Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis

Abstract

Background: Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis.

Methods: In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed.

Results: A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies.

Conclusions: In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).

Figure 1. Trial Design and Randomization and Follow-up of the Participants

The continuation criteria (i.e., the criteria required for undergoing randomization) included the following: glucocorticoid and immunosuppressive therapy stability (the dose had to be stable for ≥4 weeks before randomization); acceptable laboratory assessments, hepatitis status, and liver-function tests (see the Supplementary Appendix); and no clinically significant abnormality on electrocardiography. During the intervention period, participants in the mepolizumab group received 300 mg of mepolizumab plus standard care, and those in the placebo group received matching placebo plus standard care. Mepolizumab or placebo was administered subcutaneously. The intention-to-treat population was used for the primary analysis.

Figure 2. Remission and First Relapse of Eosinophilic Granulomatosis with Polyangiitis in the Intention-to-Treat Population

Remission was defined as a Birmingham Vasculitis Activity Score of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) and receipt of a prednisolone or prednisone dose of 4.0 mg or less per day (Panel A). Data on relapse were censored at week 52 per the statistical analysis plan (Panel B). I bars at weeks 16, 32, and 52 indicate 95% confidence intervals.