Background
Severe asthma (SA) is defined as asthma that requires the use of multiple drugs to achieve control, including high-dose inhaled corticosteroids (ICS) combined with other controller medications such as long-acting β2-adrenergic agonists (LABA) with or without oral corticosteroids (OCS). However, it may remain uncontrolled despite the use of this high intensity therapeutic approach [
1‐
4]. SA is associated with more frequent exacerbations than non-severe asthma, as well as increased use of healthcare resources [
1,
5,
6]. Asthma clinical guidelines and recommendations highlight the importance of a personalized therapeutic strategy aimed at achieving clinical improvements in several domains, including early and sustained control of symptoms, prevention or minimisation of both asthma exacerbations and lung function decline, tapering of OCS (in order to avoid OCS-related adverse effects) and a reduction in asthma-associated mortality [
3,
7].
The most common SA phenotype is type 2 (T2) severe eosinophilic asthma (SEA), which is characterised by the presence of eosinophils in blood and sputum, as well as by clinical features such as comorbid chronic rhinosinusitis with nasal polyps (CRSwNP) [
8]. SEA patients experience frequent exacerbations and often rely on high-dose OCS, which are strongly associated with major adverse events, in order to manage or prevent their occurrence [
7]. Exacerbations are also associated with reduced pulmonary function and a significant increase in hospitalizations [
5,
9].
The addition of biologics to the therapeutic armamentarium has helped to address all the clinical challenges associated with SEA, such as reducing exacerbations and/or the burden of OCS as a maintenance or sporadic treatment [
1]. Given the ability of biologics to reduce SA clinical burden, the achievement of clinical remission has recently been proposed as a goal of asthma management. Different expert consensuses have suggested different definitions for a super-response to biologics and clinical remission in SA [
10,
11].
One of the currently available biologics approved for the treatment of SEA is benralizumab, an anti-eosinophil monoclonal antibody that binds to the alpha subunit of the interleukin-5 receptor (IL-5Rα) expressed by cells such as eosinophils and basophils, inducing their apoptosis through an antibody-dependent cell-mediated cytotoxicity mechanism [
12]. The efficacy and safety of benralizumab in SA were demonstrated in three pivotal phase 3 trials: SIROCCO (ClinicalTrials.gov NCT01928771) [
13], CALIMA (ClinicalTrials.gov NCT01914757) [
14], and ZONDA (ClinicalTrials.gov NCT02075255) [
15], which included nearly 3000 patients. Based on all the findings that confirmed a reduction in asthma exacerbations, improved lung function and asthma control, and reduction or elimination of the use of OCS, benralizumab obtained its marketing authorization in Europe in 2018 and was indicated as an adjunctive maintenance therapy for the management of adult patients with uncontrolled SEA. Integrated analyses of results from the pivotal and extension studies for up to 5 years of follow-up confirmed the long-term safety and efficacy of benralizumab [
16‐
19]. The open-label, phase 3 PONENTE trial (ClinicalTrials.gov NCT03557307) showed that SEA patients treated with benralizumab could significantly reduce the use of OCS and even achieve complete OCS withdrawal, along with sustained or improved asthma control and a reduction in exacerbations using a personalised steroid-sparing strategy and an adrenal function assessment scheme that have been included in recent consensuses and guidelines [
7,
20].
SA may be associated with CRSwNP in up to 40-45% of cases [
21‐
24]. Asthma patients with concomitant CRSwNP often have increased airway obstruction, reduced asthma control, higher blood eosinophil and fraction of exhaled nitric oxide (FeNO) levels, a significantly higher number of asthma exacerbations per year, and greater reliance on OCS. Several studies, such as the phase 3 ANDHI trial (ClinicalTrials.gov, NCT03170271) have identified the presence of nasal polyposis (NP) in SA patients as a predictor of response to benralizumab and showed enhanced effects related to benralizumab in patients with concomitant CRSwNP [
25‐
27].
The aim of the retrospective ORBE II study (as part of the XALOC programme, which includes more than 1500 patients from across nine countries and aims to assess the real-world effectiveness of benralizumab) was to characterise the profile of SEA patients, including the subset of patients with concomitant CRSwNP treated with benralizumab in real-life conditions in Spain and to analyse the benefits of benralizumab in several SEA domains. In addition, we present a post-hoc analysis of response and clinical remission.
Methods
Study design
ORBE II (ClinicalTrials.gov NCT04648839) was a multicentre, observational, retrospective cohort study of adult patients (≥ 18 years) diagnosed with SEA who were prescribed benralizumab by asthma specialists (pulmonologist/allergist) as per routine clinical practice after it was granted marketing authorization in Spain (January 2019). Patients fulfilled the currently approved European indication for benralizumab as an add-on therapy for adult patients with severe eosinophilic uncontrolled asthma despite being treated with high-dosage inhaled corticosteroids and long-acting β agonists. Patients who received benralizumab in a clinical trial during the observation period were not included. The primary objective was to characterise the profile and treatment patterns of SEA patients requiring benralizumab treatment. For this objective, patients who received at least one dose of benralizumab according to clinical practice were considered. The secondary objective was to evaluate clinical outcomes in all patients included who received at least three doses of subcutaneous benralizumab (30 mg every 4 weeks for the first three doses, and every 8 weeks thereafter) during follow-up.
Data were obtained retrospectively from the electronic medical records of the 15 participating asthma units. The index date was defined as the date of the first dose of benralizumab, which had to have occurred in the period between 1 and 2019 and 3 months before the specific study site initiation. The end of the follow-up period was up to enrolment of the patient in the study, allowing for a minimum of 3 months of follow-up. In this paper, we present the results corresponding to the first 12 months of follow-up.
Baseline sociodemographic and clinical data corresponded to the closest measure to index date, within the previous 12-month period. Data collected at baseline included age, sex, smoking habits, height, weight, body mass index (BMI), biomarkers (eosinophil counts in peripheral blood, total IgE levels and FeNO), asthma medications (including previous biological treatments) and asthma comorbidities (including CRSwNP).
Data on lung function (including forced expiratory volume in 1 s [FEV
1], predicted FEV
1%, forced vital capacity [FVC], and FEV
1/FVC), asthma control (Asthma Control Test [ACT] [
28,
29]), use of systemic/oral corticosteroids (CS) and exacerbations (referred to severe exacerbations, i.e., those requiring the use of systemic CS or the increase of the maintenance dose of OCS for at least three days or, hospitalization or emergency room visits due to asthma requiring the use of systemic CS) were collected to characterise the patients’ clinical outcomes in the year prior to and after benralizumab initiation. For the purpose of this analysis, corticosteroid-dependent patients were defined as those who received maintenance systemic CS treatments for at least 3 months within the 12 months prior to the index date. All the above-listed clinical variables were assessed for the overall population (OP) during follow-up and were also evaluated in the subgroups of patients with and without concomitant CRSwNP.
Additional analyses were performed to evaluate the degree of response to benralizumab based on previously published definitions. Super-responders to benralizumab have been commonly defined as those patients achieving complete exacerbation elimination and cessation of maintenance OCS use [
11,
30]. Clinical remission is a more recent concept in SA and has been defined as the absence of exacerbations for 12 months, absence of significant symptoms, a relevant improvement in lung function, and no use of OCS for at least 12 months [
10]. Based on these definitions, the following four pre-defined key criteria were used in our analyses to identify patients achieving a super-response to benralizumab and asthma clinical remission: no exacerbations; pre-bronchodilator (BD) FEV
1 increase ≥ 100 mL; ACT score ≥ 20; and no maintenance OCS use.
Statistical analysis
A descriptive statistical analysis was performed. General descriptive statistics for continuous numerical variables included the number of observations, mean, standard deviation (SD), and additionally, the median and quartiles 1 and 3 (Q1-Q3) when considered appropriate. For categorical variables, the frequency distribution and percentage of subjects with a certain event/characteristic was presented.
Missing values were not considered for calculating percentages or any other descriptive estimator, meaning that only valid values are presented. No use of any method for the handling of missing data was anticipated.
In accordance with the original study design, the results shown are purely descriptive. No p-values are presented (i.e., no formal hypothesis testing or multivariate analysis has been performed) since neither the study design nor the corresponding sample size estimation allow for this type of analysis.
The analysis was performed using the IBM SPSS Statistics software, Version 26.0 (IBM Corp. Armonk, NY).
Discussion
The ORBE II study, as part of the XALOC programme, is one of the largest real-world studies on benralizumab at international level and the largest one presented in Spain to date. The first real-life studies assessing the therapeutic effect of benralizumab in small SEA patient cohorts confirmed a rapid gain in asthma control and lung function, a significant reduction or elimination of exacerbations and maintenance OCS use, and a decrease in the number of ED visits [
30‐
34]. More importantly, data from these studies confirmed that the improvement in all these clinical outcomes was sustained and even increased over time. Several findings from real-world studies within the XALOC programme supported the effectiveness of benralizumab and its capacity to induce clinical remission in patients [
35‐
38].
The profile of our ORBE II cohort was representative of the SEA population. This was mainly defined by: high levels of T2 inflammation biomarkers (73% of patients presented eosinophil counts ≥ 300 cells/µL and 37% of patients had FeNO levels ≥ 50ppb); CRSwNP as the most common comorbidity (36.8% of patients); late asthma onset (mean age of asthma onset was ≥ 30 years), frequent exacerbations (≥ 2 in a year); compromised lung function; poor symptom control; and high OCS use. Most of these features were indicative of a strong eosinophilic phenotype [
2,
8,
39] and, moreover, were valuable predictors of enhanced responses to benralizumab, as confirmed by previous real-world evidence [
25,
27,
30,
40]. High eosinophil counts and FeNO concentrations are indicators of increased exacerbation risk [
41]. After 1 year of FUP, we observed a significant drop in both biomarkers in patients on benralizumab. These findings are consistent with prior evidence [
36], and could be closely related to the mechanisms underlying the antibody-dependent cellular cytotoxicity of benralizumab on eosinophils and basophils [
12,
42].
Interestingly, a large subset of patients in the ORBE II cohort (1 out of 4) presented low eosinophil counts (< 300 cells/µL) at baseline, a particular subset of patients in whom a positive response to benralizumab was previously shown [
25,
32]. It is important to note that the use of high-dose ICS or OCS has been related to reduced eosinophil levels [
43,
44], and that these levels may vary over time [
45], so lower eosinophil counts at one time point may not be enough to characterise eosinophilic patients.
According to data collected on previous treatment patterns, most of the OP of our study (almost 70%) was biologic-naïve and showed marked eosinophilia, more frequent exacerbations and worse asthma control than switch patients (data not shown). Switch patients had discontinued other previous biological treatments mostly due to lack of response. The overall improved outcomes observed after 1 year of FUP were in line with previous findings showing that benralizumab could even benefit SA patients unresponsive to other biologics targeting the IL-5 or IgE pathways [
36,
46‐
49]. However, naïve patients showed a higher response, thus highlighting the importance of correct patient phenotyping and choice of biologic.
The objectives of SEA treatment have been clearly defined by clinical guidelines, and recommend a stepwise therapeutic strategy aimed at reducing the risk of severe attacks and optimizing symptom control, as well as monitoring the response to therapy to confirm that clinical objectives are achieved [
1,
3]. Asthma exacerbations are probably the main contributors to the burden of SA and are commonly defined as the requirement for systemic maintenance treatment with OCS and their association with hospitalization or ED visits and lung function deterioration [
50]. Thus, the reduction or even elimination of exacerbations, which should also have a positive impact in terms of reducing OCS use, is one of the key goals of SA management [
19,
51]. In our cohort, 81.4% of patients on benralizumab achieved zero exacerbations after 1 year of FUP and we found a remarkable 85.6% reduction in severe exacerbations, which is consistent with the results of published analyses of the XALOC programme [
38,
52].
This reduction in severe exacerbations was achieved in a context in which the median [Q1-Q3] daily dose of maintenance OCS in cortico-dependent patients was drastically reduced from 15 [6.3–29.0] to 0.0 [0.0-8.3] mg, in line with reports from other cohorts of SEA patients treated with benralizumab [
30,
36,
53]. For decades, OCS have been a valuable long-term treatment in the management of uncontrolled SA patients at risk of repeated severe exacerbations or with poor asthma control. Because of the known OCS-related adverse effects and their associated health-related costs in the short and long term [
54‐
57], current clinical guidelines recommend biologics as the preferred and safer alternative to long-term OCS [
3], and suggest that a reduction or even total elimination of OCS be pursued as a fundamental therapeutic goal in SA [
7,
58,
59].
The OCS-sparing effect of benralizumab in SEA patients was confirmed in the ZONDA clinical trial, and even expanded in the PONENTE study, which showed that this benefit was independent of the blood eosinophil count at baseline [
60,
61]. These data were further supported by real-world evidence [
15,
16,
30,
62]. In the ORBE II cohort, 53% of OCS-dependent patients on benralizumab discontinued OCS after 1 year of FUP. Furthermore, reduction or elimination of exacerbations help to minimize OCS use, as each exacerbation treated with OCS contributes to its detrimental accumulation.
A real-world study in Spain estimated the 1-year cumulative OCS dose in 2019 to be more than 1 g per SA patient [
63], showing that there is still high OCS overuse even with the current availability of alternative therapeutic approaches such as biologics. In this sense, a recent Spanish multidisciplinary consensus highlights the need to monitor the cumulative OCS dose, and strongly recommends that patients receiving a cumulative OCS dose of ≥ 0.5 g per year should be provided with alternative therapeutic options [
7]. Our own analyses estimated that the cumulative OCS dose over 1 year of FUP, if patients had remained on their baseline dose, would have been 7.1 g, which is seven times higher than the recommended annual limit of 0.5 to 1 g per year.
Benralizumab-mediated OCS tapering has been shown to effectively reduce the cumulative OCS dosage over time [
18]. Our estimations pointed to a mean reduction in cumulative OCS exposure of 5.0 g after 1-year FUP in our cohort of patients on benralizumab. It is important to highlight that these estimations did not take into account the reduction in OCS use associated with the drop in exacerbations while on benralizumab treatment.
As already mentioned, improved lung function and asthma symptom control are other fundamental goals of SA treatment. The mean (SD) increase in pre-BD FEV
1 of 331 (413) mL confirmed in our cohort after 1 year of FUP was even better than the results reported in the pivotal SIROCCO [
13] and CALIMA [
14] trials, which confirmed an FEV
1 gain of 159 mL and 116 mL vs. placebo, respectively, after benralizumab. This was accompanied by a remarkable increase in the ACT score of a mean of almost 7 points. Moreover, approximately three out of four patients in the ORBE II cohort achieved an ACT score ≥ 20, which is an indicator of well-controlled asthma [
64].
The assessment of response of SA patients to biologics must be multidimensional [
65]. Most published definitions of response and asthma clinical remission rely, in fact, on composite measures of treatment response. Up to four measurable domains are the most frequently considered at the time to evaluate the response of SA to treatment (severe exacerbations, asthma control, OCS use and lung function), although the stringency of the number of criteria and cut-offs established to determine the degree of response or clinical remission is more controversial [
4,
10,
11,
66]. The real-world studies conducted by Kavanagh et al. [
30] and Jackson et al. [
36] identified 39% and 57.2% of super-responders to benralizumab in their respective cohorts according to the combination of two pre-defined outcomes: zero exacerbations and no maintenance OCS use. Taking into account the same definition, integrated analyses of the international real-world XALOC-1 study estimated the proportion of super-responders to be 60% [
38]. Miralles-López et al. [
67] reported that 63% of patients met these super-responder criteria. Additionally, the real-world study by Padilla-Galo et al. [
68] found that 59.1% of patients met this super-responder definition. Based on these standards, a higher proportion of patients (7 out of 10) in our ORBE II cohort were identified as super-responders to benralizumab after 1-year FUP.
A more stringent definition was proposed by the Spanish Severe Asthma Consensus [
4]. The complete response criteria included all the following: absence of exacerbations; no maintenance OCS use; ACT score ≥ 20 points; and pre-BD FEV
1 ≥ 80% of predicted. Following this definition, Miralles-López et al. [
67] and Padilla-Galo et al. [
68] identified 36.6% and a 27.3% of complete responders in their cohorts, respectively.
These criteria were in line with the general framework for asthma clinical remission proposed by Menzies-Gow et al. (2020) [
10], which required the stabilisation of lung function and the absence for at least 12 months of significant asthma symptoms and severe exacerbations. The key variables of asthma remission included the elimination of asthma exacerbations, complete withdrawal of OCS, and improvement in asthma control and lung function. Based on this definition, we found that almost half of our cohort of SEA patients receiving benralizumab treatment (43.7%) fulfilled four established criteria defining clinical remission. It should be noted that most of our OP treated with benralizumab met at least 1–3 of the response criteria after 1-year FUP. Taking into account all evaluated criteria, an FEV1 ≥ 80% is the criterion that is more difficult to achieve. In fact, the results in the subset of patients with baseline FEV
1 below 80% and 60% suggests that difficulty in achieving such criterion increases with a more compromised lung function. Therefore, this may be due to the deterioration in lung function that occurred before treatment initiation and could indicate the need to start biologic treatment earlier in the course of the disease.
Data from clinical trials have suggested that SA patients presenting concomitant CRSwNP achieved enhanced responses to benralizumab and improvements in parameters linked to this comorbidity, such as SNOT-22 [
25,
27]. This was also confirmed in the real-world setting [
35,
53,
69]. In our cohort, we observed that clinically relevant responses to benralizumab were confirmed regardless of the presence of concomitant CRSwNP. Nevertheless, improved clinical outcomes in some parameters such as lung function and reduction in OCS use were observed in the subset of patients with concomitant CRSwNP, supporting the particular benefits of benralizumab in this SEA patient subpopulation.
Our study has limitations that are inherent to its retrospective and real-world nature. First of all, a single-arm study does not allow to demonstrate the benefit of a specific treatment versus a standard of care approach. Incomplete information or loss of data during patient follow-up did not allow us to provide a complete characterization of clinical outcomes in the subgroup analyses. Additionally, no sensitivity analyses were performed to discard any bias in results due to heterogeneity in selection criteria or procedures and data collection among sites. Despite these limitations, the strengths of this study include the large sample size and high number of specialised asthma units throughout Spain and the lack of highly restrictive inclusion criteria which make these results representative of the SEA real-world population treated with benralizumab. As an additional strength, this work includes information on innovative aspects such as cumulative OCS dose and asthma remission, for which there are few published studies at present.
Declarations
Competing interests
AP-G: Personal fees and non-financial support: AstraZeneca, Novartis, GSK, Sanofi-Genzyme and Teva; ALN: Personal fees: AstraZeneca; non-financial support: Sanofi-Genzyme; IMC: Personal fees: AstraZeneca and Novartis; non-financial support: AstraZeneca; PA: Personal fees and non-financial support: AstraZeneca, Sanofi-Genzyme and GSK; LCF: Personal fees: AstraZeneca, Novartis, GSK and Teva; non-financial support: Sanofi-Genzyme; IG-M: Personal fees and non-financial support: AstraZeneca, GSK, Teva, Novartis, Sanofi-Genzyme; JLV-G: Personal fees: AstraZeneca, Sanofi-Genyme and GSK; non-financial support: AstraZeneca; RA-E: Personal fees and non-financial support: AstraZeneca, GSK, Teva, Novartis and Sanofi-Genzyme; FC-M: Personal fees and non-financial support: AstraZeneca, GSK, Novartis, Sanofi-Genzyme and Teva; EM-M: Personal fees: AstraZeneca, GSK and Sanofi-Genzyme; non-financial support: AstraZeneca; CMR: Personal fees: AstraZeneca, Novartis, GSK, Teva and Sanofi-Genzyme; non-financial support: AstraZeneca, GSK and Teva; EVS: Personal fees: AstraZeneca, GSK, Novartis and Sanofi-Genzyme; non-financial support: Sanofi-Genzyme and GSK; FS-TL: Personal fees: AstraZeneca, GSK, Novartis, Teva and Sanofi-Genzyme; non-financial support: AstraZeneca, GSK, Novartis and Sanofi-Genzyme; ATA: Personal fees and non-financial support: AstraZeneca, GSK, Sanofi-Genzyme and Novartis; MBA: Personal fees and non-financial fees from AstraZeneca, Teva, Sanofi-Genzyme and GSK; MV-M: Personal fees and non-financial support: AstraZeneca and GSK; BVA: Personal fees: AstraZeneca, Novartis, GSK and Sanofi-Genzyme; non-financial support: Teva; MPC: Personal fees and non-financial support: AstraZeneca, GSK, Teva, Novartis and Sanofi-Genzyme; JN, JST, GR and EL: employees of AstraZeneca.
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