By Prof Phil Thompson, Respiratory Physician, Nedlands
Airway diseases including asthma, chronic bronchitis, bronchiectasis and rhinosinusitis are complex.
They have a variety of subsets, can co-exist, and are often confused with each other, creating challenges for patients and doctors alike.
This has encouraged a treatment paradigm focussing on treating key pathological features of a patient’s disease. The evolution of monoclonal antibodies targeting specific mediators and impacting cell function have encouraged this.
An increased understanding of biological pathways, thereby informing therapeutic choices, has supported this.
In airway diseases this has led to treatments targeting airway epithelial driven pro-inflammatory pathways that cause proliferation, migration and activation of eosinophils and/or neutrophils.
At the epithelial surface allergic (IgE mediated), non-allergic eosinophilic pathways and non-allergic neutrophilic pathways can be triggered. These three pathways are activated by alarmins/defensins (TSLP, IL25 & IL33) that sit at the epithelial surface.
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These in turn trigger cascades of cell activation and associated cytokine production which includes IL4 and IL13 and downstream IL5. Collectively these cause mast cell activation, mucus production, airway reactivity, nitric oxide (NO) production, enhanced B cell switching to generate IgE and eosinophil proliferation.
Monoclonal antibody treatments
The Anti-IgE monoclonal antibody Omalizumab was developed in 1993 gaining FDA registration in 2003. Being an early monoclonal, it was not perfect, with complex dosing schedules, an inability to measure IgE on treatment and periodic drug induced anaphylaxis.
Nevertheless, it is used therapeutically for asthma (IgE mediated), chronic rhinosinusitis and polyps, chronic urticaria and food allergy. Increasing evidence suggests limiting mast cell activation underpins its clinical benefit.
A biosimilar was approved in Europe and the USA (2024/25) and its impact on clinical practice and cost is yet to be seen.
Anti-Interleukin 5 (Anti-IL5) (mepolizumab 4 weekly), Anti-IL5 receptor (benralizumab 8 weekly) were approved for Australian use in 2016/17 by the TGA and have significantly impacted on the management of severe asthma, which is often eosinophilic and oral steroid dependent.
Anti-IL5 therapy reduces steroid dependence and improves clinical outcomes. Their side effect profiles are minimal, highlighting the specificity monoclonals provide and the relatively redundant role of eosinophils in human biology.
Eosinophil counts are a predictor of treatment response but not all eosinophilic asthma patients respond effectively to Anti-IL5 therapies. This might reflect patient selection but if persistently elevated exhaled (Ex) NO and symptoms occurs, review is warranted.
Anti IL4/IL13 -Dupilumab can knock out both IL4 & IL13 by targeting a common subunit resulting in many actions, including inhibiting the production of ExNO. As such, ExNO is a useful biomarker for likely response and outcome assessment.
Dupilumab is also extremely effective in treating eczema and rhinosinusitis/nasal polyps as well as asthma. In some patients, eosinophil counts may rise dramatically suggesting deterioration, but the cells are not active.
In patients with significant eczema there is a risk of self-limiting but severe conjunctivitis. Dupilumab is a subcutaneous injection given fortnightly. In patients with mixed disease (asthma & rhinosinusitis and/or eczema) there is an obvious therapeutic appeal.
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Similarly, patients with high or resistant ExNO production are likely to respond to Dupilumab.
Tezepelumab inhibits TSLP and so inhibits the three key pro-asthma pathways located in the airway epithelium. It can achieve the same outcomes as the other biologics but potentially more so.
Inhibiting pathways at, or near, the point of origin is appealing but comes with greater risk of side effects. However, to date this has not been the case.
It is four weekly dosing and is registered in Australia, but is not currently on the PBS
Future directions
The above represent a major turning-point in managing severe airways disease. However, the field is not standing still.
Clinical trials (SWIFT & ANCHOR) assessing a six-monthly equivalent of Mepolizumab (Depemokimab) have led to registration applications in Europe and USA.
Early phase trials of an Anti IL33 (Itepekimab) have been encouraging, as have assessments of an Ox-40 ligand inhibitor (Amlitelimab) that inhibits immune cell stimulation.
Nanobodies targeting both TSLP & IL13 (Lunsekimig) are at an early phase of clinical assessment. Oral agents targeting IL4/IL3 via STAT 6 degradation are in clinical trials in asthma and eczema.
Studies of a biosimilar for Mepolizumab (Bio-Thera:BAT2606) are underway.
A personal algorithm on the PBS
If eosinophils are consistently raised in difficult to control asthma pursue one of the Anti-IL5 therapies. If, despite this, their disease is still brittle and ExNO has not been significantly reduced, trial Dupilumab.
If there are multiple disease manifestations (nasal polyps/rhinosinusitis and/or eczema) consider Dupilumab or Mepolizumab, depending upon current PBS regulations.
Author competing interests – nil
Key messages
- Monoclonal antibody therapies are a major step forward in treating severe brittle and/or oral steroid dependent asthma
- Clinical features, eosinophil counts, exhaled nitric oxide, together with standard lung function, IgE and allergen testing are useful monitoring and decision-making tools for management
- More therapies are on the immediate horizon that will broaden treatment options for severe and difficult asthma.
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