CHAPTER IV - Biology and Treatment of Asthma
9. Recent Developments and New Treatment Options
9.1. Pharmacogenetics
More than 100 genes are considered to conduce to asthma manifestations, including primary disease conferring genes, asthma severity varying genes and treatment modifying genes. A well-investigated example that has been associated with a more severe form of asthma and a decreased response to beta agonists is the substitution of arginine with glycine at position 16 of the β2-adrenergic-receptor [254]. Recent genome-wide association studies combined with replication in additional cohorts and in vitro cell-based models identified novel pathway-related pharmacogenetic variations.
As these have the potential to influence the efficacy of therapeutic measures, a more detailed understanding of the underlying genetic mechanisms may lead to the development of biomarkers to determine the most suitable therapy for individual patients. [255]
9.2. Asthma Phenotyping and Personalized Treatment Approaches
For a long time, asthma has been viewed as a single disease characterized by chronic airway inflammation and remodeling with anti-inflammatory therapy as the major approach to treatment. But more recently, the disease is recognized to be a multidimensional syndrome involving clinical, physiologic, and pathologic domains, which may coexist, but are not necessarily related. [253] As the understanding of the heterogeneity of asthma is increasing, more and more different phenotypes and endotypes are identified, incorporating observable clinical characteristics and specific biologic mechanisms in a more complex way. [254] A phenotype can be “defined as the composite observable characteristics or traits of an organism that result from genetic as well as environmental influences” [256]. These kinds of phenotypes including
dependence on high-dose corticosteroid treatment, severe airflow obstruction and recurrent exacerbations concomitant with an allergic background and late onset of disease have been revealed by analytical clustering methods, among others in the Severe Asthma Research Program (SARP) [257]. This investigation identified five clusters of patients differing in age, sex, age of onset, presence of atopy and/or obesity, degree of lung dysfunction, and reversibility of airflow obstruction. In another approach using sputum analysis, four phenotypes based on the predominant inflammatory cell type, such as eosinophilic or neutrophilic, were found [258]. In these groupings, the most evident differentiation was between patients with mild to moderate, early-onset asthma with eosinophilic or paucigranulocytic predominant sputum patterns and patients with more severe form of asthma and greater sputum neutrophilia.
Furthermore, to comprise not only the clinical picture, but also find subtypes based on the underlying biologic mechanisms, different endotypes were defined, including biomarkers, lung physiology, genetics, histopathology, epidemiology and respective treatment response. For example, the aspirin-exacerbated respiratory disease endotype features leukotriene-related genetic polymorphisms leading to an upregulated leukotriene synthesis. As 5-lipoxygenase inhibitors block the synthesis pathway upstream, they are recognized as the superior treatment for this patient group. [259]
The allergic bronchopulmonary mycosis endotype, in contrast, is associated with colonization of the airways by mold and might therefore benefit from antifungal agents.
[254] Nevertheless, the major part of novel individual treatment approaches concentrates on biologic therapies.
9.3. Biologics
The most common grouping of asthma patients divides into allergic and non-allergic forms. While allergic asthma is present in all groups of asthma severity, with 50-80% it is of particular importance in patients with severe asthma [260], therefore finding new treatments for this population is an interesting area of research. Besides the well-known function of IgE, it is also assumed that several different cytokines and chemokines play a crucial role in the pathogenesis of the disease. A number of these have already been identified as suitable targets for therapy, demonstrating the potential
of biological drugs such as monoclonal antibodies and small-molecule inhibitors, especially as reasonable add-on treatments for those patients whose severe asthma forms do not respond to conventional therapies in a satisfactory way. While the anti-inflammatory effect of corticosteroids interferes with several pathways that are involved in asthma pathogenesis, cytokine-based therapy usually only targets a restricted cascade. As experimental anti-cytokine therapies have also been shown to induce variable responses in individual patients, the need to accurately characterize the patient’s phenotypic pattern becomes even more evident. A certain biological drug addressing the particular molecular targets relevant for each subgroup has to be found in order to achieve the best-possible outcome for individual patients. [24]
As the first biologic in asthma treatment, omalizumab (Xolair®, Novartis) has been approved in the United States in 2003. The murine monoclonal antibody (mAb) is produced by the somatic cells hybridization method and contains a paratope able to bind to high and low affinity IgE receptors on basophils and mast cells, inhibiting both degranulation and activation of respective cellular mediators. Although several clinical trials have already proven the effectiveness of omalizumab with a significant decline in asthma exacerbations, improvement of quality of life and steroid-soaring effects, it still has some limitations. To overcome those, new mAbs are currently under investigation showing a greater avidity for IgE, such as RG7449 that targets B-lymphocytes before they are activated to produce IgE. [261]
After more than a decade without any new appearances on the market, the anti-interleukin 5 (IL-5) humanized mAb mepolizumab (Nucala®) by GlaxoSmithKline was approved in the end of 2015 as an add-on treatment for patients with severe asthma and eosinophilic inflammation. IL-5 was identified as a useful target as it promotes eosinophil growth and activation and two additional mAbs, reslizumab (Cinqair®) and benralizumab are already in the pipeline. While Nucala and Cinqair both bind IL-5 directly to hinder it from tacking to its receptors on eosinophils, benralizumab targets the receptor α subunit in order to mediate the death of eosinophils by enhanced antibody-dependent cell-mediated cytotoxicity. As IL-5 is not the only cytokine promoting eosinophil growth and survival, this active cell depletion approach can potentially be even more efficient. [262]
Besides that, several different biological targets are currently explored in asthma research. In addition to the IL-5 mAbs, atopic patients with TH2-driven eosinophilic asthma could also benefit from inhibition of IL-4 and IL13. A blockade of IL-17 that also contributes to steroid resistance, instead, would most likely be useful for patients with severe neutrophilic asthma. Combinations of biologics targeting different types of cytokines could be applied for the mixed neutrophilic-eosinophilic phenotypes, a group represented quite frequently among the exacerbation-prone form of severe asthma.
Another promising approach is the neutralization of the effects of innate cytokines IL-25, IL-33 and thymic stromal lymphopoeitin (TSLP), all of which play a crucial role in the initial priming of TH2-mediated airway inflammation. This strategy could have the potential to disconnect the link between adaptive and innate immune responses which might be responsible for the development of severe subtypes of asthma that are difficult to treat. [24]
The two major hurdles yet to overcome on the way to more efficient and easily accessible biological therapies are the lack of reliable biomarkers to characterize specific phenotypes and predict medication responsiveness and the need to design reasonable clinical trials to evaluate the long-term safety of these immunomodulatory agents. Furthermore, the cost factor is not to be underestimated. As Nucala, for example, has a wholesale acquisition cost of 2500$ per single-use vial [262], it remains a demanding task to define which patients really need expensive new biologics and which are able to cope with their symptoms by using standard therapies.
Rima Kandil - 2019