As the incidence of asthma continues to rise worldwide, the need to further optimize existing treatment strategies and develop new therapeutics becomes of greater importance. In mild asthma, some patients continue to experience severe exacerbations despite adherence to current treatment guidelines, indicating a potential to refine treatment strategies.1,2 In severe asthma, patients frequently do not obtain adequate disease control using bronchodilators and inhaled corticosteroids (ICSs), leading to poor quality of life and a high healthcare burden.3 With asthma drug development increasingly focusing on specific disease phenotypes, new treatment options are becoming available to manage severe disease. Consequently, the presentation of data from trials optimizing asthma treatment, along with new data on treatments for severe asthma, were focuses of the 103rd American Thoracic Society (ATS) International Congress, held in San Diego, CA, US, on May 18–23, 2018.
Building on previous data for mepolizumab, an interleukin-5 (IL-5) monoclonal antibody, GlaxoSmithKline presented new data from the open-label COLUMBA study, which assessed long-term clinical responses to the mepolizumab in patients with severe eosinophilic asthma. In previous randomized clinical trials of 24–52 weeks duration, mepolizumab reduced exacerbation frequency, improved patient quality of life and facilitated reduced oral corticosteroid dosing.4,5 In COLUMBA, patients received mepolizumab in addition to standard of care for an average of 3.5 years. Patients demonstrated a 61% decrease in the annual rate of exacerbations during the study with mepolizumab, with consistent reductions during every full year of the study (0.71–0.82 events per year). Additionally, one third of patients reported no exacerbations during the entire study. Correspondingly, improvements in asthma control and reductions in blood eosinophil counts, seen from respective first assessments at week 12 and 4, were maintained throughout the study. Initial improvements in lung function, as measured by pre-bronchodilator forced expiratory volume in 1 second (FEV1), decreased over the duration of the study. This is likely a reflection of the general decline in lung function previously reported in patients with severe asthma.6–8 The safety and immunogenicity profile of mepolizumab over the duration of the COLUMBA study was also found to be consistent with previous studies of mepolizumab in severe asthma.9
Regeneron and Sanofi Genzyme presented the results of two randomized controlled trials investigating the IL-4 monoclonal antibody, dupilumab for the treatment of asthma. An important feature of both trials was that there was no requirement for minimum levels of any biomarkers such as eosinophil counts. The QUEST trial included patients with uncontrolled, moderate to severe asthma, who were administered dupilumab (200 mg or 300 mg), or placebo every 2 weeks for 52 weeks in addition to their existing standard of care. Compared with placebo, patients receiving either dose of dupilumab demonstrated a 46–48% reduction in the annualized rate of severe exacerbations (p<0.0001) and improvements from baseline in FEV1 at week 12 (130–140 mL; p<0.0001).10,11 The VENTURE trial focused on the effect of dupilumab in patients with severe, steroid-dependent asthma. Patients received dupilumab 300 mg or placebo every two weeks for 24 weeks in addition to standard of care. Dupilumab versus placebo-treated patients demonstrated significant reductions from baseline oral corticosteroid dose at week 24 (70.1% versus 41.9%, respectively; p<0.0001). Additionally, four out of five patients in the dupilumab group achieved at least a 50% reduction in their oral corticosteroid dose compared with only half in the placebo group. As in QUEST, significant reductions in the frequency of severe exacerbations and an improvement in lung function (p<0.001) were also seen. The most common adverse events in both studies included eosinophilia, an increase in eosinophil count, bronchitis, and sinusitis.12 Given the lack of biomarker criteria patients were required to meet for enrolment in both trials, these results hold promise for the treatment of a broad population patients with asthma.
Other highlights from this year’s congress included several reports of new treatments and methods for improving patient standard of care. AstraZeneca reported the results of the phase III SYGMA trials assessing the use of the ICS and long-acting-β2 agonist (SABA) combination, budesonide/formoterol ‘as needed’ compared with existing standards of care. Current standard of care treatment for mild asthma relies on reliever therapies such as SABAs used ‘as needed’, or maintenance ICS plus SABA ‘as needed’.2 The use of SABAs presents a particular challenge, as they provide symptomatic control but do not modify the underlying inflammatory disease, putting patients at risk of exacerbations. In the SYGMA trials, patients receiving budesonide/formoterol ‘as needed’ experienced more weeks with well-controlled symptoms (34.4% versus 31.1%) compared with SABA ‘as needed’, although fewer weeks compared with budesonide maintenance therapy (44.4%). Additionally, budesonide/formoterol ‘as needed’ reduced the rate of severe exacerbations by 64% compared with SABA ‘as needed’ and was non-inferior to ICS plus SABA ‘as needed’ in exacerbations rate reductions. The safety profile of budesonide/formoterol was consistent with previous studies.13
Finally, Koneksa Health presented results from its validation of a method for measuring FEV1 remotely. Measuring lung function remotely promises to provide earlier clinical development signal detection and reduce the need for patient study site visits. The data presented at the ATS demonstrated that remote FEV1 measurements correlate strongly with in-clinic FEV1 spirometry, and that patient compliance with the technique was generally good. Additionally, the twice daily measurements made by patients over 28 days during the study allowed consecutive FEV1 data to be averaged. Projections suggest that the use repeated remote FEV1 measurements could allow for 100 mL changes in FEV1 to be detected with as few as 18 patients compared with the 100 patients that would be required using traditional lung function measurements.14
Together, these results suggest promising advances in the current therapeutic options for patients with severe asthma, the potential for improved ‘as needed’ treatment for mild asthma, and improvements in the methodology for detecting changes in lung function. The developments for severe asthma are particularly important given that a significant proportion of patients are still currently not receiving adequate disease control, and provide the promise that more personalized medicines will soon be available.
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8. GSK. Nucala (mepolizumab) study reports long-term safety data, consistent exacerbation reduction and improved asthma control, 2018. Available at: //us.gsk.com/en-us/media/press-releases/2018/nucala-mepolizumab-study-reports-long-term-safety-data-consistent-exacerbation-reduction-and-improved-asthma-control-1/ (accessed May 30, 2018).
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10. Regeneron. New England Journal of Medicine publishes two positive phase 3 trials showing Dupixent® (dupilumab) improved moderate-to-severe asthma. Available at: //investor.regeneron.com/releasedetail.cfm?releaseid=1068022 (accessed May 30, 2018).
11. Castro M, Busse WW, Zhang B, et al. Dupilumab treatment produces rapid and sustained improvements in FEV1 in patients with uncontrolled, moderate-to-severe asthma from the LIBERTY ASTHMA QUEST Study. Am J Respir Crit Care Med. 2018;197:A6163.
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13. 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.
14. Bhatia G, Ruddy M, Jackson N, et al. Validating remote FEV1 monitoring in moderate asthmatics to increase study power. Am J Respir Crit Care Med. 2018;197:A3934.