Efficacy and Safety of Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma: Results from the Phase 3 NAVIGATOR Study

Abstract

RATIONALE: There is a lack of evidence guiding OCS withdrawal following biologic initiation in severe asthma. We aimed to demonstrate that benralizumab could eliminate or reduce OCS to physiologic dosages following a personalized OCS down-titration while monitoring for adrenal insufficiency (AI). METHODS: This single-arm study of 598 patients assessed the efficacy and safety of daily OCS dosage reduction after initiation of benralizumab 30 mg. Adults with asthma requiring high-dosage ICS and LABA for > _6 months plus OCS (> _5 mg prednisone or equivalent) for > _3 months and blood eosinophil counts > _150/mL at baseline or > _300/mL in the previous 12 months were enrolled. Four weeks after benralizumab initiation, patients began an OCS dosage-reduction algorithm with rapid down-titration, including personalized reductions if AI was present. RESULTS: Most patients (62.2% [95% CI 58.18-66.11]) eliminated OCS use, and 80.6% (95% CI 77.20-83.70) eliminated use or reduced the daily dosage to < _5 mg if AI prevented further reduction. Median OCS daily dosage was reduced by 100%, and 91.3% of patients achieved a daily OCS dosage < _5 mg. OCS reductions were achieved irrespective of baseline eosinophil count. Additionally, a lower percentage of patients had exacerbations during the OCS reduction phase than in the previous year (25.8% vs. 84.4%). Initially, 60% of patients had partial or complete AI (33% and 27%, respectively), which decreased to 38.5% (18.1% and 19.4%, respectively) 2-3 months later. CONCLUSIONS: Irrespective of baseline eosinophil count, most OCS-dependent asthmatics treated with benralizumab achieved OCS elimination or maximal possible reduction when AI was detected. RATIONALE: Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin (TSLP). NAVIGATOR evaluated the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. METHODS: NAVIGATOR was a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03347279). Patients (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210mg subcutaneously or placebo every 4 weeks for 52 weeks. The primary endpoint was annualized asthma exacerbation rate (AAER) over 52 weeks in the overall population. This was also assessed by baseline blood eosinophil count (> _300, <300 or <150 cells/mL). Key secondary endpoints included change from baseline to week 52 in forced expiratory volume in 1 second (FEV 1), Asthma Control Questionnaire-6 (ACQ-6) score and Asthma Quality of Life Questionnaire (standardized) for patients aged 12 years or older (AQLQ[S]+12) score. The safety of te-zepelumab was also assessed. RESULTS: Overall, 1061 patients were randomized (tezepelumab 210mg, n5529; placebo, n5532). Tezepelumab reduced the AAER versus placebo by 56% (95% CI, 47-63; p<0.001) in the overall population, and by 70% (95% CI, 60-78), 41% (95% CI, 25-54; p<0.001) and 39% (95% CI, 12-58) in patients with baseline blood eosinophil counts > _300, <300 and <150 cells/mL, respectively. Tezepelumab significantly improved FEV 1 and ACQ-6 and AQLQ(S)+12 scores versus placebo over 52 weeks (all p<0.001). Safety findings were similar between treatments. CONCLUSIONS: Tezepelumab reduced exacerbations, irrespective of baseline blood eosinophil count, and improved lung function, asthma control and health-related quality of life in a broad population of patients with severe, uncontrolled asthma.