Improving asthma control and mitigating exacerbation risk across disease severities
At a webinar organized by the Hong Kong Thoracic Society and the CHEST Delegation of Hong Kong and Macau, Professor Christopher Cooper of the University of California in Los Angeles, California, US, and Dr Fanny Ko of the Prince of Wales Hospital in Hong Kong discussed current recommendations and evidence on asthma assessment and treatment strategies to improve control and minimize severe exacerbations across the spectrum of disease severity.
Current approaches to asthma management
“The 2020 Global Initiative for Asthma [GINA] report acknowledges two leading management strategies for patients with mild-to-moderate asthma,” noted Cooper. “This includes the asthma control dosing approach, which involves stepping up treatment to achieve control and stepping down treatment when control is achieved, and the more flexible single maintenance and reliever therapy [SMART] strategy, which uses low-dose maintenance therapy and as-needed additional dose as reliever therapy.” [https://ginasthma.org/gina-reports/]
“The GINA 2020 report recommends as-needed low-dose combination of inhaled corticosteroid [ICS] with the long-acting β-agonist [LABA] formoterol as the preferred Step 1 controller and reliever therapy in patients with mild asthma,” said Ko.
“However, several systematic reviews and clinical studies have demonstrated only marginal benefits associated with the SMART strategy with budesonide plus formoterol vs maintenance ICS, showing similar or improved effects on reducing exacerbations but worse lung function and worse asthma control associated with the SMART strategy,” said Cooper. [Cochrane Database Syst Rev 2013;(4):CD007313; Cochrane Database Syst Rev 2013;(12):CD009019; N Engl J Med 2018;378:1865-1876]
The phase III SYGMA-1 study (n=3,849) compared the efficacy and safety of as-needed budesonide-formoterol combination therapy vs as-needed short-acting β-agonists (SABA) alone (terbutaline) vs twice-daily ICS (budesonide) plus as-needed SABA (terbutaline) in patients with mild asthma over the course of 52 weeks. Results showed that in terms of asthma symptom control, as-needed budesonide/formoterol was superior to as-needed terbutaline (odds ratio [OR], 1.14; 95 percent confidence interval [CI], 1.00 to 1.30; p=0.046], but inferior to budesonide maintenance therapy (OR, 0.64; 95 percent CI, 0.57 to 0.73). Exacerbation rates were similar between the two budesonide-containing regimens and lower with terbutaline (annual rate of severe exacerbations, 0.20 with terbutaline, 0.07 with budesonide/formoterol, 0.09 with budesonide maintenance therapy) (rate ratio [RR] for budesonide/formoterol vs terbutaline, 0.36; 95 percent CI, 0.27 to 0.49) (RR for budesonide/formoterol vs budesonide maintenance therapy, 0.83; 95 percent CI, 0.59 to 1.16). [N Engl J Med 2018;378:1865-1876]
Meanwhile, patients in the budesonide/formoterol group had worse lung function vs those in the budesonide maintenance therapy group, with mean change from baseline in forced expiratory volume in 1 second (FEV1) of 65.0 mL vs 119.3 mL. [N Engl J Med 2018;378:1865-1876]
“These results reiterate that although SMART and maintenance ICS may have similar effects on exacerbations, a SMART strategy is associated with worse lung function and worse asthma control,” said Cooper.
FF/VI vs FF/SAL in moderate asthma
Fluticasone proprionate (FP) plus salmeterol (SAL) is a commonly used ICS/LABA combination for patients with moderate asthma. The newer LABA, vilanterol (VI), has emerged as an effective agent when combined with the ICS, fluticasone furoate (FF), in reducing the risk of severe asthma exacerbations. [Thorax 2014;69:312-319; J Asthma 2019;56:748-757]
The prospective, open-label, randomized Asthma Salford Lung Study previously demonstrated the effectiveness of once-daily ICS/LABA combination of FF/VI vs continuing usual care (ie, ICS ± LABA) in patients with symptomatic asthma in the primary care setting in UK. [Lancet 2017;390:2247-2255] A secondary analysis of this study involved patients who were on baseline maintenance therapy with the commonly used ICA/LABA, fluticasone propionate/salmeterol (FP/SAL) and evaluated the relative effectiveness of initiating once-daily FF/VI (100 or 200/25 µg) vs continuing FP/SAL. [J Asthma 2019;56:748-757]
At week 24, the odds of patients being Asthma Control Test (ACT) responders (ie, total score ≥20 and/or improvement from baseline ≥3) were significantly higher with FF/VI vs FP/SAL (71 percent vs 56 percent; OR, 2.03; 95 percent CI, 1.53 to 2.68; p<0.001). Consistent findings were observed at week 24 in the total population (73 percent vs 59 percent; OR, 1.94; 95 percent CI, 1.51 to 2.50, p<0.001) and across all timepoints in the total population. (Figure 1) [J Asthma 2019;56:748-757]
“FF/VI was also associated with a significant 20 percent reduction in the mean annual rate of severe exacerbations vs FP/SAL [0.47 vs 0.59; RR, 0.80; 95 percent CI, 0.66 to 0.95; p=0.014],” added Cooper. (Figure 2) [J Asthma 2019;56:748-757]
Compared with FF/SAL, FF/VI was also associated with improved quality of life and reduced activity impairment due to asthma. No significant differences in serious adverse events were found between the two groups, indicating that FF/VI is a safe and effective alternative to FF/SAL.
Anti–IL-5s in severe eosinophilic asthma
“Guidelines of the European Respiratory Society [ERS] and American Thoracic Society [ATS] recognize that severe asthma is a heterogeneous condition and includes the eosinophilic phenotype,” said Cooper. [Eur Respir J 2014;43:343-373; Nat Med 2012;18:716-725]
“Eosinophilia, which is a marker of disease activity, is a characteristic of patients with asthma type 2 inflammation phenotype, and is found in approximately 50 percent of patients with severe asthma,” added Ko. “This phenotype is also characterized by the presence of cytokines such as interleukin [IL]-4, IL-5 and IL-13.”
Given the central role of IL-5 in the eosinophil lifecycle, the GINA 2020 report recommends initiating add-on anti–IL-5 agents in patients with severe eosinophilic asthma (SEA). [https://ginasthma.org/gina-reports/]
Mepolizumab vs other anti–IL-5 agents
“Anti–IL-5 agents deplete eosinophils at varying degrees, depending on whether they target homeostatic or inflammatory eosinophil populations in the bone marrow and blood,” said Cooper. [https://ginasthma.org/gina-reports/]
Among the approved anti–IL-5 agents, mepolizumab has emerged as a valid option for patients with severe uncontrolled asthma in view of its favourable safety and efficacy profile. Mepolizumab does not fully deplete blood eosinophil counts, which may be an important consideration due to the unknown consequences associated with eosinophil depletion. [J Allergy Clin Immunol 2019;143:1742-1751.e7; Drug Saf 2020;43:409-425; Pulm Ther 2020;6:47-66]
An indirect treatment comparison investigated the efficacy of approved doses of anti–IL-5 treatments in patients with SEA, with respect to their baseline blood eosinophil counts. Results showed that mepolizumab significantly reduced the rate of clinically significant exacerbations vs benralizumab (RR, 0.55; 95 percent CI, 0.35 to 0.87; p=0.011) in those with baseline blood eosinophil counts ≥400 cells/mL. Similar results were noted in patients with lower baseline eosinophil counts. [J Allergy Clin Immunol 2019;143:190-200.e20]
Long-term safety and efficacy of mepolizumab
The long-term safety and efficacy of mepolizumab in patients with SEA were demonstrated in COLUMBA, an open-label extension study of patients with SEA who previously participated in the DREAM study. For the 286 patients who participated in the study for ≥156 weeks, the exacerbation rate was 0.74 events/year (weeks 0–156), which represented a 56 percent reduction from the off-treatment period between DREAM and COLUMBA. [Allergy Clin Immunol 2019;143:1742-1751.e7]
Similar benefits were demonstrated in COSMEX, a multicentre, open-label, phase IIIb extension study involving patients from three previous phase III studies of mepolizumab. After a median treatment duration of 2.2 years, patients receiving mepolizumab had an on-treatment exacerbation rate of 0.93 event/year for clinically significant exacerbations, 0.13 event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 event/year for exacerbations requiring hospitalization. [Clin Ther 2019;41:2041-2056.e5]
These results indicate that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with SEA.
While SMART and maintenance ICS strategies may have similar effects on exacerbations, the former strategy is associated with worse lung function and worse asthma control. In patients with moderate asthma, FF/VI offers a well-tolerated and effective alternative to the commonly used FP/SAL, and is associated with improved asthma control and quality of life as well as reduced asthma exacerbations. In patients with severe asthma, phenotyping may be needed to identify those with SEA and determine whether an anti–IL-5 therapy is an appropriate option.