Dupilumab attenuates mannitol airway hyper-responsiveness in uncontrolled severe type 2 high asthma

<bold>Rationale:</bold> Here we evaluate the impact of IL4/13 blockade with dupilumab on mannitol airway hyper-responsiveness (AHR). <bold>Methods:</bold> Patients with T2 high severe uncontrolled asthma had an initial 4-week run-in on beclometasone/formoterol 100/6ug BDP/FM 100/6ug MART (baseline), followed by dupilumab 300mg q2wk for 12 wk (EudraCT 2021-005593-25). Mannitol challenges were performed at baseline and after 2, 4 and 12 wk. <bold>Results:</bold> 21 patients completed 12 wk post dupilumab. Mean values at baseline were: age 55, FEV1 82%, mannitol PD10 128mg, ACQ 2.60, mini-AQLQ 3.75, FeNO 50ppb, Eosinophils 490/ul, ICS dose 1314μg, CRSwNP 20/21. Improvements in mannitol PD10 and in mannitol response dose ratio (RDR) were significant by wk 4 (Figure). After 12 wk of dupi the mean (95%CI) doubling difference change from baseline for PD10 was 1.78 (0.93 to 2.62) p<0.001 and for RDR was 3.39 (1.63 to 5.15) p<0.001, with n=13/21 (62%) becoming mannitol non-responsive indicating AHR remission. Furthermore, BDP/FM MART requirement was reduced at 12 weeks vs baseline, mean difference: 1.3 puffs/day (0.3 to 3.4) p<0.01. <bold>Conclusion:</bold> Mannitol AHR was attenuated to a clinically relevant degree by dupilumab, whilst also exhibiting ICS sparing activity. Figure: Mean (95% CI) doubling difference as change from baseline for PD10 and RDR at serial time points with dupilumab. Bonferroni-corrected P values ***p<0.01 <fig><object-id>erj;64/suppl_68/PA4481/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>