Background Hypereosinophilic syndromes (HES) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid-refractory or develop corticosteroid toxicity. Mepolizumab, a humanised monoclonal anti-interleukin-5 antibody, demonstrated corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HES. Objective To evaluate long-term safety and efficacy of mepolizumab (750 mg) in HES. Methods MHE100901 is an open-label extension study. The primary endpoint was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of anti-mepolizumab antibodies were also explored. Results Seventy-eight subjects received 1–66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range 4–302). The most common dosing interval was 9–12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including one death, were reported by the investigator as possibly due to mepolizumab in three subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone-free without other HES medications for ≥12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew prior to study completion for death (n=4), lack of efficacy (n=6), or other reasons. Conclusion Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES.

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Abstractcontrol mechanism specific for eosinophil proliferation and independent of other haemo-A paradigm shift, championed largely by cellular immunologists, has redefined poietic cell lineages; (2) eosinophilia is a characteristic feature of the pulmonary late asthma as an immune mediated phenomenon characterised by an interleukin 5 phase reaction and the extent of this reaction correlates strongly with various indices of clin-(IL-5) driven eosinophilic bronchitis. This change in emphasis has provoked intense ical severity in asthma; 2 and (3) eosinophil derived granule proteins are responsible for interest in the possibility that inhibitors of IL-5 production, or antagonists of its the destruction of the respiratory epithelium, mucosal oedema, bronchial hyperreactivity, activity, will provide a new generation of anti-asthma drugs.and air flow limitation that characterise asthma.3 (Thorax 1997;52:483-485) While IL-3 and granulocyte-macrophage colKeywords: interleukin 5 inhibitors, asthma, eos-ony stimulating factor (GM-CSF), as well as inophilia.

Targeted eosinophil-directed therapy with an anti-IL-5 neutralizing monoclonal antibody reduced the need for corticosteroids in these three HES patients without disease exacerbations.

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.