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.

MethodsStudy 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 remissionDid not achieve remission0–24 weeks>24–52 weeks>52–104 weeks¶0–24 weeks>24–52 weeks>52–104 weeks¶Patients126141127244228247Age years48.4±17.348.9±17.349.0±17.950.1±16.050.1±15.550.2±15.3Female72 (57.1)81 (57.4)76 (59.8)160 (65.6)151 (66.2)158 (64.0)BMI kg·m−227.9±6.128.4±6.328.1±6.329.6±7.829.5±7.829.5±7.6ICS dose group+ Medium39 (31.0)38 (27.0)26 (20.5)53 (21.7)51 (22.4)66 (26.7) High87 (69.0)103 (73.0)101 (79.5)191 (78.3)177 (77.6)181 (73.3)Pre-BD FEV1 L1.98±0.681.94±0.691.92±0.701.76±0.691.77±0.701.78±0.70Pre-BD FEV1 % predicted64.8±16.464.9±16.764.9±16.461.2±17.660.8±17.560.8±17.5FEV1 reversibility %15.6±15.215.5±14.916.2±16.413.7±13.813.9±14.313.9±13.5Age at asthma onset years27.9±20.226.0±20.126.4±19.524.8±19.225.8±19.125.9±19.6Duration of disease years <209.5±4.89.4±5.19.9±4.89.6±5.29.8±5.19.4±5.2 ≥2034.9±12.636.0±11.636.1±12.139.3±12.439.4±12.938.9±12.7Duration of disease years <2073 (57.9)71 (50.4)67 (52.8)117 (48.0)118 (51.8)124 (50.2) ≥2053 (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 278 (61.9)92 (65.2)79 (62.2)150 (61.5)139 (61.0)154 (62.3) >248 (38.1)49 (34.8)48 (37.8)94 (38.5)89 (39.0)93 (37.7)FENO level ppb Mean±sd42.9±35.543.2±35.742.0±34.038.9±33.737.5±32.538.6±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 <2548 (38.7)52 (37.1)49 (39.8)108 (45.0)104 (46.4)109 (44.5) ≥25 to <5035 (28.2)43 (30.7)35 (28.5)66 (27.5)61 (27.2)70 (28.6) ≥5041 (33.1)45 (32.1)39 (31.7)66 (27.5)59 (26.3)66 (26.9)BEC cells·µL−1 Mean±sd380±399366±370348±373296±235291±242309±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 <15024 (19.0)28 (19.9)28 (22.0)67 (27.5)64 (28.1)65 (26.3) 150 to <30039 (31.0)42 (29.8)39 (30.7)87 (35.7)85 (37.3)89 (36.0) <30063 (50.0)70 (49.6)67 (52.8)154 (63.1)149 (65.4)154 (62.3) ≥30063 (50.0)71 (50.4)60 (47.2)90 (36.9)79 (34.6)93 (37.7) 300 to <45030 (23.8)31 (22.0)32 (25.2)44 (18.0)42 (18.4)42 (17.0) ≥45033 (26.2)40 (28.4)28 (22.0)46 (18.9)37 (16.2)51 (20.6)Serum total IgE IU·mL−1 Mean±sd518.1±833.9557.7±1207.7508.3±695.2537.7±1093.6512.6±871.0540.4±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 polyps29 (23.0)27 (19.1)25 (19.7)42 (17.2)44 (19.3)47 (19.0)

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 weeks127247 BEC <150 cells·μL−1 and FENO <25 ppb  Baseline14 (11.0)45 (18.2)  Week 2433 (26.0)65 (26.3)  Week 5242 (33.1)93 (37.7)  Week 10433 (26.0)78 (31.6) BEC ≥150 cells·μL−1 and FENO ≥25 ppb  Baseline61 (48.0)116 (47.0)  Week 2426 (20.5)45 (18.2)  Week 5219 (15.0)36 (14.6)  Week 10419 (15.0)29 (11.7)Placebo50132 BEC <150 cells·μL−1 and FENO <25 ppb  Baseline10 (20.0)18 (13.7)  Week 246 (12.0)21 (15.9)  Week 529 (18.0)21 (15.9)  Week 1048 (16.0)20 (15.2) BEC ≥150 cells·μL−1 and FENO­ ≥25 ppb  Baseline22 (44.0)51 (38.6)  Week 2417 (34.0)57 (43.2)  Week 5215 (30.0)44 (33.3)  Week 10413 (26.0)38 (28.8)

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 responseAchieved on-treatment clinical remissionPatients199108Age years48.3±16.948.3±17.6Female119 (59.8)58 (53.7)BMI kg·m−228±6.328±6.1ICS dose group¶ Medium45 (22.6)29 (26.9) High154 (77.4)79 (73.1)Maintenance OCS use18 (9.0)0 (0.0)Pre-BD FEV1 L1.80±0.692.03±0.70Pre-BD FEV1 % predicted60.6±17.566.3±16.6Exacerbations in the 12 months before enrolment in NAVIGATOR 2109 (54.8)71 (65.7) >290 (45.2)37 (34.3)FENO level ppb Mean±sd47.7±38.943.7±36.4 Median (min–max)35.0 (5.0–213.0)34.0 (5.0–213.0)FENO group ppb <2565 (32.8)37 (34.6) ≥25 to <5061 (30.8)35 (32.7) ≥5072 (36.4)35 (32.7)BEC cells·μL−1 Mean±sd406±363375±412 Median (min–max)340 (20–3650)290 (0–3650)BEC group cells·μL−1 <15035 (17.6)22 (20.4) 150 to <30053 (26.6)34 (31.5) <30088 (44.2)56 (51.9) ≥300