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.
Competing Interests: Disclosure statement Funded by an investigator-led grant from Sanofi. Sanofi had no input into design, execution, data analysis or manuscript writing. Disclosure of potential conflicts of interest: C. RW. Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and nonfinancial support from GSK outside the submitted work. R. Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. B. J. Lipworth reports nonfinancial support (equipment) from GSK; grants, personal fees (consulting, talks, advisory board), other support (attending American Thoracic Society and ERS) from AstraZeneca; personal fees (talks, consulting) from Sanofi and Regeneron, personal fees (consulting, talks, advisory board) from Circassia; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva; personal fees (talks, consulting), grants, and other support (attending ERS and British Thoracic Society) from Chiesi; personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark; personal fees (consulting) from Dr Reddy; personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, advisory board), other support (attending British Thoracic Society) from Boehringer Ingelheim; and grants and personal fees (advisory board, talks) from Mylan outside of the submitted work. B. J. Lipworth’s son is presently an employee of AstraZeneca. K. E. Stewart declares that she has no relevant conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)