Comparative analysis of marketed factor VIII products: reply

Abstract

Development of factor VIII (FVIII) inhibitors following replacement therapy with FVIII is one of the major challenges faced when treating patients with hemophilia A. Inhibitors develop in 20–32% of previously untreated patients with severe and in 3–13% with moderate or mild hemophilia A 1, 2. The cause of the immunogenicity is not well understood. There is evidence that both genetic and non-genetic factors influence patients’ susceptibility to develop these antibodies 3, 4. Novel hypothesis and research approaches are required to obtain more clarity on the molecular basis of FVIII immunogenicity and how FVIII triggers unwanted immune responses in some patients but not in others. The aim of our paper ‘Comparative analysis of marketed factor VIII products: recombinant products are not alike vis-a-vis soluble protein aggregates and subvisible particles’ 5 was to advance science and help to generate new hypotheses for future research on the molecular basis of FVIII immunogenicity. Our aim was to provide scientific transparency of our rationale and to stay on the level of a scientific debate rather than discussing brands or products. We believe that when it comes to treatment decisions clinical evidence on a robust basis is required. Disclosure of brand names as recently suggested by M Makris and A Farrugia in a letter to the editor of JTH 6 could influence treatment decisions by hypotheses rather than robust clinical evidence. Data from other protein products suggest that critical quality variables such as soluble protein aggregates (SPAs) and subvisible particles (SVPs) influence the immunogenicity of protein therapeutics 7. We analyzed SPAs and SVPs concentrations in commercially available recombinant FVIII (rFVIII) products to understand if there are differences between these products after reconstitution. Moreover, we wanted to know if and how levels of SPAs and SVPs change upon exposure of rFVIII products to relevant stress conditions such as agitation and sheer stress. Pre-existing SPAs and SVPs may act as seeds that nucleate further protein aggregation upon exposure to stress 8-10. In addition to the baseline levels of SPAs and SVPs in each rFVIII product, our data indicate that product mishandling after reconstitution can increase the concentration of SPAs and SVPs. Similar findings for FVIII products were recently published by Tsutomo et al. 15. Thus, it is important to educate end-users about proper product handling to avoid an amplification of potential adverse effects due to increases in SPAs and SVPs induced by mishandling. 15. In conclusion, we believe the research community needs to pay more attention to the presence of SPAs and SVPs in FVIII products and how these variables influence the immunogenicity of the products in patients. Our current understanding does not yet allow specific conclusions on how levels of SPAs and SVPs in FVIII products translate into product immunogenicity in patients but we believe that thorough assessment of these variables is important. B. M. Reipert wrote the manuscript. J. Anzengruber and F. Scheiflinger revised the manuscript and all authors approved the final version. We thank E. Langdon-Neuner for editing the English language of the manuscript. This work was funded by Shire. All authors are employees of Shire.