Originally published: February 2018
Patients with severe asthma continue to experience symptoms despite inhaled treatment optimisation, with even high doses of oral corticosteroids not completely controlling their disease. This group is typically treated as though it has a single underlying disease pathology, but it is now becoming clear that this assumption is incorrect.
In the era of biologic therapy we have the ability to selectively manipulate specific disease pathways, gaining an understanding of how this affects a patient’s biology and disease expression. IL-4, IL-5 and IL-13 are important drivers of the most common type of asthma. From what we know so far, IL-5 is important in eosinophil migration from bone marrow to blood, and treatment with anti-IL-5 therapy results in a fall in circulating eosinophil numbers along with a reduction in exacerbation frequency. Exhaled nitric oxide (FeNO), a biomarker associated with IL-13 in asthma, is not affected by anti-IL-5 treatments, but does suppress in response to anti-IL-13. This suggests that there must be at least two distinct disease pathways driving asthma. It is on this background that thymic stromal lymphopoietin (TSLP) has been investigated. It is released from the airway epithelium in response to environmental triggers such as allergens, smoke and diesel fumes and causes increased production of multiple pro-inflammatory cytokines, including both IL-5 and IL-13.
In a study recently published in the New England Journal of Medicine, Jonathan Corren and colleagues have investigated the use of tezepelumab, a human monoclonal antibody against TSLP, in patients with uncontrolled asthma. They recruited 584 patients into a randomised phase 2 trial where participants received one of three doses of subcutaneous tezepelumab or placebo over the course of a year. Patients were defined as being uncontrolled if, despite the use of an inhaled long acting beta agonist and medium- or high-dose inhaled corticosteroid, their asthma control questionnaire score was greater than 1.5 plus they had experienced two exacerbations, or one which required hospital treatment, in the preceding 12 months.
The results showed that the annualised exacerbation rate in the placebo group was 0.67, and in the three treatment arms was 0.19 to 0.26, depending on the dose. This is a rate reduction in frequency of exacerbations of between 61% and 71% compared wtih placebo (p<0.001 for all). If these results are sustained over time, bearing in mind this was only a year-long study, this would translate into a patient’s exacerbation frequency falling from two exacerbations in three years to one exacerbation every four or five years. There was also a 110-150ml improvement in FEV1, which may be noticeable to patients; however, there was no significant effect on asthma quality of life questionnaires, which focus on day-to-day symptom domains rather than exacerbation frequency. Interestingly, patients with a low blood eosinophil count responded as well as those with a high count, and, unlike anti-IL-5 and anti-IL-13, anti-TSLP had suppressive effects on both blood eosinophils and FeNO, suggesting that TSLP itself may be a master regulator, acting early and stimulating the different pathways that can all drive asthma.
Anti-TSLP therapy with tezepelumab appears among the most promising of the biologic treatments trialled for asthma to date, both in the magnitude of its effect and in the broad range of patients in whom there is efficacy. But, intriguingly, as some patients continue to exacerbate while on this medication there must be pathways at play that we have yet to target.
Dr Gareth Hynes is a clinical research fellow in severe asthma at the University of Oxford.
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