It is estimated that asthma affects approximately 4.9% of adults1. In Spain, the prevalence of patients with uncontrolled or refractory severe asthma to corticosteroids and β2 long acting beta agonist (LABA) treatment is approximately 3.9% of asthmatics2. Within this group, about 25% have eosinophilic asthma, characterized by a late onset, presence of eosinophils in bronchial biopsies and is usually associated with nasal polyps, rhinosinusitis and respiratory infections3,4.

Omalizumab is a monoclonal antibody indicated in uncontrolled severe allergic asthma authorized in Spain in 20065. The dosage of omalizumab is variable, ranging from a minimum of 75 mg every 4 weeks up to 600 mg every 2 weeks5. In 2015, mepolizumab is marketed. This monoclonal antibody is indicated as an additional treatment for adult patients with severe refractory eosinophilic asthma6. Mepolizumab acts by binding to interleukin 5 and preventing its interaction with the surface of eosinophils. This causes a reduction in their production and survival. The recommended dose is 100 mg every 4 weeks. Studies evaluating the dose of mepolizumab and eosinophilic response show a similar pharmacodynamics between 100 mg and 75 mg7.

In the pivotal clinical trials for authorizing mepolizumab, the effect as a main variable on the frequency of exacerbations that are clinically relevant was measured8,9. A clinically relevant exacerbation is an acute asthma attack requiring the use of systemic corticosteroids for at least three days and/or hospitalization and/or emergency room visits, or doubling the dose of systemic corticosteroids for at least three days in patients treated with oral corticosteroids as maintenance therapy8,9. Mepolizumab has proven to be effective in reducing exacerbations and daily doses of oral systemic corticosteroids (OCS) in patients with severe eosinophilic asthma not adequately controlled with high doses of inhaled systemic corticosteroids (ICS) + LABA and/or OCS (usual treatment).

However, a higher frequency of asthma attacks is associated with a high eosinophils count (> 300-400 cells/μL)10,11. In the subgroup analysis of the pivotal clinical trials, it is also observed that the relative benefit is greater in patients with higher blood levels of eosinophils8,9. Subgroup analysis is pre-specified and shows statistical interaction. The difference is consistent in studies7,12 and there is biological plausibility, as an inhibitor for eosinophils could exert a greater action, the bigger the contribution of eosinophilia is to the asthmatic process.

It should be noted that approximately 30% of diagnosed eosinophilic asthmatic patients show signs and symptoms that are consistent with the IgE-mediated persistent allergic asthma phenotype13, meeting omalizumab's treatment criteria. However, no evidence exists to opt for either therapy in this subpopulation12.

Given the differences in subgroups according to eosinophils count in severe refractory eosinophilic asthma, the existence of candidates for omalizumab patients or mepolizumab, and the economic impact resulting from the use of mepolizumab, it seems crucial to conduct a study of economic evaluation and budgetary impact that helps making efficient clinical decisions. At the time of this work, other similar action mechanism drugs to mepolizumab –reslizumab and benralizumab– were pending funding and price in Spain14,15. These drugs were not compared to mepolizumab, and it is difficult to differentiate between them. The economic comparison of these therapies in the same group is not the subject of this study.

The aim of this work is to perform a cost-efficacy and budgetary impact analysis (BIA) of mepolizumab's as treatment for severe refractory eosinophilic asthma, mediated and non mediated by elevated IgE levels in adult patients who are not adequately controlled with high dose of ICS + LABA and/or OCS in Spain.

The cost-efficacy analysis and the BIA were developed from the perspective of the Spanish National Health System (NHS). Only direct costs were quantified in euros in 2018. The BIA was carried out for a period of three years (2018-2020). Analyses were performed taking into account the latest economic assessment and BIA guidelines16,17.

The estimated study population is shown in table 1.

The emergence of high economic impact drugs makes economic studies necessary in order to favor the optimization of resources21. This economic evaluation compares two therapeutic alternatives in a group of patients diagnosed with eosinophilic asthma, showing signs that are consistent with the IgE-mediated persistent allergic asthma phenotype. The economic analysis design can help in clinical decision making to improve efficiency through price competition.

The health outcome was assessed by the number of avoided clinically relevant exacerbations with the use of mepolizumab. The selected variable is adequate to guide decision-making, as other studies assessed the decrease in hospital admissions, emergency room visits or primary care physicians22–24. On the other hand, the comparisons made regarding treatment alternatives (omalizumab and high dose of ICS + LABA and/or OCS) improve the validity of the study.

This study has limitations, such as the lack of effective comparative evidence and quality between mepolizumab and omalizumab in IgE-mediated eosinophilic asthma patients who are candidate population for both therapies, and specific intersection of the two sets, which lack empirical data. There have been two studies25,26 –one funded by GlaxoSmithKline laboratories– that performed an indirect comparison of mepolizumab against omalizumab in patients diagnosed with eosinophilic asthma and who show signs and symptoms that are consistent with the persistent allergic asthma phenotype. Although both describe no difference in efficacy between mepolizumab and omalizumab, they highlight the impossibility of making preferential use recommendations of one drug over another, due to its high heterogeneity between trials and different selection criteria for the use of both drugs. An indirect comparison analysis cannot be reliable, as mepolizumab was studied in eosinophilic component-mediated asthma, regardless of the IgE values, while omalizumab was studied in IgE-mediated asthma regardless of the eosinophilic component, and is used in patients with elevated IgE nonresponders to other treatments. These limitations were highlighted in reports evaluating mepolizumab in countries such as Canada27 and the United Kingdom28. Therefore, there has not been a cost minimization, but instead, it would be reasonable to select drugs by comparing costs, except for certain patients who, for any valid clinical reason, prefer one or avoid another.

Upon completion of the study, two other drugs with a similar mechanism of action to mepolizumab's were approved, although they were not yet sold in Spain, therefore, they were not the subject of this study14,15. Once marketed, and considering that they have not been compared to mepolizumab, an assessment on whether the possible indirect comparisons detect clinically relevant differences should be performed, taking into account the level of eosinophils in plasma. Its introduction in therapy could allow competition and reduce the budgetary impact of these agents. Its non inclusion in this study is a limitation that should be addressed in subsequent studies, which should be focused on these similar treatments’ potential competition once the first one –mepolizumab– is already marketed. Further comparison of these drugs in the same group would be appropriate, but also complex, because they have not been directly compared. These studies have different inclusion criteria and different subgroups definition, according to eosinophil count in blood.

Previous studies show that patients with elevated plasma eosinophil count benefit more patients, as opposed to low level patients8,9. It was observed in this economic analysis that patients with ≥ 500 eosinophils/µL showed a more favorable incremental cost-efficacy compared to those with lower counts. It should be stressed that subgroup analysis on pivotal trials meets the pre-specification, interaction, consistency in different studies7,12 and biological plausibility criteria. The published economic evaluation studies on mepolizumab with refractory eosinophilic asthma population, regardless of subgroup analysis, concluded that mepolizumab is not cost-effective, urging price discounts around 60-70% to become funding-recommended by the healthcare systems29,30. Bermejo I et al.28 described the assessment process on mepolizumab by the National Institute for Health and Care Excellence (NICE). In its economic assessment study, the target population was defined in terms of severity of asthma and ≥ 300 eosinophils/µL levels. They have shown to not be cost-effective for this subgroup of patients, and its use was recommended only when the laboratory provides an agreed and confidential price discount, so that it becomes cost-effective for said subgroup of patients.

To conclude, comparative clinical evidence is lacking quality between mepolizumab and omalizumab in eosinophilic component-mediated asthma and lgE mediated patients. Nor are there other economic evaluation studies comparing these two drugs. For this reason, a cost comparison in these patients was performed. From Spanish NHS perspective, and considering the high economic impact of mepolizumab, it would be reasonableto use the lower-cost drug and promote price competition. This strategy does not exclude the exceptional justified preference of a particular therapy by a patient. After this pharmacoeconomic analysis, prioritizing the use of mepolizumab in patients diagnosed with non lgE-mediated severe refractory eosinophilic asthma with high plasma levels of eosinophils (≥ 500 cells/µL), as indicated in Therapeutic Positioning Report on mepolizumab by the Spanish Agency of Medicines, would significantly improve the efficiency and reduce its budgetary impact12.

No funding.

Preliminary data as part of the work in the form of communication were presented under the name of: “Application of pharmacoeconomic evaluation by subgroups to severe refractory eosinophilic asthma”. 15th Andalusian Society of Hospital Pharmacy Congress, Almería, April 11-13, 2018.

No conflict of interest.

Study's contribution to existing knowledge: First published national data on mepolizumab's efficiency and budgetary impact for asthma patients.

Implications of the findings for practice, research, healthcare policies or general hospital pharmacy: Optimization of the use in the practice of mepolizumab by comparing costs and subgroup analysis.