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

Background Thymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, initiates production of type 2 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 In this double-blind, placebo-controlled randomised trial (UPSTREAM), 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 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 40 patients were randomised to receive either tezepelumab (n=20) or placebo (n=20). The mean change in provoking dose of mannitol causing a 15% reduction in forced expiratory volume in 1 s (PD ₁₅) with tezepelumab was 1.9 (95% CI 1.2-2.5) versus 1.0 (95% CI 0.3-1.6) doubling doses with placebo (p=0.06). Nine (45%) tezepelumab and three (16%) placebo patients had a negative PD ₁₅ test at week 12 (p=0.04). Airway tissue and bronchoalveolar lavage (BAL) eosinophil levels decreased by 74% (95% CI −53-−86%) and 75% (95% CI −53-−86%), respectively, with tezepelumab compared with an increase of 28% (95% CI −39-270%) and a decrease of 7% (95% CI −49-72%), 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.