FormalPara Key Summary Points

Why carry out this study?

Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy

In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations compared with placebo in patients with severe, uncontrolled asthma

This analysis was performed to further evaluate the effect of tezepelumab on the annualized asthma exacerbation rate in clinically relevant subgroups of patients from the NAVIGATOR study

What was learned from the study?

Tezepelumab reduced asthma exacerbations compared with placebo over 52 weeks across a wide range of patient subgroups assessed

This study further highlights and describes the efficacy of tezepelumab in patients with severe, uncontrolled asthma

Introduction

Asthma is a complex, heterogeneous disease of the airways involving multiple inflammatory pathways [1]. Most patients with asthma have mild-to-moderate disease, which can be managed with a combination of inhaled corticosteroids (ICS) and long-acting β2 agonists (LABAs) [2]. However, approximately 5–10% of patients with asthma have severe disease, and many of these patients continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy [3]; the long-term use of systemic corticosteroids to manage uncontrolled asthma is associated with an increased risk of acute and chronic adverse events, highlighting the need to consider other effective therapy options for these patients [4].

Asthma is commonly driven by allergic and/or eosinophilic inflammation, both of which may be present in severe disease. Allergic asthma is the most common phenotype and is present in approximately 60% of patients with severe asthma [5,6,7]. It has generally been defined by patient symptoms and by detection of a confirmed allergy to a perennial and/or seasonal aeroallergen and is characterized by elevated allergen-specific immunoglobulin E (IgE) levels [8, 9]. Eosinophilic asthma is present in approximately 50–60% of patients with severe asthma and is often characterized by a blood eosinophil count (BEC) of at least 300 cells/µl [10, 11]. Beyond these commonly described allergic and eosinophilic phenotypes, patients with severe asthma may be stratified according to many other clinically relevant factors.

When assessing asthma control, the Global Initiative for Asthma guidelines state that clinicians should assess risk factors for future asthma exacerbations, including poor asthma control and several other independent risk factors [10]. Some comorbidities (e.g. chronic rhinosinusitis or gastroesophageal reflux disease [GERD]), exposure to cigarette smoke and some patient characteristics (e.g. high body mass index [BMI]) are associated with exacerbations in patients with asthma [10, 12,13,14]. Notably, inflammatory diseases of the upper airways (e.g. allergic rhinitis, chronic rhinosinusitis or nasal polyps) and other asthma-relevant comorbidities (e.g. obesity or sensitivity to non-steroidal anti-inflammatory drugs [NSAIDs]) are common in patients with severe asthma [13,14,15]. Indeed, more than one of these comorbidities may be present in a single patient, such as in instances of aspirin-exacerbated respiratory disease (AERD)/NSAID-exacerbated respiratory disease (N-ERD) (also known as Samter’s triad), which is characterized by the presence of asthma, nasal polyps and sensitivity to aspirin or other NSAIDs [16]. It is important for clinicians to recognize the presence of these risk factors and to understand the effect that they may have on treatment response when making clinical decisions [17].

Tezepelumab is a human monoclonal antibody (immunoglobulin G2λ) that has been approved by the US Food and Drug Administration, the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency for the treatment of severe asthma, with no phenotype or biomarker restrictions [18,19,20]. Tezepelumab binds specifically to thymic stromal lymphopoietin (TSLP) [21]. TSLP is an epithelial cytokine that plays a key role in the initiation and persistence of multiple processes associated with asthma pathophysiology, including allergic inflammation, eosinophilic inflammation and type 2 (T2)-independent effects on mast cells, airway smooth muscle and airway hyperresponsiveness [22, 23]. By blocking the interaction between TSLP and its heterodimeric receptor, tezepelumab has been shown to act upstream of all currently clinically used biomarkers [24].

In the phase 3 NAVIGATOR study (ClinicalTrials.gov identifier: NCT03347279), tezepelumab significantly reduced exacerbations and improved lung function, asthma control and health-related quality of life over 52 weeks compared with placebo in adults and adolescents with severe, uncontrolled asthma across a broad range of patient phenotypes [25]. Further analyses of NAVIGATOR have demonstrated reductions in annualized asthma exacerbation rates (AAERs) across all seasons and in patients eligible for omalizumab, in patients aged ≥ 18 to < 65 years and ≥ 65 years at study entry and in patients aged < 18 and ≥ 18 years at asthma diagnosis [25,26,27]. Additionally, AAER reductions were observed in patients with perennial aeroallergen sensitization, high and low baseline BECs (ranging from < 150 cells/µl to ≥ 450 cells/µl), high and low baseline fractional exhaled nitric oxide (FeNO) levels, comorbid nasal polyps in the 2 years before randomization and chronic sinusitis as well as in patients receiving medium- and high-dose ICS at study entry, and patients not receiving oral corticosteroids (OCS) at baseline [25, 27, 28]; however, many other clinically relevant subgroups have yet to be reported.

This article reports reductions in AAERs in additional clinically relevant subgroups of patients with severe, uncontrolled asthma from the NAVIGATOR study, defined by patient demographics and clinical characteristics at baseline, medical history, exacerbation triggers, medication eligibility and medication use before and during the study.

Methods

Study Design

NAVIGATOR was a phase 3, global, multicentre, randomized, double-blind, placebo-controlled, parallel-group study. The full study design and inclusion and exclusion criteria have been described previously [29]. The study enrolled similar proportions of patients with baseline BECs of < 300 cells/µl (58.4%) and ≥ 300 cells/µl (41.6%) [25]. Eligible participants were 12–80 years old, with physician-diagnosed asthma, who had been receiving medium- or high-dose ICS (daily dose of ≥ 500 μg fluticasone propionate or equivalent) for at least 12 months before screening and at least one additional controller medication, with or without OCS, for at least 3 months before the date of informed consent [29]. Participants were required to be non-smokers with a smoking history of no more than 10 pack-years [29]. In addition, participants were required to have a morning pre-bronchodilator forced expiratory volume in 1 s (FEV1) of < 80% of the predicted normal value (< 90% for patients aged 12–17 years) during the run-in period; patients were also required to have an FEV1 reversibility of at least 12% and at least 200 ml documented during the 12 months before screening or a post-bronchodilator (albuterol/salbutamol) FEV1 reversibility of at least 12% and at least 200 ml during the run-in period [29]. Participants must have experienced at least two documented asthma exacerbations (defined as a worsening of asthma symptoms that led to hospitalization, an emergency department visit that resulted in the use of systemic corticosteroids for ≥ 3 consecutive days or the use of systemic corticosteroids for ≥ 3 consecutive days) in the 12 months before the date of informed consent.

Participants were randomized 1:1 to receive tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. 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 the Copernicus Central Institutional Review Board (Cary, NC, USA) and local independent ethics committees were obtained, and all patients or their guardians provided written informed consent in accordance with local requirements.

Outcomes

The primary efficacy endpoint in NAVIGATOR was the AAER over 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the AAER over 52 weeks in clinically relevant subgroups of patients defined by patient demographics and clinical characteristics at baseline, medical history, exacerbation triggers, medication eligibility and medication use before and during the study.

Patient demographics and clinical characteristics that were considered clinically significant for patients with severe asthma were examined. AAER was analysed by: sex (male or female); smoking history (former smokers [< 10 pack-years] or patients who had never smoked); baseline BMI (< 25, 25 to < 30 or ≥ 30 kg/m2); baseline percent predicted pre-bronchodilator FEV1 (< 60% or ≥ 60%, where < 60% is indicative of severe lung disease [30]); baseline post-bronchodilator FEV1 reversibility (< 20% or ≥ 20%); baseline BEC (≥ 500, ≥ 750 or ≥ 1000 cells/µl); serum specific IgE threshold (≥ 0.70, ≥ 3.5 or ≥ 17.5 kUA/l) in participants with perennial aeroallergen sensitization; and number of perennial aeroallergen sensitizations (0, 1, 2–3 or ≥ 4). Perennial aeroallergen sensitization was defined as a positive fluorescence enzyme immunoassay result (ImmunoCAP, Thermo Fisher Scientific, Waltham, MA, USA) for serum specific IgE against at least one common perennial aeroallergen (cat dander, dog dander, cockroach, house dust mite [Dermatophagoides farinae, D. pteronyssinus] or mould mix).

The medical history subgroups analysed included patients grouped by duration of disease (< 20 years or ≥ 20 years) and the presence of other relevant comorbidities (rhinitis, aspirin or NSAID sensitivity, AERD/N-ERD/Samter’s triad and GERD). The AAER was also assessed in patients grouped by the following exacerbation triggers during the study: infection, allergen exposure, other exposure (e.g. air pollution, fumes, exertion, stress) and unknown exposure.

Medication eligibility analyses were limited to patients eligible and ineligible to receive dupilumab based on the EU prescribing information, which specifies that patients must have: T2-high, severe, uncontrolled asthma; baseline FeNO levels of  ≥ 25 ppb and/or baseline BECs of ≥ 150 cells/µl; and inadequately controlled asthma despite treatment with high-dose ICS plus an additional controller medication [31]. Prior biologic use was allowed for patients enrolling in NAVIGATOR if the last dose was taken at least 4 months or five half-lives before screening (whichever was longer); consequently, the AAER was analysed in subgroups of participants with and without prior omalizumab use. There were insufficient data to analyse asthma exacerbations by prior use of other biologics and reasons for biologic discontinuation were not collected. Omalizumab may have been received through another clinical trial; in such cases, it was assumed that patients received active treatment. Finally, AAER was also analysed by the number of controller medications participants received in addition to ICS at baseline (1, 2 or ≥ 3), the types of additional controller medications participants were receiving at baseline and the types of additional controller medications received by participants who were not receiving maintenance OCS at baseline. Additional controller medications included LABAs, leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs). OCS were not included as a controller medication.

Subgroup analyses by sex were pre-specified, and analyses by baseline percent predicted pre-bronchodilator FEV1, dupilumab eligibility and number of perennial aeroallergen sensitizations were pre-specified exploratory; all the remaining analyses were post hoc.

Statistical Analyses

The AAER over 52 weeks was estimated using a negative binomial regression model. Treatment, region, age group, history of exacerbations (< 2 or ≥ 2), subgroup and treatment by subgroup were included as covariates in the model. SAS 9.4 (SAS Institute, Cary, NC, USA) was used for statistical programming. No formal hypothesis testing was performed to compare tezepelumab with placebo or to compare effects between the subgroups investigated.

Results

Overall, tezepelumab reduced asthma exacerbations over 52 weeks compared with placebo across all but one subgroup assessed (Figs. 1, 2, 3). Although statistical tests were not performed to compare the magnitude of the effect between the subgroups investigated, several trends were observed.

Fig. 1
figure 1

AAER over 52 weeks in patients with severe, uncontrolled asthma grouped by baseline demographics and clinical characteristics. n is the number of patients who contributed to each analysis. aPre-specified analysis; all other analyses shown are post hoc. b< 60% is indicative of severe lung disease [30]. cPerennial aeroallergen sensitization was defined as a positive fluorescence enzyme immunoassay result for serum specific IgE against at least one common perennial aeroallergen (cat dander, dog dander, cockroach, house dust mite [Dermatophagoides farinae, D. pteronyssinus] or mould mix). AAER annualized asthma exacerbation rate; BD bronchodilator; BEC blood eosinophil count; BMI body mass index; CI confidence interval; FEV1 forced expiratory volume in 1 s; GERD gastroesophageal reflux disease; IgE immunoglobulin E; Q4W every 4 weeks

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Fig. 2
figure 2

AAER over 52 weeks in patients with severe, uncontrolled asthma grouped by medical history and exacerbation triggers. n is the number of patients who contributed to each analysis. All analyses shown are post hoc. aOther exposure includes air pollution, fumes, exertion and stress. AAER annualized asthma exacerbation rate; AERD aspirin-exacerbated respiratory disease; CI confidence interval; GERD gastroesophageal reflux disease; N-ERD NSAID-exacerbated respiratory disease; NSAID non-steroidal anti-inflammatory drug; Q4W every 4 weeks

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Fig. 3
figure 3

AAER over 52 weeks in patients with severe, uncontrolled asthma grouped by medication eligibility and medications received before and during the study. n is the number of patients who contributed to each analysis. aPre-specified analysis; all other analyses shown are post hoc. bOther controller medications included the following in addition to ICS: xanthine derivatives, LAMA only, LTRA only, LABA + xanthine derivatives, LABA + LTRA + xanthine derivatives, LABA + LAMA + xanthine derivatives, LAMA + LTRA + xanthine derivatives, LABA + LAMA + LTRA + xanthine derivatives, LABA + LTRA + xanthine derivatives + cromolyn. AAER annualized asthma exacerbation rate; CI confidence interval; ICS inhaled corticosteroid; LABA long-acting β2 agonist; LAMA long-acting muscarinic antagonist; LTRA leukotriene receptor antagonist; n number of patients who contributed to the analysis; OCS oral corticosteroid; Q4W every 4 weeks

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Patient Baseline Demographics and Clinical Characteristics

Compared with placebo, reductions in AAER over 52 weeks with tezepelumab were similar in male participants (55%; 95% confidence interval [CI]: 37, 67) and female participants (57%; 95% CI: 45, 66) (Fig. 1). Tezepelumab reduced asthma exacerbations compared with placebo by 48% (95% CI: 21, 65) in former smokers and by 58% (95% CI: 48, 66) in never smokers (Fig. 1). Tezepelumab reduced the AAER by a similar magnitude across all BMI subgroups, with reductions in the AAER compared with placebo ranging from 54% (95% CI: 37, 66) in patients with a BMI of ≥ 30 kg/m2 to 60% (95% CI: 44, 71) in patients with a BMI of  < 25 kg/m2 (Fig. 1). Notably, tezepelumab reduced asthma exacerbations compared with placebo in patients with a very high baseline BEC (≥ 500, ≥ 750 and ≥ 1000 cells/µl), with reductions ranging from 74% (95% CI: 29, 90) in patients with a BEC of ≥ 1000 cells/µl to 77% (95% CI: 54, 89) in patients with a BEC of ≥ 750 cells/µl (Fig. 1). Tezepelumab also reduced the AAER compared with placebo across all specific IgE threshold subgroups, by 55% (95% CI: 42, 65) in patients with a sensitivity threshold of ≥ 0.70 kUA/l to 60% (95% CI: 45, 71) in patients with a sensitivity threshold of ≥ 17.5 kUA/l (Fig. 1).

Medical History and Exacerbation Triggers

Tezepelumab reduced the AAER over 52 weeks compared with placebo across all asthma-related comorbidity subgroups (Fig. 2). Reductions with tezepelumab compared with placebo in patients with asthma‑related comorbidities ranged from 58% (95% CI: 47, 67) in patients with rhinitis to 83% (95% CI: 66, 91) in patients with aspirin or NSAID sensitivity (Fig. 2). Tezepelumab also reduced the AAER compared with placebo in patients with GERD by 62% (95% CI: 45, 74) and in patients without GERD by 53% (95% CI: 42, 63) (Fig. 2). Tezepelumab reduced the AAER over 52 weeks compared with placebo irrespective of exacerbation trigger category; patients with exacerbations triggered by allergen exposure experienced the greatest reduction in AAER (71%; 95% CI: 47, 84) (Fig. 2).

Medications

Tezepelumab reduced the AAER over 52 weeks compared with placebo in both patients who were eligible and in those who were ineligible for dupilumab according to the EU prescribing information (a reduction of 64% [95% CI: 54, 71] and 34% [95% CI: 9, 52], respectively) (Fig. 3). Compared with placebo, tezepelumab reduced the AAER by 51% (95% CI: 8, 74) in patients with prior omalizumab use and by 57% (95% CI: 47, 64) in patients without prior omalizumab use (Fig. 3). In patients receiving 1, 2 or ≥ 3 controller medications in addition to ICS at baseline, tezepelumab reduced the AAER over 52 weeks compared with placebo by 41% (95% CI: 21, 55), 68% (95% CI: 56, 76) and 61% (95% CI: 40, 74), respectively (Fig. 3). When patients were grouped by the type of additional controller medication they received at baseline, the greatest reductions in AAER with tezepelumab compared with placebo were observed in patients receiving LABA and LTRA (78%; 95% CI: 66, 86) and LABA, LAMA and LTRA (73%; 95% CI: 53, 85) (Fig. 3). In the subgroup of patients receiving other additional controller medications at baseline, tezepelumab reduced the AAER by 37% (95% CI: − 3, 61) compared with placebo. Tezepelumab reduced the AAER compared with placebo in patients who were receiving additional controller medications but not maintenance OCS at baseline, irrespective of the type of additional controller medication; the greatest reductions in AAER were observed in patients receiving LABA and LTRA (78%; 95% CI: 66, 86) and LABA, LAMA and LTRA (75%; 95% CI: 53, 87) (Fig. 3).

Discussion

In these pre-specified and post hoc analyses of patients with severe, uncontrolled asthma enrolled in the phase 3 NAVIGATOR study, treatment with tezepelumab reduced the AAER over 52 weeks compared with placebo, regardless of sex, smoking history, baseline BMI, the presence of specific asthma-related comorbidities, exacerbation trigger category or the threshold of sensitivity to any perennial aeroallergen. Additionally, tezepelumab reduced exacerbations compared with placebo irrespective of dupilumab eligibility, prior omalizumab use or the number of additional controller medications used at baseline. These results underline the efficacy of tezepelumab across severe asthma phenotypes and further support the use of tezepelumab in patients with severe asthma with no phenotype or biomarker restrictions.

Several trends emerged among subgroups stratified by baseline patient characteristics and medical history. Consistent with previous analyses that showed tezepelumab was efficacious in patients with high baseline BECs (≥ 300 cells/μl and ≥ 450 cells/µl), the present study confirmed the efficacy of tezepelumab compared with placebo in patients with very high baseline BECs (≥ 500, ≥ 750 and ≥ 1000 cells/µl) [25]. Tezepelumab reduced exacerbations compared with placebo in patients with severe, uncontrolled asthma with and without each of the specific asthma‑related comorbidities assessed; however, the greatest reductions in AAER in these analyses were observed among patients with aspirin or NSAID sensitivity. When considering medication eligibility and additional controller medications, tezepelumab reduced exacerbations compared with placebo to a greater extent in patients who were eligible for dupilumab than in those who were not eligible and also in patients receiving LABA and LTRA as additional controller medications at baseline than in those receiving LABA alone. Although no formal hypothesis testing was performed, overall, these results indicate that many different factors may influence a patient’s response to tezepelumab treatment.

These findings are consistent with the previously published results from NAVIGATOR, which showed that the reductions in exacerbations were highest in patients with high baseline BECs (≥ 300 cells/µl) and high FeNO levels, which is characteristic of T2-high asthma [25]. Treatment response in patients with T2-low asthma, which can be defined using various biomarkers, is also of significant clinical interest. Patient numbers in the current study were too low to examine a subgroup of patients defined by multiple biomarkers (e.g. BEC < 150 cells/μl, FeNO levels < 25 ppb and without perennial aeroallergen sensitization), but a recent pooled analysis of participants in the NAVIGATOR and PATHWAY studies confirmed that tezepelumab was associated with a lower rate of exacerbations compared with placebo in patients with low levels of T2 inflammatory biomarkers [32].

The strengths of the phase 3 NAVIGATOR trial have been described previously; notably, the large number of participants enrolled, with varied baseline patient characteristics and comorbid conditions, facilitated these additional pre-specified and post hoc subgroup analyses [25]. The trial was limited by its strict inclusion criteria and 52-week duration, but the phase 3 long-term DESTINATION study (ClinicalTrials.gov identifier: NCT03706079) has confirmed the long-term benefits of tezepelumab in reducing exacerbations over 2 years [33]. A major limitation of the present study is the post hoc, exploratory nature of many of the analyses, without formal hypothesis testing, which means that these results should be interpreted with appropriate caution pending confirmation in follow-up studies. Furthermore, some subgroups included only small numbers of participants; notably, there were few participants with AERD/N-ERD/Samter’s triad and with baseline BECs of at least 750 cells/µl.

Future studies could examine the effect of tezepelumab on exacerbations by defined asthma phenotypes (e.g. Severe Asthma Research Program clusters, European Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes clusters and T2-high and T2-low asthma) rather than by individual factors alone [34, 35]. Further understanding of how bronchodilator response size might affect patient response to tezepelumab would also be of interest for clinical decision-making.

Conclusions

Tezepelumab reduced exacerbations compared with placebo over 52 weeks in patients with severe, uncontrolled asthma in the phase 3 NAVIGATOR study across a wide range of clinically relevant subgroups assessed. This highlights the broad impact of blocking TSLP on various asthma phenotypes and patient populations and provides further evidence that TSLP is central to asthma pathology. Cumulatively, these findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers’ treatment decisions.