O4.3 Biologic therapies

Post hoc analyses of data from a number of studies involving patients with COPD have highlighted the blood eosinophil count as a potentially important biomarker of response to glucocorticoid treatment.  Several studies have examined whether depleting eosinophils with interleukin-5 (IL-5) or IL-5 receptor antibodies could affect clinical outcomes in COPD.  Pavord and colleagues compared the IL-5 inhibitor mepolizumab with placebo in patients with COPD in two 12-month randomised, controlled, parallel-group trials (METREX and METREO) (Pavord 2017).  In METREX, the annual rate of moderate or severe exacerbations was significantly lower in the mepolizumab group than in the placebo group (1.4 versus. 1.71 per year; rate ratio, 0.82; 95% CI 0.68 to 0.98; P=0.04). The time to first exacerbation was also significantly longer in the mepolizumab group than in the placebo group, but there were no significant differences in outcomes when patients were not stratified according to eosinophilic phenotype. In contrast, no significant differences in exacerbation rates were detected in METREO.  There was no significant between-group difference in the rate of exacerbations that led to an emergency department visit or hospitalisation or in measures of patients’ symptoms in either trial.

A phase 2a trial of benralizumab, a humanized monoclonal antibody to IL-5 receptor alpha, did not demonstrate benefit in terms of exacerbations  or quality of life in a group of patients with COPD who had at least one exacerbation in the preceding year and a sputum count of ≥ 3% in the preceding year; however the investigators felt that a prespecified  subgroup analysis of patients with higher blood eosinophil counts supported further investigation of the effects of this drug in patients with COPD and eosinophilia (Brightling 2014).  Nonetheless, large trials of benralizumab in patients with moderate COPD and frequent exacerbations despite dual or triple therapy found no differences in annual rates of COPD exacerbations in patients treated with benralizumab compared with placebo, and no associations between baseline eosinophil counts and treatment effect (Criner 2019a). In a further pre-specified analysis of the combined GALATHEA and TERRANOVA studies of benralizumab (Criner 2019b), a variety of statistical techniques were used to identify “efficacy associated factors” in the two studies. These hypothesis-generating analyses were interpreted as suggesting that a subpopulation of patients with COPD, frequent exacerbations during treatment with triple therapy and higher eosinophil counts might benefit from benralizumab 100 mg every 8 weeks.

A Cochrane Systematic review of randomised controlled trials by Donovan et al (2020) comparing anti-IL-5 therapy with placebo in adults (≥40 years old) with a diagnosis of COPD (as defined by GOLD 2020) and with frequent exacerbations included three studies each of mepolizumab (1530 participants) and benralizumab (4012 participants), both comparing anti-IL-5 therapy versus placebo. No head-to-head comparison trials were identified. Mepolizumab 100 mg reduces the rate of moderate or severe exacerbations by 19% in those with an eosinophil count of at least 150/microlitre (RR 0.81, 95% CI 0.71 to 0.93; participants = 911; studies = 2, high-certainty evidence). In participants with lower eosinophils, mepolizumab 100 mg may reduce exacerbations (RR 0.92, 95% CI 0.82 to 1.03; participants = 1285; studies = 2, moderate-certainty evidence). Benralizumab 100 mg reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/ microlitre (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high-certainty evidence). Anti-IL-5 therapies appear to be safe in individuals with COPD, and are likely to reduce the rate of moderate and severe exacerbations in the highly selected group of people who have both COPD and higher levels of blood eosinophils. Lung function and health-related quality of life were not improved (Donovan 2020) [evidence level I].

Further research is needed to elucidate the role of monoclonal antibodies in the management of COPD. It is not clear whether there is a threshold blood eosinophil level above which these drugs may be effective. Cost effectiveness data are also critical to inform clinical decision making, given the high cost of these therapies.