To the editor:

As the senior authors referenced in the news article “Lessons from Eprex for biogeneric firms” (Nat. Biotechnol. 21, 956–957), we would like to point out that the news article draws conclusions that are not supported in the paper entitled “Micelle-associated protein in epoetin formulations” that is in press at the journal Pharmaceutical Research.

The opening line of the news article states: “Dutch scientists have found that aggregates of small molecules (micelles) in the formulation of erythropoietin alpha (EPO), sold as Eprex in Europe, were responsible for an immunogenic reaction that triggered severe side effects”. In the third paragraph, the article further states: “But the high concentration of the sorbitol [polysorbate 80] led to the formation of micelles, which were found to cluster with EPO in a form that triggers an immunogenic reaction. The resulting antibodies not only abrogated the effects of Eprex, but also neutralized naturally occurring EPO.”

The above statements mistakenly imply that the unpublished research paper has provided definitive proof for the cause of erythropoietin- associated pure red cell aplasia in patients with chronic renal failure. In the Pharmaceutical Research paper, we and our coauthors clearly present the development of an important hypothesis that requires further study. For example, we state that “this micellar form of epoetin may be an important risk factor for the development of antibodies in patients,” adding “we recognize that the presence of micelle-associated epoetin as a risk factor for immunogenicity in patients at the moment remains hypothetical” and “Follow-up studies in which the micelle-associated epoetin is tested in animal models may shed light on the correlation between the formulation of epoetin and its immunogenicity.”

We make no claim to a direct cause-effect relationship between the micelle-associated epoetin and immunogenicity. We only propose that such an interaction could be possible and deserves serious further investigation. Although the work published in the Pharmaceutical Research article was not supported by the manufacturer of Eprex, we are now collaborating with the company (Johnson & Johnson, Raritan, NJ, USA) to further investigate our initial results. We have joint analytical efforts ongoing to confirm and better characterize the nature of the micelle-associated erythropoietin, and we will be conducting animal studies to explore the immunogenicity of the complex. This collaboration will allow us to obtain verification of results in separate and independent laboratories.