monoclonal antibodies in severe eosinophilic asthma
Last edited 11/2022 and last reviewed 11/2022
Atopic asthma represents about 50% of asthmatic patients and probably a higher proportion in patients with severe asthma (1,2)
- thought that an excess of Th2-type lymphocytes and their secreted interleukin (IL)-4, IL-5 and IL-13 cytokines are implicated in atopic asthma
- these cytokines are responsible for the raised immunoglobulin (Ig)E levels (IL-4 and IL-13), eosinophilia (IL-5), mucus hypersecretion and airway hyper-responsiveness (both probably consequences of IL-13) (1,2)
- of note is that a subgroup of asthma patients show eosinophilia in the absence of an allergic aetiology to their asthma (3,4)
- eosinophilic inflammation is associated with frequent asthma exacerbations and disease severity and is sustained by the biological activity of IL-5 (2)
- IL-5 is the most crucial cytokine not only in recruiting eosinophils but also in prolonging their survival in tissues
- IL-5 is produced by eosinophils, mast cells, Th2 cells, natural killer cells, group 2 innate lymphoid cells (ILC2) and CD34+ progenitor cells
- pivotal for the proliferation, maturation, activation, recruitment and survival of eosinophils
- eosinophils and the lung
- eosinophils are the predominant cells of the inflammatory response in the lungs, contributing greatly to two major events: the remodeling and the hyperresponsiveness of the airways
- persistent inflammation caused by eosinophils leads to constant damage of the airways
- the regeneration process is not flawless
- causes hypertrophy of the smooth muscles, hyperplasia of goblet cells, and deposition of extracellular matrix proteins, causing membrane thickening and fibrosis (5)
- IL-5 therefore is a critical regulator of blood and tissue eosinophilia in severe eosinophilic asthma. Concomitant high blood and sputum eosinophilia correlate with poor asthma control and propensity to asthma exacerbation (6)
Mepolizumab and reslizumab target the IL-5 signalling pathway and are effective in severe eosinophilic asthma patients with or without allergies (3)
- both are anti-IL-5 monoclonal antibodies
- have both been shown to result in a marked reduction in blood eosinophil count (7)
Benralizumab is a humanised, afucosylated, monoclonal antibody that targets the IL-5 receptor alpha (8)
- in contrast to anti-IL-5 monoclonal antibodies, benralizumab exerts its effect by inducing the direct, rapid and nearly complete depletion of blood eosinophils through enhanced antibody-dependent cell-mediated cytotoxicity, an apoptotic process of eosinophil elimination involving natural killer cells (8)
NICE guidance on omalizumab, mepolizumab, reslizumab and benralizumab (9,10,11,12)
Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimised standard therapy in people aged 6 years and older:
who need continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year), and
only if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme.
Reslizumab, as an add-on therapy, is recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if:
- the blood eosinophil count has been recorded as 400cells per microlitre or more
- the person has had 3 or more severe asthma exacerbations needing systemic corticosteroids in the past 12 months and
- the company provides reslizumab with the discount agreed in the patient access scheme
- at 12 months:
- stop reslizumab if the asthma has not responded adequately or
- continue reslizumab if the asthma has responded adequately and assess response each year.
Mepolizumab, as an add-on therapy, is recommended as an option for treating severe refractory eosinophilic asthma, only if:
- it is used for adults who have agreed to and followed the optimised standard treatment plan and
- the blood eosinophil count has been recorded as 300 cells per microlitre or more
- and the person has had at least 4 exacerbations needing systemic corticosteroids in the previous 12 months, or
- has had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months
- or the blood eosinophil count has been recorded as 400 cells per microlitre or more and
- the person has had at least 3 exacerbations needing systemic corticosteroids in the previous 12 months (so they are also eligible for either benralizumab or reslizumab)
- at 12 months:
- stop mepolizumab if the asthma has not responded adequately or
- continue mepolizumab if the asthma has responded adequately and assess response each year
Benralizumab, as an add-on therapy, is recommended as an option for treating severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids and long-acting beta-agonists, only if:
- the person has agreed to and followed the optimised standard treatment plan and
- the blood eosinophil count has been recorded as 300cells per microlitre or more and
- the person has had 4 or more exacerbations needing systemic corticosteroids in the previous 12 months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5mg per day over the previous 6months (that is, the person is eligible for mepolizumab) or
- the blood eosinophil count has been recorded as 400cells per microlitre or more with 3 or more exacerbations needing systemic corticosteroids in the past 12 months (that is, the person is eligible for reslizumab)
- at 12 months:
- stop benralizumab if the asthma has not responded adequately or continue benralizumab if the asthma has responded adequately and assess response each year
An adequate response is defined as:
- a clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or
- a clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control
Mepolizumab in children with asthma:
- Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial
- in the MUPPITS-2 study (n=335) it was shown that over the 52 week study period mepolizumab was associated with a reduction in exacerbation rate (0.96 vs 1.3, p= 0.027). Adverse effects were seen in 29% vs 11% in the placebo group
Australian guidance with respect to monoclonal antibodies (14):
- four monoclonal antibody therapies (benralizumab, mepolizumab, dupilumab and omalizumab) are available in Australia for the treatment of severe asthma in patients whose asthma is uncontrolled despite optimised standard treatment
- monoclonal antibody therapy is an add-on treatment option for reducing severe flare-ups and improving symptom control in patients with severe allergic or eosinophilic asthma whose asthma is uncontrolled despite treatment with high-dose inhaled corticosteroids and long-acting beta2 agonists.
- these therapies target inflammatory pathways that activate type 2 immune responses leading to airway inflammation.
- patients using these treatments must keep taking their inhaled corticosteroid-containing preventers.
- after treatment has been initiated by a specialist, ongoing maintenance doses can be administered in primary care, or by the patient or carer, under specialist supervision.
- monoclonal antibody therapies currently available in Australia for severe asthma are generally well tolerated
- injection site reactions are among the most common adverse events. Systemic reactions, including anaphylaxis, are rare but can occur.
- like all patients with asthma, those using monoclonal antibody therapies need an up-to-date written asthma action plan.
- Caruso M, Morjaria J, Emma R, et al. Biologic agents for severe asthma patients: clinical perspectives and implications. Intern Emerg Med2018; 13: 155-176
- Fahy JV. Type 2 inflammation in asthma-present in most, absent in many. Nat Rev Immunol 2015; 15: 57-65.
- Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev2017; 9: CD010834
- Brusselle GG, Maes T and Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med2013; 19: 977-979
- Chung KF. Precision medicine in asthma: linking phenotypes to targeted treatments. Curr Opin Pulm Med 2018; 24: 4-10.
- Chakir J., Shannon J., Molet S., Fukakusa M., Elias J., Laviolette M., Boulet L.P., Hamid Q. Airway remodeling-associated mediators in moderate to severe asthma: Effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J. Allergy Clin. Immunol. 2003;111:12931298. doi: 10.1067/mai.2003.1557
- Wang Y-H and Liu Y-J. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 2009; 39: 798-806.
- Kolbeck R, Kozhich A, Koike M, et al. . MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 2010; 125: 1344-1353
- NICE (April 2013). Omalizumab for treating severe persistent allergic asthma
- NICE (October 2017). Reslizumab for treating severe eosinophilic asthma
- NICE (February 2021). Mepolizumab for treating severe eosinophilic asthma
- NICE (March 2019). Benralizumab for treating severe eosinophilic asthma
- Jackson DJ et al. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.. Lancet. 2022 Aug 13;400(10351):502-511.
- National Asthma Council - Australia. Monoclonal antibody therapy for severe asthma (accessed 17th November 2022).