Schellekens and Jiskoot respond:

In contrast to the assumption of Sharma et al., we scrutinized all the (highly redundant) publications of J&J concerning their explanation of Eprex-associated PRCA. In all of their papers, the only support for a modest adjuvant effect of leachables is a single experiment in mice immunized with ovalbumin. Because this mouse model is not based on breaking B-cell tolerance, this experiment is irrelevant for the induction of antibodies by Eprex. And as confirmed in many models, immune tolerance to soluble self proteins like erythropoietin cannot be broken by an adjuvant.

Sharma et al. refer to results of Yano et al.1 for confirmation of the immune stimulant effect of the alkyl phenols present in the leachates. In the Yano et al. paper, however, none of the compounds identified as leachates by Sharma et al.2 are studied. Yano et al. showed only that this class of compounds has no effect on interleukin 4 and interferon γ production in vitro in the concentrations present in Eprex with uncoated rubber stoppers. In higher concentrations, alkyl phenols inhibit immune stimulatory cytokine products—exactly the opposite activity that Sharma et al. claim.

Sharma et al. agree with us that analyses-based spontaneous reporting should be interpreted with caution, the same caution that the European Medicines Agency has shown by allowing the limited reintroduction of the subcutaneous use of Eprex with chronic renal failure under strict patient surveillance.

Thus, in contrast to the claim of Sharma et al., the European regulatory agencies still need further data to confirm the safety of Eprex. And even if the data were to show the reduction of Eprex-associated PRCA to background levels, this cannot be interpreted as definitive proof that leachates were responsible for the Eprex-associated cases, considering the other changes that have been introduced.

We recently published3 a detailed analysis of all the theories offered to explain the higher incidence of PRCA after the formulation change of Eprex. Our conclusion is that the formulation change resulted in a slightly less stable product with a higher tendency to form aggregates during storage or use. Although the PRCA problem is under control, unbiased explanations of the effect of the formulation change are important now that protein therapeutics are becoming a major part of the new drugs introduced.