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

Abstract

Background: Airway hyper-responsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown.

Objective: 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(BDP/FM) MART (baseline), participants with uncontrolled type-2 high severe asthma received open-label Dupi 300mg 2-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.

Results: 23 out of 24 enrolled patients completed per protocol mannitol AHR at 12 weeks. Mean baseline values were: age 52 years; FEV₁ 82%; ACQ 2.53, mini-AQLQ 3.84; ICS dose 1300μg; FeNO 50ppb; Eos 552cells/μl. Mannitol sensitivity as PD₁₀ was significantly attenuated by week 4, and reactivity as response dose ratio (RDR) by week 2. After 12 weeks of Dupi, mean (95%CI) dd for PD₁₀ was 1.78 (1.23,2.33) p<0.001 and for RDR was 3.40 (2.25,4.55) p<0.001. At week 12, ACQ improved by 1.73, (1.11,2.36) p<0.001, mini-AQLQ by 2.31 (1.57,3.05) p<0.001, FEV₁ by 0.39L (0.11,0.67) p<0.01 and PEF by 61L/min (24,98) p<0.001. BDP/FM MART requirement was reduced at 12 weeks vs baseline by 1.7 puffs/day (0.7,2.7) p<0.01. After washout at week 24 the dd change was 0.96 (0.02,1.91) p<0.05.

Conclusion: Dupilumab attenuated mannitol AHR to a clinically relevant degree despite concomitant ICS reduction, combined with improvements in lung function, asthma control and quality of life.