Benralizumab for the Prevention of COPD Exacerbations

Abstract

T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med nejm.org 1 The authors' full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. BACKGROUNDThe 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. METHODSIn 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. RESULTSIn 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. CONCLUSIONSAdd-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.)A BS TR AC T

Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

“…However, the response to anti-IL5 and IL-5R monoclonal antibodies in COPD has been disappointing with benefits related to the intensity of the blood eosinophil count as seen in asthma but the magnitude of response greatly reduced. 2,[32][33][34] Thus, both the epithelial gene expression profile and response to T2-directed biological therapies differ between eosinophilic asthma and COPD.…”

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

“…The efficacy and safety of three dosages of benralizumab for the prevention of exacerbations for patients with moderate to very severe COPD has recently been explored in two randomized, placebo-controlled phase III trials, GALATHEA (benralizumab 30 and 100 mg Q8W vs. placebo) and TER-RANOVA (benralizumab 10, 30, and 100 mg Q8W vs. placebo) [124]. GALATHEA and TERRANOVA offer insight into the safety of benralizumab in large, 56-week phase III trials, including a greater dosage of 100 mg Q8W and a different patient population.…”

Contemporary Concise Review 2019: Chronic obstructive pulmonary disease

“…Although this theory is intuitively appealing, future studies are needed to validate whether this diagnostic ‘label‐free’ approach improves health outcomes of patients with COPD. Recent ‘negative’ clinical trials of biologics that inhibit the interleukin‐5 pathway (and thus block airway eosinophilia in COPD) suggest that this approach is likely overly simplistic (in its current form) and will most likely require some refinement before it can be adopted into clinical practice …”

“…Recent 'negative' clinical trials of biologics that inhibit the interleukin-5 pathway (and thus block airway DD Sin eosinophilia in COPD) suggest that this approach is likely overly simplistic (in its current form) and will most likely require some refinement before it can be adopted into clinical practice. 36,37 In 2019, we have gained tremendous new insights on the pathophysiology of COPD, its treatments and phenotypes. Nevertheless, the overall burden of COPD is on the rise in Asia and many other parts of the world.…”