The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM)

RATIONALE AND OBJECTIVES: Thymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, initiates production of type-2 (T2) cytokines with eosinophilia and possibly airway hyperresponsiveness (AHR) in asthma.This study aimed to determine whether tezepelumab (a human monoclonal antibody targeting TSLP) decreases AHR and airway inflammation in patients with symptomatic asthma on maintenance treatment with inhaled corticosteroids.METHODS AND MEASUREMENTS: In this double-blind, placebo-controlled randomised trial adult patients with asthma and AHR to mannitol received either 700 mg tezepelumab or placebo intravenously at 4-week intervals for 12 weeks. AHR to mannitol was assessed, and a bronchoscopy was performed at baseline and after 12 weeks. The primary outcome was the change in AHR from baseline to week-12 and secondary outcomes were changes in airway inflammation.RESULTS: Forty patients were randomised to receive either tezepelumab (n=20) or placebo (n=20). The mean change in PD15 with tezepelumab was 1.9 DD (95% CI 1.2 to 2.5) versus 1·0 (95% CI 0.3 to 1.6) with placebo; p=0.06. Nine (45%) tezepelumab and three (16%) placebo patients had a negative PD15 test at week-12, p=0.04. Airway tissue and BAL eosinophils decreased by 74% (95% CI -53 to -86) and 75% (95% CI -53 to -86) respectively with tezepelumab compared with an increase of 28% (95% CI -39 to 270) and a decrease of 7% (95% CI -49 to 72) respectively with placebo, p=0.004 and p=0.01.CONCLUSIONS: Inhibiting TSLP-signalling with tezepelumab reduced the proportion of patients with AHR and decreased eosinophilic inflammation in BAL and airway tissue.