GlaxoSmithKline announced the publication of full results from the phase III studies for mepolizumab in chronic obstructive pulmonary disease (COPD). Data from the investigational clinical development program showed that treating eosinophilic COPD patients with the biologic medicine, mepolizumab, in addition to maximal guideline-recommended therapy, reduced exacerbations in these difficult-to-treat patients. Based on the full data, discussions with external experts and the recognized unmet medical need in this patient population, regulatory filings are planned for 2017. Mepolizumab is not approved for use anywhere in the world for COPD.
Results of the METREX and METREO studies, along with data from a pre-specified meta-analysis combining both studies, have been published in the New England Journal of Medicine (NEJM), with simultaneous presentation at the European Respiratory Society (ERS) International Congress 2017.
The studies were designed to evaluate the efficacy and safety of mepolizumab as add-on therapy in the reduction of moderate to severe COPD exacerbations in patients at high risk of exacerbations and to identify the patients with COPD most likely to respond to treatment using blood eosinophils (a type of white blood cell known to play a role in some inflammatory diseases) as a biomarker. In addition, METREO investigated efficacy and safety at different doses of mepolizumab. Patients included in the studies had a history of frequent exacerbations, despite receiving optimal standard of care treatments, with the majority categorized as Stage D, patients with the most advanced disease, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.
Overall, COPD patients with blood eosinophil counts of >150 cells/µL at study entry or >300 cells/µL within the past year treated with add-on 100mg mepolizumab showed a consistent 18–20% reduction in the primary endpoint of annual rate of moderate and severe exacerbations.
The reduction in the frequency of exacerbations observed in the METREX study was statistically significant (18%, p=0.036 after multiplicity adjustment).
In METREO, the reduction was not statistically significant (20%, p=0.068 after multiplicity adjustment).
The pre-specified meta-analysis evaluated the association between screening blood eosinophil counts and treatment response. The analysis showed that rates of exacerbation reduction increased as blood eosinophil counts increased, signifying the relevance of blood eosinophils as a biomarker to help identify COPD patients most likely to respond to treatment with mepolizumab.
There was no evidence of greater treatment effect in patients treated with a higher (300mg) dose of mepolizumab investigated in the dose ranging METREO study. In the METREX study, patients with blood eosinophil counts of less than 150 cells/µL at the start of the study (i.e. patients with non-eosinophilic COPD) were not found to benefit from mepolizumab.
For the secondary endpoints, there was a statistically significant increase in the time to first moderate and severe exacerbation in METREX, with numerical, but not significant, increase in time to first exacerbation in METREO. There were no significant differences between mepolizumab and placebo in either study on the remaining secondary endpoints: annual rate of exacerbations requiring emergency department visit and/or hospitalization, St George’s Respiratory Questionnaire score and COPD assessment test score.
Steve Yancey, Vice President and Medicine Development Lead for mepolizumab, GSK said: “We believe the data published today in the New England Journal of Medicine demonstrate the benefits of a personalized medicine approach in the treatment of COPD with mepolizumab, using blood eosinophils as a biomarker. Based on the clinically meaningful reductions in exacerbations shown in these studies, we plan to progress regulatory filings this year.”
Professor Ian Pavord, University of Oxford said: “For people living with COPD, a sudden worsening of their symptoms, known as an exacerbation, causes them to struggle to breathe despite receiving the available guideline recommended treatment. For these patients, there are currently no other treatment options. When considering the challenges these patients face, the exacerbation reduction shown in the METREX and METREO studies is a clinically important outcome.”
No new safety concerns to the known safety profile of mepolizumab were identified on review of the data from these studies. The proportion of patients experiencing adverse events and serious adverse events while receiving treatment was similar for mepolizumab and placebo. In the METREX study, the frequency of adverse events was 80% in the mepolizumab 100mg group and 82% in the placebo group, and the frequency of serious adverse events was 28% in the mepolizumab 100mg group and 31% in the placebo group. In the METREO study, the frequency of adverse events was 86% in the mepolizumab 100mg group, 87% in the mepolizumab 300mg group 82% in the placebo group, and the frequency of serious adverse events was 26% in the mepolizumab 100mg group, 27% in the mepolizumab 300mg group and 30% in the placebo group.
The phase III studies were multi-center, randomized, placebo controlled, double blind, parallel group design with treatment administered by subcutaneous (SC) injection every four weeks in COPD patients at high risk of exacerbations despite the use of optimal standard of care background therapy which employed inhaled triple therapy consisting of an inhaled corticosteroid (ICS), long-acting beta agonist (LABA) and long-acting muscarinic antagonist (LAMA). The total duration of the studies was approximately 62 weeks consisting of a 1-2 week screening period, 52-week treatment period and eight-week follow-up period.
The METREX study (117106) was designed to evaluate mepolizumab 100mg or placebo across a range of baseline blood eosinophil counts. Patients were stratified according to i) blood eosinophil count of >150 cells/µL at study entry or >300 cells/µL within the past year (higher eosinophil group) or ii) blood eosinophil count of <150 cells/µL at study entry and no evidence of >300 cells/µL within the past year. For the primary endpoint in patients with higher eosinophils, there was a statistically significant reduction in the frequency of moderate and severe exacerbations for mepolizumab 100mg compared to placebo (18%, p=0.036 after multiplicity adjustment).
The METREO study (117113) was designed as a dose-ranging study. Patients with a blood eosinophil count of >150 cells/µL at study entry or >300 cells/µL within the past year (higher eosinophil group) were randomized to receive mepolizumab 100mg, mepolizumab 300mg or placebo. For the primary endpoint in patients with higher eosinophils, a reduction in the frequency of moderate and severe exacerbations for mepolizumab compared to placebo was seen which was not statistically significant (20% for 100mg, p=0.068; 14% for 300mg, p=0.140 after multiplicity adjustment).
Moderate exacerbations were defined as those requiring treatment with systemic corticosteroids and/or antibiotics. Severe exacerbations were those requiring hospitalization or resulted in death.