Center of Excellence and our colleagues for their contributions to some of the work reviewed herein. The authors thank medical graphic artist Fabrizio Fiorbianco for the elaboration of the figure.

Declaration of interest

The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors was supported in part by Regione Campania CISILab and TIMING Project.