Graphical abstract
Tezepelumab treatment was associated with an increased likelihood of achieving a complete clinical response and on-treatment clinical remission versus placebo in patients with severe, uncontrolled asthma. Clinical response data are taken from the NAVIGATOR phase 3 trial (52 weeks). Clinical remission data are taken from the DESTINATION phase 3 trial (104 weeks). BD: bronchodilator; BEC: blood eosinophil count; FENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s.
Abstract
Background
In asthma, clinical response is characterised by disease improvement with treatment, whereas clinical remission is characterised by long-term disease stabilisation with or without ongoing treatment. The proportions of patients receiving tezepelumab who responded to treatment and who achieved on-treatment clinical remission were assessed in the NAVIGATOR (ClinicalTrials.gov identifier NCT03347279) and DESTINATION (ClinicalTrials.gov identifier NCT03706079) studies of severe, uncontrolled asthma.
Methods
NAVIGATOR and DESTINATION were phase 3, randomised, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physician's assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed.
Results
Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0–52 (46% versus 24%; OR 2.83, 95% CI 2.10–3.82) and on-treatment clinical remission over weeks 0–52 (28.5% versus 21.9%; OR 1.44, 95% CI 0.95–2.19) and weeks >52–104 (33.5% versus 26.7%; OR 1.44, 95% CI 0.97–2.14). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarker levels at baseline, and fewer exacerbations in the 12 months before the study.
Conclusions
Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes, but may be driven by different patient characteristics.
Shareable abstract
Tezepelumab treatment was associated with an increased likelihood of achieving a complete clinical response over 52 weeks as well as achieving on-treatment clinical remission over 2 years in patients with severe, uncontrolled asthma https://bit.ly/3TiAkA7
Introduction
Globally, ∼262 million people are affected by asthma [1], resulting in a significant healthcare and economic burden [2]. Asthma is a heterogeneous, chronic lung disease that affects both adults and children [2]. Different underlying disease processes give rise to multiple clinical asthma phenotypes, thereby contributing to the complexity of treatment strategies, particularly because many patients with asthma have overlapping phenotypes (e.g. both eosinophilic and allergic) [3].
Severe asthma may be defined as asthma that remains uncontrolled despite treatment with high-dose inhaled corticosteroids (ICS) plus a long-acting β2-agonist (with or without oral corticosteroids (OCS)) and treatment of contributory factors, or as asthma that worsens when high-dose treatment is decreased [4, 5]. Patients with severe asthma may be prescribed biologic therapies as adjuncts to reduce exacerbations, reduce OCS exposure and improve disease control [5]. Tezepelumab targets thymic stromal lymphopoietin (TSLP), an epithelial cytokine that has multifaceted effects on the initiation and persistence of inflammation in asthma [6]. Inhibition of TSLP by tezepelumab is associated with reduced numbers of occlusive mucus plugs and reduced airway hyperresponsiveness, probably due to effects on eosinophils, mucus production, mast cells and airway smooth muscle cells [6–9]. Tezepelumab is approved for the treatment of severe asthma without phenotypic restrictions [10, 11]. In the phase 3 NAVIGATOR study (ClinicalTrials.gov identifier NCT03347279), tezepelumab reduced the annualised asthma exacerbation rate and improved lung function, asthma control and health-related quality of life (HRQoL) compared with placebo in patients with severe, uncontrolled asthma [12]. Patients who completed treatment in NAVIGATOR could enrol into the DESTINATION long-term extension study (ClinicalTrials.gov identifier NCT03706079). In DESTINATION, tezepelumab treatment was well tolerated for up to 2 years and, consistent with the NAVIGATOR study, resulted in sustained, clinically meaningful reductions in asthma exacerbations, with improved lung function, asthma control and HRQoL [13].
In recent years, the treatment goals for severe asthma have shifted from clinical response to clinical remission and, ultimately, to disease modification. Clinical response is typically based on achieving improvements surpassing minimum clinically important differences (MCIDs) in single outcome measures of symptoms, asthma control or HRQoL [14]. However, definitions are not standardised [15]. Some patients with severe asthma achieve a good response to biologics which can be predicted to some extent by their baseline inflammatory profile [14, 16], but may never achieve disease remission. It is anticipated that earlier intervention with potentially disease-modifying therapies such as biologics will provide long-term benefits to patients with severe asthma [17, 18].
Remission now appears to be a feasible treatment goal in asthma, having been successfully implemented as a goal in other chronic inflammatory conditions [18–20]. Currently, there are no standard, globally accepted criteria for asthma remission; however, the concept has been incorporated into several national guidelines for asthma [21]. Proposed criteria for achieving clinical remission from asthma societies and consensus groups generally include ≥12 months with no significant symptoms, no exacerbations, stable and optimised lung function and no use of systemic corticosteroids [17, 22–30], although some recent studies have also assessed remission both with and without using a lung function criterion [31–33]. Patients meeting some but not all criteria achieve partial clinical remission. Clinical remission definitions may be used for patients on treatment or off treatment, but definitions for patients off treatment typically also require no asthma treatment for ≥12 months [22]. Complete remission requires both clinical remission and normalisation of the underlying pathology (i.e. biological remission), indicated by low levels of inflammatory biomarkers and, if appropriate, negative bronchial hyperresponsiveness [22].
This study assessed the effect of tezepelumab on clinical response (in NAVIGATOR) and on-treatment clinical remission (in DESTINATION) in patients with severe, uncontrolled asthma.
Methods
Study design
NAVIGATOR and DESTINATION were phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies of patients with severe, uncontrolled asthma. Patients who were randomised to receive tezepelumab 210 mg every 4 weeks for 52 weeks in NAVIGATOR continued receiving this dosing regimen for 52 weeks in DESTINATION, whereas those who received placebo in NAVIGATOR were re-randomised 1:1 to receive either tezepelumab 210 mg every 4 weeks or placebo in DESTINATION [13].
Participants
Patients (aged 12–80 years) in NAVIGATOR had physician-diagnosed asthma and had been receiving medium- or high-dose ICS (fluticasone propionate ≥500 µg·day−1 or equivalent) for ≥12 months before screening and at least one additional controller medication, with or without OCS, for ≥3 months before the date of informed consent [12].
Patients must have had an Asthma Control Questionnaire (ACQ)-6 score of ≥1.5 and at least two asthma exacerbations in the previous year that led to hospitalisation or an emergency department visit that resulted in systemic corticosteroid treatment. A broad population of adults and adolescents were enrolled in NAVIGATOR, including those with baseline blood eosinophil counts (BECs) of <300 cells·μL−1 (58.4% of patients) and ≥300 cells·μL−1 (41.6% of patients). Full details of the study design and inclusion and exclusion criteria have been published previously [12, 13].
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Council for Harmonisation good clinical practice guidelines, and applicable regulatory requirements. Approvals from local independent ethics committees were obtained, and all patients or their legal guardians provided written informed consent in accordance with local requirements.
Outcomes
As part of a pre-specified exploratory analysis, the proportions of partial and complete clinical responders in NAVIGATOR over 52 weeks were assessed. The proportions of clinical responders were evaluated for each of the four clinical response criteria assessed: a reduction in exacerbations of ≥50% versus the previous year; physician's assessment of improvement, expressed as a Clinical Global Impression of Change score (minimally improved, much improved or very much improved); improvement from baseline of ≥100 mL (the MCID) or ≥5% in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1); and improvement from baseline of ≥0.5 (the MCID) in ACQ-6 score. Partial clinical responders were defined as those who met between one and three of these criteria, and complete clinical responders were defined as those meeting all four criteria in this analysis (figure 1).
FIGURE 1.
Clinical response and clinical remission definitions used in this analysis and summary of clinical remission definitions from the literature. CGI-C: Clinical Global Impression of Change; ACQ: Asthma Control Questionnaire; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; OCS: oral corticosteroid; BEC: blood eosinophil count; FENO: fractional exhaled nitric oxide; ACAAI: American College of Allergy, Asthma and Immunology; AAAAI: American Academy of Allergy, Asthma, and Immunology; ATS: American Thoracic Society; ACT: Asthma Control Test; AirQ: Asthma Impairment and Risk Questionnaire; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; GINA: Global Initiative for Asthma; SABA: short-acting β2-agonist. #: clinical response was measured at week 52 of NAVIGATOR; ¶: physician's assessment of improvement was expressed as a CGI-C score and was defined as minimally improved, much improved or very much improved; +: the minimum clinically important difference in ACQ-6 score is 0.5; §: on-treatment clinical remission was measured across multiple time points over the 2 years of DESTINATION.
As part of a post hoc analysis, the proportions of patients in NAVIGATOR who achieved on-treatment clinical remission in DESTINATION were assessed over the following time points: weeks 0–24, weeks >24–52, weeks 0–52 and weeks >52–104. On-treatment clinical remission was defined as meeting all of the following criteria (figure 1): ACQ-6 total score ≤1.5 (controlled asthma) at the end of the period assessed; a pre-BD FEV1 of >95% of the baseline level at the end of the period assessed; no use of OCS during the period assessed; and no asthma exacerbations during the period assessed. Spirometry assessments in clinical practice have inherent variability and two FEV1 measurements within 5% of each other are generally considered to be an acceptably reproducible result [34]. Therefore, for the lung function criterion, a pre-BD FEV1 of >95% of the baseline value was selected for this analysis to be confident that a patient's lung function was stable from baseline to the end of the treatment period and that it had not declined. Additional details and end-points related to clinical remission can be found in the supplementary methods.
Statistical analyses
Clinical response and on-treatment clinical remission rates were compared between treatment groups using logistic regression models, with treatment, region and age group as covariates. Full details of the statistical analyses are provided in the supplementary methods.
Results
Overall, in NAVIGATOR, 528 patients received tezepelumab and 531 received placebo, of whom 431 and 420, respectively, both completed the on-treatment period and had data available to assess clinical response criteria. Across the individual clinical response criteria, there were higher proportions of responders in the tezepelumab group than in the placebo group (figure 2 and supplementary figure S1). Compared with placebo, a higher proportion of patients who received tezepelumab achieved a complete clinical response (i.e. met all four response criteria) over 52 weeks (24% versus 46%, respectively (figure 2); OR 2.83, 95% CI 2.10–3.82 (supplementary figure S1)). There were 19 (4.0%) and 35 (7.6%) patients in the tezepelumab and placebo groups, respectively, who did not meet any of the four clinical response criteria (nonresponders). Baseline demographics and clinical characteristics were generally similar between on-treatment complete and partial/nonresponder subgroups (supplementary table S1). Compared with placebo, a greater proportion of complete clinical responders in the tezepelumab group were receiving maintenance OCS at baseline, had more than two exacerbations in the 12 months before the study, had higher baseline BECs and had higher baseline fractional exhaled nitric oxide (FENO) levels.
FIGURE 2.
The proportion of patients receiving a) tezepelumab 210 mg every 4 weeks and b) placebo with individual and overlapping components of clinical response at week 52. Results are reported as n (%). ACQ: Asthma Control Questionnaire; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; CGI-C: Clinical Global Impression of Change.
Of the patients included in the on-treatment clinical remission analysis, the baseline demographics and clinical characteristics were generally well balanced between those receiving tezepelumab (n=379) and placebo (n=187) (supplementary table S2). Over weeks 0–52 (year 1), 28.5% of patients receiving tezepelumab and 21.9% of patients receiving placebo achieved on-treatment clinical remission (OR 1.44, 95% CI 0.95–2.19) (figure 3). Over weeks >52–104 (year 2), 33.5% of patients receiving tezepelumab and 26.7% of patients receiving placebo achieved on-treatment clinical remission (OR 1.44, 95% CI 0.97–2.14) (figure 3). The proportion of patients receiving tezepelumab versus placebo who achieved on-treatment clinical remission was 33.3% versus 30.5%, respectively, over weeks 0–24 (OR 1.15, 95% CI 0.79–1.69), and 37.2% versus 26.2%, respectively, over weeks >24–52 (OR 1.69, 95% CI 1.14–2.50) (figure 4). Findings over weeks >52–104 where patients with missing data at week 104 were assumed not to have achieved clinical remission (supplementary figure S2) were similar to those presented in figures 3 and 4. Experiencing an exacerbation was the most frequent reason why clinical remission was not achieved over year 1 or year 2 among patients receiving tezepelumab (supplementary figure S3; data for placebo are shown in supplementary figure S4).
FIGURE 3.
The proportion of patients receiving tezepelumab 210 mg every 4 weeks or placebo who achieved on-treatment clinical remission during weeks 0–52 and weeks >52–104. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. An OR of >1 favours tezepelumab. There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
FIGURE 4.
The proportion of patients receiving a) tezepelumab 210 mg every 4 weeks and b) placebo who achieved on-treatment clinical remission criteria over weeks 0–24, >24–52 and >52–104. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire (ACQ)-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. Blue shading indicates the proportion of patients over weeks 0–24, >24–52 and >52–104 who met all four remission criteria since the previous period. At baseline, the purple shading represents patients who met both the study inclusion criterion and the remission criterion for ACQ-6 score (i.e. a score of ≤1.5). There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
The proportions of patients who achieved on-treatment clinical remission over weeks 0–24 and remained in clinical remission throughout the on-treatment period are shown in figure 5.
FIGURE 5.
The proportions of patients receiving tezepelumab 210 mg every 4 weeks or placebo who achieved clinical remission in weeks 0–24, and then remained in clinical remission throughout the on-treatment period. In this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-bronchodilator forced expiratory volume in 1 s criteria. There was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52.
Among patients receiving tezepelumab, those who achieved on-treatment clinical remission over weeks 0–24, >24–52 and >52–104 had a higher baseline pre-BD FEV1 and higher baseline BECs and FENO levels than those who did not achieve on-treatment clinical remission over these time points (table 1; data for placebo are shown in supplementary table S3). Tezepelumab treatment was associated with a reduction in baseline BECs and FENO levels from baseline to week 104, in patients regardless of on-treatment clinical remission status over weeks >52–104, indicated by an increase in the proportion of patients with a BEC of <150 cells·μL−1 and a FENO level of <25 ppb (table 2).
TABLE 1.
Baseline demographics and clinical characteristics for patients receiving tezepelumab 210 mg every 4 weeks who achieved and did not achieve clinical remission over weeks 0–24, >24–52 and >52–104#
| Achieved remission | Did not achieve remission | |||||
|---|---|---|---|---|---|---|
| 0–24 weeks | >24–52 weeks | >52–104 weeks¶ | 0–24 weeks | >24–52 weeks | >52–104 weeks¶ | |
| Patients | 126 | 141 | 127 | 244 | 228 | 247 |
| Age years | 48.4±17.3 | 48.9±17.3 | 49.0±17.9 | 50.1±16.0 | 50.1±15.5 | 50.2±15.3 |
| Female | 72 (57.1) | 81 (57.4) | 76 (59.8) | 160 (65.6) | 151 (66.2) | 158 (64.0) |
| BMI kg·m−2 | 27.9±6.1 | 28.4±6.3 | 28.1±6.3 | 29.6±7.8 | 29.5±7.8 | 29.5±7.6 |
| ICS dose group + | ||||||
| Medium | 39 (31.0) | 38 (27.0) | 26 (20.5) | 53 (21.7) | 51 (22.4) | 66 (26.7) |
| High | 87 (69.0) | 103 (73.0) | 101 (79.5) | 191 (78.3) | 177 (77.6) | 181 (73.3) |
| Pre-BD FEV1 L | 1.98±0.68 | 1.94±0.69 | 1.92±0.70 | 1.76±0.69 | 1.77±0.70 | 1.78±0.70 |
| Pre-BD FEV1 % predicted | 64.8±16.4 | 64.9±16.7 | 64.9±16.4 | 61.2±17.6 | 60.8±17.5 | 60.8±17.5 |
| FEV1 reversibility % | 15.6±15.2 | 15.5±14.9 | 16.2±16.4 | 13.7±13.8 | 13.9±14.3 | 13.9±13.5 |
| Age at asthma onset years | 27.9±20.2 | 26.0±20.1 | 26.4±19.5 | 24.8±19.2 | 25.8±19.1 | 25.9±19.6 |
| Duration of disease years | ||||||
| <20 | 9.5±4.8 | 9.4±5.1 | 9.9±4.8 | 9.6±5.2 | 9.8±5.1 | 9.4±5.2 |
| ≥20 | 34.9±12.6 | 36.0±11.6 | 36.1±12.1 | 39.3±12.4 | 39.4±12.9 | 38.9±12.7 |
| Duration of disease years | ||||||
| <20 | 73 (57.9) | 71 (50.4) | 67 (52.8) | 117 (48.0) | 118 (51.8) | 124 (50.2) |
| ≥20 | 53 (42.1) | 70 (49.6) | 60 (47.2) | 127 (52.0) | 110 (48.2) | 123 (49.8) |
| Exacerbations in the 12 months before enrolment in NAVIGATOR | ||||||
| 2 | 78 (61.9) | 92 (65.2) | 79 (62.2) | 150 (61.5) | 139 (61.0) | 154 (62.3) |
| >2 | 48 (38.1) | 49 (34.8) | 48 (37.8) | 94 (38.5) | 89 (39.0) | 93 (37.7) |
| FENO level ppb | ||||||
| Mean±sd | 42.9±35.5 | 43.2±35.7 | 42.0±34.0 | 38.9±33.7 | 37.5±32.5 | 38.6±33.7 |
| Median (min–max) | 33.5 (5.0–213.0) | 33.0 (5.0–213.0) | 33.0 (6.0–173.0) | 29.0 (5.0–198.0) | 27.5 (5.0–198.0) | 28.0 (5.0–213.0) |
| FENO group ppb | ||||||
| <25 | 48 (38.7) | 52 (37.1) | 49 (39.8) | 108 (45.0) | 104 (46.4) | 109 (44.5) |
| ≥25 to <50 | 35 (28.2) | 43 (30.7) | 35 (28.5) | 66 (27.5) | 61 (27.2) | 70 (28.6) |
| ≥50 | 41 (33.1) | 45 (32.1) | 39 (31.7) | 66 (27.5) | 59 (26.3) | 66 (26.9) |
| BEC cells·µL−1 | ||||||
| Mean±sd | 380±399 | 366±370 | 348±373 | 296±235 | 291±242 | 309±256 |
| Median (min–max) | 295 (0–3650) | 300 (0–3650) | 280 (0–3650) | 235 (10–1680) | 220 (10–1680) | 240 (0–1680) |
| BEC group cells·µL−1 | ||||||
| <150 | 24 (19.0) | 28 (19.9) | 28 (22.0) | 67 (27.5) | 64 (28.1) | 65 (26.3) |
| 150 to <300 | 39 (31.0) | 42 (29.8) | 39 (30.7) | 87 (35.7) | 85 (37.3) | 89 (36.0) |
| <300 | 63 (50.0) | 70 (49.6) | 67 (52.8) | 154 (63.1) | 149 (65.4) | 154 (62.3) |
| ≥300 | 63 (50.0) | 71 (50.4) | 60 (47.2) | 90 (36.9) | 79 (34.6) | 93 (37.7) |
| 300 to <450 | 30 (23.8) | 31 (22.0) | 32 (25.2) | 44 (18.0) | 42 (18.4) | 42 (17.0) |
| ≥450 | 33 (26.2) | 40 (28.4) | 28 (22.0) | 46 (18.9) | 37 (16.2) | 51 (20.6) |
| Serum total IgE IU·mL−1 | ||||||
| Mean±sd | 518.1±833.9 | 557.7±1207.7 | 508.3±695.2 | 537.7±1093.6 | 512.6±871.0 | 540.4±1136.3 |
| Median (min–max) | 225.9 (1.5–6412.4) | 239.0 (1.5–12 823.2) | 235.5 (1.5–3664.7) | 193.6 (1.5–12 823.2) | 194.0 (1.5–6412.4) | 194.4 (1.5–12 823.2) |
| FEIA positive for any perennial aeroallergen§ | 81 (64.3) | 90 (63.8) | 78 (61.4) | 154 (63.1) | 145 (63.6) | 160 (64.8) |
| Nasal polyps | 29 (23.0) | 27 (19.1) | 25 (19.7) | 42 (17.2) | 44 (19.3) | 47 (19.0) |
Data are presented as n, mean±sd or n (%), unless otherwise stated. BMI: body mass index; ICS: inhaled corticosteroid; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; FENO: fractional exhaled nitric oxide; BEC: blood eosinophil count; Ig: immunoglobulin; FEIA: fluorescence enzyme immunoassay. #: there was one patient receiving tezepelumab who stopped oral corticosteroid use in DESTINATION and did achieve on-treatment clinical remission at week 52; ¶: in this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-BD FEV1 criteria; +: medium-dose ICS: fluticasone propionate 500 µg·day−1 or equivalent; high-dose ICS: fluticasone propionate >500 µg·day−1 or equivalent; §: positive for at least one perennial aeroallergen (cat dander, dog dander, cockroach, dust mite (Dermatophagoides farinae, D. pteronyssinus) and mould mix).
TABLE 2.
Proportions of patients who achieved and did not achieve clinical remission at week 104 with low or high levels of inflammatory biomarkers at time points from baseline to week 104
| Achieved remission at week 104# | Did not achieve remission at week 104# | |
|---|---|---|
| Tezepelumab 210 mg every 4 weeks | 127 | 247 |
| BEC <150 cells·μL−1 and FENO <25 ppb | ||
| Baseline | 14 (11.0) | 45 (18.2) |
| Week 24 | 33 (26.0) | 65 (26.3) |
| Week 52 | 42 (33.1) | 93 (37.7) |
| Week 104 | 33 (26.0) | 78 (31.6) |
| BEC ≥150 cells·μL−1 and FENO ≥25 ppb | ||
| Baseline | 61 (48.0) | 116 (47.0) |
| Week 24 | 26 (20.5) | 45 (18.2) |
| Week 52 | 19 (15.0) | 36 (14.6) |
| Week 104 | 19 (15.0) | 29 (11.7) |
| Placebo | 50 | 132 |
| BEC <150 cells·μL−1 and FENO <25 ppb | ||
| Baseline | 10 (20.0) | 18 (13.7) |
| Week 24 | 6 (12.0) | 21 (15.9) |
| Week 52 | 9 (18.0) | 21 (15.9) |
| Week 104 | 8 (16.0) | 20 (15.2) |
| BEC ≥150 cells·μL−1 and FENO ≥25 ppb | ||
| Baseline | 22 (44.0) | 51 (38.6) |
| Week 24 | 17 (34.0) | 57 (43.2) |
| Week 52 | 15 (30.0) | 44 (33.3) |
| Week 104 | 13 (26.0) | 38 (28.8) |
Data are presented as n or n (%). BEC: blood eosinophil count; FENO: fractional exhaled nitric oxide. #: in this analysis, for patients who completed treatment with data missing at week 104, the next available off-treatment measurement was input at week 104 for the Asthma Control Questionnaire-6 and pre-bronchodilator forced expiratory volume in 1 s criteria.
The baseline clinical characteristics of patients receiving tezepelumab who achieved complete clinical response versus those who achieved on-treatment clinical remission at week 52 were evaluated (table 3). Patients who achieved on-treatment clinical remission had a higher baseline pre-BD FEV1, fewer exacerbations in the 12 months before the study, lower baseline BECs and lower baseline FENO levels than those who achieved a complete clinical response.
TABLE 3.
Baseline demographics and clinical characteristics for patients receiving tezepelumab 210 mg every 4 weeks who achieved complete clinical response versus those who achieved clinical remission over weeks 0–52#
| Achieved complete clinical response | Achieved on-treatment clinical remission | |
|---|---|---|
| Patients | 199 | 108 |
| Age years | 48.3±16.9 | 48.3±17.6 |
| Female | 119 (59.8) | 58 (53.7) |
| BMI kg·m−2 | 28±6.3 | 28±6.1 |
| ICS dose group¶ | ||
| Medium | 45 (22.6) | 29 (26.9) |
| High | 154 (77.4) | 79 (73.1) |
| Maintenance OCS use | 18 (9.0) | 0 (0.0) |
| Pre-BD FEV1 L | 1.80±0.69 | 2.03±0.70 |
| Pre-BD FEV1 % predicted | 60.6±17.5 | 66.3±16.6 |
| Exacerbations in the 12 months before enrolment in NAVIGATOR | ||
| 2 | 109 (54.8) | 71 (65.7) |
| >2 | 90 (45.2) | 37 (34.3) |
| FENO level ppb | ||
| Mean±sd | 47.7±38.9 | 43.7±36.4 |
| Median (min–max) | 35.0 (5.0–213.0) | 34.0 (5.0–213.0) |
| FENO group ppb | ||
| <25 | 65 (32.8) | 37 (34.6) |
| ≥25 to <50 | 61 (30.8) | 35 (32.7) |
| ≥50 | 72 (36.4) | 35 (32.7) |
| BEC cells·μL−1 | ||
| Mean±sd | 406±363 | 375±412 |
| Median (min–max) | 340 (20–3650) | 290 (0–3650) |
| BEC group cells·μL−1 | ||
| <150 | 35 (17.6) | 22 (20.4) |
| 150 to <300 | 53 (26.6) | 34 (31.5) |
| <300 | 88 (44.2) | 56 (51.9) |
| ≥300 | 111 (55.8) | 52 (48.1) |
| 300 to <450 | 44 (22.1) | 21 (19.4) |
| ≥450 | 67 (33.7) | 31 (28.7) |
| Serum total IgE IU·mL−1 | ||
| Mean±sd | 514.4±756.4 | 591.9±1339.7 |
| Median (min–max) | 206.1 (1.5–4357.4) | 237.4 (1.5–12 823.2) |
| FEIA positive for any perennial aeroallergen+ | 116 (58.3) | 69 (63.9) |
| Nasal polyps | 43 (21.6) | 23 (21.3) |
Data are presented as n, mean±sd or n (%), unless otherwise stated. BMI: body mass index; ICS: inhaled corticosteroid; OCS: oral corticosteroid; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; FENO: fractional exhaled nitric oxide; BEC: blood eosinophil count; Ig: immunoglobulin; FEIA: fluorescence enzyme immunoassay. #: there was one patient receiving tezepelumab who stopped OCS use in DESTINATION and did achieve on-treatment clinical remission at week 52; ¶: medium-dose ICS: fluticasone propionate 500 µg·day−1 or equivalent; high-dose ICS: fluticasone propionate >500 µg·day−1 or equivalent; there was one patient in the placebo group who received fluticasone propionate <500 µg·day−1 or equivalent; +: positive for at least one perennial aeroallergen (cat dander, dog dander, cockroach, dust mite (Dermatophagoides farinae, D. pteronyssinus) and mould mix).
Discussion
In this analysis of patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response over 52 weeks compared with placebo. Additionally, tezepelumab was associated with an increased likelihood of achieving and sustaining on-treatment clinical remission over 52 weeks and 104 weeks compared with placebo.
Almost half of tezepelumab recipients achieved a complete clinical response, compared with one-quarter of placebo recipients. The magnitude of clinical response to tezepelumab appeared to be greater in patients with more severe and uncontrolled disease and elevated inflammation at baseline. This was indicated by a higher proportion of complete responders in the tezepelumab group versus the placebo group having received maintenance OCS at baseline and experiencing more than two exacerbations in the past 12 months, as well as having higher baseline BECs and FENO levels.
Approximately one-third of patients receiving tezepelumab achieved on-treatment clinical remission at the time points assessed. Across all time points assessed, clinical remission among tezepelumab recipients was associated with higher BECs and FENO levels at baseline, suggesting that these characteristics may help to predict patients more likely to achieve clinical remission with tezepelumab. BECs and FENO levels were reduced with tezepelumab treatment versus placebo from baseline to week 104, irrespective of whether the patients achieved on-treatment clinical remission at week 104; this indicates that low levels of type 2 inflammation achieved after treatment do not necessarily predict clinical remission. It is yet to be fully understood how biomarker changes following TSLP blockade with tezepelumab relate to clinical response and remission, including whether biomarker reductions are required for clinical remission.
Interestingly, the odds of achieving a complete clinical response to treatment with tezepelumab in this analysis were higher than the odds of achieving on-treatment clinical remission. This may be because the patients included in NAVIGATOR and DESTINATION had long-term, severe, uncontrolled asthma. As response to treatment is a comparison to a patient's relative baseline status, patients with the most severe and uncontrolled underlying disease often demonstrate the largest response to biologic therapy. However, large clinical responses may not always translate to long-term disease stability. Remission is restoration to a state of relative wellbeing, which is best achieved by patients with less severe disease at baseline. Consequently, those with the most severe disease may never achieve disease remission, which is a limitation of clinical response as an asthma outcome. Additional consideration should be given to the presence of comorbidities or other conditions, such as obesity, when evaluating clinical response and clinical remission, because these factors may influence symptom control and HRQoL scores (e.g. ACQ-6) in patients with asthma [35].
It should be noted that a considerable number of placebo recipients in this study achieved clinical remission. Strong clinical improvements in patients receiving placebo have been observed previously in randomised controlled trials (RCTs) of biologics [36], probably because of optimisation of patients’ inhaler technique and patient education regarding ICS adherence, as well as the specialised care and monitoring that is provided by asthma experts during the trials.
Other RCTs of biologics have evaluated clinical remission using criteria similar to those used in this analysis [37], although differences in disease characteristics between patient populations should be considered when comparing remission rates. In the phase 3 SIROCCO and CALIMA studies in patients with severe eosinophilic asthma, 23.9% (140 out of 586) of patients not receiving OCS at baseline who received benralizumab and 14.8% (92 out of 620) of patients who received placebo achieved clinical remission at 12 months. This was defined as zero exacerbations, zero OCS use, an ACQ-6 score of ≤1.5 (≤0.75 was also evaluated) and a pre-BD FEV1 increase of ≥100 mL after 12 months. Using equivalent criteria at 6 months, 26.3% (160 out of 609) of benralizumab recipients and 19.0% (122 out of 643) of placebo recipients met remission criteria [38]. In the phase 3 QUEST study in patients with uncontrolled, moderate-to-severe, type 2 inflammatory asthma (as defined by a BEC of ≥150 cells·μL−1 or a FENO level of ≥20 ppb), 35.0% (364 out of 1040) of dupilumab recipients and 20.4% (111 out of 544) of placebo recipients achieved clinical remission at 12 months. This was defined as no exacerbations, no OCS use, an ACQ-5 score <1.5 and either an improvement in pre-BD FEV1 of ≥100 mL or a post-BD FEV1 of ≥80% predicted [39]. Furthermore, in the open-label TRAVERSE study, 36.1% of dupilumab recipients achieved clinical remission after an additional year of treatment [39]. The patient population evaluated in the QUEST and TRAVERSE studies of dupilumab included ∼50% of patients on medium-dose ICS who were consequently classified as having uncontrolled, moderate asthma. It is expected that these patients would be more likely to achieve clinical remission than clinical trial participants with severe, uncontrolled asthma, because those with moderate asthma have less severe disease at baseline.
Clinical remission with biologics has also been assessed in real-world observational studies using similar definitions. In the REDES study in patients with severe eosinophilic asthma who were newly prescribed mepolizumab in Spain, on-treatment clinical remission was defined as no OCS use, no exacerbations and an Asthma Control Test score of ≥20, with or without a post-BD FEV1 of ≥80% predicted normal. When the lung function component was included in the remission criteria, 30% of patients achieved clinical remission [32]. Lastly, in an Australian study of patients with severe asthma, clinical remission at 12 months was defined as zero exacerbations and zero OCS use during the previous 6 months and an ACQ-5 score of ≤1, with or without a post-BD FEV1 of either ≥80%, or ≤5% decline from baseline. When the lung function component was included in the remission criteria, 25.2% and 19.1% receiving mepolizumab and omalizumab, respectively, achieved clinical remission [31]. In summary, although definitions of clinical remission consistently use the criteria of “no exacerbations” and “no OCS use”, there is variation in how adequate symptom control is defined and in the inclusion of a lung function criterion, including whether lung function should be stable or improved (and how these are defined).
With improvements in asthma therapies in recent years, including the introduction of personalised, potentially disease-modifying biologic therapies, treatment goals have evolved from short-term control of symptoms and exacerbations to disease remission, a more meaningful long-term goal for the patient. In contrast to clinical remission, clinical response is influenced by baseline inflammation and disease severity before treatment is received, which was observed in our results. Therefore, treating patients sooner after diagnosis, before the disease progresses, could help to achieve remission; however, this needs to be assessed in appropriately designed RCTs [29]. Globally accepted criteria used to define clinical remission, biological remission and complete remission could assist in the design of such trials. Given the notable proportion of patients in the present study who achieved remission at 6 months and remained in remission at 12 months, we suggest that the 6-month time point should be considered by asthma societies and consensus groups developing definitions of remission. It is in the interest of patients and clinicians to know whether patients are achieving clinical remission earlier than 12 months into receiving a biologic therapy, because this may allow for earlier reduction in background medication use. Accordingly, the ARRIVAL study plans to assess the potential for patients receiving tezepelumab to reduce maintenance inhaled asthma therapy and will evaluate remission at 6 months.
There was a notable proportion of patients in the present study with severe asthma for ≥20 years, and this is likely to have impacted the proportion of patients achieving on-treatment clinical remission in this analysis. The concept of earlier intervention with biologic therapy to increase the chances of achieving remission before asthma becomes too severe or uncontrolled has been comprehensively explored in a longitudinal analysis using data from the International Severe Asthma Registry [40]. This should be explored in future clinical trials of biologics; the ARRIVAL study of tezepelumab will recruit patients with a shorter duration of asthma than in the present study and this will provide valuable insights into earlier biologic intervention, particularly for those with severe disease.
Strengths of this analysis include the robustness of the DESTINATION dataset, based on the large number of patients who continued from NAVIGATOR into DESTINATION. Additionally, the duration of DESTINATION allowed remission criteria to be assessed from 6 months to 2 years, and the effect of tezepelumab on remission could be evaluated versus placebo in year 2, which, to date, is an outcome not previously evaluated in RCTs of biologics in severe asthma. Further investigation into off-treatment clinical remission will be evaluated in the DESTINATION study.
A limitation of this analysis is the impact of the coronavirus disease 2019 pandemic, which coincided with year 2 of the study (i.e. DESTINATION). The pandemic may have influenced exacerbation rates, lung function and symptom control metrics because of the reduced risk of viral infections due to increased isolation arising from lockdown measures. Indeed, it was notable that exacerbations in both treatment groups decreased from year 1 to year 2 [12, 13]. In addition, the pandemic contributed to increased missing data at week 104. To evaluate potential bias from these missing data, a sensitivity analysis of the remission analyses was performed, which assumed nonremission for patients in instances where data were missing (rather than using imputed data); the findings were similar between the two analyses.
Conclusion
Tezepelumab treatment was associated with an increased likelihood of achieving a complete clinical response over 52 weeks as well as achieving on-treatment clinical remission over 2 years in patients with severe, uncontrolled asthma. Clinical response as an asthma outcome is more likely to occur in those with high baseline inflammation and severe, uncontrolled disease; therefore, as a treatment goal, it has less relevance for the long-term needs of the patient. In contrast, clinical remission and complete remission in asthma appear to be much more meaningful goals. Further exploration of how baseline characteristics may help to predict remission, and how biomarker changes relate to response and remission, would be valuable to understand how patients may best benefit from biologic treatment.
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Acknowledgements
Medical writing support was provided by Lisa Simpson (PharmaGenesis London, London, UK), with funding from AstraZeneca and Amgen Inc.
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.01908-2024
Conflict of interest: M.E. Wechsler is an employee of National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, resTORbio, Sanofi and Teva Pharmaceuticals. G. Brusselle has received fees for participation in advisory boards and/or speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MSD, Novartis and Sanofi. J.C. Virchow has received grants for research or clinical trials from the German Research Foundation, GSK and MSD, has received consulting fees from Avontec, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron Pharmaceuticals, Revotar, Roche, Sandoz-Hexal, Sanofi-Aventis, Teva Pharmaceuticals and UCB Schwarz-Pharma, has received fees for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergenes Greer, Teva Pharmaceuticals, UCB Schwarz-Pharma and Zydus Cadila, has received fees for data safety-monitoring board participation from Chiesi, and has received travel support from Boehringer Ingelheim and Sanofi. A. Bourdin has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva Pharmaceuticals, GSK, Novartis and Sanofi-Regeneron, has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron, and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GSK, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex Pharmaceuticals. K. Kostikas has received fees for presentations and/or consultancy fees from Alector Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, Gilead, GSK, Menarini, Novartis, Pfizer, Sanofi, Specialty Therapeutics and WebMD, and his department has received funding and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Innovis, Menarini, Novartis and NuvoAir. J-P. Llanos is an employee of Amgen and owns stock in Amgen. S.L. Roseti, C.S. Ambrose, G. Hunter and N. Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. D.J. Jackson has received consultancy fees and speaker fees from AstraZeneca, GSK, Novartis, Sanofi and Teva Pharmaceuticals. M. Castro reports grants/research support from ALA, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Patient-Centered Outcomes Research Institute, Pulmatrix, Sanofi-Aventis, Shionogi Theravance and the US National Institutes of Health, consulting fees from Allakos, Amgen, Arrowhead, AstraZeneca, Genentech, Merck, Novartis, OM Pharma, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received royalties from Aer Therapeutics and Elsevier. N. Lugogo has received consultancy fees for participation in advisory boards from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received fees for non-speaker bureau presentations from AstraZeneca and GSK, has received travel support from AstraZeneca, and her institution has received research support from Amgen, AstraZeneca, Avillion, Genentech, Gossamer Bio, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals. I.D. Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough and Teva Pharmaceuticals, has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received a research grant from Chiesi. C.E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, Global Access Diagnostics (formerly Mologic), GSK, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi.
Support statement: This study was funded by AstraZeneca and Amgen Inc. Funding information for this article has been deposited with the Crossref Funder Registry.
Data availability
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
References
- 1.World Health Organization . Asthma. www.who.int/news-room/fact-sheets/detail/asthma. Date last accessed: 19 August 2022. Date last updated: 6 May 2024.
- 2.Global Asthma Network . The Global Asthma Report 2022. https://globalasthmareport.org/. Date last accessed: 12 October 2023.
- 3.Bernstein JA, Llanos JP, Hunter G, et al. Efficacy of biologics in patients with allergic severe asthma, overall and by blood eosinophil count: a literature review. Adv Ther 2023; 40: 4721–4740. doi: 10.1007/s12325-023-02647-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–373. doi: 10.1183/09031936.00202013 [DOI] [PubMed] [Google Scholar]
- 5.Global Initiative for Asthma . Global Strategy for Asthma Management and Prevention 2023. https://ginasthma.org/wp-content/uploads/2023/05/GINA-2023-Full-Report-2023-WMS.pdf. Date last accessed 3 May 2023.
- 6.Gauvreau GM, Sehmi R, Ambrose CS, et al. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets 2020; 24: 777–792. doi: 10.1080/14728222.2020.1783242 [DOI] [PubMed] [Google Scholar]
- 7.Diver S, Khalfaoui L, Emson C, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2021; 9: 1299–1312. doi: 10.1016/S2213-2600(21)00226-5 [DOI] [PubMed] [Google Scholar]
- 8.Sverrild A, Hansen S, Hvidtfeldt M, et al. The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM). Eur Respir J 2021; 59: 2101296. doi: 10.1183/13993003.01296-2021 [DOI] [PubMed] [Google Scholar]
- 9.Nordenmark LH, Hellqvist Å, Emson C, et al. Tezepelumab and mucus plugs in patients with moderate-to-severe asthma. NEJM Evid 2023; 2: EVIDoa2300135. doi: 10.1056/EVIDoa2300135 [DOI] [PubMed] [Google Scholar]
- 10.European Medicines Agency (EMA) . Tezspire (Tezepelumab) Medicine Overview. 2022. www.ema.europa.eu/en/documents/overview/tezspire-epar-medicine-overview_en.pdf. Date last accessed: 14 April 2023.
- 11.U.S. Food and Drug Administration (FDA). Tezspire (Tezepelumab) Prescribing Information. 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2021/761224s000lbl.pdf. Date last accessed 14 April 2023.
- 12.Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med 2021; 384: 1800–1809. doi: 10.1056/NEJMoa2034975 [DOI] [PubMed] [Google Scholar]
- 13.Menzies-Gow A, Wechsler ME, Brightling CE, et al. Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. Lancet Respir Med 2023; 11: 425–438. doi: 10.1016/S2213-2600(22)00492-1 [DOI] [PubMed] [Google Scholar]
- 14.Scelo G, Tran TN, Le TT, et al. Exploring definitions and predictors of response to biologics for severe asthma. J Allergy Clin Immunol Pract 2024; 12: 2347–2361. doi: 10.1016/j.jaip.2024.05.016 [DOI] [PubMed] [Google Scholar]
- 15.Khaleva E, Rattu A, Brightling C, et al. Definitions of non-response and response to biological therapy for severe asthma: a systematic review. ERJ Open Res 2023; 9: 00444-2022. doi: 10.1183/23120541.00444-2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kroes JA, Zielhuis SW, van Roon EN, et al. Prediction of response to biological treatment with monoclonal antibodies in severe asthma. Biochem Pharmacol 2020; 179: 113978. doi: 10.1016/j.bcp.2020.113978 [DOI] [PubMed] [Google Scholar]
- 17.Lommatzsch M, Brusselle GG, Levy ML, et al. A2BCD: a concise guide for asthma management. Lancet Respir Med 2023; 11: 573–576. doi: 10.1016/S2213-2600(22)00490-8 [DOI] [PubMed] [Google Scholar]
- 18.Lommatzsch M, Brusselle GG, Canonica GW, et al. Disease-modifying anti-asthmatic drugs. Lancet 2022; 399: 1664–1668. doi: 10.1016/S0140-6736(22)00331-2 [DOI] [PubMed] [Google Scholar]
- 19.Schlager L, Loiskandl M, Aletaha D, et al. Predictors of successful discontinuation of biologic and targeted synthetic DMARDs in patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review. Rheumatology 2020; 59: 324–334. doi: 10.1093/rheumatology/kez278 [DOI] [PubMed] [Google Scholar]
- 20.Nakase H, Uchino M, Shinzaki S, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol 2021; 56: 489–526. doi: 10.1007/s00535-021-01784-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lommatzsch M, Buhl R, Canonica GW, et al. Pioneering a paradigm shift in asthma management: remission as a treatment goal. Lancet Respir Med 2024; 12: 96–99. doi: 10.1016/S2213-2600(23)00415-0 [DOI] [PubMed] [Google Scholar]
- 22.Menzies-Gow A, Bafadhel M, Busse WW, et al. An expert consensus framework for asthma remission as a treatment goal. J Allergy Clin Immunol 2020; 145: 757–765. doi: 10.1016/j.jaci.2019.12.006 [DOI] [PubMed] [Google Scholar]
- 23.Blaiss M, Oppenheimer J, Corbett M, et al. Consensus of an American College of Allergy, Asthma, and Immunology, American Academy of Allergy, Asthma, and Immunology, and American Thoracic Society workgroup on definition of clinical remission in asthma on treatment. Ann Allergy Asthma Immunol 2023; 131: 782–785. doi: 10.1016/j.anai.2023.08.609 [DOI] [PubMed] [Google Scholar]
- 24.Canonica GW, Blasi F, Carpagnano GE, et al. Severe Asthma Network Italy definition of clinical remission in severe asthma: a Delphi consensus. J Allergy Clin Immunol Pract 2023; 11: 3629–3637. doi: 10.1016/j.jaip.2023.07.041 [DOI] [PubMed] [Google Scholar]
- 25.Lommatzsch M, Criée CP, de Jong CCM, et al. S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023. [Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 published by the German Respiratory Society (DGP)]. Pneumologie 2023; 77: 461–543. doi: 10.1055/a-2070-2135 [DOI] [PubMed] [Google Scholar]
- 26.Plaza Moral V, Alobid I, Álvarez Rodríguez C, et al. GEMA 5.3. Spanish guideline on the management of asthma. Open Respir Arch 2023; 5: 100277. doi: 10.1016/j.opresp.2023.100277 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Oishi K, Hamada K, Murata Y, et al. A real-world study of achievement rate and predictive factors of clinical and deep remission to biologics in patients with severe asthma. J Clin Med 2023; 12: 2900. doi: 10.3390/jcm12082900 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hansen S, Baastrup Søndergaard M, von Bülow A, et al. Clinical response and remission in severe asthma patients treated with biologic therapies. Chest 2024; 165: 253–266. doi: 10.1016/j.chest.2023.10.046 [DOI] [PubMed] [Google Scholar]
- 29.Thomas D, McDonald VM, Pavord ID, et al. Asthma remission: what is it and how can it be achieved? Eur Respir J 2022; 60: 2102583. doi: 10.1183/13993003.02583-2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.McDowell PJ, McDowell R, Busby J, et al. Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry. Eur Respir J 2023; 62: 2300819. doi: 10.1183/13993003.00819-2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Thomas D, McDonald VM, Stevens S, et al. Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients. Allergy 2024; 79: 384–392. doi: 10.1111/all.15867 [DOI] [PubMed] [Google Scholar]
- 32.Pavord I, Gardiner F, Heaney LG, et al. Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: analysis of the REDES study. Front Immunol 2023; 14: 1150162. doi: 10.3389/fimmu.2023.1150162 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Milger K, Suhling H, Skowasch D, et al. Response to biologics and clinical remission in the adult German Asthma Net severe asthma registry cohort. J Allergy Clin Immunol Pract 2023; 11: 2701–2712. doi: 10.1016/j.jaip.2023.05.047 [DOI] [PubMed] [Google Scholar]
- 34.Moore VC. Spirometry: step by step. Breathe 2012; 8: 232–240. doi: 10.1183/20734735.0021711 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Dias-Junior SA, Reis M, de Carvalho-Pinto RM, et al. Effects of weight loss on asthma control in obese patients with severe asthma. Eur Respir J 2014; 43: 1368–1377. doi: 10.1183/09031936.00053413 [DOI] [PubMed] [Google Scholar]
- 36.McGregor MC, Krings JG, Nair P, et al. Role of biologics in asthma. Am J Respir Crit Care Med 2019; 199: 433–445. doi: 10.1164/rccm.201810-1944CI [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Lugogo NL, Mohan A, Akuthota P, et al. Are we ready for asthma remission as a clinical outcome? Chest 2023; 164: 831–834. doi: 10.1016/j.chest.2023.04.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Menzies-Gow A, Hoyte FL, Price DB, et al. Clinical remission in severe asthma: a pooled post hoc analysis of the patient journey with benralizumab. Adv Ther 2022; 39: 2065–2084. doi: 10.1007/s12325-022-02098-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Pavord ID, Israel E, Szefler SJ, et al. Dupilumab induces clinical remission in patients with uncontrolled, moderate-to-severe, type 2 inflammatory asthma. Am J Respir Crit Care Med 2023; 207: A5995. [Google Scholar]
- 40.Perez-de-Llano L, Scelo G, Tran TN, et al. Exploring definitions and predictors of severe asthma clinical remission post-biologic in adults. Am J Respir Crit Care Med 2024; 210: 869–880.https://doi.org/https://doi.org/ [DOI] [PMC free article] [PubMed] [Google Scholar]
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Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.