Effects of dupilumab on mannitol airway hyperresponsiveness in uncontrolled severe asthma

Background Airway hyperresponsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown. Objectives This study sought to investigate the effect of 12 weeks of Dupi on AHR, asthma control, and quality of life. Methods 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 PD 10 FEV 1 threshold at week 12. Results Of 24 enrolled patients, 23 completed per protocol mannitol AHR at 12 weeks. Mean baseline values were age 52 years, FEV 1 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 PD 10 was significantly attenuated by week 4, and reactivity as response dose ratio by week 2. After 12 weeks of Dupi, mean dd for PD 10 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); FEV 1 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). Conclusions 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.