Evolution of recombinant factor VIII safety: KOGENATE® and Kogenate® FS/Bayer

Abstract

The use of factor VIII (FVIII) concentrates in the treatment of hemophilia A has raised important safety issues, historically of pathogen transmission and increasingly of inhibitor development to FVIII treatment. While manufacturing processes of current recombinant FVIII products have been shaped entirely around preventing pathogen transmission, the same modifications that afford a greater margin of safety could affect immunogenicity of the product, consequences of which could only be seen through long-term clinical experience. This review summarizes pathogen safety and inhibitor reports from clinical trials, post-marketing surveillance studies, and study reports on KOGENATE and its successor, Kogenate FS/Bayer. Although KOGENATE and Kogenate FS/Bayer are nearly identical products, subtle manufacturing improvements to address the need for greater margins of safety from a pathogen transmission perspective have also led to a potentially improved immunogenicity profile (15% in previously untreated/minimally treated patients with severe hemophilia A for Kogenate FS/Bayer). Notably, there has been no occurrence of pathogen contamination, and minimal de novo inhibitor formation in previously treated patients throughout the use of both products. Overall, KOGENATE and Kogenate FS/Bayer have a long history of safety in a variety of clinical settings, including treatment of bleeding, surgical management, and prophylaxis therapy.

Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A

“…Changes in BHK manufacturing practices between Product B and Product D might have led to increased immunogenicity, 36 but the number of patients treated with Product B in both the RODIN study and in our cohort was too small for comparison with Product D. rFVIII molecules produced by BHK and CHO cells differ in several respects, such as the degree of tyrosine residue sulphation and type of glycosylation. 37 The presence of specific glycan chains might affect dendritic cell uptake and thereby modify rFVIII immunogenicity.…”

Products Used to Treat Hemophilia: Recombinant Products

“…Sixteen of these 32 patients had high-titer antibodies and 16 had low (<5 BU/mL) and/or transient titers [9]. Sixteen of these 32 patients had high-titer antibodies and 16 had low (<5 BU/mL) and/or transient titers [9].…”

“…A metaanalysis of the clinical trials demonstrated that cumulatively, the incidence of de-novo inhibitor development was 8.2% in PUPs with <20 EDs, 1.5% in those with 20-100 EDs and 0.2% in PTPs with >100 EDs [9].…”

Managing Haemophilia for Life: 4th Haemophilia Global Summit

“…In the 1980s, the increased demand for clotting factor concentrates, combined with concerns over the safety of pdCFCs, led to the development of recombinant clotting factor concentrates (recombinant CFCs) . The manufacturing and purification processes involved are designed to reduce the risk of viral contamination .…”