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

Abstract

Rationale and objectivesThymic 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 measurementsIn 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.ResultsForty 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.ConclusionsInhibiting TSLP-signalling with tezepelumab reduced the proportion of patients with AHR and decreased eosinophilic inflammation in BAL and airway tissue.

Biologics in Asthma: A Molecular Perspective to Precision Medicine

“…The first landmark trial to assess the efficacy of tezepelumab was carried out in mild asthmatics, which showed significant improvement in FEV 1 and reduction of peripheral and sputum eosinophils, along with decreased FeNO levels during the late phase response post-allergen provocation ( Gauvreau et al, 2014 ). Subsequent RCTs in severe asthmatics showed that tezepelumab treatment resulted in a 44–71% reduction in AAER, irrespective of baseline peripheral eosinophilia ( Table 6 ) ( Marone et al, 2019 ; Corren et al, 2021a ; Menzies-Gow et al, 2021 ; Sverrild et al, 2021 ). Patients were also shown to have improvements in FEV 1 and symptoms, with a coinciding reduction in peripheral eosinophils and serum IgE.…”

Missing sputum samples are common in asthma intervention studies and successful collection at follow-up is related to improvement in clinical outcomes

“…The UPSTREAM study was a placebo-controlled intervention study (add-on of anti-TSLP(n=20) or placebo(n=20) for 12 weeks) of predominantly moderate-to-severe asthma patients with airway hyperreactivity to mannitol (12).…”

“…The RECONSTRUCT study was a single-arm intervention study (1600 µg inhaled budesonide once daily for 16 weeks) of steroid-free asthma patients with airway hyperreactivity (AHR) to mannitol ( www.clinicaltrials.gov identifier number NCT03034005). The UPSTREAM study was a placebo-controlled intervention study (add-on of anti-thymic stromal lymphopoietin (n=20) or placebo (n=20) for 12 weeks) of predominantly moderate-to-severe asthma patients with AHR to mannitol [ 12 ]. The SIGNATURE study was a single-arm intervention study (add-on of 37.5 mg oral prednisolone for 2 weeks) of patients with moderate-to-severe asthma [ 7 ].…”

“…In all three studies, sputum was collected following a mannitol challenge test in a specimen jar (Petri dish) with the sample quality continuously evaluated by a trained laboratory technician. Samples were processed using the plug selection method, and cut-off values for eosinophilia and neutrophilia were ≥3% and ≥61%, respectively [ 7 , 12 ].…”

Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

“…Tezepelumab is also expected to be effective in airway remodeling, but at present, there are no available studies of its in vitro or in vivo effects on airway remodeling. An RCT showed that tezepelumab induced a numerical improvement in the provoking dose of mannitol causing a 15% reduction in FEV1 (PD15) compared with placebo, and at the end of the treatment period, the proportion of patients without AHR to mannitol was significantly ( p < 0.05) higher in the tezepelumab group than in the placebo group [ 93 ].…”