Effectiveness of Mepolizumab in Patients with OCS-Dependent Severe Asthma: A Real-World Study

Abstract

Introduction

Before the availability of biologic therapies, the main treatment for patients with severe asthma in Asia, Latin America, and the Middle East was oral corticosteroids (OCS), despite long-term use causing serious adverse effects. This post hoc analysis of the NUCALA Effectiveness Study (NEST) evaluated the effectiveness of mepolizumab, an anti-interleukin-5 monoclonal antibody, in patients with severe asthma and OCS dependence from regions with limited representation in real-world studies.

Methods

NEST was a multicountry, observational cohort study in adults with severe asthma from Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Patients received ≥ 1 dose of 100 mg mepolizumab. OCS dependence was defined as receiving maintenance OCS at mepolizumab initiation or for ≥ 26 weeks during the 12 months prior. Data were collected 12 months pre- and post-initiation. Outcomes included OCS use, rate of clinically significant exacerbations (CSEs), and level of asthma symptom control.

Results

Of 524 patients with OCS use data, 58.4% (n = 306) had OCS dependence pre-initiation. Mean (standard deviation) age was 49.2 (13.4) years; 73.9% (n = 226) were women. Of 251 patients with available data, 87.6% (n = 220) received lower OCS doses post-initiation and 68.9% (n = 173) stopped OCS use altogether. CSEs were reduced by 76.9% post-initiation. Of 222 patients with available data, 72.5% (n = 161) had improvements in Asthma Control Test scores post-initiation.

Conclusion

In patients with severe asthma and OCS dependence from the countries studied, mepolizumab reduced OCS use and dose, asthma exacerbations, and improved symptom control.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03338-w.

Plain Language Summary

Severe asthma is a long-term disorder of the lungs. Symptoms can be difficult to control, despite treatment. Asthma treatment can differ depending on the healthcare services and treatments available, with some countries having more extensive research and access to asthma medications than others. People with severe asthma often receive high doses of oral corticosteroids (OCSs) over prolonged time periods which can cause side effects and affect quality of life. Mepolizumab is a medication used to treat severe asthma. Studies show that mepolizumab treatment can reduce the use of OCS, as well as the risk of major asthma attacks, and improve control of symptoms. The NUCALA Effectiveness Study was carried out to see how well mepolizumab works in real-life clinical practice for treatment of severe asthma in patients living in Colombia, Chile, India, Türkiye, Saudi Arabia, United Arab Emirates, Kuwait, Oman, and Qatar. Here, we looked at how effective mepolizumab was at reducing OCS use for people who required OCS consistently before they started taking mepolizumab (OCS dependence). We found that fewer people relied on OCS following mepolizumab treatment, with nearly 90% receiving a lower dose following treatment with mepolizumab. Almost 70% of these people had their dose reduced entirely so they no longer needed OCS. Additionally, mepolizumab treatment significantly reduced the number of major asthma attacks people experienced and led to better asthma symptom management. These results suggest that mepolizumab could be beneficial for people with severe asthma, in regions where asthma symptoms and the use of OCS are high.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03338-w.

Key Summary Points

Why carry out this study?

Patients with severe asthma in low-middle income countries are disproportionately affected by associated disease burden. Mepolizumab (anti-interleukin-5 monoclonal antibody) demonstrated real-world effectiveness in patients from Asia, Latin America, and the Middle East (NUCALA Effectiveness Study [NEST] primary analysis).

The objective of this post hoc analysis of NEST was to assess the effectiveness of mepolizumab in patients with severe asthma and oral corticosteroid (OCS) dependence, with a focus on the OCS-sparing effect of mepolizumab.

What was learned from the study?

In patients with OCS dependence (defined as receiving maintenance OCS at mepolizumab initiation or for ≥ 26 weeks during the 12 months pre-initiation), mepolizumab treatment reduced OCS use and dose; 68.9% of patients stopped use post-initiation.

These results capture the real-life patterns of OCS use in countries in Asia, Latin America, and the Middle East, helping to inform prescribing practices and reduce OCS use and associated burden.

Introduction

Severe asthma is defined by the Global Initiative for Asthma as asthma remaining uncontrolled in spite of optimized high-dose inhaled corticosteroid/ long-acting β₂-agonist (ICS/LABA) treatment, or requiring high-dose ICS/LABA to prevent it from becoming uncontrolled [1]. The greatest proportion of people with severe asthma reside in low-middle income countries (LMICs) and are disproportionately affected by disease burden, with high disease-related morbidity and mortality [2–5]. Asthma-related burden is also high in other countries across Asia, Latin America, and the Middle East, with patients experiencing frequent exacerbations and poor control of symptoms [6–9]. Oral corticosteroid (OCS) dependence is common in these countries [2], emphasizing the importance of optimizing therapy and enhancing asthma management.

Several factors have led to this reliance on OCS, such as limited access to other treatment options (including ICS) caused by high costs, high demand, and prioritization of treatment for other diseases over asthma [10–12]. Limited awareness of OCS-associated adverse events (AEs) and barriers within healthcare systems, in addition to the immediate availability of OCS, have further perpetuated use [2, 11–13]. Given the longstanding history of OCS use, it is not surprizing that prescription of OCS has become common practice in the management of severe asthma in countries across Asia, Latin America, and the Middle East (including LMICs) [6, 11, 12]. This highlights an urgent need to improve asthma management and optimize therapy by prioritizing personalized treatment approaches for patients with severe asthma [14].

Anti-interleukin-5 (IL-5) biologic therapies have been shown to provide an effective option for the treatment of type 2-driven diseases such as severe asthma [15, 16]. One such anti-IL-5 biologic is mepolizumab, a first-in-class humanized monoclonal antibody that is approved as an add-on treatment for severe asthma with an eosinophilic phenotype (SAEP) in adults and children ≥ 6 years of age [17]. Mepolizumab works by inhibiting free IL-5, thereby blocking its interaction with its receptor, IL-5 receptor alpha (IL-5Rα), and reducing the proliferation of eosinophils which in turn prevents eosinophilic inflammation and asthma exacerbations [18, 19]. Randomized controlled trials (RCTs) and real-world evidence (RWE) studies have provided evidence for the effectiveness of mepolizumab in reducing OCS use and clinically significant exacerbations (CSEs), as well as improving control of symptoms in patients with severe asthma [20–22]. Biologic therapies, such as mepolizumab, provide more targeted treatment options for patients with asthma based on their treatment needs and disease phenotype, for example through the use of biomarkers [23]. Such therapies are paving the way to personalized strategies for the management of severe asthma.

The NUCALA Effectiveness Study (NEST) was designed to evaluate the effectiveness of mepolizumab in reducing rates of CSEs in patients with severe asthma from countries across Asia, Latin America, and the Middle East (including LMICs) which have previously been underrepresented in clinical trials [24]. The objective of this post hoc analysis of NEST was to evaluate the effectiveness of mepolizumab in patients with severe asthma and OCS dependence, with a focus on the OCS-sparing effect of mepolizumab.

Methods

Study Design

This was a post hoc analysis of data from NEST, focusing specifically on mepolizumab effectiveness in patients with severe asthma and OCS dependence.

NEST was a multicountry, bidirectional, self-controlled, observational cohort study, whose primary outcome was the overall rate of CSEs [24]. Patients were recruited by convenience sampling; physicians were not encouraged to prescribe mepolizumab to avoid potential sources of enrolment bias. Data were collected from November 2021 to March 2023, and extracted from patients’ medical records 12 months prior to the mepolizumab initiation date (index) as baseline history. The follow-up period was 12 months post-mepolizumab initiation.

NEST was a RWE study for which no standardized protocols for OCS reduction were implemented. Use of OCS and decisions regarding OCS tapering were left to the discretion of treating physicians, reflecting real-world clinical practice. Demographic variables collected pre-initiation included age at index date, sex (men or women) and body mass index (BMI). Race and ethnicity data were collected pre-initiation and entered into an electronic Case Report Form (eCRF) by the clinician according to the following pre-determined categories: White or Caucasian; Black or African American; Asian; Arab; Mixed-race; Other (which was evaluated to check the need to create another category). Further study design methodologies are available in the primary analysis publication (Fig. 1) [24].

Fig. 1.

NEST study design. Figure from Al-Lehebi RO, et al., Real-world effectiveness of mepolizumab in severe asthma: Results from the multicountry, self-controlled NUCALA effectiveness study (NEST). Adv Ther 2024.

© 2024 (Creative Commons Attribution Non-Commercial 4.0 International licence). Mo month, NEST NUCALA Effectiveness Study

Study Population

Patients were enrolled from Türkiye, Colombia, India, Chile, Saudi Arabia, Kuwait, Oman, Qatar, and the United Arab Emirates (UAE). Adult patients (aged ≥ 18 years) who had already been prescribed mepolizumab by their physician to treat severe asthma, had paper or electronic medical records available for the 12-month period pre-initiation, and had provided written informed consent prior to study commencement were eligible for inclusion. Patients were excluded if they were enrolled in a clinical trial for which their treatment regimen and/or monitoring was dictated by a protocol during the 12-month pre-/post-initiation periods. In this post hoc analysis, patients with OCS dependence (defined as those who received maintenance OCS (mOCS) at the time of mepolizumab initiation or for ≥ 26 weeks within the previous 12 months) included in the primary analysis were enrolled.

Outcomes

Primary outcomes were the reduction in OCS use and dose from pre- to post-initiation amongst those with OCS dependence. Other outcomes included the change in the rate of CSEs (defined as asthma exacerbation that required systemic corticosteroids [OCS for ≥ 3 days or a single dose of intravenous/intramuscular corticosteroid] and/or an emergency room visit and/or hospitalization) and exacerbations, and the change in the level of asthma symptom control, assessed by Asthma Control Test (ACT) scores. For comparison, all outcomes were also assessed in those without OCS dependence (Supplementary Material).

Statistical Analyses

All data available ≤ 12 months post-initiation were included in these analyses irrespective of whether or not a patient discontinued prematurely (either by withdrawal of consent or loss of follow-up), and were summarized using descriptive statistics. As a result of the nature of post hoc analyses, results were only presented for patients with available data. Continuous data summaries included the sample size (n), mean and standard deviation (SD), and median and interquartile range. Categorical data were summarized according to the number and percentage of patients in each category of interest. OCS doses were presented as prednisolone equivalent doses (mg/day).

The incident rate ratio (IRR), mean, SD and 95% confidence intervals (CI) of CSEs were estimated using generalized estimating equation models assuming a negative binomial distribution (of CSEs) and a log-link function, allowing for straightforward interpretation of the linear relationship between pre- and post-initiation periods. A covariate for treatment period (i.e., pre- or post-initiation) was included and the logarithm of time was used as an offset variable. An autoregressive correlation structure of order 1 was used to correct within-participant correlation.

Ethical Considerations

The study protocol was reviewed and approved by an institutional review board, and the study was conducted in accordance with the International Council on Harmonisation, Good Pharmacoepidemiology Practice, Good Clinical Practice, and all applicable patient privacy requirements and country-specific requirements relevant for an observational study. Data were collected from existing medical records and ethical committee reviews were conducted for all included countries. Informed consent to participate was obtained for patients in countries where a waiver for informed consent was not requested or granted. The data collected were anonymized and non-identifiable.

Results

Participants

Of 525 patients included in the overall NEST study population, OCS dependence data were available and collected for 524 patients. Overall, 58.4% (n = 306) had OCS dependence pre-initiation, and of these, 56.9% (n = 174) were receiving mOCS at the time of mepolizumab initiation while 43.1% (n = 132) had received mOCS for ≥ 26 weeks in the 12 months prior to initiation.

Patient Characteristics Pre-initiation

The mean (SD) age of patients was 49.2 (13.4) years; the majority of patients were women (73.9% [n = 226]; Table 1). Most patients were from Türkiye (43.1% [n = 132]) and the majority were of White/Caucasian ethnicity (55.6% [n = 170]). Of 292 patients, the mean (SD) BMI score was 29.2 (6.2) kg/m²; 39.7% (n = 116) of patients were considered obese (BMI of ≥ 30.0 kg/m²). Overall, 68.0% (n = 208) of patients had ≥ 1 comorbidity of interest: 45.8% (n = 140) had rhinosinusitis, 31.4% (n = 96) had nasal polyps, and 16.0% (n = 49) had diabetes (type 1 or 2). For 288 patients, the geometric mean (SD) blood eosinophil count (value nearest to index date pre-initiation) was 494.5 (2.7) cells/µL. Of 61 patients, the mean (SD) pre-bronchodilator forced expiratory volume/second was 63.9 (20.9)%. Pre-bronchodilator forced vital capacity (FVC) was available for 62 patients; of these, the mean (SD) FVC was 73.4 (19.8)%. Of 241 patients with available data, the mean (SD) asthma duration (which considered the period between asthma diagnosis and index date) was 14.9 (11.0) years. Of 250 patients with available data, 81.6% (n = 204) had never smoked; only 2.8% (n = 7) of patients were current smokers.

Table 1.

Characteristics of patients with OCS dependence pre-initiation

Characteristic	n	Pre-mepolizumab initiation n = 306
Age, years	306
Mean (SD)		49.2 (13.4)
Median (IQR)		50.0 (40.0–59.0)
Sex, n (%)	306
Women		226 (73.9)
Men		80 (26.1)
Country of residence, n (%)	306
Türkiye		132 (43.1)
Saudi Arabia		52 (17.0)
Arab Gulf countries (Kuwait, Oman, Qatar, and the UAE)		49 (16.0)
Colombia		33 (10.8)
India		29 (9.5)
Chile		11 (3.6)
Race and ethnicity, n (%)a	306
White/Caucasian		170 (55.6)
Arab		71 (23.2)
Asian		30 (9.8)
Mixed race		20 (6.5)
Non-disclosed		15 (4.9)
BMI, kg/m2	292
Mean (SD)		29.2 (6.2)
Median (IQR)		28.3 (24.9–32.0)
Categories, n (%)
≤ 24.9		75 (25.7)
25.0–29.9		101 (34.6)
≥ 30.0		116 (39.7)
Comorbidities, n (%)	306
≥ 1 comorbidity of interestb		208 (68.0)
Rhinosinusitis		140 (45.8)
Nasal polyps		96 (31.4)
Diabetes (type 1 or 2)		49 (16.0)
EGPA		23 (7.5)
COPD		18 (5.9)
Number of comorbidities of interest per patientb	306
Mean (SD)		1.1 (0.9)
Median (IQR)		1.0 (0.0–2.0)
Asthma duration considering period between asthma diagnosis and index date, years	241
Mean (SD)		14.9 (11.0)
Median (IQR)		13.0 (7.0–20.0)
Smoking history, n (%)c	250
Never		204 (81.6)
Current or former		46 (18.4)
Asthma treatment used pre-initiation, n (%)	306
ICS/LABA		275 (89.9)
SABA		127 (41.5)
ICS		37 (12.1)
Theophylline and its derivatives		20 (6.5)
ICS/LABA/LAMAd		16 (5.2)
ICS dose among those with use (alone or in combination), n (%)e	304
High		153 (50.3)
Medium		115 (37.8)
Low		29 (9.5)
As needed		7 (2.3)
Prior omalizumab use, n (%)	306	106 (34.6)
Reasons for stopping omalizumab, n (%)	106
Lack of efficacy		95 (89.6)
Side effects		3 (2.8)
Total IgE level, IU/mL3f	157
Mean (SD)		250.4 (269.1)
Median (IQR)		142.0 (38.0–408.0)
Categories, n (%)
< 76		61 (38.9)
≥ 76		96 (61.1)
Positive skin prick test, n (%)	103	40 (38.8)
Healthcare resource used to treat exacerbations, n (%)g	306
Physician office/clinic visit		108 (35.3)
Emergency room		99 (32.4)
Hospitalization		70 (22.9)
At home		47 (15.4)
Unknown		5 (1.6)
Pre-bronchodilator FEV1, %	61
Mean (SD)		63.9 (20.9)
Median (IQR)		70.0 (49.0–77.0)
Pre-bronchodilator FVC, %	62
Mean (SD)		73.4 (19.8)
Median (IQR)		70.5 (62.0–86.0)
BEC, geometric mean (SD), cells/µL	288	494.5 (2.7)

AIDS acquired immunodeficiency syndrome, BEC blood eosinophil count, BMI body mass index, COPD chronic obstructive pulmonary disease, eCRF electronic Case Report Form, EGPA eosinophilic granulomatosis with polyangiitis, FEV₁ forced expiratory volume/second, FVC forced vital capacity, HES hypereosinophilic syndrome, HIV human immunodeficiency virus, ICS inhaled corticosteroids, IgE immunoglobulin E, IQR interquartile range, IU international units, LABA long-acting β₂-agonist, LAMA long-acting muscarinic antagonist, mL milliliters, OCS oral corticosteroids, SABA short-acting β₂-agonist, SD standard deviation, UAE United Arab Emirates

^aRace and ethnicity data were collected pre-initiation and entered into the eCRF by the clinician according to the following pre-determined categories: White or Caucasian; Black or African American; Asian; Arab; Mixed-race; Other (which was evaluated to check the need to create another category)

^bComorbidities of interest included myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, diabetes type 1 and 2, hemiplegia, moderate-to-severe renal disease, diabetes with end-organ damage, any tumor, leukemia, lymphoma, moderate or severe liver disease, metastatic solid tumor, AIDS/HIV, nasal polyps, rhinosinusitis, allergic history (positive allergy testing), obesity, EGPA, HES

^cFormer smoker defined as not smoking for ≥ 6 months; current smoker defined as being an actual smoker or having quit smoking within the last 6 months

^dOne device

^eICS dose classification based on total daily doses for “low”, “medium”, and “high” for adults/adolescents published in the Global Initiative for Asthma (2021) [26]

^fValue nearest to index date

^gMaximum of 15 exacerbations reported per patient

Most patients (99.7% [n = 305]) reported ICS as a pre-index asthma treatment; 50.3% (n = 153) of these reported receiving a high dose and 89.9% (n = 275) were using ICS/LABA pre-initiation. Overall, 34.6% (n = 106) of patients had previously used omalizumab (an anti-immunoglobulin E monoclonal antibody) [25]; most (89.6% [n = 95]) reported stopping treatment due to lack of efficacy.

OCS Use and Dose Pre- Versus Post-initiation

Of 306 patients with OCS dependence, consistent and valid OCS use and dosage data were only available for 251 patients, all of whom reported OCS use pre-initiation (Table 2). Of those, most patients stopped using OCS altogether by the end of the 12-month post-initiation period (68.9% [n = 173]). The mean (SD) OCS dose received was 23.2 (20.5) mg/day pre-initiation, compared with 4.7 (11.6) mg/day post-initiation, reflecting a mean (SD) reduction in the OCS dose from pre- to post-initiation of 18.5 (20.8) mg/day. Overall, 87.6% (n = 220) of patients who received OCS pre-initiation had reduced their OCS dose post-initiation. Pre-initiation, 33.5% (n = 84) of patients were receiving OCS at a dose ≥ 30 mg/day, compared with 6.0% (n = 15) post-initiation (Fig. 2). Both pre- and post-initiation, methylprednisolone was the most frequently used OCS (pre-initiation, 50.2% [n = 126]; post-initiation, 39.7% [n = 31]).

Table 2.

Change in OCS use and dose pre- versus post-initiation

Variable	Patients with OCS dependence (n = 306)
	n	Pre-initiation	n	Post-initiation
OCS use, n (%)	298		298
OCS use		251 (84.2)		78 (26.2)
No OCS use		47 (15.8)		220 (73.8)
Change in OCS use pre- versus post-initiation, n (%)			306
Stopped OCS use				173 (56.5)
Continued OCS use				78 (25.5)
Never used OCS				47 (15.4)
Unknown				8 (2.6)
Started OCS use				0
Change in OCS use post-initiation among patients using OCS pre-initiation, n (%)			251
Stopped OCS use				173 (68.9)
Continued OCS use				78 (31.1)
OCS dose, mg/daya	251		251
Mean (SD)		23.2 (20.5)		4.7 (11.6)
Median (IQR)		20.0 (6.3–40.0)		0.0 (0.0–5.0)
Change in OCS dose, mg/daya			251
Mean (SD)				18.5 (20.8)
Median (IQR)				10.0 (5.0–30.0)
Category, n (%)
Decrease				220 (87.6)
No change				23 (9.2)
Increase				8 (3.2)
OCS treatment, n (%)	251		78
Methylprednisolone		126 (50.2)		31 (39.7)
Prednisolone		77 (30.7)		25 (32.1)
Prednisone		44 (17.5)		20 (25.6)
Deflazacort		3 (1.2)		1 (1.3)
Dexamethasone		1 (0.4)		1 (1.3)

IQR interquartile range, OCS oral corticosteroid, SD standard deviation

^aPrednisone equivalent

Fig. 2.

Change in OCS dose from pre- to post-initiation (n = 251)^a. ^aIncludes patients that received OCS pre-initiation. Patients who did not have available, consistent, or valid dosage data were excluded. OCS oral corticosteroids

Change in Rate of CSEs and Exacerbations in Patients with OCS Dependence Pre- Versus Post-initiation

Pre-initiation, the mean (95% CI) number of CSEs per patient was 2.2 (1.9–2.5; Table 3) per year. Post-initiation, there was a significant reduction in mean (SD) CSEs per patient to 0.5 (0.4–0.6), representing an absolute difference of − 1.68. The IRR (95% CI) was 0.21 (0.16–0.28; P < 0.001), reflecting a 79% reduction in CSEs post-initiation. Of the 203 patients with available asthma exacerbation data, 74.9% (n = 152) of patients experienced a reduction in asthma exacerbations of ≥ 50–100%; 23.2% (n = 47) of patients experienced no change or an increase in asthma exacerbations.

Table 3.

Change in CSEs and asthma control pre- versus post-initiation

Variable	Patients with OCS dependence (n = 306)
	n	Pre-initiation	n	Post-initiation
CSEs, mean (95% CI)a	306	2.2 (1.9–2.5)	306	0.5 (0.4–0.6)
Absolute difference				− 1.7
Relative difference, %				− 76.9
IRR (95% CI)			306	0.21 (0.16–0.28)
P value				< 0.001
Reduction in asthma exacerbation, n (%)			203
No change/increase				47 (23.2)
> 0–50% decrease				4 (2.0)
≥ 50–100% decrease				152 (74.9)
ACT scoreb	234		244
Mean (SD)		13.6 (5.4)		20.0 (5.3)
Median (IQR)		13.0 (9.0–18.0)		22.0 (17.0–24.0)
Improvement in ACT post-initiation, n (%)c			222
Improvement				161 (72.5)
No improvement				61 (27.5)

ACT Asthma Control Test, CI confidence interval, CSE clinically significant exacerbation, IQR interquartile range, IRR incident rate ratio, OCS oral corticosteroids, SD standard deviation

^aEstimated via generalized estimating equation models assuming a negative binomial distribution (of CSEs) and a log link function. A covariate for treatment period (i.e., pre- or post-initiation) was included and the logarithm of time was used as an offset variable. An autoregressive correlation structure of order 1 was used to correct for within-participant correlation

^bOnly patients with ACT scores (at the relevant time points) were included in ACT score analyses

^cImprovement measured by an increase of three points

Change in Asthma Symptom Control in Patients with OCS Dependence Pre- Versus Post-initiation

Of 234 patients, the mean (SD) ACT score pre-initiation was 13.6 (5.4); only 17.5% (n = 41) of patients had a score of ≥ 20 (meaning well controlled; Table 3; Fig. 3). Post-initiation, the mean (SD) ACT score among patients (n = 244) was 20.0 (5.3) and 63.1% (n = 154) of patients had an ACT score of ≥ 20. Overall, 72.5% (n = 161) of patients had an improvement (an increase of ≥ 3 points) in their ACT score from pre- to post-initiation (n = 222).

Fig. 3.

Change in ACT scores from pre- to post-initiation in patients with OCS dependence ACT Asthma Control Test, OCS oral corticosteroid

For comparison, results for patients without OCS dependence are presented in the Supplementary Material (Fig. 1, Tables 1–2).

Discussion

This post hoc analysis of NEST demonstrated clinically meaningful reductions in OCS use and dose for patients with severe asthma and OCS dependence following treatment with ≥ 1 dose of 100 mg mepolizumab. These results reinforce the effectiveness of mepolizumab in reducing CSEs and improving control of symptoms in patients with severe asthma who responded poorly to previous treatments including high dose ICS/LABA.

Asthma prevalence and severity are typically higher among adult women than men [1, 27, 28], as demonstrated in our study where 73.9% of patients were women. This could be due to several social and environmental factors or physiological differences including fluctuations in sex hormones during puberty, the menstrual cycle, pregnancy, and menopause; pre- and perimenstrual asthma can increase OCS use as well as social and environmental factors [27, 28].

The results of this post hoc analysis align with those of RCTs, including the Steroid Reduction with Mepolizumab Study (SIRIUS), a randomized, placebo-controlled double-blind trial designed to assess the glucocorticoid-sparing effect of mepolizumab in patients with SAEP who had ≥ 6 months mOCS use prior to mepolizumab initiation [20]. After 24 weeks, a median percentage reduction in daily OCS dose from baseline of 50% was observed in patients receiving mepolizumab (P = 0.007) [20]. Whilst a significant reduction in OCS dose was observed in SIRIUS, no patients stopped OCS following mepolizumab treatment unlike in NEST and other RWE studies [20], highlighting a difference between our data and this RCT as well as the benefits of mepolizumab treatment for patients in real life. Furthermore, the results of our study suggest that the reduction in OCS doses continues with long-term mepolizumab treatment.

The OCS-sparing effect of mepolizumab has been further demonstrated in several RWE studies. The REAL world effectiveness of mepolizumab In paTIent care (REALITI-A) study was a multinational, prospective, observational cohort study that involved 84 centers across Europe, Canada, and the United States, designed to investigate the effectiveness and safety of mepolizumab for patients with severe asthma [22, 29]. In an interim analysis of REALITI-A, the OCS-sparing effect of mepolizumab was assessed, demonstrating a 75% reduction in the median daily mOCS dose from baseline to weeks 53–56 [22]. In REALITI-A, fewer patients became OCS-free post-mepolizumab in comparison to our study (43% vs. 68.9% of patients, respectively) [22]. This highlights the real-life benefits of mepolizumab for patients living in countries with significant OCS burden, such as those involved in NEST.

The REal-worlD Effectiveness and Safety (REDES) study, a multicenter observational cohort study designed to evaluate the effectiveness and safety of mepolizumab in patients with SAEP in Spain, also demonstrated substantial reductions in OCS use and daily dose [21]. Akin to the results of this NEST post hoc analysis in which 68.9% of patients who used OCS pre-initiation stopped use post-initiation, in REDES, 47.8% of patients who used OCS at baseline were OCS-free post-mepolizumab [21]. In REDES, after 12 months, the mean daily OCS dose decreased by 7.2 mg/day; in NEST, this OCS-sparing effect was even greater with a mean decrease from pre- to post-initiation of 18.5 mg/day [21].

Whilst the results of other RWE studies reinforce mepolizumab as an effective treatment to reduce OCS burden, OCS dependence and burden was higher among the patients enrolled in our study than in other studies. This important feature of NEST distinguishes it from other RWEs, highlighting the effectiveness of mepolizumab in reducing OCS burden in particularly affected populations.

Prior to the availability of biologic therapy, mOCS use was largely the only treatment option available for patients with uncontrolled severe asthma [6, 11, 12]. However, today, inconsistent availability of biologics, outdated guidelines, as well as lower associated costs and over-the-counter availability of OCS, have meant that OCS are still regularly prescribed in many practices [6, 11, 12, 30, 31]. Generally, a patient’s limited awareness of AEs associated with long-term OCS use and a perceived rapid improvement in symptoms due to OCS treatment also contribute to OCS dependence as patients can often feel reluctant to taper use or try alternative treatments [30]. Furthermore, insufficient referral pathways to specialists leads to loss of patient follow-up [12], as well as the possibility of prolonged mOCS use going unnoticed. In a survey of 200 patients with asthma conducted in the UAE, only 17% of patients had a scheduled follow-up appointment with their healthcare professional (HCP) [32]. This highlights the factors that can perpetuate OCS dependence in the countries studied.

Currently, in practices in the Arab Gulf, Latin America, and Türkiye, patients are often prescribed burst OCS treatment, presumably to treat CSEs [11, 33–35]. However, burst and short courses of OCS still greatly increase the risk of OCS-associated morbidity [36], suggesting that treatment optimization is still required in these countries. In many countries in Latin America [11], and for 17.9% of the countries collaborating with the International Severe Asthma Registry, long-term OCS use is part of the criteria for the prescription of mepolizumab, meaning OCS is often prescribed by HCPs without consideration of biologic options first [37]. This creates barriers in the treatment pathway to biologics, resulting in increased OCS prescription and contributing to the overall OCS dependence in these regions. The results of this post hoc analysis demonstrate the OCS-sparing effect of mepolizumab, not only in patients with OCS dependence but also those without, reinforcing the benefits of mepolizumab treatment for patients with severe asthma burden, and highlighting the potential for mepolizumab to reduce overreliance on OCS in the countries studied.

Despite the disease burden of patients included in NEST, there was a significant reduction in the IRR of CSEs observed 12 months post-initiation; these results were similar regardless of OCS dependence pre-initiation. These results suggest that by reducing CSEs, mepolizumab treatment could contribute to a reduction in burst OCS use. Overall, both patients with and without OCS dependence experienced improvements in asthma management and were able to control their asthma symptoms better, as demonstrated by substantial increases in the proportion of patients with higher ACT scores (≥ 20) post-initiation.

To our knowledge, NEST was the first multinational study to evaluate the effectiveness of mepolizumab in patients with severe asthma in real-world clinical practice from countries underrepresented in previous RWE studies of mepolizumab (including LMICs). These results capture the real-life patterns of use of OCS and can help to strengthen the knowledge base within these countries and improve prescribing practices to help reduce OCS dependence. As one of the largest multinational, real-world studies of mepolizumab, these data further reinforce mepolizumab as an effective treatment option for patients with severe asthma around the world, including regions with high disease burden and OCS dependence. Furthermore, utilization of the same eCRF across all countries enabled standardized data collection, and internal validity was provided via patients acting as their own control. However, despite training and adoption of a standard eCRF, there may have been inconsistencies in data entry from the source data (medical records) into the eCRF.

Despite the strengths of our study, limitations include missing, unavailable, underreported, or inconsistent data, which is reflective of real-world practice in that data may not always be completely or accurately recorded. Furthermore, the use of convenience rather than random sampling in study recruitment may affect how representative this cohort is of the overall severe asthma population. Differences in effectiveness seen in our study and other clinical and RWE studies may be due to the use of different definitions of OCS dependence. While our definition closely aligns with that of an RCT and another RWE study [20, 38], some studies use a lower threshold to determine OCS dependence [39], which could impact clinical outcomes. As our study collected only single OCS dose values at baseline (pre-mepolizumab) and post-mepolizumab time points, without information on the duration of OCS use or related safety endpoints, it was not possible to calculate a precise cumulative OCS dose or analyze the safety impact with the current dataset. While a strength of the bidirectional nature of this study was efficiency of data use, patients with the earliest index dates may have different baseline characteristics compared with patients with later index dates.

Conclusion

The results of this post hoc analysis of NEST reinforced mepolizumab as an effective treatment to reduce OCS use, dose, and CSEs, and improve control of symptoms in patients with severe asthma and OCS dependence in real-world clinical practice in the countries studied. Use of biologics such as mepolizumab has the potential to reduce OCS dependence and improve patient outcomes.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Sevim Bavbek: Investigation, Formal analysis, Review & Editing. Mona Al-Ahmad: Investigation, Formal Analysis, Review & Editing. Hala Samaha: Investigation, Formal Analysis, Review & Editing. Pooran Chand Kathuria: Investigation, Formal Analysis, Review & Editing. Patricia Fernandez: Investigation, Formal Analysis, Review & Editing. Nasser Al Busaidi: Investigation, Formal Analysis, Review & Editing. Tayseer Ibrahim: Investigation, Formal Analysis, Review & Editing. Bassam Mahboub: Conceptualization, Investigation, Formal Analysis, Review & Editing. Seema Haider: Formal Analysis, Review & Editing. Saeed Noibi: Conceptualization, Formal Analysis, Review & Editing. Gur Levy: Formal Analysis, Review & Editing. Riyad Omar Al-Lehebi: Conceptualization, Investigation, Formal Analysis, Review & Editing. All authors agree to be 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.

Funding

GSK funded this research (study number 213475) and were responsible for all costs associated with the development and the publishing of this manuscript.

Data Availability

The study data may be provided by reasonable request to the corresponding author.

Declarations

Conflict of Interest

Sevim Bavbek has given lectures at meetings supported by AstraZeneca, GSK, and Novartis, and reports receipt of advisory board fees from AstraZeneca, GSK, and Novartis. Mona Al-Ahmad has received lecture and advisory board honoraria from AstraZeneca, GSK, Novartis, and Sanofi. Hala Samaha has received lecture and advisory board honoraria from AstraZeneca, GSK, and Sanofi. Pooran Chand Kathuria has no conflicts of interest to report. Patricia Fernandez reports having been a speaker for AstraZeneca, GSK, Sanofi, and Teva, and participated in advisory boards with AstraZeneca, GSK, and Sanofi. Nasser Al Busaidi has received lecture and advisory board honoraria from AstraZeneca, GSK, and Sanofi. Tayseer Ibrahim has received lecture honoraria from AstraZeneca, GSK, and Sanofi. Bassam Mahboub has received lecture and advisory board honoraria from AstraZeneca, GSK, and Sanofi. Seema Haider and Gur Levy are employed by and hold financial equities in GSK. Saeed Noibi is employed by GSK. Riyad Omar Al-Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, GSK, and Sanofi, and received advisory board fees from GSK.

Ethical Approval

The study protocol was reviewed and approved by an institutional review board, and the study was conducted in accordance with the International Council on Harmonisation, Good Pharmacoepidemiology Practice, Good Clinical Practice, and all applicable patient privacy requirements and country-specific requirements relevant for an observational study. Data were collected from existing medical records and ethical committee reviews were conducted for all included countries. Informed consent to participate was obtained for patients in countries where a waiver for informed consent was not requested or granted. The data collected were anonymized and non-identifiable.