Gerard J Criner1, Bartolome R Celli1, Christopher E Brightling1, Alvar Agusti1, Alberto Papi1, Dave Singh1, Don D Sin1, Claus F Vogelmeier1, Frank C Sciurba1, Mona Bafadhel1, Vibeke Backer1, Motokazu Kato1, Alejandra Ramírez-Venegas1, Yu-Feng Wei1, Leif Bjermer1, Vivian H Shih1, Maria Jison1, Sean O'Quinn1, Natalya Makulova1, Paul Newbold1, Mitchell Goldman1, Ubaldo J Martin1. 1. From the Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia (G.J.C.); Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston (B.R.C.); the Institute for Lung Health, Leicester National Institute for Health Research Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B.), the University of Manchester, Manchester University NHS Hospital Trust, Manchester (D.S.), and the Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford (M.B.) - all in the United Kingdom; Respiratory Institute, Hospital Clinic, University of Barcelona, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBER) Enfermedades Respiratorias, Barcelona (A.A.); the Department of Medical Sciences, University of Ferrara, Ferrara, Italy (A.P.); the Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada (D.D.S.); the Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, German Center for Lung Research (DZL), Marburg, Germany (C.F.V.); University of Pittsburgh School of Medicine, Pittsburgh (F.C.S.); the Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen (V.B.); Kishiwada City Hospital, Osaka, Japan (M.K.); the Departamento de Investigación en Tabaquismo y EPOC, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City (A.R.-V.); the Division of Respiratory and Chest Medicine, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan (Y.-F.W.); the Department of Respiratory Medicine and Allergology, Skane University Hospital, Lund University, Lund, Sweden (L.B.); and AstraZeneca, Gaithersburg, MD (V.H.S., M.J., S.O., N.M., P.N., M.G., U.J.M.).
Abstract
BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).
BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).
Authors: Nirupama Putcha; Han Woo; Meredith C McCormack; Ashraf Fawzy; Karina Romero; Meghan F Davis; Robert A Wise; Gregory B Diette; Kirsten Koehler; Elizabeth C Matsui; Nadia N Hansel Journal: Am J Respir Crit Care Med Date: 2022-02-15 Impact factor: 21.405
Authors: Elizabeth A Jacobsen; David J Jackson; Enrico Heffler; Sameer K Mathur; Albert J Bredenoord; Ian D Pavord; Praveen Akuthota; Florence Roufosse; Marc E Rothenberg Journal: Annu Rev Immunol Date: 2021-03-01 Impact factor: 28.527