Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma

Abstract

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma.This analysis used pooled data from the SIROCCO (ClinicalTrials.gov identifier NCT01928771) and CALIMA (ClinicalTrials.gov identifier NCT01914757) Phase III studies. Patients aged 12-75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting β₂-agonists received benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks (Q4W)), Q4W or placebo. Baseline factors that influenced benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s at treatment end relative to placebo.Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·μL^-1 relative to the overall population. OCS use, nasal polyposis and FVC <65% of predicted were associated with greater benralizumab Q8W responsiveness for reduced exacerbation rate for patients with <300 eosinophils·μL^-1Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to benralizumab.

FIGURE 1

Forest plot of baseline factor effect on annual exacerbation rate ratio with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid (ICS) plus long-acting β₂-agonist (LABA) for the overall population (full analysis set (FAS), pooled). OCS: oral corticosteroid; BD: bronchodilator; FVC: forced vital capacity. Data are from the pooled intention-to-treat population from the high-dosage ICS/LABA treatment cohorts of the SIROCCO and CALIMA studies. Estimates were reweighted to account for the 2:1 stratification for baseline blood eosinophil counts (≥300 and <300 cells·μL⁻¹). Estimates were calculated by using a negative binomial model with adjustment for study code, region, OCS use at time of randomisation where applicable, prior year exacerbations and treatment. The log of each patient's corresponding follow-up time was used as an offset variable in the model to adjust for different exposure times during which the events occurred.

FIGURE 2

Influence of baseline factors on annual exacerbation rate reduction with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid plus long-acting β₂-agonist (full analysis set (FAS), pooled): a) overall, b) ≥300 eosinophils·μL⁻¹ and c) <300 eosinophils·μL⁻¹. OCS: oral corticosteroid; BD: bronchodilator; FVC: forced vital capacity. ^#: nominal p-value <0.001; ^¶: nominal p-value ≥0.001– ≤0.01; ⁺: nominal p-value >0.01– ≤0.05. n-values for number of benralizumab Q8W patients included in the model presented (placebo cohort n-values in supplementary tables E1–E3).

FIGURE 3

Forest plot of baseline factor effect on pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV₁) (L) change (end-of-treatment (EOT)−baseline) improvements with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid (ICS) plus long-acting β₂-agonist (LABA) for the overall population (full analysis set (FAS), pooled). OCS: oral corticosteroid; BD: bronchodilator; FVC: forced vital capacity. Data are from the pooled intention-to-treat population from the high-dosage ICS/LABA treatment cohorts of the SIROCCO and CALIMA studies. Estimates were reweighted to account for the 2:1 stratification for baseline blood eosinophil counts (≥300 and <300 cells·μL⁻¹). Pre-BD FEV₁ change is from baseline (i.e. last value before randomisation) to EOT (SIROCCO: week 48; CALIMA: week 56). Estimates were calculated by using a mixed-effects model for repeated measures analysis with adjustment for study code, treatment, baseline value, region, OCS use at time of randomisation where applicable, visit and visit×treatment.

FIGURE 4

Influence of baseline factors on pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV₁) (L) change (end-of-treatment (EOT)−baseline) improvements with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid plus long-acting β₂-agonist (full analysis set (FAS), pooled): a) overall, b) ≥300 eosinophils·μL⁻¹ and c) <300 eosinophils·μL⁻¹. LS: least squares; OCS: oral corticosteroid; FVC: forced vital capacity. ^#: nominal p-value <0.001; ^¶: nominal p-value ≥0.001– ≤0.01; ⁺: nominal p-value >0.01– ≤0.05. n-values for number of benralizumab Q8W patients included in the model presented (placebo cohort n-values in supplementary tables E4–E6).

FIGURE 5

Influence of baseline factors on total asthma symptom score (TASS) change (end-of-treatment (EOT)−baseline) improvements with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid plus long-acting β₂-agonist (full analysis set (FAS), pooled): a) overall, b) ≥300 eosinophils·μL⁻¹ and c) <300 eosinophils·μL⁻¹. LS: least squares; OCS: oral corticosteroid; BD: bronchodilator; FVC: forced vital capacity. ^#: nominal p-value <0.001; ^¶: nominal p-value ≥0.001– ≤0.01; ⁺: nominal p-value >0.01– ≤0.05. n-values for number of benralizumab Q8W patients included in the model presented (placebo cohort n-values in supplementary tables E7–E9).

FIGURE 6

Influence of baseline factors on Asthma Control Questionnaire 6 (ACQ-6) change (end-of-treatment (EOT)−baseline) improvements with benralizumab every 8 weeks (Q8W, first three doses every 4 weeks) and high-dosage inhaled corticosteroid plus long-acting β₂-agonist (full analysis set (FAS), pooled): a) overall, b) ≥300 eosinophils·μL⁻¹ and c) <300 eosinophils·μL⁻¹. LS: least squares; OCS: oral corticosteroid; BD: bronchodilator; FVC: forced vital capacity; ND: not determined because of small sample size. ^#: nominal p-value <0.001; ^¶: nominal p-value ≥0.001– ≤0.01; ⁺: nominal p-value >0.01– ≤0.05. n-values for number of benralizumab Q8W patients included in the model presented (placebo cohort n-values in supplementary tables E10–E12).