Investigational Biologic Holds Promise for Steroid-Sparing Treatment of Devastating Blood Syndrome, Says Cincinnati Children's Researcher

Antibody-based Therapy, Mepolizumab, for Hypereosinophilic Syndrome Patients Reported in The New England Journal of Medicine

Thursday, April 03, 2008

CINCINNATI – For the first time, the long-term use of an investigational antibody-based medication, mepolizumab, designed to target a type of white blood cell, has resulted in steroid-sparing treatment for patients with the devastating blood disorder, hypereosinophilic syndrome (HES), that can lead to heart failure and death, according to a Phase III study published in the March 20 The New England Journal of Medicine. 

"The current standard treatment for the majority of HES patients is the chronic, systemic use of corticosteroids, such as prednisone, which can have considerable side effects. We found that mepolizumab enabled study patients to significantly reduce their doses of steroids and, often, even withdraw from steroid use," says Marc Rothenberg, MD, PhD, director of allergy and immunology at Cincinnati Children's Hospital Medical Center and the study's lead author.

In the study, an injected 750 milligram (mg) dose of mepolizumab every four weeks enabled 84 percent of the 43 patients, significantly more than the 43 percent of the 42 patients on placebo, to reduce their daily prednisone doses to just 10 milligrams (mg) or less for eight or more weeks, the study's primary endpoint (p <0.001). Moreover, of 30 mepolizumab patients on daily prednisone doses of 30 mg or more, 77 percent reduced their steroid use to 10 mg or less by study end (p<0.001).

Because the steroid threshold associated with significant toxicity previously was established at ~7.5 mg daily doses, Rothenberg and his co-investigators noted that 86 percent of the mepolizumab group, significantly more than the 50 percent of the placebo group, achieved prednisone dosing of 7.5 mg or less for more than one study day, (p<0.001). Importantly, 47 percent of the mepolizumab-treated patients, significantly more than the 5 percent of placebo patients, became prednisone-free during the study and remained so until the study ended (p<0.001).

"The findings suggest the high likelihood of achieving reduced steroid use in patients with HES-related respiratory, cardiac, gastrointestinal, musculoskeletal and nerve system organ involvement as well as potential benefit to addressing the high counts of the eosinophil white blood cells occurring in HES disease," Rothenberg says.

Of those treated with mepolizumab, 95 percent, significantly more than the 45 percent on placebo (p<0.001), achieved reduction and stabilization in the numbers of eosinophils, the white blood cell that underlies HES, to below 600 per microliter (μL). HES, which affects about 2000 people annually, is characterized by severely elevated levels of eosinophils, the immune cells involved with the killing of parasites, destruction of cancer cells and responding to allergens. Eosinophils normally reside in lung and gastrointestinal tissues, but blood levels above 1500/μL usually indicate an eosinophil-related disorder, while levels below 350/μL are considered normal. In HES, eosinophils grow in an uncontrolled manner and can attack many parts of the body.

The primary stimulus to produce eosinophils is a normally occurring immune system protein interleukin (IL)–5. Mepolizumab is a fully humanized protein, investigational therapeutic or biologic, designed to block IL-5, thwarting its ability to help in regulating eosinophil production, activation, mobilization and survival. Specifically, mepolizumab tightly attaches with great specificity to IL-5, preventing it from attaching to a receptor on immature and mature eosinophils.

"Mepolizumab has strong potential to become the first in a new class of therapies designed to specifically target eosinophils," says Dr. Rothenberg. "The success of the study is a credit to the international community of physician scientists dedicated to developing a HES treatment. The study proves the success of fundamental research, as IL-5 was originally identified based on fundamental basic science studies."

Mepolizumab (SB 240563) is under development by GlaxoSmithKline. The study, conducted by the HES study group at 26 sites in the United States, Canada, Belgium, France, Germany, Italy and Austria between 2004 and 2006, received support from GlaxoSmithKline, the U.S. National Institute of Allergy and Infectious Diseases and the U.S. National Center for Research Resources. Dr. Rothenberg receives support as an investigator from GlaxoSmithKline.

For the study, the HES study group enrolled 84 patients diagnosed with HES, randomly assigning half of them to receive mepolizumab and half to placebo every four weeks for 36 weeks, yet neither the scientists nor the patients knew to which group they were assigned until the end of the treatment period. The prednisone dose was tapered using a predefined algorithm based on eosinophil counts and HES clinical symptoms.

Adverse events considered to be related to the medications were similar among both treatment groups, even though the duration of exposure to mepolizumab was approximately 56 percent longer than that of placebo, owing to greater dropout rate, for lack of efficacy, in the placebo group. Additionally, some of the adverse events in both groups may have resulted from prednisone withdrawal, rather than mepolizumab, the authors note.

Dr. Rothenberg directs the Cincinnati Center for Eosinophilic Disorders (CCED), an international leader in caring for patients with these conditions and conducting research to find cures. The CCED is supported in part by a foundation called CURED (Campaign Urging Research for Eosinophilic Disorders), which was created by Ellyn Kodroff, the mother of a patient helped by Cincinnati Children's.

Cincinnati Children's, one of the top five children's hospitals in the nation according to Child magazine, is a 475-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to providing care that is timely, efficient, effective, family-centered, equitable and safe. For its efforts to transform the way health care is provided, Cincinnati Children's received the . Cincinnati Children's ranks second nationally among all pediatric centers in research grants from the National Institutes of Health and is a teaching affiliate of the University of Cincinnati College of Medicine. The Cincinnati Children's vision is to be the leader in improving child health.