Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials

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; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) 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 (NCT02054130 [PATHWAY], NCT03347279 [NAVIGATOR]).

Keywords: asthma; biomarkers; eosinophil; thymic stromal lymphopoietin.

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; Fe_NO = 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 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; Fe_NO = 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 Fe_NO 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; Fe_NO = fractional exhaled nitric oxide; Q4W = every 4 weeks.

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; Fe_NO = 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.