Our understanding of asthma, the impact of its pathology on patients, and the best treatment strategies to employ, continues to progress. For severe asthma not well-controlled by existing therapies, research into new phenotype-driven therapies is providing new management options for these patients. For mild asthma, the removal of the recommendation for short-acting β2-agonist reliever inhaler monotherapy due to exacerbation risk from the soon-to-be-published Global Initiative for Asthma (GINA) 2019 strategy document, underpins some of the biggest changes in asthma treatment for several decades.1–3 The identification of individuals at risk of developing asthma also continues to be of interest. These themes were reflected in the highlights of the 104th American Thoracic Society international congress, held in Dallas, Texas, United States on 17–22 May, 2019.
AstraZeneca presented their latest data on the biologic anti-interleukin-5 (anti-IL-5) receptor, benralizumab. Using integrated efficacy data from four clinical trials (SIROCCO, CALIMA, ZONDA, and BORA) assessing the effects of benralizumab treatment in patients with severe asthma, they were able to demonstrate a 44% reduction from baseline in exacerbation rates over two years. Continued improvements in lung function and asthma symptoms, and reduction from baseline in oral corticosteroid (OCS) use were maintained throughout the two years of benralizumab treatment, with the incidence of adverse events (AEs) remaining similar to placebo.4 Also presented were the results of a post hoc analysis of the effect of benralizumab on a novel endpoint of asthma worsening, the Composite Endpoint for Exacerbations (CompEx), which takes into account changes in peak expiratory flow, reliever medication use, and asthma symptoms. It was found that 43% of the 1,039 patients treated with benralizumab experienced at least one CompEx event, compared with 58–63% receiving placebo, corresponding to a 35–45% risk reduction in CompEx events with benralizumab versus placebo.5
GlaxoSmithKline presented the results of two clinical trials to determine whether patients and caregivers could successfully self-administer the anti-IL-5 monoclonal antibody mepolizumab at home, either as a liquid formulation in either a pre-filled syringe or via an autoinjector.6,7 Currently, mepolizumab is licensed as a lyophilised formulation for subcutaneous administration in a clinical setting and self-administration holds the promise of at-home treatment, reducing patient burden. Both studies found that patients and caregivers were able to successfully administer mepolizumab in-clinic and at-home. Additionally, patients found the devices easy to use, and in the case of the prefilled safety syringe, the overwhelming majority (96%) of the 22 patients with previous experience of the approved mepolizumab formulation preferred the new method of administration. Importantly, the safety profile of the new administration methods was found to be consistent with the approved formulation.6,7 Results on the long-term efficacy of mepolizumab in children were also presented in an open-label, uncontrolled study enrolling children 6–11 years of age with severe eosinophilic asthma.8 After 72 weeks of mepolizumab treatment, more than 50% of patients demonstrated clinically meaningful (≥0.5 points) reductions from baseline in Asthma Control Questionnaire (ACQ)-7 and ACQ-5 questionnaires scores, indicating patients had fewer symptoms and 80% of patients had at least a 50% reduction in asthma exacerbation rates compared with the 12 months before screening. No new safety concerns were identified.
Sanofi and Regeneron presented pre-specified and post hoc analysis findings from a range of different patient groups treated with dupilumab, an anti-IL-4 monoclonal antibody, in the Phase III LIBERTY ASTHMA VENTURE study. In patients with OCS-dependent severe asthma, dupilumab versus placebo, improved patient asthma control (p=0.002) and symptoms (p<0.05) from as early as Week 2, with benefits sustained until Week 24; significant (p=0.008) improvements in health related quality of life with dupilumab versus placebo were observed at Week 24.9,10 In patients with uncontrolled, moderate-to-severe asthma experiencing exacerbations during the study period, those receiving placebo experienced worsening from baseline of lung function, whereas those receiving dupilumab demonstrated improvements from baseline, although this effect was reduced with each additional exacerbation during the study period.11 Finally, in patients with late-onset asthma, with or without fixed airway obstruction, dupilumab versus placebo reduced the rate of severe exacerbations by 51–76% (p<0.05) and improved lung function from baseline over 52 weeks.12 In all analyses, the incidence of AEs was similar between treatment groups.9–12
Data were also presented that may inform the future treatment of patients with mild asthma. AstraZeneca investigated the incidence of asthma exacerbations in 668 patients with mild asthma, treated with albuterol, budesonide with albuterol, or budesonide-formoterol, all administered on an as-needed basis for 52 weeks.13 Budesonide-formoterol reduced the rate of exacerbations by 51% compared with albuterol (p<0.001) but not compared with budesonide alone (p=0.65). Similarly, the number of severe exacerbations were more than halved with budesonide-formoterol versus albuterol (9 versus 23 events, respectively) and versus budesonide alone (9 versus 21, respectively).13
The double-blind, crossover SIENA trial evaluated the efficacy of mometasone, tiotropium and placebo over 42 weeks in patients with mild persistent asthma based on sputum eosinophil count.14 Of the 295 patients enrolled, 73% had low (<2%) eosinophil sputum counts, challenging the assumption that the majority of asthma cases are Th2-eosinophil dominated. In patients who had a differential response to treatment (a composite measure based on treatment failures, asthma control days and lung function), no significant differences were found in the proportion of patients with a better response to mometasone versus placebo (57% versus 43%; p=0.14) or tiotropium versus placebo (60% versus 40%; p=0.029). The opposite was true among patients with sputum eosinophil counts ≥2%, with 74% of patients receiving mometasone responding to treatment versus 26% receiving placebo. The authors highlight that until further research is conducted, physicians should maintain their current treatment regime, except in cases where patients with low eosinophil counts and mild persistent asthma are not responding well to inhaled corticosteroids.14
Also presented was new research on the prediction of individuals at risk of developing asthma. The Pediatric Asthma Risk Score (PARS) integrates six demographic and clinical factors known to be associated with the development of asthma, including early wheeze and allergy skin testing, to generate a score indicating asthma risk and likelihood of asthma development by 7 years of age.15 PARS was found to be 11% more sensitive than the existing Asthma Predictive Index, a measure with low specificity, and PARS was better at predicting the development of mild-to-moderate asthma in children. As mild-to-moderate asthma is relatively common but difficult to predict, PARS may allow interventions to be made at an earlier stage.
In summary, further progress has been made in the treatment of patients with severe eosinophilic asthma, which only a decade ago had limited options beyond high dose OCS. The use of as-needed inhaled corticosteroids promises to reduce the incidence of exacerbations in mild asthma. Finally, an improved ability to predict an individual’s risk of developing asthma may facilitate preventative strategies to reduce the incidence of asthma worldwide.
1. GAA-INTERASMA Global Asthma Association, GINA: 2019 updates to the pocket guide for asthma management and prevention, 2019. Available at: https://interasma.org/2019/04/25/gina-2019-updates-to-the-pocket-guide-for-asthma-management-and-prevention/ (Accessed 12 June 2019).
2. Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378:1877–87.
3. O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378:1865–76.
4. Fitzgerald JM, Bleecker ER, Bourdin A, et al. A2676/511 Two-Year integrated efficacy and safety analysis of benralizumab SIROCCO, CALIMA, ZONDA, and BORA trials in severe asthma. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
5. Harrison T, Fuhlbrigge AL, Fagerås M, et al. A7087/509 Benralizumab reduces asthma worsening episodes. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
6. Bradford ES, Bernstein D, Bjermer L, et al. A1306/P697 Self-administration of mepolizumab liquid using a single-use prefilled syringe. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
7. Chapman KR, Bernstein D, Pavord ID, et al. A1305/P696 Self-administration of mepolizumab liquid using a single-use prefilled autoinjector. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
8. Steinfeld J, Gupta A, Ikeda M, et al. A7192/817 The Long-term efficacy and safety of mepolizumab in children from 6 to 11 years of age with severe eosinophilic asthma. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
9. Ford LB, Rabe KF, Wolfe RN, et al. A2666/501 Dupilumab improved asthma control and health-related quality of life in patients with oral-corticosteroid-dependent severe asthma in the Phase 3 LIBERTY ASTHMA VENTURE Study. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
10. Sher L, Rabe KF, Wolfe RN, et al. American Thoracic Society International Conference; May 17-22, 2019; 2019.
11. Rabe KF, Castro M, Wenzel SE, et al. A2668/503 Dupilumab improved lung function in patients with uncontrolled, moderate-to-severe asthma despite exacerbation events during the LIBERTY ASTHMA QUEST study. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
12. Hanania NA, Bateman ED, Castro M, et al. A2667/502 Dupilumab reduces severe exacerbations and improves lung function in late-onset, uncontrolled, moderate-to-severe asthma patients enrolled in the LIBERTY ASTHMA QUEST study. Presented at: The American Thoracic Society International Conference, Dallas, Texas, USA, 17–22 May 2019.
13. Beasley R, Holliday M, Reddel HK, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Eng J Med. 2019;380:2020–30.
14. Lazarus SC, Krishnan JA, King TS, et al. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Eng J Med. 2019;380:2009–19.
15. Biagini Myers JM, Schauberger E, He H, et al. A Pediatric Asthma Risk Score to better predict asthma development in young children. J Allergy Clin Immunol. 2019; 143: 1803–10.e2.