Tezepelumab as an Emerging Therapeutic Option for the Treatment of Severe Asthma: Evidence to Date

Abstract

Asthma is a complex heterogeneous disease defined by chronic inflammation of the airways. Patients present with wheezing, chest tightness, cough and shortness of breath. Bronchial hyperresponsiveness and variable expiratory airflow limitation are hallmark features. About 3.6–6.1% of patients, despite receiving high-dose inhaled corticosteroids (ICS) and a second controller medication, report persistent symptoms referred to as severe asthma. Uncontrolled severe asthma is associated with increased mortality, morbidity, diminished quality of life and increased health expenditures. The development of modern biological therapy has revolutionized severe asthma treatment. By targeting specific chemokines, asthma control has drastically improved, resulting in better quality of life, less emergency department visits and inpatient admissions, and decreased chronic systemic corticosteroid utilization. Despite these advances, there remains a subset of asthma patients who remain symptomatic with poor quality of life and heavy utilization of the healthcare system. Recently attention has been given to pharmaceutical therapy directed at receptors and cytokines on the epithelial layer of the lung referred to as “alarmins”. Thymic stromal lymphopoietin (TSLP) is an interleukin-7-like receptor family found on the epithelial layer of the lung that releases a cytokine cascade inducing eosinophilic inflammation, mucus production and airflow obstruction in asthmatics. Tezepelumab is the first investigational monoclonal antibody that inhibits TSLP. Proof of concept study and phase IIb studies demonstrated reduced asthma exacerbations, improvement in quality of life, less decline in FEV 1 and decrease in biochemical inflammatory markers in comparison to placebo. It is presently undergoing three phase III studies and an additional phase II study.

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

“…However, the remarkable preventive action exerted by tezepelumab on asthma exacerbations occurred regardless of baseline levels of blood eosinophils or other indicators of T2-high inflammation [ 80 ], and this result can undoubtedly represent a relevant advantage for tezepelumab with respect to most of the currently approved anti-asthma biologics. Tezepelumab also decreased blood levels of IL-5, IL-13, periostin, and thymus and activation-regulated chemokine (TARC) [ 83 ].…”

“…Ongoing phase 2 and 3 studies, aiming to evaluate the efficacy and safety of tezepelumab, include the NAVIGATOR, SOURCE, DESTINATION, and CASCADE trials [ 83 ].…”

“…NAVIGATOR is a multicenter, placebo-controlled, double-blind and randomized trial, recruiting more than 1000 adults (18–80 years old) and adolescents (12–17 years) with severe asthma not adequately controlled by medium-to-high dosages of ICS, associated with at least another controller drug [ 83 ]. The study protocol is based on a 5/6-week screening phase, followed by a 52-week treatment and a 12-week follow-up period.…”

“…Secondary outcomes include the therapeutic effects of tezepelumab on asthma control, health-related quality of life, and lung function [ 84 ]. Preliminary results suggest that tezepelumab, administered subcutaneously at the dosage of 210 mg every 4 weeks, was able to achieve the primary goal of lowering AAER at week 52 [ 83 ]. This effect was detected across all enrolled patients, and even in those having less than 300 and 150 blood eosinophils/μL.…”

Emerging Evidence for Pleiotropism of Eosinophils

“…Tezepelumab is a humanized monoclonal antibody, which targets the previously mentioned TSLP. This cytokine activates type 2 innate lymphoid cells (ILC2) which are able to trigger T2 immune response inflammation with an important role of eosinophils [230].…”