To the Editor:
Patients with severe eosinophilic asthma have a high risk of exacerbations requiring rescue oral corticosteroid treatment. Monoclonal antibody treatments inhibiting IL-5 directly or via IL-5Rα or IL-13/IL-4 via IL-4Rα reduce exacerbations of severe, eosinophilic asthma with evidence of type 2 inflammation, as shown by a raised peripheral blood eosinophil (PBE) count or fractional exhaled nitric oxide (FeNO) (1, 2). Both these biomarkers have been associated with an increased risk for exacerbations (3).
The key cytokine for the development of eosinophils is IL-5, whereas FeNO is regulated by the IL-13–dependent inducible nitric oxide pathway (4), suggesting that their combination might provide additive prognostic and predictive information. We tested this hypothesis in a post hoc analysis of a placebo-controlled trial of anti–IL-5 (mepolizumab) in patients with severe asthma.
We undertook a post hoc analysis of a phase 2b study of mepolizumab in patients with severe eosinophilic asthma (DREAM [Mepolizumab for Severe Eosinophilic Asthma: A Multicentre, Double-Blind, Placebo-controlled Trial]) (1). We selected this study as it was the only mepolizumab study to assess FeNO and blood eosinophils at baseline.
DREAM evaluated placebo and three doses of mepolizumab (75, 250, and 750 mg i.v. once every 4 wk) for 52 weeks. Participants had a history of two or more exacerbations requiring oral corticosteroids in the previous year, and evidence of eosinophilic inflammation as reflected by one of more of the following: a PBE count ≥300 cells/μl, a sputum eosinophil count ≥3%, FeNO ≥ 50 ppb, and prompt deterioration of asthma control after a 25% or less reduction in regular maintenance inhaled or oral corticosteroids. As the DREAM study did not show a dose-related effect of active treatment or evidence of an interaction between dose and predictive value of biomarkers, our analysis is based on the combined effect of the different doses.
Participants were divided into subgroups depending on their baseline PBE count and FeNO. PBEs were defined as high (≥150 cells/μl) or low (<150 cells/μl), and FeNO as high (≥25 ppb) or low (<25 ppb). We chose these cut points because of preexisting evidence linking them to eosinophilic airway inflammation and response to corticosteroids (5). Baseline demographics, clinical characteristics, and annualized exacerbation rates were calculated on the basis of four biomarker subgroups: PBE high–FeNO high, PBE high–FeNO low, PBE low–FeNO high, and PBE low–FeNO low. An additional analysis was performed using a PBE cut point of 300 cells/μl.
The DREAM study was a multicenter, randomized, double-blind, placebo-controlled trial. Our primary interest was severe exacerbation rate, defined as the requirement for rescue oral corticosteroids, as the main benefit of mepolizumab treatment is to reduce the rate of exacerbations, and exacerbation rate was the primary outcome measure of the trial. We also present the change in prebronchodilator FEV1 after 52 weeks of treatment.
A total of 606 DREAM participants had baseline blood eosinophil and FeNO measurements. The study population had a mean of 3.6 exacerbations per patient per year in the year before study enrollment. Lung function was reduced, with a mean FEV1 of 60% predicted, and there was a high symptom burden with a mean asthma control questionnaire 6 score of 2.3 (with <1.5 indicating good control). The baseline demographics and clinical characteristics of the study patients across biomarker subgroups and treatment are shown in Table 1.
|PBE < 150 cells/μl, Feno < 25 ppb||PBE < 150 cells/μl, Feno ≥ 25 ppb||PBE ≥ 150 cells/μl, Feno < 25 ppb||PBE ≥ 150 cells/μl, Feno ≥ 25 ppb||Total|
|Placebo (n = 18)||Mepolizumab (n = 57)||Placebo (n = 14)||Mepolizumab (n = 57)||Placebo (n = 35)||Mepolizumab (n = 127)||Placebo (n = 84)||Mepolizumab (n = 214)||Placebo (n = 151)||Mepolizumab (n = 455)|
|Age, mean (SD), yr||44.3 (12.07)||52.7 (11.79)||45.5 (10.55)||50.6 (8.27)||45.9 (11.05)||48.0 (10.99)||46.9 (11.54)||49.2 (11.49)||46.2 (11.33)||49.5 (11.10)|
|Sex, F, n (%)||11 (61)||38 (67)||7 (50)||34 (60)||29 (83)||83 (65)||49 (58)||132 (62)||96 (64)||287 (63)|
|ICS dose, mean (SD), μg/d*||1,053 (356)||1,108 (434)||1,033 (115)||1,077 (567)||1,175 (464)||1,150 (523)||1,169 (608)||1,094 (447)||1,145 (523)||1,109 (483)|
|Maintenance OCS use, n (%)||2 (11)||18 (32)||5 (36)||22 (39)||8 (23)||25 (20)||27 (32)||75 (35)||42 (28)||140 (31)|
|Prebronchodilator FEV1, mean (SD), ml||2,253 (812.2)||1,747 (631.1)||2,105 (811.7)||1,888 (647.0)||1,611 (506.3)||1,845 (636.2)||1,919 (605.8)||1,911 (678.8)||1,905 (656.9)||1,869 (657.4)|
|Prebronchodilator %predicted FEV1, mean (SD)||66.3 (17.05)||59.2 (14.99)||58.2 (12.90)||60.6 (15.22)||53.9 (12.77)||59.3 (16.57)||60.5 (15.54)||60.3 (16.24)||59.4 (15.21)||59.9 (16.01)|
|Post-bronchodilator FEV1, mean (SD), ml||2,688 (821.8)||2,008 (706.1)||2,648 (948.3)||2,178 (725.5)||1,927 (652.8)||2,154 (680.0)||2,311 (725.0)||2,297 (764.4)||2,298 (777.1)||2,206 (733.8)|
|ACQ-6 score, mean (SD)||2.6 (1.20)||2.1 (1.02)||2.5 (0.82)||2.5 (0.98)||2.4 (1.11)||2.1 (1.13)||2.5 (1.08)||2.4 (1.11)||2.5 (1.07)||2.3 (1.10)|
|PBE count, geometric mean (SD logs), cells/μl||80 (0.57)||50 (0.95)||50 (0.89)||80 (0.72)||350 (0.66)||350 (0.54)||450 (0.61)||410 (0.63)||280 (1.01)||240 (1.03)|
|Feno count, geometric mean (SD logs), ppb||14.6 (0.39)||12.3 (0.45)||42.3 (0.49)||54.0 (0.47)||14.4 (0.34)||15.2 (0.42)||55.5 (0.55)||51.2 (0.50)||33.7 (0.79)||30.7 (0.79)|
|Exacerbations in year before study, mean (SD)||2.7 (1.87)||3.3 (2.50)||3.5 (1.99)||3.9 (3.06)||2.9 (1.09)||3.0 (2.03)||4.4 (4.87)||3.8 (3.16)||3.8 (3.83)||3.5 (2.81)|
|Requiring hospitalization, n (%)||4 (22)||20 (35)||3 (21)||17 (30)||7 (20)||28 (22)||25 (30)||44 (21)||39 (26)||109 (24)|
The risk for exacerbations was highest in placebo-treated patients with high baseline PBE count and FeNO. The efficacy of active treatment was most marked in this group, with mepolizumab showing 62% exacerbation rate reduction compared with 36% exacerbation rate reductions in the PBE high–FeNO low group. Mepolizumab did not have a significant effect on exacerbation rate in the PBE low subgroups, regardless of FeNO. Similar findings were seen for change in prebronchodilator FEV1 (Figure 1) and when patients were stratified by a PBE count of 300 cells/μl (Figure 2).
We found that in patients with severe asthma treated with placebo who had high blood eosinophil counts and FeNO, the rate of severe exacerbations requiring oral corticosteroid treatment was up to twice that seen in placebo-treated patients with low or discordant biomarker results. The different biomarker groups had similar baseline lung function, symptom scores, and exacerbation risk, indicating that the increased risk for exacerbation events is independent of these other markers of asthma control and risk, indicating that biomarker profiling of patients with severe asthma adds predictive value to a traditional risk assessment.
To evaluate the relationship between biomarker profile and treatment efficacy, we compared our findings with published results of the phase 3 trial of monoclonal antibody dupilumab (QUEST [A Randomized, Double Blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Persistent Asthma]), a monoclonal antibody that blocks IL-13 and IL-4 by binding to the IL-4 receptor-α (2). This study evaluated two doses of dupilumab (200 or 300 mg subcutaneously once every 2 wk) for 52 weeks in 1,902 patients with moderate-severe persistent, uncontrolled asthma, as per the Global Initiative for Asthma guidelines (6). Both doses had equivalent efficacy, and as combined data are not available, we present data from the 934 patients randomly assigned to dupilumab 200 mg every 2 weeks or matched placebo. Information on change in prebronchodilator FEV1 by biomarker profile was not available for QUEST (Figure 1). The efficacy of dupilumab on exacerbations was most marked in the PBE high–FeNO high group with a 68% reduction. There was also an exacerbation rate reduction of 33% in the PBE high–FeNO low group, which was similar to the effect seen in this subgroup with mepolizumab treatment. In the PBE low–FeNO low group, neither biologic had a significant effect on exacerbations. In the PBE low–FeNO high group, a 39% exacerbation rate reduction was seen with dupilumab. Although not statistically significant, this finding contrasts the absence of effect seen with mepolizumab in this subgroup.
The study populations differed significantly, with the DREAM population having a higher exacerbation risk and a higher proportion of patients using high-dose inhaled or regular oral corticosteroids. However, the higher risk for exacerbation in patients with higher blood eosinophils and FeNO was seen in both populations, suggesting a true effect seen across a range of asthma severity. This is in keeping with earlier studies showing that a composite profile of biomarkers of type 2 airway inflammation provides prognostic information over and above an assessment of risk for exacerbation based on traditional asthma measures, although this earlier study used a composite score of blood eosinophils, serum periostin, and FeNO biomarkers (7). We extend these earlier findings by showing that patients with both high blood eosinophil counts and FeNO also had the greatest response to biological treatment with mepolizumab and dupilumab, indicating that biomarker profiles have predictive as well as prognostic value.
These greater prognostic values of the combined biomarker profile make biological sense, given that the biomarkers relate to different aspects of type 2 immune responses in the airway. The PBE count reflects airway and systemic IL-5 production and is reduced markedly by anti–IL-5 (1) but not dupilumab (2). In contrast, FeNO reflects airway IL-13 activity, as it is reduced markedly by anti–IL-13 and dupilumab (2) but not anti–IL-5 (1). Thus, the two measures provide a more complete assessment of type 2 immune responses in the airway. It is also likely that the combination of a systemic and local airway measure adds precision to an assessment in only one of these compartments. We did not find a point estimate improvement for mepolizumab in patients with high FeNO but low PBE count, as might be expected, as FeNO is a marker of IL-13 activity in the airway. In contrast, there was a trend for benefit of dupilumab in this group.
Caution is required in interpreting this post hoc subgroup analysis, as the number of patients in some subgroups is small and the populations studied in DREAM and QUEST were different. We acknowledge that the relative efficacy of mepolizumab and dupilumab treatment in subgroups may reflect the play of chance or differences in patient populations, as well as the different cytokine associations of the biomarkers. However, it is striking that the relative exacerbation rate reductions in three of the four subgroups were very similar. Our findings suggest that biomarker profiles might have value in identifying patients suitable for different biological agents. Formal head-to-head studies in similar patient populations are needed to assess this possibility prospectively. Future studies should also model the relationship between biomarker values and exacerbations more completely, allowing more accurate inferences to be drawn on individual patient responses.
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|6.||Global Initiative for Asthma. Global strategy for asthma management and prevention; 2016 [accessed 2016 May 11]. Available from: www.ginasthma.org.|
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