An international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial has evaluated the effects of mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, on therapeutic prednisone dose requirements, eosinophil levels, signs and symptoms of disease in patients with hypereosinophilic syndrome (HES). The trial enrolled 85 patients (mean age 48.1 years) with HES (blood eosinophil count >1500/μl with evidence of eosinophil-related organ involvement or dysfunction and no known cause of eosinophilia), who tested negative for the FIP1L1-PDGFRα gene rearrangement and required 20–60 mg/day prednisone monotherapy to maintain blood eosinophils at <1000 cells/μL during a run-in period of ≤6 weeks. Patients were randomized to treatment with intravenous mepolizumab 750 mg (n=43) or saline (placebo; n=42) every 4 weeks for 36 weeks (final infusion at Week 32). The prednisone dose was tapered at weekly intervals following the first infusion according to a predefined algorithm based on blood eosinophil counts and HES clinical activity criteria. A total of 84% of patients in the mepolizumab group vs 43% in the placebo group (P<0.001) achieved the primary endpoint (≤10 mg/day prednisone for ≥8 consecutive weeks within the 36-week treatment period). Time to achievement of the primary endpoint, a post-hoc analysis, was significantly shorter in mepolizumab- vs placebo-treated patients (P=0.002). Significantly higher proportions of patients on mepolizumab achieved pre-defined secondary steroid-sparing and eosinophil endpoints vs placebo (Table). Initial assessments of cutaneous disease (based on pruritus visual analog scales and erythema/edema scores) did not differ between the treatment groups. This study, the largest placebo-controlled trial to be conducted in patients with HES to date, has shown that mepolizumab is more effective than placebo at reducing therapeutic prednisone use and stabilizing eosinophil counts in patients with HES. Importantly, a significantly higher proportion of HES patients treated with mepolizumab than placebo achieved the primary endpoint and required ≤10 mg/day prednisone for at least 8 consecutive weeks. These findings indicate that mepolizumab will be an effective therapy for FIP1L1-PDGFRα negative patients with HES.Primary and secondary endpointsEndpointPlacebo (n=42)Mepolizumab (n=43)P-value (95% CI)Patients on ≤10 mg/day prednisone for ≥8 weeks (primary endpoint), %43%84%<0.001 (2.69, 23.78)Patients with eosinophils <600 μL for ≥8 weeks, %45%95%<0.001 (4.74, 75.17)Primary endpoint in patients on ≤30 mg/day prednisone at baseline, %57% (n=30)87% (n=30)0.011 (1.39, 17.82)Primary endpoint in patients on >30 mg/day prednisone at baseline, %8% (n=12)77% (n=13)<0.001 (3.26, 412.26)Patients achieving ≤7.5 mg/day prednisone during the treatment period, %50%86%<0.001 (2.04, 15.00)Mean (±SE) prednisone dose at Week 36 (adjusted), mg/day21.8±1.926.2±1.87<0.001