Mepolizumab Reduces Exacerbations in Eosinophilic COPD

Ricki Lewis, PhD

November 10, 2017

Mepolizumab may reduce exacerbation frequency in patients with chronic obstructive pulmonary disease (COPD) who have eosinophilia, two studies have found.

"[A]mong patients with COPD who were already receiving maximal inhaled glucocorticoid–based triple inhaled maintenance therapy, mepolizumab resulted in lower rates of moderate or severe exacerbations than placebo and in longer times to a first exacerbation, and the extent of these effects was related to blood eosinophil count," the researchers write. "With the use of mepolizumab as a targeted treatment to reduce blood eosinophil counts, these trials show the importance of blood eosinophils in COPD exacerbations."

Ian Pavord, FMedSci, professor of respiratory medicine at Nuffield Department of Medicine at the University of Oxford, United Kingdom, and colleagues published their findings online October 26 in The New England Journal of Medicine.

People with COPD and eosinophilia have a 40% or greater risk for moderate or severe exacerbations, often despite adhering to standard triple inhaled therapy consisting of a glucocorticoid, a long-acting β2-agonist, and a long-acting muscarinic antagonist, the researchers explain.

Mepolizumab, a monoclonal antibody–based drug that targets interleukin-5, lowers the incidence of exacerbations and improves quality of life for patients with severe eosinophilic asthma. Because some patients who responded to the drug in those studies were identified post hoc to also have clinical manifestations of COPD, the researchers conducted two 12-month, multicenter, parallel randomized placebo-controlled clinical trials to assess efficacy for COPD.

METREX (Mepolizumab vs Placebo as Add-on Treatment for Frequently Exacerbating COPD Patients) stratified patients by eosinophilia phenotype, and METREO (Mepolizumab vs Placebo as Add-on Treatment for Frequently Exacerbating COPD Patients Characterized by Eosinophil Level) tested 100 mg or 300 mg of mepolizumab in patients with COPD and eosinophilia. Both trials defined eosinophilia as an eosinophil count of 150 cells/mm3 or greater at screening or 300 cells/mm3 or greater at any time during the past year. Participants in both studies received subcutaneous injections of the study drug or placebo every 4 weeks for 52 weeks, with 8 weeks of follow-up.

METREX included 836 patients who received at least one dose of drug or placebo (a modified intention-to-treat design), of whom 462 had eosinophilia and 374 did not. In those with eosinophilia, the mean annual rate of moderate or severe exacerbations, the primary outcome, was 1.40 per year in the mepolizumab group compared with 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 - 0.98; adjusted P = .04). There was no significant difference between number of exacerbations on drug or placebo in the overall group, which included participants with or without eosinophilia (1.49 vs 1.52 per year).

In METREO (n = 674 patients), the mean annual rate of moderate or severe exacerbations was 1.19 for participants who took 100 mg of the drug and 1.27 for those who took 300 mg, compared with 1.49 per year in the placebo group (rate ratio [100 mg vs placebo], 0.80; 95% CI, 0.65 - 0.98; adjusted P = .07; rate ratio [300 mg vs placebo], 0.86; 95% CI, 0.70 - 1.05; adjusted P = .14).

Overall, mepolizumab had a greater (albeit modest) effect on exacerbation rate among patients with higher percentages of eosinophils, suggesting a contribution of these cells to the pathology. Differences were seen in METREX but not in METREO; however, METREX compared eosinophilia to noneosinophilia, whereas all the participants in METREO had eosinophilia.

In METREX the time to first exacerbation was longer for patients taking the drug compared with placebo for patients who had eosinophilia, but not for the overall modified intention-to-treat group. METREO showed no significant difference for any secondary endpoint for drug compared with placebo.

The investigators performed three post hoc analyses: participants with eosinophil counts below 150 cells/mm3, those with counts above 300 cells/mm3, and the effect of the drug on the rate of exacerbations that required treatment with glucocorticoids or antibiotics. 

The post hoc analyses suggested that patients with higher eosinophil counts are more likely to benefit from mepolizumab. Patients with counts of 300 cells/mm3 or higher had a mean annual rate of moderate or severe exacerbations that was 23% lower among the participants taking 100 mg mepolizumab compared with the placebo group (rate ratio, 0.77; 95% CI, 0.63 - 0.94).

"Overall, patients with an eosinophilic phenotype who were treated with 100 mg of mepolizumab had an annual rate of moderate or severe exacerbations…that was consistently 18% to 20% lower than that among patients who received placebo. There was no evidence of greater effects of mepolizumab at higher doses," the investigators conclude.

Limitations of the study include stricter adherence to the triple inhaled drug regimen once patients were enrolled in the study and not considering coexisting conditions, smoking status, or triggers for exacerbations.

Blood Eosinophil Count "An Imperfect Biomarker"?

The researchers call the use of the eosinophil phenotype as a biomarker of response to mepolizumab a "precision-medicine approach." That label may go back even farther, as a manifestation of the classic "lumping and splitting" paradigm from evolutionary biology that Christine F. McDonald, MB, PhD, from the University of Melbourne, Victoria, Australia, alludes to in an accompanying editorial. She terms the study a "renaissance" of the "Dutch hypothesis" from the 1960s that viewed COPD as a consequence of several interacting factors that results in clinical subgroups.

"The results of the current trials indicate that a subgroup of patients with COPD may benefit from biologic therapies, but I think that blood eosinophil count is an imperfect biomarker and that other disease factors confound the eosinophil signal, even in carefully selected subgroups," Dr McDonald writes. She encourages further study of the function of eosinophils in COPD that also considers such factors as allergy and smoking behavior when stratifying patients.

As reported previously by Medscape Medical News, the researchers presented their results earlier this year at European Respiratory Society International Congress 2017.

The authors report a variety of financial relationships, including receipt of personal fees, grant support, and stock ownership, with companies including GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, Boston Scientific, ALK, Johnson & Johnson, Merck Sharp & Dohme, Sanofi, SNCF, Centocor, Almirall, Roche, and Boehringer Ingelheim. A complete list is available on the journal website. All authors report nonfinancial support from GSK. Dr McDonald reports receipt of personal fees from Novartis and Pfizer outside the study.

N Engl J Med. Published online October 26, 2017. Abstract

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