“Monoclonal Antibodies and Severe Asthma” presented by Prof. Peter Wark

As part of our ongoing seminar series, the Centre of Excellence in Severe Asthma hosted Prof. Peter Wark, for a webinar on “Monoclonal Antibody Therapy and Severe Asthma” on 08 December 2016.

Presentation Summary:

Significant heterogeneity exists in asthma. Different disease processes underlie pathology in different people. For example, severe asthma can be subdivided based on the presence or absence of eosinophilic airway inflammation. Effective asthma treatment requires a personalised approach.

New treatments are now available that target specific disease processes in asthma. These approaches require a detailed understanding of the mechanisms causing disease in each patient. Careful phenotyping is required to identify patient populations likely to respond to each targeted therapy.

Monoclonal antibodies have emerged as options for severe, treatment-refractory asthma. Omalizumab (anti-IgE) is approved for the treatment of severe allergic asthma. Treatment reduces exacerbation rates in patients with persistent elevated IgE. Mepolizumab (anti-IL-5) treatment reduces exacerbations in patients with severe eosinophilic asthma. Additional monoclonal antibodies are currently in development that target allergic and eosinophilic inflammation.

The mechanisms causing non-eosinophilic or non-allergic asthma are less understood. Limited treatment options are available. An improved understanding of the mechanisms causing disease is required to inform the development of targeted therapies in this patient population.

Key Points:

• Severe asthma is asthma that requires treatment with high dose inhaled corticosteroids (ICS) plus a controller and/or systemic corticosteroids (OCS) to prevent symptoms becoming uncontrolled or which remains uncontrolled despite treatment
• Difficult asthma includes patient populations with the following features; persistent symptoms despite treatment, recurrent exacerbations, requiring regular doses of OCS and life-threatening asthma attacks
• Asthma pathogenesis involves airway inflammation, basement membrane thickening within the lung and airway smooth muscle hypertrophy
• Heterogeneity exists in asthma pathology between individuals
• Severe asthma can be divided into two inflammatory phenotypes; based on the presence or absence of eosinophilic airway inflammation
• Cluster analyses identify asthma phenotypes based on differing clinical characteristics and patterns of inflammation
• In some groups, symptoms are proportional to the degree of eosinophilic inflammation, while in other populations symptoms are discordant
• In some patients, inflammation is “Type-2”, triggered by allergen exposure, activation of T_H2 T cells, eosinophils and mast cells and a range of cytokines (including TSLP, IL-25, IL-33, IL-4, IL-5 and IL-13)
• Corticosteroids broadly reduce Type-2 inflammation
• Monoclonal antibodies that target specific inflammatory molecules are a useful approach to reduce pathology, while limiting treatment side effects
• The mechanisms underlying disease in patients with non-Type-2 inflammation are less clear; proposed mechanisms include activation of T_H1 and/or T_H17 cells, macrophages and neutrophils and increased cytokines (e.g. IFNg and IL-6)
• A detailed understanding of asthma pathophysiology is critical for the development of targeted therapies
• Monoclonal antibodies are produced by clonal B cells, bind to a single specific epitope, and can be used to target and block specific molecule functions
• Omalizumab binds IgE and is approved for the treatment of severe allergic asthma. Treatment reduces exacerbations requiring OCS treatment and hospitalisations. Treatment is most effective in patients with persistent Type-2 inflammation, increased fractional exhaled nitric oxide (FeNO), blood eosinophils and serum periostin
• Antibodies blocking the IL-5 pathway (mepolizumab, reslizumab and benralizumab) reduce eosinophilic inflammation
• Mepolizumab reduces blood and sputum eosinophil numbers, but only reduces exacerbations in populations with persistent eosinophilic inflammation
• Benralizumab reduces exacerbations, improves lung function (FEV₁) and improves asthma symptoms, particularly in a population with elevated blood eosinophil counts
• Antibodies targeting IL-13 (tralokinumab and lebrikizumab) have had limited efficacy in clinical trials
• Dupilumab blocks IL-4 receptor alpha, which interferes with IL-4 and IL-13 signalling pathways. Treatment reduces symptoms, eosinophil counts and exacerbations following ICS withdrawal. Improvements in lung function and exacerbations were greater in those with elevated blood eosinophil counts.
• Strategies blocking TNFa (etanercept and golimumab), IL-17 (brodalumab) have had limited success
• Many additional monoclonal antibodies are currently under development
• Further work is required to understand the processes underlying non-allergic, non-eosinophilic asthma to identify targets for future treatments

About Prof. Peter Wark:

Prof. Peter Wark is a senior staff specialist and a conjoint professor with the John Hunter Hospital and the University of Newcastle.

His research focuses on the impact of infections on airways disease, with a particular interest in viral infections and acute exacerbations of chronic airways disease.

To view other webinars on Severe Asthma please click here