Effects of dupilumab on mannitol airway hyperresponsiveness in uncontrolled severe asthma.

Abstract

Airway hyperresponsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown. This study sought to investigate the effect of 12 weeks of Dupi on AHR, asthma control, and quality of life. After a 4-week run-in on beclomethasone/formoterol maintenance and reliever therapy (baseline), participants with uncontrolled type-2 high severe asthma received open-label Dupi 300 mg twice weekly, for 12 weeks. Mannitol challenges were done at baseline, 2, 4, and 12 weeks and following a 12-week washout. Study power was 90% to detect 1 doubling difference (dd) in mannitol PD₁₀ FEV₁ threshold at week 12. Of 24 enrolled patients, 23 completed per protocol mannitol AHR at 12 weeks. Mean baseline values were age 52 years, FEV₁ 82%, Asthma Control Questionnaire 2.53, mini-Asthma Quality of Life Questionnaire 3.84, inhaled corticosteroids dose 1300 μg; fractional exhaled nitric oxide 50 parts per billion; Eosinophils 552 cells/μL. Mannitol sensitivity as PD₁₀ was significantly attenuated by week 4, and reactivity as response dose ratio by week 2. After 12 weeks of Dupi, mean dd for PD₁₀ was 1.78 (95% CI: 1.23-2.33; P < .001) and for response dose ratio was 3.40 (95% CI: 2.25-4.55; P < .001). At week 12, Asthma Control Questionnaire improved by 1.73 (95% CI: 1.11-2.36; P < .001); mini-Asthma Quality of Life Questionnaire by 2.31 (95% CI: 1.57-3.05; P < .001); FEV₁ by 0.39 L (95% CI: 0.11-0.67; P < .01); and PEF by 61 L/min (95% CI: 24-98; P < .001). Beclomethasone/formoterol maintenance and reliever therapy requirement was reduced at 12 weeks versus baseline by 1.7 puffs/d (95% CI: 0.7-2.7; P < .01). After washout at week 24, the dd change was 0.96 (95% CI: 0.02-1.91; P < .05). Dupilumab attenuated mannitol AHR to a clinically relevant degree despite concomitant inhaled corticosteroid reduction, combined with improvements in lung function, asthma control, and quality of life.