FormalPara Key Summary Points

Why carry out this study?

In many countries in the Middle East, Asia, Latin America and the Arab Gulf, asthma-related burden is high; there is an urgent need to optimise management in these regions

Mepolizumab is a humanised anti-interleukin-5 monoclonal antibody that has been approved as an add-on treatment for severe asthma with an eosinophilic phenotype in patients ≥ 6 years of age

In the Nucala Effectiveness Study, 525 patients with severe asthma burden received at least one dose of mepolizumab 100 mg subcutaneously; data were collected for 12 months pre- and post-mepolizumab initiation

What was learned from the study?

Post-initiation, a significant reduction in clinically significant exacerbations (CSE) was observed (76% [p < 0.001]; incident rate ratio [95% confidence interval] 0.24 [0.19–0.30])

Post-initiation, 36.1% of patients became oral corticosteroid-free and 72.0% had no CSEs; mepolizumab treatment led to reductions in hospitalisations and an improvement in overall asthma management

Digital Features

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Introduction

An estimated 5–10% of patients with asthma have severe asthma [1], characterised by frequent exacerbations despite controller medication (including high dose of inhaled corticosteroids [ICS]/long-acting beta2-agonist combination therapy) [2], high oral corticosteroid (OCS) use and poor quality of life (QoL) [1, 3,4,5]. Among patients with asthma, asthma-related healthcare resource use (HCRU) and costs are substantially greater for patients with severe asthma. Studies from the UK and France have reported morbidity and mortality of severe asthma to constitute > 50% of the total healthcare costs of asthma management [6, 7].

Whilst prevalence is likely underestimated, a high proportion of patients with asthma reside in low-middle-income countries (LMICs). Patients from these countries represent approximately 90% of the global burden of asthma with disproportionately high asthma-related morbidity and mortality [4, 5, 8, 9]. Moreover, asthma-related burden is substantial in many countries in the Middle East, Asia, Latin America and the Arab Gulf [4] and there is an urgent need to optimise therapy. Here, poor asthma control and management is common, as evidenced by frequent exacerbations, high OCS use (for example, in a multicentre, observational study in the Gulf region, OCS was used by 37.3% of patients in the United Arab Emirates [10], whereas in a UK-based historical follow-up study, the proportion of patients with severe uncontrolled eosinophilic asthma aged 18–64 who used maintenance OCS was reported to be 16.5% [6]) and low Asthma Control Test (ACT) scores [3, 4, 10,11,12,13,14,15]. Literature on the impact of severe asthma on HCRU and costs for patients from these countries is limited [10, 13]; however, treatment costs are considerably higher in LMICs than in high-income countries [16,17,18]. A systematic review of 60 LMICs reported a 1-month supply of ICS to cost 2–7 days’ worth of wages in most countries for which treatment affordability was assessed [19]. Furthermore, in a study conducted in Colombia, the mean annual direct costs of outpatient care for severe asthma was 4743.6 ± 6331.1 US dollars, with medication constituting 98% of overall costs [16]. Furthermore, an unmet need exists to improve prescription practices in countries in the Middle East, where under-prescription of ICS, poor adherence to prescribed medication and patient-perceived lack of guidance from physicians is common [20].

Prolonged OCS use is associated with an increased risk of adverse events (AEs), complications and OCS-induced morbidity including stroke, heart failure, diabetes, cataracts, osteoporosis, depression, anxiety and infections, as well as a reduction in QoL over time [21,22,23,24]. Even receipt of short courses of OCS treatment can significantly increase the risk of AEs in patients [24]. Despite this, OCS use remains high in LMICs and countries in the Middle East, Asia, Latin America and the Arab Gulf, likely because of low cost and greater accessibility compared to biologic treatment options [4, 8, 25, 26].

Type 2 inflammation is a key feature of severe asthma, which can be categorised as either eosinophilic or neutrophilic [27, 28]. Most patients with severe asthma (> 80%) present with an eosinophilic phenotype (severe asthma with an eosinophilic phenotype [SAEP]) [29]. The cytokine, interleukin-5 (IL-5) is a key factor in regulating the growth, differentiation, activation and survival of eosinophils, the production of which results in inflammation and triggers asthma exacerbations [30, 31]. Often, treatment with inhaled and/or systemic corticosteroids is ineffective in patients with severe asthma (with or without an eosinophilic phenotype) [27]. In these patients, add-on biologic therapy is recommended [2]. Mepolizumab is an anti-IL-5 antibody used to treat SAEP by binding to and neutralising soluble IL-5, inhibiting its interaction with its receptor, IL-5Rα [32]. This action suppresses the downstream signalling cascade thereby inhibiting eosinophil proliferation [27]. Mepolizumab is approved as an add-on treatment for SAEP in patients ≥ 6 years of age [33, 34].

Evidence from the randomised controlled trial (RCT) Dose Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) demonstrated significant reductions in rates of clinically significant exacerbations (CSEs; defined as an asthma exacerbation that requires systemic corticosteroids [OCS for ≥ 3 days or a single dose of intravenous/intramuscular corticosteroid] and/or an emergency room (ER) visit and/or hospitalisation) [35] and clinically meaningful improvements in health-related QoL in patients with SAEP following treatment with mepolizumab [36]. Furthermore, The Steroid Reduction with Mepolizumab Study (SIRIUS) demonstrated significant reductions in exacerbations and a median reduction in OCS dose of 50% (p = 0.007) following 20 weeks of treatment with mepolizumab [37].

Real-world evidence (RWE) studies in Europe and North America have further demonstrated effectiveness of mepolizumab in patients with SAEP [38, 39]. The REAL world effectiveness of mepolizumab In paTIent care (REALITI-A) study was a 24-month multi-country, prospective, observational cohort study investigating the real-world OCS-sparing effect of mepolizumab in adults with severe asthma across 84 sites in Europe, Canada and the US [38]. REALITI-A reported significant reductions in the rates of CSEs as well as the use of OCS [38, 40]. Similar results were observed in the REal-worlD Effectiveness and Safety (REDES) study, a multicentre, observational cohort study designed to evaluate the effectiveness and safety of mepolizumab in patients with severe asthma in Spain, whereby significant reductions in CSEs (77.5% [p < 0.001]) and OCS use were reported [39].

Patients from LMICs and countries in the Middle East, Asia, Latin America and the Arab Gulf have been underrepresented in previous RWE studies [10]. The objective of the Nucala Effectiveness Study (NEST; GSK study number 213475) was to generate evidence of the effectiveness of mepolizumab in optimising asthma management and reducing CSEs in a diverse and heterogeneous population of patients with severe asthma living in underrepresented countries.

Methods

Study Design and Setting

NEST was a multi-country, bi-directional (both historical and prospective data considered), self-controlled, observational cohort study conducted in Colombia, Chile, India, Türkiye, Saudi Arabia and Arab Gulf countries (United Arab Emirates, Kuwait, Oman and Qatar). From each participating country, patients with a clinical diagnosis of severe asthma who had already been prescribed mepolizumab as add-on therapy for severe asthma as per their physician’s decision, and already received at least one dose were considered for recruitment by convenience sampling. To address potential sources of enrolment bias, physicians were not encouraged to prescribe mepolizumab to enrol patients into NEST.

The enrolment date was defined as the date patients entered the study; the index date was defined as the date of mepolizumab treatment initiation (Fig. 1). Data collection was from 1 November 2021, to 1 March 2023. Data were extracted from medical records (paper or electronic) 12 months prior to the index date for all patients (pre-initiation). This allowed for a standardised period of baseline history to describe patient demographics, disease burden and previous medication use. Data were collected from medical records up to 12 months following the index date (post-initiation). All data up to 12 months post-index were included in these analyses, including patients who discontinued prematurely. All patients were followed for 12 months following index, meaning for a patient who enrolled on the last day of the enrolment period, the data collection could have lasted up to 18 months following the start. Data were collected using a study electronic case report form (eCRF). All centres underwent standardised training and utilised standardised documentation for completion of eCRFs at enrolment and for each assessment during the observation period.

Fig. 1
figure 1

Study design. Mo month

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Patients

Eligible patients were aged ≥ 18 years, had a clinical diagnosis of severe asthma, were prescribed ≥ 1 dose (any dosage) of mepolizumab and had 12 months of historical data (obtained from paper and electronic medical records) prior to the index date (pre-initiation). Patients had to provide written informed consent and were required to have already initiated mepolizumab treatment for severe asthma, based on their physician’s decision. In countries where a waiver for informed consent was requested or granted, informed consent was not obtained for each patient. Patients who were participating in a clinical trial for which the treatment regimen and/or monitoring took place during the periods pre- and post-initiation were not eligible for inclusion.

Populations

Patients who met the eligibility criteria and received at least one dose of 100 mg subcutaneous mepolizumab following physician decision are the focus of this analysis. The target sample size for this multi-country study was 550 patients. An initial sample size calculation estimated a final number of 219 patients, assuming an effect size of 0.6, or 315 patients, assuming an effect size of 0.5.

Endpoints

The primary outcome was the overall rate of CSEs. The frequency of CSEs was collected pre- and post-initiation to calculate the rate of CSEs for both periods.

Key secondary outcomes included: asthma-related HCRU including count and length of hospital admissions, intensive care unit and ER visits, and visits with healthcare professionals; change in OCS dose from pre- to post-initiation among patients receiving OCS maintenance treatment at index; and changes in lung function (forced expiratory volume in one second [FEV1] and forced vital capacity [FVC]) were compared using the historical value nearest to the index date pre-initiation and available data post-initiation. ACT scores were collected in all participating countries during the pre-initiation period and at 12 months post-initiation; in the Arab Gulf countries, ACT scores were collected pre-initiation and at 3, 6 and 12 months post-initiation. As the total number of doses received across the study population may have varied, only patients who received 12 doses of mepolizumab 100 mg over the 12-month period were included in the analyses of asthma control (ACT scores) to minimise bias.

Additional endpoints included: physicians’ perceptions of how patients responded to mepolizumab treatment and patterns of mepolizumab treatment (including dose, treatment duration, adherence [defined as the proportion of days covered] and total number of doses over 12 months) were described. Where available, peripheral blood eosinophil count (BEC) was collected using the closest historical value to the index date pre-initiation.

Statistical Analyses

The mean and 95% confidence intervals (CI) of CSEs were estimated from a univariate negative binomial regression. CSE rates were estimated via generalised 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. All other exposure and outcome variables were analysed descriptively.

A sensitivity analysis was performed to compare differences between the primary endpoint in patients who were followed from index until the date of last mepolizumab dose + 28 days (referred to as the ‘on-treatment’ group) vs. those who were followed for 12 months irrespective of when their last mepolizumab dose was received (Supplementary Results).

Ethics and Good Clinical Practice Declarations

The study protocol was reviewed and approved by the respective institutional review boards and ethics committees of the participating countries, and the study was conducted in accordance with the International Conference on Harmonisation, Good Pharmacoepidemiology Practice, Good Clinical Practice and all applicable patient privacy requirements and country-specific requirements relevant for an observational study.

Results

Patient Disposition

Of 581 patients screened, 531 met the eligibility criteria and received at least one dose of subcutaneous mepolizumab following physician decision and were enrolled in the study; six of these received at least one dose of 300 mg mepolizumab. The treated population comprised 525 patients who received at least one dose of mepolizumab 100 mg.

Patient Characteristics Pre-initiation

The mean (standard deviation [SD]) age of the study population patients was 49.6 (13.4) years and most patients were female (72.8%) (Table 1). Overall, 69.4% of patients had at least one comorbidity, of which rhinosinusitis (n = 226; 62.3%) and self-reported nasal polyps (n = 144; 39.7%) were the most common. Furthermore, 27.8% (n = 101) of the study population had a history of allergies. Of note, four (1.1%) patients had hypereosinophilic syndrome. Overall, 37.3% of patients were obese (defined as having a body mass index score of ≥ 30 kg/m2).

Table 1 Baseline characteristics of patients who received ≥ 1 dose mepolizumab 100 mg/ml
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Patients demonstrated substantial severe asthma burden pre-initiation with 306 of 524 (58.4%) patients recorded as being OCS-dependent, i.e. were receiving OCS at the time of mepolizumab initiation or had received OCS for 26 weeks in the past year. For 277 patients with available data, the mean (SD) OCS dose was 23.2 (20.0) mg/day (Table 2). Of these, 167 (60.3%) patients were using maintenance OCS in the pre-initiation period at a mean (SD) dose of 22.8 (21.9) mg/day. Most patients reported using ICS in the pre-initiation period (521 of 525 [99.4%]), with 291 (56.0%) of those patients receiving a high dose. Of 466 patients with available data, the geometric mean BEC was 490.7 cells/µl (value nearest to the index date in the pre-initiation period); 264 of 479 (55.1%) patients with available data reported a BEC of ≥ 500 cells/µl pre-initiation. Overall, 165 of 525 patients (31.4%) had reported previous use with omalizumab; one patient reported use of dupilumab in the pre-initiation period. Of the patients with available data (n = 240), most had poor asthma control (ACT score < 20) at baseline (n = 204 [85.0%]). Pre-initiation, the mean (SD) predicted pre-bronchodilator FEV1 was 62.8% (20.2) for 129 patients with available data.

Table 2 Clinical characteristics of patients who received ≥ 1 dose mepolizumab 100 mg/ml pre- vs. post-mepolizumab initiation
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Characteristics of Patients with No CSEs Pre-initiation

Of patients for whom asthma CSE information was documented at baseline, 178 of 472 (37.7%) had no CSEs. Over half (53.4%) of patients without CSEs at baseline were OCS dependent. Of those, the mean dose of OCS was 21.6 mg/day with 37.6% of patients receiving a dose of ≥ 30 mg/day. Overall, 33.2% of these patients were biologic-experienced. Of the patients with reported BEC (n = 156), the geometric mean (geometric SD) BEC was 485.9 (3.0) cells/µl with 91 of 156 (58.3%) patients with ≥ 500 cells/µl. There was a paucity of other measures such as ACT scores for these patients.

Patterns of Mepolizumab Use

Most patients (491 of 519 [94.6%]; 6 patients from the treated population were excluded from this calculation as they had missing data regarding their last dose of mepolizumab) had ≥ 90% adherence over 12 months; the mean (SD) number of days covered was 360 (74.3) days. Further details regarding the number of refills/doses over 12 months and the reasons why patients were prescribed mepolizumab are provided in the Supplementary Material.

CSE Rates Pre- and Post-initiation

Overall, 472 and 493 patients had pre- and post-initiation CSE data, respectively. The number of patients who experienced at least one CSE was lower in the post-initiation period (138 [28.0%] patients) compared to the pre-initiation period (294 [62.3%] patients; Fig. 2). The mean (95% CI) number of CSEs per patient was lower post-initiation (1.8 [1.5–2.0]) compared to the pre-initiation period (3.1 [2.7–3.4]). The incidence rate ratio (95% CI) of CSEs pre- vs. post-initiation was 0.24 (0.19–0.30; p < 0.001), representing a 76% reduction in the CSE rate post-initiation. The proportion of patients who experienced no CSEs increased from 37.7% pre-initiation to 72.0% post-initiation.

Fig. 2
figure 2

Distribution of CSEs pre- vs. post-mepolizumab initiation. Data available for 472 patients pre-mepolizumab initiation and 493 patients in the post-mepolizumab initiation; proportions calculated with appropriate denominator. CSE clinically significant exacerbation

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Of the patients that had no CSEs documented at baseline (n = 178), 141 of 172 (82.0%) with available data reported no CSEs post-initiation; 31 of 172 (18.0%) patients reported ≥ 1 CSE post-initiation.

Asthma-related HCRU: CSEs Requiring Hospitalisation or an ER Visit

Overall, there was a reduction in the number of patients who required an ER visit or hospitalisation due to CSE. In total, 106 of 472 (22.5%) patients were hospitalised pre-initiation vs. 34 out of 493 (6.9%) patients post-initiation (Fig. 3). The mean (SD) length of hospital stay was lower post-initiation compared to pre-initiation (8.2 [5.0] days vs. 11.3 [10.0] days). Of the 294 patients with at least one CSE in the pre-initiation period, 36.1% (n = 106) were hospitalised, 51.4% (n = 151) visited the ER and 23.1% (n = 68) visited their physician. In comparison, HCRU for the patients with at least one CSE post-initiation (n = 138) was lower, with 24.6% (n = 34) of patients being hospitalised, 36.2% (n = 50) of patients visiting the ER and 33.3% (n = 46) of patients visiting their physician.

Fig. 3
figure 3

CSEs that required hospitalisation (i) and length of hospital stay (ii). Values displayed as text in the graphs are (i) the proportion of patients and (ii) the mean length of hospital stay. CSE clinically significant exacerbation, SD standard deviation

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Changes in OCS Dose and Usage From Pre- to Post-initiation

Pre-initiation, 132 (25.2%) patients had previously used OCS (defined as ≥ 26 weeks of use in the 12 months pre-initiation) and 174 (33.2%) patients were receiving OCS at mepolizumab initiation. Of 525 patients, the proportion who received OCS was lower post-initiation compared with pre-initiation (16.6% vs. 52.8%; Fig. 4); the mean (SD) OCS dose was also lower (16.3 [17.4] mg/day vs. 23.2 [20.0] mg/day; Table 2). Of the patients who used OCS, 67 of 277 patients (24.2%) used 5 mg OCS pre-initiation compared with 39 of 87 patients (44.8%) post-initiation. Of 274 patients with available data, 226 (82.5%) patients were able to have their OCS dose reduced by ≥ 50% post-initiation; 11 (4.0%) patients had their dose reduced by < 50%. The remaining 37 (13.5%) patients had no change to their OCS dose. Overall, 188 of 521 patients (36.1%) were OCS-free post-initiation.

Fig. 4
figure 4

Proportion of patients who used OCS (i) and the changes in OCS usage (ii) pre- vs. post-mepolizumab initiation. OCS oral corticosteroid

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Only 66 of the 167 patients (39.5%) who used maintenance OCS therapy at index continued its use post-initiation. Of those using maintenance OCS at index (n = 167), the mean change in maintenance OCS dose post-initiation was − 17.7 (22.4) mg, representing a mean (SD) reduction of 87.5 (22.0)%.

Of the 31 patients who reported ≥ 1 CSE post-initiation despite having no CSEs documented pre-initiation, 61.3% (n = 19) were on OCS maintenance therapy pre-initiation compared to 35.5% (n = 11) post-initiation.

Changes in Lung Function

Change in Pre-bronchodilator FEV1

Overall, 129 of 340 (37.9%) patients pre-initiation and 87 of 229 (38.0%) patients post-initiation had pre-bronchodilator FEV1 (%) results. The mean (SD) predicted pre-bronchodilator FEV1 was 62.8 (20.2)% pre-initiation compared to 73.0 (22.7)% post-initiation (Fig. 5); the mean (SD) change in pre-bronchodilator FEV1 between the pre- and post-initiation periods was 23.8 (59.0)%.

Fig. 5
figure 5

Pre-bronchodilator FEV1 and pre-bronchodilator FVC pre- vs. post-mepolizumab initiation. FEV1 data only available for 129 and 87 patients pre- and post-mepolizumab initiation, respectively. FVC data only available for 131 and 88 patients pre- and post-mepolizumab initiation, respectively. FEV1 forced expiratory volume in one second, FVC forced vital capacity, SD standard deviation

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For patients with no documented CSEs pre-initiation (n = 178) and who had available pre-bronchodilator FEV1 data (pre-initiation, n = 41; post-initiation, n = 28), the mean (SD) pre-bronchodilator FEV1 was 68.6 (21.3)% pre-initiation vs. 80.54 (24.9)% post-initiation.

Change in Pre-bronchodilator FVC

In total, 131 of 341 (38.4%) patients pre-initiation and 88 of 227 (38.8%) patients post-initiation had pre-bronchodilator FVC (%) results. The mean (SD) predicted pre-bronchodilator FVC was 72.6 (18.7)% and 81.1 (20.8)% pre- and post-initiation, respectively. From pre- to post-initiation, a mean (SD) difference of 16.0 (41.5)% was observed for pre-bronchodilator FVC.

For patients with no CSEs documented pre-initiation (n = 178), 41 and 29 patients had pre-bronchodilator FVC data pre- and post-initiation, respectively. The mean (SD) pre-bronchodilator FVC of these patients was 75.6 (18.0)% pre-initiation, vs. 84.0 (28.5)% post-initiation.

Measures of Asthma Control and Overall Health State Post-initiation

In patients who received 12 doses of mepolizumab 100 mg over 12 months (data available for 240 patients pre-initiation and 172 patients post-initiation), an improvement in ACT score was observed (Fig. 6). The proportion of patients with a score of 20–25, i.e. well-controlled asthma, increased (15.0% pre-initiation vs. 64.5% post-initiation). The mean (SD) difference in ACT score between the pre- and post-initiation periods was 7.6 (5.8).

Fig. 6
figure 6

ACT scores pre- vs. post-mepolizumab initiation. Results from patients that received 12 doses of mepolizumab 100 mg over the 12-month period post-mepolizumab initiation (data available for: pre-mepolizumab initiation, n = 240; post-mepolizumab initiation, n = 172); proportions calculated with appropriate denominator. ACT Asthma Control Test

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Based on physicians’ evaluation, the overall health state (regarding asthma) for 447 of 484 (92.4%) patients from the total enrolled population (n = 531) had improved following mepolizumab treatment, with the majority of physicians reporting “much better” results (289 of 484 [59.7%] patients).

Key Biomarkers

The highest recorded BEC values were reported for 141 and 276 patients in the pre- and post-initiation periods, respectively. The mean (SD) highest value recorded decreased from 1247.1 (1235.1) cells/µl in the pre-initiation period to 316.0 (654.3) cells/µl in the post-initiation period. Of those with available data, the number of patients with BEC ≥ 500 cells/µl pre-initiation was 119 of 141 (84.4%) compared with 50 of 276 (18.1%) post-initiation.

At baseline, 29 of 31 patients who experienced ≥ 1 CSE post-initiation (but who had no documented CSEs pre-initiation) had BEC data; the geometric mean (geometric SD) BEC for these patients was 526.1 (2.5) cells/µl.

Discussion

In this real-world study of patients with severe asthma from countries in the Middle East, Asia, Latin America and the Arab Gulf, a significant reduction in CSE rates was observed (76%; p < 0.001). Following treatment with mepolizumab, the proportion of patients receiving OCS treatment decreased. The mean OCS dose decreased post-initiation (mean [SD] change in OCS dose, − 18.1 [20.7] mg) and 36.1% of patients became OCS-free.

The results of NEST were comparable with RCTs, including the DREAM study [36] and other RWE studies investigating mepolizumab treatment in patients with severe asthma. REALITI-A demonstrated a significant reduction in CSEs by 71% (rate ratio [95% CI], 0.29 [0.26, 0.32]) and a reduction in median maintenance OCS dose by 75% 1 year post-initiation [38]. In REDES, a significant reduction in the number of CSEs was observed (77.5% [p < 0.001]) and 50.6% of patients experienced no CSEs within the first year of mepolizumab treatment [39]. This proportion is comparatively higher in NEST whereby 72.0% of patients reported no CSEs in the 12 months post-initiation.

As noted, OCS use is common in LMICs and countries in the Middle East, Asia, Latin America and the Arab Gulf despite the fact that prolonged use is associated with an increased risk of adverse events [21,22,23,24]. The results observed in NEST revealed substantial reductions in OCS use and dosage post-initiation, reinforcing the effectiveness of mepolizumab. Furthermore, the overall HCRU and burden on healthcare systems in LMICs and the countries involved in NEST are considerably high [13, 15]. The proportion of patients hospitalised due to CSEs was reduced following receipt of at least one dose of 100 mg mepolizumab. Moreover, 94.6% of patients had ≥ 90% treatment adherence and the overall health state of 92.4% of patients had improved according to their physician, illustrating mepolizumab as an effective treatment option that could help to improve prescription practices in the countries studied [20]. Together, these results reinforce the benefits of mepolizumab for this population of patients with severe asthma whilst also highlighting the importance of optimal biologic intervention which is essential to improve patient outcomes and to avoid the systemic corticosteroid-associated morbidity.

In NEST, mepolizumab treatment led to improved lung function and asthma control, as evidenced by the improved pre-bronchodilator FEV1 and FVC results observed post-initiation and improvements in ACT scores with more patients achieving well-controlled asthma (score of 20–25) post-initiation. The mean (SD) difference in ACT score between the pre- and post-initiation periods was greater than the minimally important difference (post-initiation, 7.6 [5.8]; minimally important difference, 3.0) [41].

The benefits of mepolizumab for these patients with severe asthma are further evidenced by the substantial reduction in BEC (mean [SD] highest value recorded pre-initiation, 1247.1 [1235.1] cells/µl vs. post-initiation, 316.0 [654.3] cells/µl). As a marker of eosinophilic airway inflammation and a predictor of clinical outcomes (including exacerbations and treatment response) in severe asthma [42], it is pertinent to note the reduction in mean BEC post-initiation which may be associated with fewer CSEs following biologic treatment.

Achieving clinical remission (meaning to have a high level of disease control [including no asthma symptoms or exacerbations] and optimisation of lung function without the need for ongoing treatment [43]) is an advanced care goal in asthma and is of increasing interest within clinical and real-world trials [44, 45]. Although not specifically assessed, the endpoints considered in NEST align with those that are used to assess clinical remission, which suggests that these data could form the basis for future analyses to estimate the proportion of patients who may achieve clinical remission.

In NEST, a high proportion of patients experienced no CSEs pre-initiation (178 of 472 [37.7%] patients). This could simply be due to recall bias, which is more likely to occur in a real-world setting than within the conditions of an RCT. Another potential reason is that a large proportion of these patients were biologic-experienced (33.2%) and there may have been residual effects of previous biologic treatment for severe asthma pre-initiation. Overall, 53.4% of these patients were OCS-dependent prior to mepolizumab initiation and may have been switched to mepolizumab therapy to reduce the burden of OCS dependence. Together, this demonstrates that despite having no CSEs documented prior to mepolizumab initiation, these patients presented with asthma severity for which the treating physicians in actual clinical practice made the decision to prescribe mepolizumab. In these patients, mepolizumab was effective in improving outcomes (including CSEs, OCS use and lung function). Among the 31 patients who experienced ≥ 1 CSE post-initiation (despite having no CSEs documented pre-initiation), there was a reduction in the proportion of patients using maintenance OCS post-initiation. A plausible explanation for the number of documented CSEs among these patients post-initiation could be the result of OCS sparing. Notably, these patients had a higher geometric mean BEC at baseline (526.1 cells/µl) than those who experienced no CSEs pre- and post-initiation (485.9 cells/µl). As higher BEC levels are associated with an increased risk of exacerbations [42], this could explain the increase in CSEs post-initiation in these patients.

NEST was the first study to our knowledge in which physicians described the management of patients with severe asthma and to evaluate the effectiveness of mepolizumab in patients in real-world clinical practice from LMICs and countries underrepresented in previous RWE studies of mepolizumab. The clinically meaningful results of NEST can benefit asthma research groups in these countries, helping to strengthen the evidence base for asthma treatment in this specific population. Patients enrolled in NEST were reflective of those in the real world, where 69.0% of patients with severe asthma are reported to have at least 1 type-2 related comorbidity, such as chronic rhinosinusitis and nasal polyposis [46]. Similarly, in NEST, 69.1% of patients reported ≥ 1 comorbidity at baseline, of which rhinosinusitis and nasal polyps were the two most common. NEST demonstrated the effectiveness of mepolizumab in improving outcomes for these patients, reinforcing the value of these results for real-life patients and healthcare professionals in the countries studied. Furthermore, utilisation of the same eCRF across all countries enabled standardised data collection. Finally, unlike other RWE studies that do not typically have a control population, patients in NEST acted as their own control, which helped to provide internal validity, making it possible to see clear improvements in multiple outcomes post-initiation.

There are limitations to this study including the fact patients were selected by a convenience sampling method, meaning it is possible that despite being reflective of the general population of patients with severe asthma, the study population may not be fully representative of the target severe asthma population per country. Furthermore, all data were collected retrospectively from medical charts which could have led to information bias associated with patients with the earliest index dates who may have had different baseline characteristics to those whose index date was closer to the enrolment period. Finally, despite training and adoption of a standard eCRF, inconsistent interpretation of the eCRF by participating centres may have occurred.

Conclusion

These results confirm that mepolizumab treatment is effective in reducing CSEs, hospitalisations due to CSEs and OCS use as well as improving lung function and asthma control in patients with severe asthma in countries in the Middle East, Asia, Latin America and the Arab Gulf. These results further support the use of biologic treatment in patients with severe asthma and high disease burden, thus providing evidence for healthcare practitioners to inform their treatment decision-making for patients in the countries studied.