Steven G Kelsen1, Ioana O Agache2, Weily Soong3, Elliot Israel4, Geoffrey L Chupp5, Dorothy S Cheung6, Wiebke Theess6, Xiaoying Yang6, Tracy L Staton6, David F Choy6, Alice Fong6, Ajit Dash6, Michael Dolton6, Rajita Pappu6, Christopher E Brightling7. 1. Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States. 2. Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University, Brasov, Romania. 3. Alabama Allergy & Asthma Center and Clinical Research Center of Alabama, Birmingham, AL, United States. 4. Divisions of Pulmonary & Critical Care Medicine and Allergy and Immunology, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA, United States. 5. Division of Pulmonary and Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, United States. 6. Genentech, Inc., South San Francisco, CA, United States. 7. Department of Respiratory Sciences, University of Leicester, Leicestershire, United Kingdom. Electronic address: ceb17@leicester.ac.uk.
Abstract
BACKGROUND: The interleukin (IL)-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 monoclonal antibody, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (Type 2-high), but limited options are available for patients with low blood eosinophils (Type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVE: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at Week 54. Enrollment caps ensured ∼30 eosinophil-high (≥300 cells/μL) and ∼95 eosinophil-low (<300 cells/μL) patients per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (p=0.005), 22% (p=0.18), and 37% (p=0.01) for 490-mg, 210-mg, and 70-mg astegolimab, respectively. Adjusted AER reductions for eosinophil-low patients were comparable to reductions in the overall population: 54% (p=0.002), 14% (p=0.48), and 35% (p=0.05) for 490-mg, 210-mg, and 70-mg astegolimab. Adverse events were similar in astegolimab and placebo-treated groups. CONCLUSION: Astegolimab reduced AER in a broad population of patients, including eosinophil-low patients, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated. TRIAL REGISTRATION: EudraCT 2016-001549-13; ClinicalTrials.gov, NCT02918019 CLINICAL IMPLICATIONS: Inhibiting IL-33/ST2-mediated inflammation with astegolimab reduces asthma exacerbations in a broad population of patients with severe, uncontrolled asthma, including those with low blood eosinophils who have limited treatment options.
RCT Entities:
BACKGROUND: The interleukin (IL)-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 monoclonal antibody, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (Type 2-high), but limited options are available for patients with low blood eosinophils (Type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVE: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at Week 54. Enrollment caps ensured ∼30 eosinophil-high (≥300 cells/μL) and ∼95 eosinophil-low (<300 cells/μL) patients per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (p=0.005), 22% (p=0.18), and 37% (p=0.01) for 490-mg, 210-mg, and 70-mg astegolimab, respectively. Adjusted AER reductions for eosinophil-low patients were comparable to reductions in the overall population: 54% (p=0.002), 14% (p=0.48), and 35% (p=0.05) for 490-mg, 210-mg, and 70-mg astegolimab. Adverse events were similar in astegolimab and placebo-treated groups. CONCLUSION:Astegolimab reduced AER in a broad population of patients, including eosinophil-low patients, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated. TRIAL REGISTRATION: EudraCT 2016-001549-13; ClinicalTrials.gov, NCT02918019 CLINICAL IMPLICATIONS: Inhibiting IL-33/ST2-mediated inflammation with astegolimab reduces asthma exacerbations in a broad population of patients with severe, uncontrolled asthma, including those with low blood eosinophils who have limited treatment options.