Comparative Effectiveness of Mepolizumab and Omalizumab in Patients Eligible for Both: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-7970972/v1

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Comparative Effectiveness of Mepolizumab and Omalizumab in Patients Eligible for Both: A Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-7970972/v1

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Background

Omalizumab and mepolizumab are effective biologic therapies for severe asthma. However, their comparative effectiveness in patients eligible for both treatments remains unclear in routine care. Therefore, the aim of this study was to compare the real-world efficacies of mepolizumab and omalizumab in these patients.

Methods

This retrospective cohort study included patients with asthma who were treated with omalizumab or mepolizumab. Eligible patients had a blood eosinophil count ≥ 150/µL (or ≥ 300/µL within the prior year), total Immunoglobulin E (IgE) ≥ 30 IU/mL, and sensitization to a perennial inhalant allergen. The primary endpoint was the adjusted incidence rate ratios (IRRs) for asthma exacerbation during the first year of treatment. Secondary endpoints were IRRs for emergency room (ER) visits and hospitalizations, subgroup IRRs stratified by eosinophil count (< 300/µL vs ≥ 300/µL), and change in oral corticosteroid (OCS) dose. Poisson regression models were adjusted for BMI, eosinophil count, and prior-year exacerbations; ER and hospitalization models additionally adjusted for prior ER visits and hospitalizations. Follow-up time was accounted for via an offset term.

Results

We included 49 patients (omalizumab, n = 25; mepolizumab, n = 24). Mepolizumab significantly reduced asthma exacerbations compared with omalizumab (IRR, 0.37; 95% confidence interval [CI], 0.19–0.69). In the subgroup analyses, this effect was significant in patients with eosinophil counts < 300/µL (IRR, 0.38; 95% CI, 0.14–0.88) but not in those with eosinophil counts ≥ 300/µL (IRR, 0.47; 95% CI, 0.15–1.35). There were no significant between-group differences in the number of ER visits or hospitalizations. The OCS dose was reduced in both groups, with no significant between-group difference in the mean dose reduction.

Conclusions

In patients eligible for both therapies, mepolizumab reduced clinically significant exacerbations more than omalizumab in real-world practice. Although ER visits, hospitalizations, and OCS-sparing were comparable, these findings support an exacerbation-focused approach when selecting biologics for overlap-eligible severe asthma. Confirmation in larger multicenter cohorts is warranted.

Asthma

Disease exacerbation

Mepolizumab

Omalizumab

Retrospective studies

Asthma remains a major public health issue, affecting about 300 million people worldwide and causing roughly 1,000 daily deaths [1]. Notably, approximately 3.6% of patients are classified as having severe asthma, with symptom control often remaining inadequate despite optimal treatment with inhaled therapies and long-term oral corticosteroid (OCS) [2]. Severe asthma is relatively intensive on healthcare resources; furthermore, it results in decreased productivity, which leads to significant physical, social, and economic challenges [3].

Approximately 70%–80% of patients with asthma have elevated type 2 inflammation, which is commonly characterized by high eosinophil counts and serum total Immunoglobulin E (IgE) levels [4, 5]. Biological therapies that target type 2 inflammation, including omalizumab (an anti-IgE monoclonal antibody) and mepolizumab (a humanized monoclonal antibody against interleukin-5, which is closely associated with eosinophilic inflammation), can reduce asthma exacerbations, improve symptoms and lung function, enhance quality of life, and decrease OCS requirements [6–9].

These biologic agents are selected based on type 2 inflammatory biomarkers including blood eosinophil counts, serum IgE levels, and evidence of perennial inhalant allergen sensitization [10]. However, patients presenting with elevated levels of multiple biomarkers may be eligible for multiple biologic agents [4, 5]. It remains unclear which biological agent offers the most appropriate therapeutic benefit for these patients.

Switching from omalizumab to mepolizumab has been shown to improve exacerbation rates and lung function [11]. In contrast, another study showed that mepolizumab may reduce the annual asthma exacerbation rate compared with omalizumab [12]. However, this previous study included patients with blood eosinophil counts ≥ 300/µL, which may have biased the population in favor of mepolizumab. Other studies have reported no significant between-group differences in exacerbation reduction [13, 14]; moreover, there have been no head-to-head trials indicating the most appropriate biologic agent for patients [15].

The aim of this study was to compare the real-world effectiveness of mepolizumab and omalizumab in patients who meet the eligibility criteria for both treatments. Additionally, we evaluated the efficacy of each drug in patient subgroups stratified based on baseline blood eosinophil counts.

Study design and study population

This single-center, retrospective, observational cohort study included patients with asthma aged ≥ 12 years who received omalizumab or mepolizumab at Kameda Medical Center between January 1, 2009, and July 31, 2023. The inclusion criteria were as follows: i) an eosinophil count ≥ 150/µL prior to omalizumab/mepolizumab administration or ≥ 300/µL within the prior year (in patients receiving long-term OCS, ≥ 150/µL was considered sufficient) and ii) serum total IgE levels ≥ 30 IU/mL and a positive result for specific IgE or skin prick testing for at least one perennial inhalant allergen (dust mite, Aspergillus, Alternaria, dog dander, cat dander, moth, or cockroach) [1, 16]. A positive result for specific IgE was defined as a level ≥ 0.35 kU/L [17]. The exclusion criteria were as follows: use of a biologic agent for an indication other than asthma (e.g., eosinophilic pneumonia, allergic bronchopulmonary mycosis, or eosinophilic granulomatosis with polyangiitis) and use of another biologic agent within 1 year prior to treatment initiation. Although previous studies have adopted shorter washout periods [18], we adopted a conservative 12-month washout period to minimize the potential carryover effects from previous biological therapies. The study protocol was reviewed and approved on 17 September 2024 by the Research Ethics Committee of Kameda Medical Center (#24–067). The requirement for informed consent was waived given the retrospective study design and anonymity of patient information.

Outcomes

The primary endpoint was the incidence rate ratio (IRR) of clinically significant asthma exacerbations within the first year of treatment. The secondary endpoints included the IRRs for exacerbations stratified by baseline eosinophil count (< 300/µL vs ≥ 300/µL), IRRs for emergency room (ER) visits and hospitalizations, and changes in OCS dosage.

Definition of acute asthma exacerbation

Based on previous reports and established guidelines, clinically significant exacerbations were indicated by use of systemic steroids for ≥ 3 days or a hospitalization or ER visit requiring systemic corticosteroid administration [19, 20]. Exacerbations that occurred within 14 days of each other were considered as single events.

Data collection

We collected the following data from the medical records: age; sex; body weight; smoking history; comorbidities (allergic rhinitis, chronic sinusitis, atopic dermatitis, and chronic urticaria); type of inhaled medication; number of asthma exacerbations; corticosteroid dosage; number of hospitalizations and ER visits before and after treatment; and laboratory results such as white blood cell count, eosinophil count, and serum total IgE level.

Other variables

We performed subgroup analysis based on the baseline peripheral blood eosinophil count using a cutoff value of 300/µL (< 300/µL vs. ≥300/µL), with the treatment effectiveness being assessed separately in each group.

Statistical analysis

Given the retrospective and observational nature of this study, we did not perform formal sample size calculation; instead, we conducted analysis using all available cases. Continuous and categorical variables are presented as means ± standard deviation and percentages, respectively. Between-group comparisons of continuous and categorical variables were performed using the t-test and chi-square test, respectively. IRRs were estimated using Poisson regression with a log-link function. All models were adjusted for baseline body mass index (BMI), blood eosinophil count and number of exacerbations within the previous year; furthermore, the ER and hospitalization models were additionally adjusted for baseline ER visits and hospitalizations, respectively. Given the limited sample size, we selected covariates for adjustment based on established predictors. Specifically, we selected the number of exacerbations within the prior year as a predictor of future exacerbations [21], blood eosinophil count as a predictor of treatment response to both biologics [1], and BMI as a risk factor for severe asthma and predictor of treatment response [22]. Additionally, baseline ER visits and hospitalizations were adjusted in the respective models based on prior research [11]. The observation period was defined as up to 1 year after treatment initiation. Patients who switched to another biologic agent during the observation period were censored at the time of switching. For patients who discontinued treatment within 1 year, the data collection period was defined as up to 4 weeks after the last dose. To account for variability in the follow-up duration, we included the natural logarithm of the treatment period as an offset term in all Poisson models. Additionally, we conducted subgroup analyses stratified by eosinophil count to assess differential treatment effects. Within-group post-treatment changes in the rates of asthma exacerbations, hospitalizations, ER visits, and OCS doses were assessed using the Wilcoxon signed-rank test. Furthermore, between-group comparisons of OCS dose reduction were performed using the Mann–Whitney U test. All statistical analyses were performed using R software (version 4.2.1), with a two-tailed p-value < 0.05 indicating statistical significance.

Patient selection

Figure 1 shows a flowchart of the patient selection process. Among 61 patients who met the initial eligibility criteria, we excluded 8 patients who received other biologic agents within 1 year before treatment initiation, 3 patients who received biologic agents for reasons other than asthma, and 1 patient who met both the exclusion criteria. Finally, 25 and 24 patients were included in the omalizumab and mepolizumab groups, respectively.

Patient characteristics

Table 1 presents the baseline clinical characteristics of the two groups. There were no significant between-group differences in age, sex, BMI, smoking history, type of inhaled medication, use of OCSs, or OCS dosage. However, the omalizumab group had a significantly higher mean number of clinically significant asthma exacerbations and ER visits within the previous year than the mepolizumab group. There were no significant between-group differences in the number of hospitalizations in the previous year. Similarly, there were no significant between-group differences in comorbidities. Although there were no significant between-group differences in blood eosinophil counts and maximum eosinophil counts over the past year, serum total IgE levels were significantly higher in the mepolizumab group than in the omalizumab group.

Table 1
Baseline clinical characteristics of the study population (before omalizumab or mepolizumab administration)
Variable	Omalizumab (n = 25)	Mepolizumab (n = 24)	p-value
Age (years)	62.04 (± 14.57)	63.67 (± 19.22)	0.739
Male, n (%)	7 (28.0)	12 (50.0)	0.198
BMI (kg/m²)	24.60 (± 5.67)	23.26 (± 2.85)	0.302
Smoking status			0.587
Current, n (%)	1 (4.0)	0 (0.0)
Former, n (%)	9 (36.0)	10 (41.7)
Never, n (%)	15 (60.0)	14 (58.3)
Inhaler			0.153
ICS, n (%)	2 (8.0)	3 (12.5)
ICS/LABA, n (%)	13 (52.0)	6 (25.0)
ICS/LABA/LAMA, n (%)	10 (40.0)	15 (62.5)
Oral glucocorticoid therapy
Receiving OCS, n (%)	10 (40.0)	12 (50.0)	0.677
Dose in LTOCS users (mg/day, prednisolone equivalent)	10.55 (11.07)	6.54 (3.45)	0.247
Asthma Events in Prior Year
Number of exacerbations	4.08 (± 3.58)	1.42 (± 1.72)	0.002
Number of ER visits	1.04 (± 1.43)	0.33 (± 0.56)	0.029
Number of hospitalizations	0.56 (± 0.92)	0.17 (± 0.38)	0.058
Comorbidities
Allergic rhinitis, n (%)	7 (28.0)	8 (33.3)	0.924
Chronic sinusitis, n (%)	2 (8.0)	4 (16.7)	0.625
Chronic urticaria, n (%)	1 (4.0)	0 (0.0)	1.000
Atopic dermatitis, n (%)	1 (4.0)	1 (4.2)	1.000
Blood test findings
White blood cell count (/µL)	8,792.00 (± 3,448.66)	8,279.17 (± 3,308.22)	0.598
Eosinophil count (/µL)	428.81 (± 434.14)	606.09 (± 553.88)	0.218
Maximum eosinophil count (/µL) ^a	658.17 (± 428.89)	1845.35 (± 3,596.11)	0.108
Low eosinophil group (< 300/µL), n (%)	13 (52.0)	10 (41.7)	0.661
Total IgE (IU/mL)	540.59 (± 710.97)	1,646.47 (± 2,617.31)	0.047
Continuous variables are expressed as the mean ± standard deviation, and categorical variables are expressed as numbers (%).
BMI: body mass index, ICS: inhaled corticosteroid, LABA: long-acting β-agonists, LAMA: long-acting muscarinic antagonist, LTOCS: long-term oral corticosteroid, ER: emergency room.
^a The maximum eosinophil count was recorded within 1 year before treatment initiation.

Annual mean number of asthma-related events

Table 2 shows the average number of pre- and post-treatment significant asthma exacerbations, ER visits, and hospitalizations. In the omalizumab group, there was a significant decrease in ER visits (p = 0.005) but not exacerbations and hospitalizations. In contrast, the mepolizumab group showed a significant decrease in exacerbations (p = 0.005) but not ER visits and hospitalizations.

Table 2
Annual mean number of asthma-related events before and after treatment with omalizumab or mepolizumab
	Omalizumab (n = 25)			Mepolizumab (n = 24)
	Pre-administration	Post-administration	p-value	Pre-administration	Post-administration	p-value
Exacerbations	4.08 (± 3.58)	2.68 (± 3.76)	0.054	1.42 (± 1.72)	0.54 (± 1.02)	0.005
ER visits	1.04 (± 1.43)	0.40 (± 1.08)	0.005	0.33 (± 0.56)	0.12 (± 0.34)	0.109
Hospital admissions	0.56 (± 0.92)	0.24 (± 0.83)	0.098	0.17 (± 0.38)	0.04 (± 0.20)	0.233

P-values were calculated using the Wilcoxon signed-rank test for within-group comparisons.

The median treatment duration was 365 days in both groups.

ER, emergency room.

Adjusted IRRs for asthma-related events

Figure 2 shows the adjusted IRRs from multivariate Poisson regression analysis. The mepolizumab group showed a significant reduction in the annual rate of asthma exacerbations by 63% compared with the omalizumab group (IRR 0.37; 95% confidence interval [CI], 0.19–0.69). In the subgroup analyses stratified by blood eosinophil count, mepolizumab significantly reduced the exacerbation rate in patients with eosinophil counts < 300/µL (IRR 0.38; 95% CI, 0.14–0.88) but not in those with eosinophil counts ≥ 300/µL (IRR 0.47; 95% CI, 0.15–1.35). There were no significant between-group differences in ER visits (IRR 1.52; 95% CI, 0.23–11.90) and hospitalizations (IRR 0.67; 95% CI 0.03–6.49).

OCS dose reduction

Both groups showed a significant reduction in the mean OCS dose (Fig. 3). In the mepolizumab group, the dose decreased from 6.54 (± 3.45) mg/day at baseline to 1.62 (± 1.80) mg/day (p = 0.004). In the omalizumab group, the dose decreased from 10.55 (± 11.07) mg/day to 4.05 (± 5.01) mg/day (p = 0.027). However, there was no significant between-group difference in the magnitude of OCS dose reduction (p = 0.473).

Our findings indicated that mepolizumab significantly lowered the annual exacerbation rate in patients with severe asthma compared with omalizumab. Subgroup analyses revealed that mepolizumab had a significant benefit in patients with eosinophil counts < 300/µL but not in those with counts ≥ 300/µL. There were no notable between-group differences in terms of the number of hospitalizations or ER visits. Both groups showed significant reductions in the OCS dosage, with no significant between-group difference.

Both omalizumab and mepolizumab are effective biologic therapies for severe asthma associated with type 2 inflammation. Typically, omalizumab is administered to patients with high serum IgE levels and perennial inhalant allergen sensitivity, whereas mepolizumab is recommended for patients with elevated eosinophil counts [1, 23]. However, the best treatment for patients who qualify for both biologics remains unclear. Previous indirect comparison studies have reported no significant differences in major exacerbations or hospitalizations between these treatments [24]. However, a recent prospective study on patients with eosinophil counts ≥ 300/µL showed that the annual exacerbation rate was significantly lower with mepolizumab than with omalizumab. Moreover, there were no notable between-treatment differences in the number of ER visits or hospitalizations [12]. Our study, which used real-world data from a relatively broader patient population, including those with eosinophil counts < 300 cells/µL, confirmed that mepolizumab significantly reduced the number of exacerbations.

Our finding that mepolizumab significantly reduced exacerbations—including in patients with eosinophil counts < 300/µL—may be attributed to the variability in peripheral blood eosinophil counts. Approximately 50% of patients with severe asthma show eosinophilic airway inflammation [25]; furthermore, high eosinophil counts have been associated with reduced lung function and frequent exacerbations [26]. Mepolizumab targets IL-5, which is a crucial cytokine that promotes eosinophil growth and differentiation; accordingly, mepolizumab helps lower eosinophil counts and leads to fewer exacerbations and a better quality of life [9]. However, blood eosinophil levels can be affected by time and environment; moreover, they are not always consistent with tissue eosinophilia [27]. Therefore, mepolizumab may be effective even if a patient's blood eosinophil count temporarily drops below 300/µL.

Inconsistent with a prospective study [11], we observed a significant benefit of mepolizumab in patients with a blood eosinophil count < 300/µL but not in those with a count ≥ 300/µL. This finding could be attributed to several factors. First, the predictors of response to omalizumab remain unestablished. In contrast, elevated eosinophil counts (≥ 150/µL) and a history of frequent exacerbations are well-established predictors of response to mepolizumab [28]. Omalizumab targets the Fc portion of IgE and reduces the circulating free IgE levels [10]. However, total serum IgE levels are unreliable indicators of treatment response [29]; furthermore, omalizumab has demonstrated benefits in a wide range of patients, regardless of biomarker profiles [30]. Additionally, post-hoc analyses have suggested that a baseline eosinophil count ≥ 260 cells/µL is a predictor of good response to omalizumab [31, 32]. This may have contributed to the relatively greater effect of omalizumab in our high-eosinophil subgroup, and therefore narrowed the efficacy gap with mepolizumab. Second, the small sample size and possible differences in baseline severity may have contributed to the lack of significant between-group differences. Further studies are warranted to elucidate these factors.

In our study, both groups showed OCS dose reduction, with no significant between-group difference in the dose reduction. The steroid-sparing effect of mepolizumab was demonstrated in the SIRIUS trial, which included patients with severe eosinophilic asthma [33], and in observational studies evaluating outcomes after switching from omalizumab to mepolizumab [34]. However, real-world studies have shown that both omalizumab and mepolizumab can reduce dependence on OCSs [34]. Notably, there remain no reliable predictive biomarkers for this effect on OCS dependence. This may explain the OCS dose reduction in both groups without a significant between-group difference. Furthermore, the relatively small number of OCS users at baseline, as well as the retrospective design in which tapering strategies were left to the physician’s discretion, may have led to an underestimation of the OCS-sparing effect of mepolizumab.

This study has some limitations. First, this was a small-scale, single-center study, which may have limited the statistical power to detect small between-group differences. Second, given the retrospective design, the risk of selection bias could not be ruled out. Additionally, some patients did not receive long-acting β-agonists or muscarinic antagonists, which suggests possible inclusion of cases with suboptimal inhaled therapy. Third, the omalizumab group had a significantly higher baseline frequency of clinically significant exacerbations and ER visits, which suggests worse disease severity at baseline. Fourth, although we adjusted for potential confounders, including eosinophil count, BMI, prior exacerbation, and hospitalization frequency, residual confounding factors may have affected the results. Fifth, we defined sensitization to perennial allergens as a specific IgE level ≥ 0.35 kU/L, which may have led to inclusion of patients with clinically minor sensitization and limited comparability with other studies. Sixth, our cohort comprised patients with total IgE levels > 1500 IU/mL despite these levels being outside the typically approved indications for omalizumab. This may limit the generalizability of our results to populations managed with strict adherence to the prescription guidelines. Future research should use multicenter, prospective designs—ideally pragmatic, biomarker-stratified, head-to-head comparisons—to validate these findings and refine biologic selection for overlap-eligible patients.

In patients with severe asthma characterized by high eosinophil counts and perennial inhalant allergen sensitization, mepolizumab may be more effective than omalizumab in decreasing clinically significant exacerbations. Our findings offer insights into how these agents compare in real-world clinical settings and may guide their selection in patients eligible for both treatments. However, further prospective studies, including randomized controlled trials, are warranted to confirm these findings.

IgE: Immunoglobulin E

IRR: incidence rate ratio

ER: emergency room

OCS: oral corticosteroid

BMI: Body Mass Index

CI: Confidence Interval

LTOCS: long-term oral corticosteroid.

Ethics approval and consent to participate: This study is a retrospective cohort study and not a clinical trial. Therefore, the clinical trial number is not applicable. The study protocol received approval from the Research Ethics Committee of Kameda Medical Center (#24-067). Given the retrospective nature of the study and the anonymization of patient data, the requirement for written informed consent was waived, with approval from the respective ethics committees.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: Not applicable.

Authors' contributions: T.N. contributed to the conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, supervision, validation, visualization, and writing of the original draft and final manuscript. N.I. contributed to the conceptualization, data curation, investigation, providing resources, and review and editing of the manuscript. H.M. contributed to the conceptualization, data curation, formal analysis, methodology, resources, software, validation, visualization, and review and editing of the manuscript. K.N. contributed to the conceptualization, providing resources, and review and editing of the manuscript. N.K., Y.F., A.O., and H.I. contributed to providing resources and the review and editing of the manuscript.

Acknowledgements: We thank Editage (www.editage.jp) for English language editing. We appreciate the help of our colleagues at the Kameda Medical Center.

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Comparative Effectiveness of Mepolizumab and Omalizumab in Patients Eligible for Both: A Retrospective Cohort Study

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study design and study population

Outcomes

Definition of acute asthma exacerbation

Data collection

Other variables

Statistical analysis

Results

Patient selection

Patient characteristics

Annual mean number of asthma-related events

Adjusted IRRs for asthma-related events

OCS dose reduction

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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Version 1