Safety and Tolerability of Anti-IL-5 Monoclonal Antibody (Mepolizumab) Therapy in Patients with HES: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Mepolizumab is a fully humanized monoclonal IgG antibody which binds to interleukin 5 (IL-5) with high affinity and specificity, preventing it from binding to IL-5 receptors on the eosinophil cell surface. Since IL-5 is central in eosinophil proliferation, differentiation, mobilization, activation, and survival, yet has limited effects on other cell types, IL-5 inhibition should inhibit the production and activity of eosinophils without affecting the function of other immune cells. Reducing the blood eosinophil count is a critical therapeutic objective in patients with eosinophil-driven diseases, such as hypereosinophilic syndrome (HES). The safety and tolerability of mepolizumab has been evaluated, as a secondary endpoint, in a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. The trial enrolled 85 patients with HES (blood eosinophil count >1500/μl for ≥6 months with documented eosinophilia-related organ involvement or dysfunction and no known cause of eosinophilia), who were negative for the FIP1L1-PDGFRα gene rearrangement. Blood eosinophil levels were stabilized at <1000 cells/μL on 20–60 mg/day prednisone monotherapy during a run-in period of up to 6 weeks, then patients were randomized to intravenous mepolizumab 750 mg (n=43) or saline (placebo; n=42) every 4 weeks for 36 weeks (final infusion at Week 32). Overall, 98% of placebo-treated and 93% of mepolizumab-treated patients reported an adverse event during treatment. The most common of these were fatigue (26% on placebo vs 30% on mepolizumab), pruritus (21% vs 28%), headache (21% vs 23%), and arthralgia (17% vs 21%). The only significant differences between the treatment groups were in pharyngolaryngeal pain (14% on placebo vs 2% on mepolizumab; P=0.027) and pain in extremity (12% on placebo vs 2% on mepolizumab; P=0.047); none of the adverse events was significantly more frequent with mepolizumab than with placebo. A greater than 8% difference in adverse event reporting for the mepolizumab vs placebo arms was noted for upper respiratory tract infections, myalgia, rhinitis, bronchitis, and urticaria. Serious adverse events were reported in 5 patients on placebo (7 events) and 7 patients on mepolizumab (14 events, including 1 death due to a cardiac arrest), but none was considered treatment related. Withdrawals due to adverse events (4 patients on placebo; 1 patient on mepolizumab) were also considered unrelated to treatment. Laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and ECG findings did not raise any major safety concerns. In conclusion, this study, which is currently the largest placebo-controlled trial involving exclusively patients with HES, indicates that mepolizumab is safe and well tolerated in this patient population.