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What considerations are needed to choose an anti-IL-5 treatment in severe asthma?

Published online: September 8, 2018

Severe eosinophilic asthma is characterized by persistent symptoms, decreased lung function, an increased risk for asthma exacerbations and a lack of asthma control on guideline directed medications. The associated morbidity of this phenotype of asthma, its higher health care costs, and high probability to develop significant side-effects from the frequent use of systemic corticosteroids makes this population of patients a major unmet need in asthma care. Biomarkers provide insight into underlying inflammation and disease severity and are noted by a persistent presence of blood eosinophils, which likely reflects a Type-2 pattern of inflammation. Although a number of immune pathways may contribute to the presence of eosinophils, interleukin (IL)-5 is a major factor in their production, survival and inflammatory biology. Consequently, peripheral blood eosinophils may serve as a potential guide for selecting treatment with anti-IL-5 medications.

Currently there are three FDA-approved monoclonal antibodies directed against IL-5, or its receptor: mepolizumab, reslizumab and benralizumab. All three have been shown to be effective in reducing asthma exacerbations as well as improving lung functions and achieving symptom control. Because the criteria for selecting anti-IL-5 pathway treatment are not agent specific, at present, the clinician is faced with a difficult decision – which of these three agents will be most effective for my patient? Although an obvious answer to this clinical dilemma could be solved by direct comparative studies between the various anti-IL-5 pathway treatments, such a comparative effectiveness trial is unlikely to happen, or happen soon.

To address this key clinical question, Busse et al in an original research paper recently published in The Journal of Allergy and Clinical Immunology (JACI) used statistical methodologies of an indirect treatment comparison (ITC) and a Cochrane analysis to assess the comparative efficacy of the three individual anti-IL-5 pathway-directed biologics in severe asthma. In formulating these analyses, the investigators took care to assure that similarities of their comparisons in the various treatment groups were available and considered in the assessments; for example, frequency of exacerbations, level of symptom scores, and lung functions, and that these outcomes were compared at different thresholds of blood eosinophils:  ≥150 cells/µL, ≥300 cells/µL, and 400-450 cells/µL.

For inclusion on this Network Meta-Analysis (NMA), it was necessary for the evaluated studies to meet pre-defined criteria, or PICOS – Population, Intervention, Comparator, Outcomes, and Study Design. The study population included only subjects ≥12 years of age and only those studies that used the approved doses were included in the comparative analysis. The comparators also included a placebo. A comparison of the three anti-IL-5 pathway interventions was made on  relevant clinical outcomes that included significant exacerbations (requiring systemic corticosteroids) or, separately, exacerbations requiring an ER visit or hospitalization; any version of ACQ (Asthma Control Questionnaire); and change from baseline pre-bronchodilator FEV1. Finally, all studies used in these analyses were part of a randomized, double-blind, placebo-controlled trial design.

By unadjusted analyses, compared with placebo, all anti-IL-5 pathway treatments significantly reduced the rates of significant exacerbations in each of the baseline blood eosinophil threshold subgroups. When the comparisons on the reductions of exacerbations were made at the selected eosinophil counts, mepolizumab was found to significantly reduce exacerbations compared to benralizumab and reslizumab at eosinophils ≥400 cells/µL. Similarly, a comparison at ≥150 cells/µL and ≥300 cells/µL also found the reduction of exacerbations by mepolizumab to be significant from benralizumab. A similar pattern of significant improved patient-reported asthma outcomes was found with mepolizumab at all eosinophil cut-points, ≥400, ≥300, and ≥150 cells/µL.

Mepolizumab, benralizumab, and reslizumab all significantly improved the pre-bronchodilator FEV1 values. Among participants with eosinophils ≥400 cells/µL, benralizumab ranked highest for improvements in pre-bronchodilator FEV1 followed by mepolizumab and reslizumab. In contrast, mepolizumab ranked higher than benralizumab at ≥300 and ≥150 cells/µL for improved FEV1.

These observations indicate that an assessment of efficacy with the three anti-IL-5 pathways intervention needs to consider a number of factors, including blood eosinophil concentrations and reductions in exacerbations or improved lung function. There are obvious limitations to such analyses that need to be considered when comparisons are not head-to-head. For example, blood eosinophils are variable and not a fixed value in individual patients. Also, it is not known whether the eosinophil-lowering effects will be reflected to a similar degree in a more heterogeneous asthma population as is found in clinical practice, whether there is an equivalent reduction in airway vs. peripheral circulation eosinophils, or whether the reductions in eosinophils translate to improved clinical outcomes. Attempts to prioritize treatments are important but, not surprisingly, are as complex as is asthma. The comparative approaches used by Busse et al, such as ITC, are an initial step, and method, to provide helpful information and guidance on the relative efficacy of the individual anti-IL-5 antibodies to practicing clinicians. What is needed next, however, is greater insight into how one can predict which antibody will work in which patient with the ultimate goal of identifying information that will make possible “to give the right drug, to the right person and at the right time.”

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

Anti-IL5 treatments in severe asthma by blood eosinophil thresholds: indirect treatment comparison