Abstract
Rationale
Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT 02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT 03347279) trials.
Objectives
To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR.
Methods
PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18–75 years old; NAVIGATOR, 12–80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics.
Measurements and Main Results
Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34–0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2–high and type 2–low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups.
Conclusions
Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups.
Clinical trials registered with www.clinicaltrials.gov (NCT 02054130 [PATHWAY], NCT 03347279 [NAVIGATOR]).
Keywords: asthma, eosinophil, biomarkers, thymic stromal lymphopoietin
At a Glance Commentary
Scientific Knowledge on the Subject
Several biologics have demonstrated benefits in specific subsets of patients with severe, uncontrolled asthma; however, type 2–targeted biologics have limited efficacy in patients with low blood eosinophil counts (BECs) or low fractional exhaled nitric oxide (FeNO) levels. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis. In randomized, placebo-controlled trials, tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma with high or low baseline BECs or FeNO levels and irrespective of allergy status.
What This Study Adds to the Field
This post hoc analysis evaluated the efficacy and safety of tezepelumab using pooled data from two randomized, double-blind, placebo-controlled trials in patients with severe, uncontrolled asthma. Tezepelumab reduced exacerbations in the overall population and in a range of patient subgroups. Clinically meaningful reductions in exacerbations compared with placebo were observed in tezepelumab-treated patients with type 2–low disease, defined by low (<300 cells/μl) or very low (<150 cells/μl) baseline BEC, low FeNO levels (<25 ppb), and negative perennial allergy status in the absence of maintenance corticosteroid use at baseline. Tezepelumab is the first biologic to demonstrate efficacy independent of asthma phenotype or endotype.
Asthma is a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, and airway hyperresponsiveness (AHR), leading to various symptoms including wheezing, chest tightness, cough, shortness of breath, impaired lung function, acute asthma exacerbations, and limitation of daily activities. All these symptoms result in reduced health-related quality of life (HRQoL) (1). In most patients, asthma can be managed with inhaled corticosteroid (ICS) and long-acting β-agonist therapy. However, some patients with severe asthma have uncontrolled disease despite treatment and may experience exacerbations, which can lead to hospitalization and/or emergency department (ED) visits (2).
Biologics that target IgE (omalizumab) or type 2 (T2) cytokine signaling (i.e., IL-5 [mepolizumab, reslizumab], IL-5 receptors [benralizumab], and IL-4 receptors [dupilumab]), are beneficial for patients with severe, uncontrolled asthma and are indicated for allergic or eosinophilic asthma (3–5). However, these biologics are most effective in patients with high blood eosinophil counts (BECs), demonstrating limited efficacy in patients with low levels of T2 inflammatory biomarkers (BEC ⩽ 260–300 cells/μl or fractional exhaled nitric oxide [FeNO] level < 25 ppb) (6–9). Therefore, an unmet need remains in many patients with severe, uncontrolled asthma, particularly those with low T2 inflammatory biomarker levels (10).
Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in asthma pathogenesis. TSLP is released by airway epithelial cells in response to allergens and other environmental triggers and drives airway inflammation by initiating both T2 and non-T2 processes through its downstream inflammatory effects involving the T2 cytokines IL-4, IL-5, and IL-13, as well as effects on mast cells and other immune cells. TSLP can also play a key role in asthma pathophysiology by driving AHR, mucus overproduction, and potential airway remodeling (11). In a proof-of-concept study, tezepelumab reduced allergen-induced early- and late-phase asthmatic response, reduced AHR to methacholine, and suppressed asthma-associated T2 inflammatory biomarkers (12). Subsequently, the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma were evaluated in the randomized, placebo-controlled phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT 02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT 03347279) trials (13, 14). Treatment with tezepelumab reduced the annualized asthma exacerbation rate (AAER) compared with placebo in patients from both trials, including in those with high or low baseline BECs or FeNO levels, and regardless of allergy status (13, 14). Tezepelumab also improved lung function, asthma control, and HRQoL and reduced T2 inflammatory biomarker levels (BEC, FeNO, IgE, IL-5, and IL-13) compared with placebo (13–15). In addition, in the phase 2 CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults with Uncontrolled Asthma) trial, treatment with tezepelumab resulted in a numerically greater reduction in AHR to mannitol than placebo. Collectively, these studies suggest that tezepelumab reduces airway inflammation and AHR, both of which play key roles in asthma pathophysiology (16). Tezepelumab received U.S. Food and Drug Administration approval in December 2021 as the first and only biologic treatment for severe asthma with no biomarker or phenotypic restrictions (17).
In this post hoc analysis, we evaluated the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma using pooled data from PATHWAY and NAVIGATOR. Data were pooled to increase statistical precision across multiple clinically relevant patient subgroups, notably those with low T2 inflammatory biomarker levels, which have not been thoroughly investigated previously and may be difficult to manage in a clinical setting. The pooling of data also allowed the assessment of the effects of tezepelumab on less frequent outcomes, including exacerbation-related hospitalizations or ED visits.
Some of the results of this analysis have been previously reported in an abstract (18).
Methods
Study Design
PATHWAY (phase 2b) and NAVIGATOR (phase 3) were multicenter, randomized, double-blind, placebo-controlled, parallel-group, 52-week trials with similar designs and eligibility criteria in patients with severe, uncontrolled asthma. Full design details and patient eligibility criteria for both trials have been described previously (13, 14), and additional details are outlined in the online supplement.
Both trials were conducted in accordance with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. Approvals from independent ethics committees were obtained, and all patients provided written informed consent in accordance with local requirements.
Outcomes
All endpoints in this analysis were assessed in the pooled patient population of the PATHWAY (tezepelumab 210 mg every 4 weeks [Q4W] and placebo groups only) and NAVIGATOR trials.
The primary endpoint of interest in this analysis was the AAER over 52 weeks in the overall pooled population and in subgroups on the basis of centrally assessed baseline BEC, baseline FeNO, baseline perennial allergy status (positive status defined as at least one positive fluorescence enzyme immunoassay test result for serum-specific IgE against one or more of the following perennial aeroallergens: cat dander, dog dander, cockroach, dust mite [Dermatophagoides farinae or Dermatophagoides pteronyssinus], and mold mix), the number of exacerbations in the previous year, ICS dose, oral corticosteroid (OCS) use, history of nasal polyps, and body mass index (BMI).
To examine the reduction in the AAER over 52 weeks in patients across the spectrum of T2 inflammation, the AAER was also assessed in patients grouped by combinations of baseline BEC, FeNO levels, and perennial allergy status, including “T2-high” subgroups with multiple elevated biomarkers and “T2-low” subgroups with low levels of multiple biomarkers. Across biomarker subgroups, the AAER over 52 weeks was evaluated in patient subgroups, including and excluding those receiving maintenance OCS at baseline, to account for the reduction in biomarker levels due to OCS use.
A secondary endpoint was the annualized rate of asthma exacerbations associated with hospitalization or an ED visit over 52 weeks in the overall pooled population and in individual subgroups. In patients grouped by combinations of BEC (<150 or ≥150 cells/μl) and FeNO levels (<25 or ≥25 ppb), the total number of exacerbations that were associated with hospitalization or an ED visit was also assessed. Additional secondary endpoints are outlined in the online supplement.
The safety of tezepelumab was evaluated in the pooled population on the basis of the incidence of adverse events (AEs), serious AEs, injection site reactions, and reasons for treatment discontinuation.
Statistical Analyses
Rate ratios (RRs) and 95% confidence intervals (CIs) for AAER and the annualized rate of asthma exacerbations that were associated with hospitalization or an ED visit over 52 weeks were estimated using a negative binomial regression analysis with treatment, trial (PATHWAY or NAVIGATOR), history of exacerbations, treatment group, subgroup (when relevant), and treatment-by-subgroup interaction (when relevant) as covariates.
A locally estimated scatterplot smoothing (LOESS) regression model was fitted for each treatment arm separately and applied to the AAER over 52 weeks by baseline BEC, FeNO level, and IgE concentration.
Results
Baseline Demographics and Clinical Characteristics
Overall, 1,334 patients were included in this pooled analysis, including 275 patients from PATHWAY and 1,059 patients (including 82 adolescents) from NAVIGATOR, who received tezepelumab 210 mg Q4W (n = 665) and placebo (n = 669) (see Figure E1 in the online supplement). The number of patients who did not complete the respective trials was low (13, 14). Baseline demographics and clinical characteristics of the pooled population were generally similar between the treatment groups (Table 1). The vast majority of patients (>99%) had at least two exacerbations during the 12 months before entry into the respective trials (Table 1).
Table 1.
Baseline Demographics and Clinical Characteristics
| Demographic or Characteristic | Tezepelumab 210 mg Q4W (n = 665) |
Placebo (n = 669) |
|---|---|---|
| Age, yr, mean (SD) | 50.5 (15.6) | 49.7 (15.2) |
| Female, n (%) | 422 (63.5) | 431 (64.4) |
| BMI, kg/m2, mean (SD) | 28.7 (6.7) | 28.3 (6.6) |
| ICS dose subgroup,* n (%) | ||
| Medium | 201 (30.2) | 205 (30.6) |
| High | 464 (69.8) | 463 (69.2) |
| Maintenance OCS use, n (%)† | 58 (8.7) | 65 (9.7) |
| Prebronchodilator FEV1, L, mean (SD) | 1.8 (0.7) | 1.8 (0.7) |
| Prebronchodilator FEV1, % predicted, mean (SD) | 62.0 (17.1) | 62.2 (17.2) |
| Number of exacerbations in the past 12 mo,‡ n (%) | ||
| 1 | 3 (0.5) | 4 (0.6) |
| 2 | 412 (62) | 431 (64.4) |
| ≥3 | 250 (37.6) | 234 (35.0) |
| FeNO level, ppb | ||
| Mean (SD) | 39.4 (35.3) | 44.5 (43.8) |
| Median (min, max) | 28 (4, 235) | 28 (4, 276) |
| FeNO subgroup, ppb, n (%) | ||
| <25 | 291 (43.8) | 294 (43.9) |
| ≥25–<50 | 191 (28.7) | 181 (27.1) |
| ≥50 | 175 (26.3) | 189 (28.3) |
| Blood eosinophil count, cells/μl | ||
| Mean (SD) | 335 (306) | 359 (460) |
| Median (min, max) | 260 (0, 3,650) | 260 (0, 8,170) |
| Blood eosinophil count subgroup, cells/μl, n (%) | ||
| <300 | 379 (57.0) | 382 (57.1) |
| ≥300 | 286 (43.0) | 287 (42.9) |
| <150 | 166 (25.0) | 171 (25.6) |
| 150–<300 | 213 (32.0) | 211 (31.5) |
| 300–<450 | 127 (19.1) | 116 (17.3) |
| ≥450 | 159 (23.9) | 171 (25.6) |
| Serum total IgE, IU/ml | ||
| Mean (SD) | 509.1 (1,064.9) | 585.3 (1,183.8) |
| Median (min, max) | 177.1 (1.5, 12,823.2) | 182.8 (1.5, 11,859.6) |
| FEIA positive for any perennial aeroallergen,§ n (%) | 410 (61.7) | 405 (60.5) |
Definition of abbreviations: BMI = body mass index; FEIA = fluorescence enzyme immunoassay; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; max = maximum; min = minimum; NAVIGATOR = Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; OCS = oral corticosteroid; PATHWAY = Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma; Q4W = every 4 weeks.
Medium-dose ICS: fluticasone propionate 500 μg/d (in NAVIGATOR) or 250 to <500 μg/d (in PATHWAY) or equivalent; high-dose ICS: fluticasone propionate >500 μg/d or equivalent. There was one patient in the placebo group who received fluticasone propionate <500 μg/d or equivalent.
Mean daily maintenance OCS dose of 11 mg (min, 2.5 mg; max, 40 mg).
Patients in PATHWAY were required to have a history of at least two asthma exacerbations that led to systemic corticosteroid treatment, or at least one severe exacerbation that was associated with hospitalization, in the 12 months before study entry.
Positive for at least one perennial aeroallergen (cat dander, dog dander, cockroach, dust mite [Dermatophagoides farinae or Dermatophagoides pteronyssinus], and mold mix).
Exacerbations
In the overall pooled population, tezepelumab reduced the AAER over 52 weeks compared with placebo by 60% (RR, 0.40 [95% CI, 0.34–0.48]). Tezepelumab also reduced the AAER over 52 weeks compared with placebo in patients grouped by baseline inflammatory biomarkers, with reductions ranging from 40% (RR, 0.60 [95% CI, 0.46–0.79]) in patients with FeNO levels <25 ppb to 78% (RR, 0.22 [95% CI, 0.15–0.33]) in patients with BECs ≥450 cells/μl (Figure 1A). Reductions in the AAER over 52 weeks were also observed with tezepelumab compared with placebo in these subgroups after excluding patients who were receiving maintenance OCS (Figure 1B). The AAER over 52 weeks was consistently lower in the tezepelumab group than the placebo group across the spectrum of biomarker levels when assessed using LOESS plots (Figure 2) and by defined BEC and FeNO level cutoffs (see Figure E2). Among placebo recipients, the AAER over 52 weeks increased with increasing baseline BECs and FeNO levels but was consistent across baseline IgE concentrations (Figure 2).
Figure 1.
(A and B) Annualized asthma exacerbation rate over 52 weeks compared with placebo (A) in the overall pooled population and in individual subgroups at baseline and (B) biomarker subgroups excluding patients who received mOCS and in combined biomarker subgroups. Rate ratio is displayed on a log scale. Data are from a negative binomial regression analysis with treatment, study (PATHWAY and NAVIGATOR), history of exacerbations (two or fewer or more than two in the previous 12 mo), subgroup, and treatment-by-subgroup interaction as covariates. BEC = blood eosinophil count; BMI = body mass index; CI = confidence interval; excl = excluding; FEIA = fluorescence enzyme immunoassay; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; mOCS = maintenance oral corticosteroid; OCS = oral corticosteroid; NAVIGATOR = Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; PATHWAY = Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma; Q4W = every 4 weeks.
Figure 2.
(A–C) Locally estimated regression and smoothing scatterplot (LOESS) showing the AAER over 52 weeks in the overall pooled population compared with placebo by (A) baseline eosinophil count, (B) baseline FeNO level, and (C) total IgE concentration. LOESS regression was fitted for each treatment arm separately. The bands on the curves represent 95% confidence intervals. AAER = annualized asthma exacerbation rate; FeNO = fractional exhaled nitric oxide; Q4W = every 4 weeks.
Tezepelumab reduced the AAER over 52 weeks compared with placebo by 62% (RR, 0.38 [95% CI, 0.30–0.47]) and by 54% (RR, 0.46 [95% CI, 0.34–0.62]) in patients with and without perennial aeroallergen sensitivity, respectively (Figure 1A). The AAER over 52 weeks was also lower in the tezepelumab group than in the placebo group in patients receiving high- or medium-dose ICS at baseline, patients with a history of nasal polyps, in those with OCS use at baseline, and across BMI subgroups and geographical regions (Figures 1A and E3A).
In the analysis of subgroups based on multiple biomarker levels, the AAER over 52 weeks was consistently lower with tezepelumab compared with placebo for patients grouped by combinations of BEC and perennial allergy status, with reductions ranging from 38% in patients with BECs <300 cells/μl and without perennial allergy to 71% in patients with BECs ≥300 cells/μl and with perennial allergy. Similarly, in patients grouped by combined BEC and FeNO level, the AAER was consistently lower in the tezepelumab group, with reductions ranging from 37% to 77%. Results were similar among these groups after excluding those receiving maintenance OCS (Figure 1B).
In patients with BECs <150 cells/μl, with FeNO levels <25 ppb, and without perennial allergies (i.e., the “triple T2-low” subgroup), the AAER over 52 weeks was 34% (RR, 0.66 [95% CI, 0.34–1.30]) lower with tezepelumab compared with placebo. When excluding patients receiving maintenance OCS at baseline from the triple T2-low subgroup, the AAER over 52 weeks with tezepelumab was 45% (RR, 0.55 [95% CI, 0.27–1.12]) lower than with placebo (Figure 1B).
Exacerbations Associated with Hospitalization or ED Visits
Tezepelumab reduced the annualized rate of exacerbations that were associated with hospitalization or an ED visit over 52 weeks compared with placebo by 79% (RR, 0.21 [95% CI, 0.13–0.35]) in the overall population and from 60% to 94% across all subgroups assessed, including in patients with BECs <150 cells/μl (RR, 0.40 [95% CI, 0.18–0.93]), in patients with FeNO levels ≥50 ppb (RR, 0.09 [95% CI, 0.03–0.25]) and in patients with a history of nasal polyps (RR, 0.06 [95% CI, 0.01–0.52]) (Figure 3).
Figure 3.
Annualized rate of asthma exacerbations that were associated with hospitalization or an emergency department visit over 52 weeks compared with placebo in the overall pooled population and in individual subgroups at baseline. Rate ratio is displayed on a log scale. Data are from a negative binomial regression analysis with treatment, study (PATHWAY or NAVIGATOR), history of exacerbations (two or fewer or more than two in the previous 12 mo), subgroup (if not already included), and treatment-by-subgroup interaction as covariates. BEC = blood eosinophil count; BMI = body mass index; CI = confidence interval; FEIA = fluorescence enzyme immunoassay; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; NAVIGATOR = Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; OCS = oral corticosteroid; PATHWAY = Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma; Q4W = every 4 weeks.
In patients grouped by combinations of BEC (<150 or ≥150 cells/μl) and FeNO level (<25 or ≥25 ppb), the total number of exacerbations that were associated with hospitalization or an ED visit was lower in the tezepelumab group than in the placebo group, irrespective of combined biomarker levels (see Table E1).
The effect of tezepelumab treatment on the rate of exacerbations that were associated with hospitalization or an ED visit was corroborated by LOESS plots showing that reductions were consistent across baseline biomarker levels (see Figure E4).
Among placebo recipients, the annualized rate of exacerbations that were associated with hospitalization or an ED visit over 52 weeks remained consistent across baseline BECs but increased with baseline FeNO levels and was inversely correlated with baseline IgE concentrations (see Figure E4).
Tezepelumab treatment reduced the rate of exacerbations that were associated with hospitalization or an ED visit compared with placebo by 80% (RR, 0.20 [95% CI, 0.10–0.39]) and by 74% (RR, 0.26 [95% CI, 0.12–0.59]) in patients with and without perennial aeroallergen sensitivity, respectively (Figure 3). Reductions were also observed in patients receiving high- or medium-dose ICS at baseline, in those with a history of nasal polyps, in those with OCS use at baseline, and across BMI subgroups and geographical regions (Figures 3 and E3B). Similar trends were observed for exacerbations that were associated with hospitalization (ignoring events that resulted in ED visits only) (see Figure E5).
Prebronchodilator FEV1, Asthma Control Questionnaire 6, and Asthma Quality of Life Questionnaire (Standardized) for Patients 12 Years and Older
In the overall population, tezepelumab improved prebronchodilator FEV1 at Week 52 compared with baseline. Prebronchodilator FEV1 at Week 52 increased by 0.09 L in the placebo group and by 0.22 L in the tezepelumab group compared with baseline, with a least-squares mean difference compared with placebo of 0.13 L (95% CI, 0.09–0.18 L) (Table 2). Numerical improvements in FEV1 with tezepelumab compared with placebo were also observed in patients with baseline BECs of ≥150 cells/μl and across baseline FeNO level subgroups (see Table E2 and Figure E6) and in combined biomarker subgroups (see Table E3). Improvements were observed with tezepelumab compared with placebo in patients with or without perennial allergies and irrespective of maintenance OCS use at baseline (see Table E2).
Table 2.
Change from Baseline in Prebronchodilator FEV1 and Asthma Control Questionnaire 6 and Asthma Quality of Life Questionnaire (Standardized) for Patients 12 Years and Older Scores at Week 52 Compared with Placebo in the Overall Pooled Population
| Tezepelumab 210 mg Q4W (n = 665) |
Placebo (n = 669) |
|
|---|---|---|
| Prebronchodilator FEV1, L | ||
| Mean (SD) at baseline | 1.83 (0.69) | 1.85 (0.68) |
| n* | 624 | 619 |
| LS mean change | 0.22 | 0.09 |
| LS mean difference, tezepelumab vs. placebo (95% CI) | 0.13 (0.09 to 0.18) | |
| ACQ-6 score | ||
| Mean (SD) at baseline | 2.80 (0.81) | 2.76 (0.79) |
| n* | 529 | 525 |
| LS mean change | −1.41 | −1.07 |
| LS mean difference, tezepelumab vs. placebo (95% CI) | −0.33 (−0.45 to −0.22) | |
| AQLQ(S)+12 score | ||
| Mean (SD) at baseline | 3.93 (1.01) | 3.94 (0.98) |
| n* | 521 | 514 |
| LS mean change | 1.40 | 1.07 |
| LS mean difference, tezepelumab vs. placebo (95% CI) | 0.33 (0.20 to 0.45) | |
Definition of abbreviations: ACQ-6 = Asthma Control Questionnaire 6; AQLQ(S)+12 = Asthma Quality of Life Questionnaire (standardized) for patients 12 years and older; CI = confidence interval; LS = least-squares; NAVIGATOR = Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; PATHWAY = Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma; Q4W = every 4 weeks.
The mean change from baseline to Week 52 in the tezepelumab group is compared with the placebo group using a repeated-measures analysis and reported as LS means. Treatment, study (PATHWAY and NAVIGATOR), visit, treatment by visit, and baseline value (of FEV1, ACQ-6 score, or AQLQ[S]+12 score) were used as covariates.
The number of patients with data at Week 52. All patients with at least one change from baseline at an overlapping visit were included in the analysis. Only data from the overlapping visits (Weeks 4, 8, 12, and 52) across NAVIGATOR and PATHWAY were included in the analyses.
Numerical improvements in Asthma Control Questionnaire 6 (ACQ-6) and Asthma Quality of Life Questionnaire (standardized) for patients 12 years and older (AQLQ[S]+12) scores from baseline to Week 52 with tezepelumab were observed in the overall population (Table 2) and in patients grouped by baseline BEC, FeNO level, perennial allergy status, and maintenance OCS use (see Table E2). The greatest improvements were observed in patients with high baseline BECs or high baseline FeNO levels.
Safety
Overall, the proportions of patients reporting on-treatment AEs were 75% (n = 496 of 665) and 77% (n = 512 of 669) in the tezepelumab and placebo groups, respectively. The overall number of patients with any serious AE was low. On-treatment serious AEs were reported for 9% (n = 57 of 665) and 13% (n = 87 of 669) of patients in the tezepelumab and placebo groups, respectively (Table 3). No tezepelumab-related anaphylactic reactions were reported. The incidences of benign and malignant neoplasms and of severe infections were similar in the tezepelumab and placebo groups. Serious AEs of cardiac disorders were reported in 0.8% (n = 5 of 665) and 0.3% (n = 2 of 669) of patients in the tezepelumab and placebo groups, respectively. A summary of serious AEs is provided in Table E4.
Table 3.
Summary of On-Treatment Adverse Events in the Overall Pooled Population
| Tezepelumab 210 mg Q4W (n = 665) |
Placebo (n = 669) |
|
|---|---|---|
| Any AE | ||
| n (%) | 496 (74.6) | 512 (76.5) |
| Number of events | 1,933 | 2,095 |
| Any AE resulting in death | ||
| n (%) | 0 (0.0) | 0 (0.0) |
| Number of events | 0 | 0 |
| Any SAE | ||
| n (%) | 57 (8.6) | 87 (13.0) |
| Number of events | 82 | 160 |
| Any AE leading to discontinuation of treatment | ||
| n (%) | 13 (2.0) | 20 (3.0) |
| Number of events | 15 | 24 |
| Most common AEs (reported in ≥3% of patients who received tezepelumab), n (%) | ||
| Nasopharyngitis | 130 (19.5) | 128 (19.1) |
| Upper respiratory tract infection | 62 (9.3) | 89 (13.3) |
| Headache | 52 (7.8) | 50 (7.5) |
| Asthma | 49 (7.4) | 105 (15.7) |
| Bronchitis | 29 (4.4) | 36 (5.4) |
| Hypertension | 26 (3.9) | 27 (4.0) |
| Arthralgia* | 25 (3.8) | 16 (2.4) |
| Bronchitis bacterial | 25 (3.8) | 17 (2.5) |
| Urinary tract infection | 24 (3.6) | 23 (3.4) |
| Back pain† | 23 (3.5) | 20 (3.0) |
| Sinusitis | 23 (3.5) | 42 (6.3) |
| Pharyngitis | 20 (3.0) | 17 (2.5) |
| Viral upper respiratory tract infection | 20 (3.0) | 14 (2.1) |
Definition of abbreviations: AE = adverse event; n = number of patients; OCS = oral corticosteroid; Q4W = every 4 weeks; SAE = serious adverse event.
Any AE start date, or any safety assessment date (e.g., laboratory, vital signs), that occurred between the date of first dose of tezepelumab and minimum (date of last dose of tezepelumab + 33 d, date of death, date of study withdrawal) was considered on treatment.
Patients with arthralgia AEs had median AE durations of 31 and 25.5 days in the tezepelumab and placebo groups, respectively; daily OCS use was reported at baseline in 24% and 0% of patients, respectively. When rated, severity/intensity was mild or moderate in all cases. The study drug was discontinued in one tezepelumab recipient with an arthralgia AE.
Patients with back pain AEs had a median AE duration of 7.5 d in the tezepelumab and placebo groups; daily OCS use was similar in both groups. When rated, severity/intensity was mild or moderate in all cases, except for one placebo case rated as severe. The study drug was not discontinued in any patients with back pain AEs.
The most common AEs reported in ≥3% of patients across both treatment groups were nasopharyngitis, upper respiratory tract infection, headache, and asthma. The incidence of AEs was generally similar between the tezepelumab and placebo groups, with asthma and sinusitis reported in more placebo recipients than tezepelumab recipients (Table 3).
Overall, 2% (n = 13 of 665) and 3% (n = 20 of 669) of patients in the tezepelumab and placebo groups, respectively, discontinued treatment because of AEs. Treatment discontinuation because of serious AEs was reported in 1% (n = 6 of 665) and 2% (n = 12 of 669) of patients in the tezepelumab and placebo groups, respectively (see Table E5). When assessed by causality, 9% (n = 60 of 665) and 8% (n = 54 of 669) of patients in the tezepelumab and placebo groups reported AEs related to treatment, respectively, whereas 66% (n = 436 of 665) and 69% (n = 458 of 669) reported AEs that were unrelated to treatment, respectively. Injection-site reactions were reported in 4% (n = 25 of 665) and 3% (n = 21 of 669) of patients in the tezepelumab and placebo groups, respectively (see Table E6). No on-treatment deaths were reported. Two deaths were reported in the placebo group during the safety follow-up.
Discussion
This post hoc analysis of pooled data from PATHWAY and NAVIGATOR allowed the efficacy of tezepelumab to be assessed with greater statistical precision in clinically relevant patient subgroups and allowed less frequent outcomes to be assessed. The findings demonstrated that tezepelumab treatment resulted in clinically meaningful reductions in exacerbations, including those associated with hospitalization or an ED visit, across patient subgroups defined by various inflammatory biomarker levels or clinical characteristics, including subgroups with evidence of high or low T2 inflammation. This also included patients receiving maintenance OCS, in which exacerbations associated with hospitalization or an ED visit were reduced by 79% with tezepelumab versus placebo. Tezepelumab was also generally associated with improved lung function, asthma control, and HRQoL compared with placebo.
Tezepelumab demonstrated efficacy compared with placebo in reducing exacerbations in patients with low levels of inflammatory biomarkers at baseline, specifically BEC < 150 cells/μl and FeNO level < 25 ppb. No other biologic has consistently demonstrated robust exacerbation reductions in these populations in randomized, placebo-controlled trials. This led to tezepelumab becoming the first biologic approved by the U.S. Food and Drug Administration for patients with severe asthma without phenotypic or biomarker limitations (13, 14, 17).
In patients with low levels of inflammatory biomarkers, clear exacerbation reductions were seen in subgroups with BECs of <150 cells/μl (48%; RR, 0.52 [95% CI, 0.36–0.74]) or FeNO levels <25 ppb (40%; RR, 0.60 [95% CI, 0.46–0.79]), with CIs clearly excluding 1. To further understand efficacy trends, exacerbation rates with tezepelumab compared with placebo were examined in additional subgroups on the basis of combined biomarker levels. Although BEC and FeNO levels are often correlated, they may be discordant in some patients. In patients with both BECs <150 cells/μl and FeNO levels <25 ppb, exacerbations were reduced by 37% (RR, 0.63 [95% CI, 0.40–1.00]). The wider CIs for the RRs for the AAERs in the subgroups reflect the smaller subgroup sample sizes; however, the point estimates (ranging from 32% to 49% reductions in exacerbations) across the subgroups investigated are clinically meaningful and consistent and suggest efficacy in patients with low T2 inflammation, with the limitation that some of the RR CIs failed to exclude 1.
Other available biologics are indicated for allergic asthma (omalizumab) or asthma with an eosinophilic phenotype or endotype (reslizumab, benralizumab, mepolizumab, and dupilumab) (7, 19–23). Consequently, many patients are ineligible for these biologics (24, 25). Furthermore, these biologics have demonstrated reduced or negligible efficacy in patients with low BECs or low FeNO levels. In the phase 3 LIBERTY ASTHMA QUEST (Evaluation of Dupilumab in Patients With Persistent Asthma) study, dupilumab 200 mg every 2 weeks reduced exacerbations compared with placebo by 48% (RR, 0.52 [95% CI, 0.41–0.66]) overall, by 66% (RR, 0.34 [95% CI, 0.24–0.48]) in patients with baseline BECs ≥300 cells/μl, and by 7% (RR, 0.93 [95% CI, 0.58–1.47]) in those with baseline BECs <150 cells/μl (7). Similarly, dupilumab 200 mg every 2 weeks reduced exacerbations compared with placebo by 69% (RR, 0.31 [95% CI, 0.18–0.52]) in patients with FeNO levels ≥50 ppb, compared with 25% (RR, 0.75 [95% CI, 0.54–1.05]) in those with FeNO levels <25 ppb (7). Similar trends were observed with benralizumab, reslizumab, mepolizumab, and omalizumab as a function of baseline BEC and with omalizumab as a function of baseline FeNO level (6, 8, 9, 19, 20, 22).
Improvements in prebronchodilator FEV1 were observed with tezepelumab across FeNO levels in the present pooled analysis, in patients with BECs of ≥150 cells/μl, in those with and without perennial allergies, and irrespective of maintenance OCS use. Improvements in ACQ-6 and AQLQ(S)+12 scores were observed across baseline BECs and FeNO levels, although the greatest improvements were observed in patients with high baseline levels. The 95% CIs for the improvements in ACQ-6 and AQLQ(S)+12 scores did not exclude 0 in the subgroups with BEC < 150 cells/μl and FeNO < 25 ppb, which may be explained in part by the placebo effect often observed in randomized clinical trials (as indicated by the strong improvement in ACQ-6 and AQLQ[S]+12 scores at Week 52 among placebo recipients).
The pooling of data from the PATHWAY and NAVIGATOR trials is justified because of their similarities in study design, population, tezepelumab dose (210 mg Q4W), and endpoints. There were some differences in eligibility criteria between the trials, primarily that a small cohort of adolescents was recruited in NAVIGATOR but not in PATHWAY, as well as slightly different ICS dosing requirements before the trials and number of exacerbations in the previous 12 months; however, these differences are not expected to confound a pooled analysis. In addition, the large number of recruitment sites was a strength but also a potential limitation given the wide variability of resources and practice patterns in the treatment of severe asthma. However, all sites followed the study protocols to ensure a consistent patient population and consistent data collection.
The safety profile of tezepelumab in this pooled analysis was consistent with that in the individual trials and demonstrated that tezepelumab was well tolerated (13, 14). The incidence and pattern of AEs were similar between treatment groups. Notably, the frequency of severe upper respiratory tract infections was similar between tezepelumab and placebo recipients, consistent with a post hoc analysis of samples from the phase 2 UPSTREAM (Effects of Anti-TSLP in Patients with Asthma) trial, which used in vitro methods to demonstrate that viral response is not reduced with tezepelumab (26). Serious AEs were reported in a smaller proportion of tezepelumab recipients than placebo recipients. The incidences of other serious AEs were similar between treatment groups. No anaphylactic or hypersensitivity events were reported.
As with the other approved biologics for asthma, there is a need for additional studies on the long-term safety and real-world effectiveness of tezepelumab. The DESTINATION (Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma) trial (NCT 03706079) is a long-term extension of the NAVIGATOR and SOURCE (Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma; NCT 03406078) trials and has shown that tezepelumab is well tolerated in patients with severe, uncontrolled asthma over 2 years (27, 28).
Conclusions
In this pooled analysis of the PATHWAY and NAVIGATOR trials, tezepelumab treatment resulted in meaningful reductions in asthma exacerbations, including those associated with hospitalization or an ED visit, across patient subgroups defined by inflammatory biomarker levels or clinical characteristics. In addition to reductions in exacerbations in patients with high baseline BEC and FeNO levels, meaningful reductions were also observed in patients with low levels of T2 inflammatory biomarkers and across subgroups with varying perennial allergy status, maintenance OCS use, exacerbation history, ICS dose, history of nasal polyps, and BMI. Notably, tezepelumab recipients had a consistently lower rate of exacerbations than placebo recipients across combined biomarker subgroups of low BEC and low FeNO level, or low BEC and the absence of perennial aeroallergen sensitization, as well as the triple T2-low subgroup, defined by low BEC, low FeNO level, and absence of perennial aeroallergen sensitization. Tezepelumab also improved lung function, asthma control, and HRQoL compared with placebo. Safety findings were generally similar between the tezepelumab and placebo groups. Together, these findings further support the benefits of tezepelumab in a broad population of patients with severe, uncontrolled asthma.
Acknowledgments
Acknowledgment
Medical writing support was provided by Priyanka Narang, Ph.D., of PharmaGenesis London, London, UK, with funding from AstraZeneca and Amgen Inc.
Footnotes
Supported by AstraZeneca and Amgen Inc. The funders of the study contributed to the study design and data interpretation. The study sponsor (AstraZeneca) conducted the study, coordinated the data management, and did the statistical analysis in collaboration with investigators at the academic centers.
Author Contributions: Substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work: all authors. Drafting the work or revising it critically for important intellectual content: all authors. Final approval of the version to be published: all authors. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors.
Data availability statement: Data underlying the findings described in this article may be obtained in accordance with AstraZeneca’s data-sharing policy, described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202210-2005OC on April 4, 2023
Author disclosures are available with the text of this article at www.atsjournals.org.
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