New research shows that the asthma drug benralizumab did not statistically decrease annual COPD exacerbation rates for patients with moderate to very severe COPD, a history of frequent moderate and/or severe exacerbations, and eosinophilic inflammation; although the team did report numeric decreases (GALATHEA/TERRANOVA trials). The data were published in the New England Journal of Medicine in conjunction with Prof. Gerard Criner’s (Temple University, USA) presentation [1,2].
The eosinophilic asthma drug benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody benralizumab which induces rapid and nearly complete eosinophil depletion. COPD is often also associated with eosinophilic inflammation which ultimately affects patients’ responsiveness to glucocorticoid medication. The complementary phase 3, randomised, double-blind, placebo-controlled, parallel-group clinical trials GALATHEA (n=1120) and TERRANOVA (n=1545) evaluated the efficacy and safety of benralizumab for the prevention of exacerbations in patients with moderate to very severe COPD, eosinophilic inflammation, and increased risk of exacerbations. GALATHEA and TERRANOVA sought to determine whether benralizumab’s ability to deplete the airways of blood eosinophils in patients with eosinophilic inflammation would lead to a reduction in COPD exacerbations.
Eligible patients (aged 40-85) were randomised in a 1:1:1 ratio (GALATHEA) or 1:1:1:1 ratio (TERRANOVA) to either receive benralizumab or placebo via subcutaneous injection every 4 weeks. Doses of benralizumab were administered for asthma treatment at either 30 mg or 100 mg in the GALATHEA trial and at either 10 mg, 30 mg, or 100 mg in the TERRANOVA trial. The primary endpoint of both trials were the treatment effects of benralizumab vs placebo, determined by the rate of COPD exacerbations after 56 weeks of treatment. Secondary endpoints included changes in FEV1, changes in the St. George’s Respiratory Questionnaire (SGRQ) score, and occurrence of any adverse events. The annual COPD exacerbation rate in GALATHEA was noted to be 1.19 per year among patients receiving 30 mg benralizumab (95% CI 1.04 to 1.36) and 1.03 among patients randomised to receive 100 mg benralizumab (95% CI 0.90 to 1.19) vs 1.24 in the placebo group (95% CI 1.08 to 1.42). The annual COPD exacerbation ratio in TERRANOVA was noted to be 0.99 in the 10 mg benralizumab group (95% CI 0.87 to 1.13), 1.21 in the 30 mg benralizumab group (95% CI 1.08 to 1.37), 1.09 in the 100 mg benralizumab group (95% CI 0.96 to 1.23), and 1.17 in the placebo group (95% CI 1.04 to 1.32). In the GALATHEA trial, the mean change from baseline in FEV1 was 7 mL in the 30 mg benralizumab group (95% CI -35 to 48) and 21 mL in the 100 mg benralizumab group (95% CI -12 to 62). Changes in SGRQ scores were noted to be -1.011 in the 30 mg benralizumab group (95% CI -2.887 to 0.865) and -2.136 in the 100 mg benralizumab group (95% CI -4.020 to -0.251, see Table).
Table: Efficacy of benralizumab in GALATHEA trial in treatment of patients with COPD and baseline blood eosinophils ≥220 cells/μL. Data summarised from 
CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; LS, least squares; pre-BD, prebronchodilator; Q8W, every 8 weeks (first 3 doses every 4 weeks); SGRQ, St George’s Respiratory Questionnaire (score range: 100=worse, 0=best). a Negative binomial model adjusting for treatment, eosinophil group (220-299 cells/μL, ≥300 cells/μL), geographic region, background therapy, (inhaled corticosteroids [ICS]/long-acting β2-agonists [LABA], LABA/long-acting muscarinic antagonists [LAMA], ICS/LABA/LAMA), and number of prior exacerbations. b Not adjusted for multiplicity, nominal P-value. c Gatekeeping procedure strategy to control for overall type 1 error at level 0.05; mixed effects model for repeated measures adjusting for treatment, baseline value, eosinophil group (220-299 cells/μL, ≥300 cells/μL), geographic region, and background therapy (ICS/LABA, LABA/LAMA, ICS/LABA/LAMA).
In the TERRANOVA group the mean change from baseline in FEV1 was 15 mL in the 10 mg benralizumab group (95% CI -29 to 59), -7mL in the 30 mg benralizumab group (95% CI -51 to 37), and 20 mL in the 100 mg benralizumab group (95% CI -24 to 64). Differences in SGRQ scores were -1.011 (95% CI -3.192 to 1.171) in the 10 mg group, -1.388 in the 30 mg group (95% CI -3.562 to 0.786) and -0.602 in the 100 mg group (95% CI -2.763 to 1.560). In terms of safety events, both trials led to eosinophil depletion among patients who took benralizumab; however, adverse events occurred at a similar rate in both trial and placebo groups.
“The findings in these two trials suggest that eosinophil depletion may not completely ameliorate exacerbation outcomes for patients with COPD,” concluded Prof. Criner.
- Criner GJ, et al. Benralizumab for Chronic Obstructive Pulmonary Disease: Results of the Phase III GALATHEA Trial. A2626, ATS 2019, 17-22 May, Dallas, Texas, USA.
- Criner GJ, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med. 2019 May 20.
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