Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma

Background: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma.

Objective: We investigated whether eosinophil depletion with benralizumab (Benra) might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open label design.

Methods: After a 4-week run-in period on usual ICS/LABA (baseline), adults with mannitol responsive uncontrolled severe eosinophilic asthma received 3 doses of open label Benra 30mg every 4 weeks followed by 16 weeks washout after the last dose. The primary outcome was doubling difference (DD) in mannitol PD10 at end point after 12 weeks, powered at 90% with n=18 patients required to detect 1 DD. Secondary outcomes included asthma control questionnaire (ACQ) and mini asthma quality of life questionnaire (mini-AQLQ).

Results: 21 patients completed 12 weeks with Benra at end point at week 12. Mean (SEM) age was 53 (4) years, FEV1 80.2 (4.1) %, ICS dose 1895 (59)μg, n=12 on LAMA, n=13 on LTRA. Improvement in AHR was significant by 8 weeks with a mean 2.1 DD (95%CI 1.0, 3.3; p<0.01) change in PD10 at week 12, while mean changes in ACQ and mini-AQLQ were significant by week 2 and sustained over 12 weeks both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μl). No significant improvements occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms were also improved with Benra.

Conclusion: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients