Pulmonary – Treatable traits
Vibeke Backer, Peter G. Gibson, Ian D. Pavord in The Asthmas, 2023
The targets for biological agents are shown in Figure 2.7 and their clinical effects and effects on biomarkers are summarised in Table 2.6. Monoclonal antibodies inhibiting the effect of IL-5 (Mepolizumab, Reslizumab and Benralizumab), IL-4 and IL-13 (Dupilumab, which inhibits both cytokines by targeting the common IL-4 receptor alpha), TSLP (Tezepelumab) and IgE (Omalizumab) are available for use in patients with severe asthma who continue to have asthma attacks despite optimum inhaled treatment with inhaled corticosteroids and LABA. Their effects are greater in subgroups identified using biomarkers and to a large extent, the most predictive biomarker is that most closely associated with the cytokine that is being blocked (i.e. blood eosinophils for anti-IL-5 and FeNO for anti-IL-4/13).
The Pharmacotherapy of Rhinitis and Asthma
Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial in Textbook of Allergy for the Clinician, 2021
Since most of the Th2-low patients have a poor response to oral steroids, other pharmacologic therapies have shown promise in reducing exacerbations and improving symptoms. Azithromycin used as add-on therapy in patients with uncontrolled, persistent asthma on medium-to-high ICS plus LABA has shown significant reductions in asthma exacerbations and improved asthma-related quality of life compared to a placebo (Gibson et al. 2017). Tiotropium and bronchial thermoplasty can provide benefit for asthma patients, regardless of the type of inflammation driving their disease. Other interventions targeting non-type-2 inflammation in asthma including IL-17 and CXCR2 have been disappointing in clinical trials (Busse et al. 2013, O’Byrne et al. 2016). IL-6 and CRP have been shown to be elevated in Th2-low asthmatics, particularly those with obesity. There have been promising reductions in neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice using antibody-mediated neutralization of IL-6 (Chu et al. 2015). Tezepelumab (anti-TSLP monoclonal antibody) has shown, small but significant exacerbation reduction in patients with low FeNO in phase 2 clinical trials suggesting it may be beneficial in Th2-low inflammation patients (Corren et al. 2017).
Bronchus-associated lymphoid tissue and immune-mediated respiratory diseases
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
Tezepelumab/AMG157 (Amgen) has been shown to reduce airway changes following allergen challenge in patients with mild to moderate asthma, suggesting an important role for TSLP in asthma. Tezepelumab is currently being studied in patients with asthma and with atopic dermatitis.
Cost-effectiveness of tezepelumab in Canada for severe asthma
Published in Journal of Medical Economics, 2023
Mara Habash, Hannah Guiang, Irvin Mayers, Anna Quinton, Vivian Vuong, Aidan Dineen, Sumeet Singh, Danny Gibson, Adrian P. Turner
Although severe asthma affects a minority of the population with asthma, it is associated with disproportionate humanistic and economic burden, accounting for 50% of total asthma direct costs2. Currently available biologics in Canada for severe asthma target specific phenotypes, potentially leaving other pathways of airway inflammation wholly unaddressed. Eligibility for current biologics is dependent on biomarker profile; however, studies have demonstrated that approximately half of patients with severe asthma have been shown to change phenotypes in one year6. Furthermore, up to 49% of severe asthma patients exhibit multiple drivers of inflammation4,61,62. In addition, there are no biologics indicated for patients with severe, non-allergic, non- EOS asthma. Hence, there remains significant unmet need for patients with severe asthma. Tezepelumab has been demonstrated to be an effective treatment that reduces exacerbations and provides effective asthma control across inflammatory phenotypes, regardless of biomarker status, and will help address these unmet needs that remain in severe asthma.
Phenotyping severe asthma: a rationale for biologic therapy
Published in Expert Review of Precision Medicine and Drug Development, 2020
Alessandro Vatrella, Angelantonio Maglio, Simona Pellegrino, Corrado Pelaia, Cristiana Stellato, Girolamo Pelaia, Carolina Vitale
Tezepelumab is a fully humanized IgG2λ monoclonal antibody, that neutralizes TSLP impeding its binding to TSLPR, and the subsequent recruitment of IL-7Rα in the signaling complex, thus inhibiting multiple downstream inflammatory pathways. Given the upstream role of TSLP in the inflammatory pathway of asthma, tezepelumab is able to simultaneously reduce the concentration of different inflammatory biomarkers unlike other biological drugs that mainly act on a specific biomarker [68]. For this reason, tezepelumab represents a new biological therapy that can potentially be used in different asthma phenotypes. This drug has proven to be effective in phase II clinical trials where it significantly decreases asthma exacerbations, irrespectively of baseline blood eosinophil counts and Th2 status [67]. Moreover, tezepelumab has been shown to reduce blood eosinophils, serum IgE, FeNO, and to improve FEV1 and symptom scores [67]. In addition, another study showed that tezepelumab attenuates allergen-induced early and late asthmatic responses, with a decrease in bronchoconstriction and in airway inflammation indexes such as sputum eosinophilia and FeNO [70].
Novel therapeutic approaches targeting endotypes of severe airway disease
Published in Expert Review of Respiratory Medicine, 2021
Maria De Filippo, Martina Votto, Amelia Licari, Fabio Pagella, Marco Benazzo, Giorgio Ciprandi, Gian Luigi Marseglia
To date, up to 50% of patients with severe non-eosinophilic asthma have limited treatment options. Tezepelumab is the first drug of a new category for severe asthma treatment, targeting thymic stromal lymphopoietin (TSLP), a protein of the cytokine family that is recognized as having an important role in the maturation of T cells. Specifically, tezepelumab is a humanized monoclonal antibody designed to bind specifically to human TSLP, preventing its interaction with its receptor complex. TSLP blockade obtained with tezepelumab prevents the release of pro-inflammatory cytokines by immune system cells ‘marked’ by the presence of TSLP. Due to tezepelumab activity ‘upstream’ of the inflammatory cascade, it could be helpful in a large population of patients with severe uncontrolled asthma, including those whose asthmatic condition is not driven by T2 inflammation [162]. Based on the findings from PATHWAY, tezepelumab was granted a breakthrough.
Related Knowledge Centers
- Asthma
- Monoclonal Antibody
- Thymic Stromal Lymphopoietin
- First-In-Class Medication
- Indication
- Phases of Clinical Research