Florence Roufosse, MD, PhD, on Mepolizumab for Treating Hypereosinophilic Syndrome

The findings of a recent study1 show that mepolizumab is an effective treatment for patients with hypereosinophilic syndrome (HES), as it was found to significantly reduce flare occurrence in these patients.

To further understand the efficacy and safety of mepolizumab, Consultant360 reached out to the study’s first author Florence Roufosse, MD, PhD, who is a professor and senior research fellow in the Department of Internal Medicine at the Hospital Erasme in Brussels, Belgium.


Consultant360: In this international multi-center clinical trial, a group of experts sought to examine the clinical efficacy and safety of mepolizumab for patients with HES. What is HES, and why is it important to study new therapeutics for this condition?

Florence Roufosse: HES is a heterogeneous group of rare disorders characterized by persistent tissue eosinophilia (often in conjunction with blood hypereosinophilia) associated with eosinophil-mediated organ damage and/or dysfunction. Target organs include most commonly the lungs, digestive tract, skin, heart, and nervous system. The goal of therapy is to reduce blood and tissue eosinophilia in order to reverse and prevent organ damage. With the exception of patients with FIP1L1/PDGFRA-positive disease (a myeloproliferative variant of HES) who respond exquisitely well to the tyrosine kinase inhibitor imatinib mesylate, most patients require prolonged treatment with oral corticosteroid (OCS) and/or cytotoxic or immunosuppressive corticosteroid-sparing agents. Maintenance therapy is associated with significant morbidity and may not achieve complete remission in patients with more refractory disease. Finding new treatment options for this chronic inflammatory disease, with better efficacy and tolerance, is critical to improving patient outcomes.

CON360: Participants of this trial were patients with HES who had experienced 2 or more flares in the previous year. How did treatment affect the risk for flares in patients with HES?

FR: To be eligible for this trial, patients had to have experienced at least 2 flares, defined on the basis of a need for an increase in therapy, during the year preceding enrollment. One of these flares had to occur in the absence of a decrease in background treatment during the preceding month.

The mean annual flare rate of the entire patient population prior to enrollment was 2.7 per year. During the trial, background therapy was not to be decreased, and flares were recorded either when the investigator increased background prednisone-equivalent dose by at least 10 mg for at least 5 days for clinical worsening or when eosinophil counts increased above a predefined threshold, thereby triggering rescue blinded OCS treatment.

The proportion of patients who experienced a flare in the active treatment arm (the primary endpoint of this trial) was 50% lower than in the placebo arm (28% vs 56% experiencing a flare). The risk of experiencing a flare during the 32-week trial and the annualized flare rate (adjusted mean rate 0.5 vs 1.46/year) were both reduced by 66% compared with patients receiving placebo.

CON360: How does mepolizumab add to the treatment landscape for patients with HES?

FR: Treatment targeting the interleukin-5 (IL-5) pathway specifically depletes eosinophils in humans, as these are the only cells with high-level expression of receptors for this cytokine (low-level expression is also observed on basophils). Together with the other monoclonal antibodies targeting IL-5 and its receptor, mepolizumab therefore offers the advantage of reducing eosinophilia while leaving other immune pathways and cells intact. This specificity accounts for the good tolerance and adverse event profile similar to placebo observed in the clinical trials conducted in patients with asthma, eosinophilic granulomatosis with polyangiitis, and HES. Furthermore, in the first randomized controlled trial conducted in patients with HES more than 10 years ago, mepolizumab was shown to enable a significant OCS dose reduction and even complete withdrawal of background OCS treatment in some patients with FIP1L1/PDGFRA-negative HES, further reducing treatment-related morbidity. 

CON360: What are the clinical pearls from your study?

FR: This is the first study ever to assess HES disease activity on the basis of occurrence of flares. There is no validated tool to measure disease activity in HES given the extremely heterogeneous clinical presentations. Although it is a risk to define a primary endpoint on the basis of an unprecedented disease outcome in a clinical trial, the study drug achieved this endpoint, opening avenues for future trials assessing efficacy of novel treatment options in this disease.

The striking reduction in eosinophil counts with mepolizumab and the favorable tolerance profile had already been established in prior studies, but this study has added improved control of clinical disease activity to the benefits experienced by HES patients receiving this treatment.

CON360: What are the next steps for research in this area?

FR: There are still a number of unmet needs in the field of HES treatment, some regarding anti-IL-5 treatment itself, others that extend beyond eosinophils and IL-5. Among the former, research efforts should be directed toward exploring the impact of treatment on tissue eosinophilia, investigating optimal mepolizumab dosing regimens (dose administered and interval between doses), and relative efficacy in different disease forms. Understanding the mechanisms that account for the flares that still occur despite anti-IL-5 therapy will advance knowledge on pathogenic disease mechanisms. Whether eosinophil subsets that are less dependent on IL-5 exist and/or other eosinophil-activating factors may be operative in certain locations and disease variants are important issues to address. Furthermore, other cell types and mediators not targeted by anti-IL-5(R) may contribute to pathology in some instances and explain partial or absence of treatment response.

Although a wealth of data from clinical trials indicates that mepolizumab is safe, potential adverse effects of long-term reduced eosinophil counts should continue to be monitored.

Another important step will be the development and validation of a reliable tool to quantify disease activity in order to facilitate clinical trial design for this rare disease in the future.




Roufosse F, Kahn JE, Rothenberg ME, et al; HES Mepolizumab study group. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. Published online September 17, 2020. doi:10.1016/j.jaci.2020.08.037