Relationship between Benralizumab Exposure and Asthma Exacerbation Rate for Patients with Severe Asthma

Introduction:

Benralizumab is an anti-eosinophil monoclonal antibody targeting human IL-5Rα. In the randomized, controlled Phase III SIROCCO (Lancet. 2016;388:2115 – 27) and CALIMA (Lancet. 2016;388:2128 – 41) trials, benralizumab 30 mg every 4 weeks (Q4W) and 30 mg every 8 weeks (Q8W; first three doses Q4W) significantly improved asthma exacerbation rates (AER; primary endpoint) for patients with severe asthma receiving high-dosage inhaled corticosteroids/long-acting β₂-agonists (ICS/LABA) with baseline blood eosinophils ≥300 cells/µL. We aimed to evaluate the relationship between benralizumab pharmacokinetic (PK) exposure and AER for all patients with severe asthma receiving high-dosage ICS/LABA.

Methods:

An empirical assessment was conducted to correlate steady-state trough PK quartiles with observed AER. A population PK exposure-response model was developed to characterize benralizumab treatment effect on AER.

Results:

In the empirical assessment, AER ratios in SIROCCO were similar across trough PK quartiles, whereas patients in CALIMA in the lowest trough PK quartile had a smaller AER response than those in other quartiles. In population modeling, the estimated benralizumab 90% effective concentration for AER was 927 ng/mL, which was lower than the typical steady-state average PK concentration (1,066 ng/mL) for the Q8W regimen. Number of exacerbations in the past 12 months, Central/Eastern Europe region, and oral corticosteroid use were significant covariates for base AER. There was a positive trend toward improved benralizumab efficacy for patients with higher baseline eosinophil counts.

Conclusions:

Both empirical and population-based analyses of AER confirmed 30 mg Q8W as the optimal 90% effective dose of benralizumab for patients with severe asthma.