SELECTED ARTICLES FROM THE RECENT LITERATURE 2008

4/1/08

Proof of concept for mepolizumab

Summary
Hypereosinophilic syndrome is a heterogenous group of disorders and represent the prototypical eosinophilic syndrome. It is diagnosed in a patient with more than 1500 eosinophils per microliter, evidence of organ involvement, with no diagnosable etiology.

An international group of investigators recently employed mepolizumab, a monoclonal anti-interleukin-5 antibody, to treat patients with hypereosinophilic syndrome. These patients had disease significant enough to require 20 to 60 mg of prednisone a day to remain stable and maintain an eosinophil count of less than 1,000 cells per cubic microliter. The goal, and primary endpoint, was to be able to reduce the prednisone dose to 10 mg a day or less for eight consecutive weeks.

Eighty-four percent of the patients treated with mepolizumab as compared to 43% of the patients on placebo were able to achieve the primary endpoint without an increase in activity of the disease.

Ninety-five percent of patients receiving mepolizumab as compared with 45% receiving placebo manifested a blood eosinophil count of less than 600 per microliter for eight or more consecutive weeks.

The time to treatment failure (the time required to enlist the therapy or increase the prednisone dose to greater than 60 mg per day) in the mepolizumab group was significant longer than the placebo group. Nine of 43 patients (21%) receiving mepolizumab and 29 of 42 patients (69%) receiving placebo demonstrated treatment failure. The median time in the placebo group was 136.5 days; corresponding data could not be calculated for mepolizumab, since less than 50% of drug treated subjects demonstrated treatment failure.

The authors concluded that mepolizumab was an effective corticosteroid-sparing agent for patients with hypereosinophilic syndrome. It should be noted that these patients were negative for the FIP1L1-PDGFRA mutation.

Editor's Comments
This study is strong proof of concept that mepolizumab is an effective anti-eosinophil therapy in patients with hypereosinophilic syndrome. It demonstrates in this disorder that interleukin-5 is a potent stimulus for eosinophil production. In this situation, mepolizumab not only reduced blood eosinophil levels, but also, by virtue of the fact that significantly diminished prednisone doses were achievable without flares in disease activity, at least indirectly proved the disease state itself. That is, reduced end-organ damage as evidenced by a lack of exacerbation of the illness with lowering of the prednisone dose.

What then is the difference between the results of this study and other investigations focusing on the effect of mepolizumab in asthma?

Certainly the lack of effect in asthma is not due to failure of the agent to lower blood and sputum eosinophilia. The agent was effective, in the studies performed in asthma, in reducing eosinophil levels in the blood, sputum, and bronchial secretions, as it was in the blood in the hypereosinophilic investigation.

Fortunately, we have no definitive answer for the disappointing results in asthma compared to the very encouraging results in the hypereosinophilic syndrome. However, one leading possibility is that studies in asthma were carried out for a much shorter period of time. In the hypereosinophilic syndrome, patients were treated for 36 weeks whereas in studies of asthma, the duration of treatment was no more than 12 weeks. Another possibility is that in the actual bronchial tissue, IL-5 may no longer be a potent growth factor, perhaps being supplanted by IL-3 and GNCSF. However, this seems unlikely because the effectiveness of this drug in other tissues in the therapy of hypereosinophilic syndrome, in spite of the fact that eosinophil levels were much higher in this disorder than they are in asthma.

Regardless of the reason for the discrepancy in therapeutic value of mepolizumab between treatment of hypereosinophilia per se and treatment of an eosinophilic lung condition, asthma, the encouraging results achieved in treatment of the hypereosinophilic syndrome will hopefully encourage longer term studies in asthma.

Reference
Rothenberg ME, et al. Treatment of patients with hypereosinophilic syndrome with mepolizumab. New England Journal of Medicine, March 20, 2008; 358:1215-1228.

 

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