Efficacy and safety of mepolizumab in severe eosinophilic asthma: a systematic review and meta-analysis

Introduction

Asthma is a common chronic inflammatory respiratory disease, affecting over 300 million individuals globally and imposing a significant disease burden (1-3). Eosinophilic asthma, characterized by T helper 2 (Th2)-type inflammation, represents the most prevalent phenotype and accounts for 50–60% of all asthma patients (4); studies have confirmed that eosinophils and Th2 cytokines are involved in the inflammatory processes within the airways of this phenotype (4). Within this phenotype, the key Th2 cell cytokine interleukin-5 (IL-5) governs the maturation, differentiation, recruitment, activation, and survival of eosinophils (5). Research has confirmed elevated IL-5 levels in the airways of asthma patients, which correlate closely with disease severity (6-8), thereby establishing IL-5 as a critical therapeutic target for this subtype.

Despite Global Initiative for Asthma (GINA) guideline recommendations for high-dose inhaled corticosteroids (ICS) combined with long-acting β2-agonists (LABA), at least 40% of asthma patients experience suboptimal symptom control, of whom approximately 5–10% have severe asthma (9-11). For severe patients with persistent blood eosinophilia, existing treatment regimens often face challenges of insufficient efficacy or potential long-term adverse effects. Addressing this significant unmet need, the humanized anti-interleukin-5 (anti-IL-5) monoclonal antibody mepolizumab emerged. It specifically blocks the IL-5 signaling pathway, precisely inhibiting eosinophil-mediated airway inflammation. Pivotal randomized controlled trials (RCTs) have demonstrated that in this specific severe population, mepolizumab significantly reduces the frequency of asthma exacerbations, decreases maintenance doses of oral corticosteroids (OCS), and improves patient-reported symptom scores compared to placebo (12-17), laying a critical foundation for its clinical application. Recent studies further confirmed these benefits, with Lugogo et al. demonstrating sustained efficacy in long-term open-label extension studies (18), while Magnan and Shimoda established consistent treatment responses across different ethnic populations (19,20). Subsequent trials by Chupp and Khatri provided robust evidence for quality of life improvements and long-term safety profiles (21,22).

Eosinophilic asthma, characterized by persistent airway eosinophilia, represents a major therapeutic challenge. Mepolizumab, an anti-IL-5 monoclonal antibody, has demonstrated significant clinical efficacy: the Dose Ranging Efficacy And safety with Mepolizumab (DREAM) trial reported a 52% reduction in exacerbation rates (P<0.001) (13), while histopathological studies confirmed 83% bronchial eosinophil depletion (P<0.01) (14). Sputum eosinophil monitoring has been validated as a reliable biomarker, showing 87% reduction (P<0.001) (15) and correlating with 87% lower exacerbation risk (P=0.002) (17). Mechanistic studies reveal tissue-specific effects, including complete blood eosinophil clearance without airway reactivity impairment (23), contrasted with only partial depletion in mucosal (60%) (24) and bronchoalveolar lavage (BAL) (55%) samples (25). However, prior studies have exhibited inconsistencies due to small sample sizes, and early meta-analyses, limited by underpowered RCTs (some with n≤20), failed to confirm significant lung function benefits (26). To address these limitations, this updated systematic review and meta-analysis will rigorously assess mepolizumab’s effects on exacerbations, lung function, quality of life, and safety using large-scale RCTs, providing robust evidence for clinical practice. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1596/rc).

Methods

Data sources and searches

A systematic literature search was conducted across three major databases (PubMed, Embase, and the Cochrane Library) to identify potentially relevant studies published from inception to May 2025. The search employed key terms including asthma, eosinophilic, mepolizumab, IL-5, and anti-IL-5. The search was restricted to human studies without language restrictions. Additionally, reference lists of identified clinical trials and relevant reviews were manually searched to supplement electronic retrieval. Only completed, peer-reviewed RCTs evaluating the efficacy or safety of mepolizumab in asthma populations were considered eligible.

Inclusion and exclusion criteria

Inclusion criteria encompassed randomized double-blind placebo-controlled trials evaluating subcutaneous (SC) or intravenous (IV) mepolizumab (any dose) in adults/adolescents (≥12 years) with severe eosinophilic asthma, defined by baseline peripheral blood eosinophil counts ≥150 cells/µL, reporting ≥1 primary outcome: lung function [forced expiratory volume in 1 second (FEV1)], acute exacerbation incidence (defined as events requiring systemic corticosteroids, asthma-related hospitalization, or emergency department visit), asthma control [Asthma Control Questionnaire-5 (ACQ-5)], or adverse events (AEs)/serious adverse events (SAEs). Exclusion criteria eliminated non-RCTs, observational studies, reviews, trials with <50 participants, non-placebo controls, non-standard mepolizumab dosing, methodologically low-quality studies, or incomplete outcome data. Two authors independently conducted screening, with disagreements resolved by consensus or third-author adjudication.

Data extraction and quality assessment

Two investigators independently extracted data, with discrepancies resolved through consensus or third-party adjudication. Extracted information covered study characteristics (authors, year, design, country, sample size, follow-up duration, patient demographics including age and sex), intervention specifications (mepolizumab dosage: 75–750 mg; administration route: SC or IV) and core outcomes (FEV1, acute exacerbation rate, ACQ-5 score, AEs, and SAEs). Baseline maintenance therapies (ICS/LABA doses, OCS use) were documented where reported in original RCTs, though inconsistent reporting precluded pooled stratification. Study quality was systematically evaluated using the Cochrane Risk of Bias tool across key domains: randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting.

Statistical analyses

Statistical analyses were performed using RevMan 5.4 and Stata 16.0 software. For continuous variables (FEV1, ACQ-5), the weighted mean difference (WMD) was adopted as the effect measure. For dichotomous variables (acute exacerbation rate, AEs), relative risk (RR) was calculated. Both are reported with 95% confidence intervals (CIs). Heterogeneity was assessed using Cochran’s Q test and the I² statistic (a random-effects model was employed when I²>40%). Prespecified subgroup analyses examined the impact of baseline eosinophil counts (≤300 vs. >300 cells/µL) and dose subgroups (low-dose 75–100 mg vs. high-dose 250–750 mg) on treatment efficacy. Sensitivity analyses validating result robustness were conducted by excluding individual studies one by one. Publication bias was evaluated using Begg’s funnel plots and rank correlation tests.

Results

Search results

A comprehensive search across PubMed (n=147), Embase (n=244), and the Cochrane Library (n=328) identified 719 records. After excluding 143 duplicates and 163 irrelevant/incomplete records, 413 studies underwent title/abstract screening. Of these, 391 non-relevant records were excluded, leaving 22 full-text reports for eligibility assessment. Two non-RCTs, four studies lacking outcomes of interest, three with low methodological quality, and three with inadequate sample size were excluded, resulting in 10 high-quality RCTs that informed this systematic review (Figure 1). These studies provided a rigorous evidence base for subsequent analyses.

Figure 1 PRISMA flowchart of the meta-analysis. RCTs, randomized controlled trials.

Characteristics of studies

This systematic analysis evaluated nine multicenter and one single-center, randomized, double-blind, parallel-group trials involving 4,471 participants from seven countries (Australia, UK, USA, France, Japan). Follow-up durations ranged from 20–60 weeks (primarily 32–52 weeks), with cohort sizes of 61–651 participants and mean ages of 36–52 years. Interventions compared subcutaneous/intravenous mepolizumab (75–750 mg) versus placebo. All trials required stable high-dose ICS + LABA therapy per GINA criteria (Table 1). Concomitant therapies were balanced between arms, but heterogeneous reporting formats precluded regimen-specific analyses. Trial populations included eight studies on severe eosinophilic asthma, one on refractory eosinophilic asthma, and one on moderate persistent asthma with ICS use. Primary outcomes comprised FEV1, asthma exacerbation rates, AEs, SAEs, and ACQ-5 scores (Table 1).

Primary outcomes

FEV1

This meta-analysis revealed that mepolizumab treatment significantly improved the primary endpoint of FEV1 compared to placebo (MD =0.06 L, 95% CI: 0.02–0.10, P=0.008; Figures 2,3), although substantial heterogeneity was observed. Notably, after excluding the Lugogo_100 2016 study, heterogeneity was significantly reduced, while the pooled effect remained unchanged, further supporting the therapeutic efficacy of mepolizumab. Subgroup analyses demonstrated greater benefits in patients with baseline blood eosinophil counts ≤300 cells/µL (MD =0.07 L, 95% CI: 0.02–0.12, P=0.01). Additionally, low-dose regimens (75/100 mg) showed superior efficacy in improving FEV1 compared to high-dose regimens (250/750 mg) (MD =0.08 L, 95% CI: 0.02–0.13, P=0.01). However, the limited data on high-dose groups necessitate cautious interpretation of optimal dosing strategies. These findings emphasize the clinical importance of patient stratification and dose optimization in enhancing therapeutic outcomes with mepolizumab for respiratory diseases.

Figure 2 The effect of mepolizumab versus placebo on FEV1 by different baseline blood eosinophil counts. CI, confidence interval; FEV1, forced expiratory volume in 1 second; SD, standard deviation.

Figure 3 The effect of different doses of mepolizumab versus placebo on FEV1. CI, confidence interval; FEV1, forced expiratory volume in 1 second; SD, standard deviation.

Asthma exacerbations

The meta-analysis demonstrated that mepolizumab significantly reduced asthma exacerbation rates in patients with eosinophilic asthma compared to placebo (RR =0.58, 95% CI: 0.51–0.67; P<0.001), equating to a 42% risk reduction. Subgroup analyses revealed consistent efficacy across baseline eosinophil thresholds (<300 cells/µL: RR =0.58, 95% CI: 0.51–0.67; ≥300 cells/µL: RR=0.61, 95% CI: 0.40–0.93) and dose regimens (low-dose: RR=0.57, 95% CI: 0.49–0.68; high-dose: RR =0.61, 95% CI: 0.48–0.78; P=0.70 for subgroup differences). Moderate heterogeneity was observed among studies (I²=42–78%), but the overall treatment effect remained statistically significant (Figures 4,5).

Figure 4 The effect of mepolizumab versus placebo on exacerbations by different baseline blood eosinophil counts. CI, confidence interval;

Figure 5 The effect of different doses of mepolizumab versus placebo on exacerbations. CI, confidence interval.

ACQ-5

Ten studies evaluated asthma control using the ACQ-5, a validated tool wherein higher scores (0–6) reflect poorer symptom control and correlate with increased exacerbation risk (Figures 6,7). The meta-analysis demonstrated a statistically significant reduction in asthma exacerbations with mepolizumab versus placebo (MD =−0.29, 95% CI: −0.40, −0.17; P<0.001), indicating improved asthma control. Subgroup analyses stratified by baseline eosinophil counts revealed greater efficacy in patients with counts <300 cells/µL (MD =−0.32, 95% CI: −0.44, −0.20; P<0.001) compared to those with counts ≥300 cells/µL (MD =−0.10, 95% CI: −0.46, 0.26; P=0.59). Similarly, low-dose mepolizumab (75–100 mg) significantly reduced exacerbations (MD =−0.34, 95% CI: −0.48, −0.21; P<0.001), whereas high-dose regimens (250–750 mg) showed no statistically significant effect (MD =−0.15, 95% CI: −0.34, 0.04; P=0.13). Substantial heterogeneity was observed across studies (I²=65%), potentially driven by variability in dosing protocols, baseline eosinophil measurement methods, or patient characteristics. Collectively, these findings support the efficacy of mepolizumab in reducing exacerbations, particularly among patients with lower baseline eosinophil counts, and align with the clinical relevance of ACQ-5 improvements in mitigating asthma morbidity.

Figure 6 The effect of mepolizumab versus placebo on ACQ-5 by different baseline blood eosinophil counts. ACQ-5, Asthma Control Questionnaire-5; CI, confidence interval; SD, standard deviation.

Figure 7 The effect of different doses of mepolizumab versus placebo on ACQ-5. ACQ-5, Asthma Control Questionnaire-5; CI, confidence interval; SD, standard deviation.

Secondary outcomes

AEs

This meta-analysis of 10 RCTs demonstrated comparable safety profiles between mepolizumab and placebo (Figures 8,9). The pooled analysis showed no significant difference in overall AEs (RR =0.96, 95% CI: 0.93–1.00, P=0.03; I²=2%). Subgroup analyses revealed that low-dose mepolizumab (75/100 mg) showed non-significant reduction in AEs (RR =0.97, 95% CI: 0.94–1.00, P=0.07) but significantly lower SAEs (RR =0.61, 95% CI: 0.51–0.73, P<0.0001), while high-dose regimens (250/750 mg) exhibited similar AE patterns (RR =0.90, 95% CI: 0.75–1.08, P=0.26) without significant SAE reduction (RR =0.77, 95% CI: 0.54–1.09, P=0.14). These findings confirm mepolizumab’s safety profile remains comparable to placebo across all tested doses, with particular benefits in SAE reduction observed in low-dose regimens.

Figure 8 The effect of different doses of mepolizumab versus placebo on adverse events. CI, confidence interval.

Figure 9 The effect of different doses of mepolizumab versus placebo on serious adverse events. CI, confidence interval.

Risk of bias

The risk of bias varied across studies, with most demonstrating low risk in key domains (as summarized in Figure 10). However, some studies exhibited unclear or high risk in specific domains, which may affect their findings’ validity. These assessments remain essential for interpreting meta-analysis results, providing critical insights into potential bias impact on the overall evidence.

Figure 10 Risk of bias summary of included studies.

Sensitivity analyses

Sensitivity analyses were performed through sequential exclusion of individual studies to evaluate their influence on pooled outcomes (Figure S1). The primary outcome FEV1 demonstrated stability across all methodological scenarios. Exacerbation risk ratios maintained consistent directional associations, while ACQ-5 score variations remained below clinically significant thresholds. AE and SAE profiles exhibited no statistically significant deviations. These comprehensive sensitivity assessments confirm that no individual study materially altered the pooled results, thereby validating the robustness and reliability of our meta-analysis conclusions regarding asthma control outcomes and safety profiles.

Publication bias

Visual inspection of Begg’s funnel plots for the 10 included studies demonstrated essential symmetry in the assessment of mepolizumab’s efficacy and safety profiles for asthma treatment (Figure S2). Begg’s test revealed no significant publication bias for the outcomes of FEV1%, exacerbation rate, ACQ-5 score, and SAEs (all P>0.05, z<1.96). However, analysis of total AEs indicated statistically significant evidence of publication bias (P=0.006, z=2.75), suggesting this potential bias cannot be definitively excluded for this specific outcome.

Discussion

This meta-analysis, incorporating 10 high-quality, large-sample RCTs (n=4,471), confirms that mepolizumab significantly improves lung function (FEV1), reduces the risk of acute exacerbations, and enhances quality of life (ACQ-5 score significantly decreased) in patients with severe eosinophilic asthma. Furthermore, the drug demonstrated a favorable overall safety profile comparable to placebo. Critically, subgroup analyses revealed dose-response effects and the influence of baseline blood eosinophil levels on treatment efficacy, providing vital evidence for individualized clinical decision-making.

The observed efficacy is underpinned by a solid pathophysiological rationale. Asthma is characterized by significant eosinophilic inflammatory infiltration in the bronchial mucosa (27). Levels of eosinophils in peripheral blood and BAL fluid correlate positively with disease severity (27) and contribute to tissue remodeling processes. As a core cytokine regulating eosinophil bone marrow differentiation and recruitment/activation at inflammatory sites (28), elevated IL-5 levels drive disease progression. The significant reduction in acute exacerbation risk observed with mepolizumab (approximately 40% RR reduction) is of major clinical importance. Given that acute exacerbations are directly linked to increased patient morbidity and mortality (3), and eosinophilia has been established as an independent predictor in multiple studies (29,30), research specifically inhibiting eosinophils further supports their central role in exacerbation pathogenesis (31,32). This provides a mechanistic explanation for mepolizumab effectively reducing exacerbation rates through precise blockade of the IL-5 pathway. Concurrently, the improvement in patient-reported ACQ-5 scores can reasonably be attributed to the overall reduction in symptom burden resulting from fewer exacerbations. The translational value of these clinical benefits has been validated in pivotal trials: Chupp et al.’s 2017 MUSCA study first demonstrated quality-of-life improvement (ACQ-5 reduction ≥0.5 points) (21), Khatri et al.’s 52-week follow-up in 2018 established long-term safety with a 12.3% incidence of SAEs (22), and Lugogo et al.’s 2016 open-label extension showed sustained efficacy up to 3 years (18). Ethnic-specific data from Magnan and Shimoda revealed minimal FEV1 improvement disparities (<5%) between Asian and European populations (19,20), directly informing the 2024 GINA guideline update on dosing recommendations.

Subgroup analyses provided key insights for optimizing mepolizumab treatment strategies. In the patient subgroup with baseline blood eosinophil counts (EOS) ≤300 cells/µL, mepolizumab demonstrated more consistent and significant clinical benefits across lung function (FEV1) improvement, acute exacerbation risk reduction, and quality of life enhancement. This underscores the value of EOS as a predictive biomarker, supporting a precision medicine model for patient selection based on this marker. The low-dose mepolizumab regimen (75–100 mg) demonstrated superior safety and comparable efficacy compared to the high-dose regimen (250–750 mg) across all major trials. Notably, the 75–100 mg dose showed a trend toward improved lung function (FEV1) and quality of life (ACQ-5) while achieving a 61% reduction in SAE risk (HR 0.39, 95% CI: 0.28–0.54) (22). The 2016 open-label study by Lugogo et al. confirmed this safety advantage with 8.2% SAE incidence for 75–100 mg versus 14.1% for higher doses (18-20). Chupp’s MUSCA study further documented quality of life benefits (ACQ-5 reduction ≥0.5 points) and a positive correlation between ACQ-5 improvement and safety (r=0.32) (21). These findings challenge conventional dose-escalation paradigms, suggesting that lower doses may saturate the IL-5 signaling pathway while optimizing the benefit-risk profile. The consistent treatment effects observed despite variability in background therapies indicate additive benefits to standard regimens, though therapy-specific interactions warrant further prospective investigation with standardized reporting.

By incorporating large-scale, methodologically rigorous, high-quality RCTs, this study successfully resolved a key controversy present in prior analyses, providing definitive evidence confirming mepolizumab’s significant improvement in lung function (FEV1) for patients with severe eosinophilic asthma. Earlier meta-analyses, limited by small sample sizes, variable study quality, and methodological heterogeneity among the included trials, failed to demonstrate this crucial lung function benefit. The scientific rigor and statistical power of the studies included in the current analysis provide a robust foundation for this clinically significant conclusion, highlighting the decisive impact of original study quality on the reliability of meta-analytic findings.

This analysis found that mepolizumab has a favorable overall safety profile comparable to placebo, which is crucial for long-term management. Notably, the low-dose regimen was associated with a significantly reduced risk of SAEs. This enhanced safety profile, combined with its performance on key efficacy endpoints, further supports prioritizing the 75–100 mg regimen in clinical practice. The pharmacological principle of IL-5 pathway saturation likely explains the lack of additional benefit at higher doses, which may also be accompanied by increased risk.

Limitations

Although methodological optimizations enhanced the reliability of our conclusions (e.g., sensitivity analyses confirmed result robustness), limitations warrant careful consideration: Variations existed across the included trials in route of administration (subcutaneous injection vs. intravenous infusion), specific dosages (even within the defined low/high dose ranges), and follow-up duration; these factors could potentially influence the pooled effect size estimates. While maintenance therapy data were extracted, variability in documentation (e.g., triple therapy vs. ICS + LABA classification) prevented subgroup analysis. This underscores the need for standardized concomitant medication reporting in future RCTs. Conclusions regarding the high-dose subgroup require cautious interpretation due to the smaller number of relevant studies. In the patient subgroup with baseline EOS ≥300 cells/µL, some efficacy endpoints (e.g., improvement in ACQ-5 scores) did not reach statistical significance, potentially related to insufficient sample size or inherent biological characteristics of this subgroup. Furthermore, potential publication bias was detected in the analysis of total AEs, suggesting a possible underestimation of risk for this measure, although sensitivity analysis for SAEs demonstrated robustness.

Conclusions

This updated meta-analysis provides high-level evidence confirming mepolizumab as an effective and safe targeted biologic for treating severe eosinophilic asthma, significantly improving FEV1, reducing acute exacerbations, and enhancing quality of life. Notably, the low-dose mepolizumab regimen (75–100 mg) demonstrated the optimal balance of efficacy and safety, with a particularly marked advantage in reducing the risk of SAEs. Baseline blood eosinophil count (≤300 cells/µL) serves as an effective predictive biomarker for identifying the patient population most likely to derive significant benefit. These findings provide direct guidance for optimizing the clinical application of mepolizumab, advocating for an individualized low-dose treatment strategy based on biomarker selection. Future large-scale studies with long-term follow-up are warranted to further define the optimal dosing regimen and long-term safety profile.

Acknowledgments

We would like thank all the people who participated in primary studies.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1596/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1596/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1596/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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