Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial

Abstract

Background: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear.

Objective: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES.

Methods: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed.

Results: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]).

Conclusions: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.

Trial registration: ClinicalTrials.gov NCT02836496.

Keywords: Hypereosinophilic syndrome; efficacy; flare; mepolizumab; safety.

FIG 1.

Study design and enrolment and follow-up of patients. A, The design of the study. B, The screening, enrolment, randomization, treatment, and follow-up of patients. *Following study completion, patients could be entered in an open-label extension (mepolizumab 300 mg SC, every 4 weeks; GSK study ID: 205203; ClinicalTrials.gov No. NCT03306043). Patients who continued with open-label mepolizumab had their last assessment at week 32. †Patients who did not continue with open-label mepolizumab had an additional 8-week follow-up period, concluding with a final visit 12 weeks after their last dose. ‡Two patients (1 in the placebo group, 1 in the mepolizumab group) discontinued treatment and remained in the study off-treatment until week 32. The patient in the placebo group discontinued owing to a lack of willingness to regularly fill out the eDiary; the patient in the mepolizumab group discontinued owing to patient/proxy decision. §The patient in the mepolizumab group who discontinued owing to AE experienced 4 serious AEs (HES flare, pneumonia, respiratory failure, and septic shock). These were fatal, and were not considered by the investigator to be treatment-related. SC, Subcutaneous.

FIG 2.

Flares, fatigue severity, and blood eosinophil counts in the intent-to-treat population. A, The cumulative number of flares over the study period. B, A Kaplan-Meier cumulative incidence curve for probability of first flare over time. C, Adjusted mean change from baseline in fatigue severity.* D, The adjusted geometric mean blood eosinophil count over time. Vertical bars in Fig 2, B, C, and D, represent 95% CI. *Fatigue severity assessed on the basis of BFI item 3 recorded daily; for each patient the mean score over the 7 days before each time point was analyzed (range 0–10; higher score indicates worse fatigue severity; minimal clinically important difference for patients in HES not determined). SC, Subcutaneous; SCR, screening.