BAY 81‐8973, a full‐length recombinant factor VIII: manufacturing processes and product characteristics

Abstract

BAY 81-8973 (Kovaltry â , Bayer, Berkeley, CA, USA) is an unmodified, full-length recombinant human factor VIII (FVIII) approved for prophylaxis and on-demand treatment of bleeding episodes in patients with haemophilia A. The BAY 81-8973 manufacturing process is based on the process used for sucrose-formulated recombinant FVIII (rFVIII-FS), with changes and enhancements made to improve production efficiency, further augment pathogen safety, and eliminate animal-and human-derived raw materials from the production processes. The baby hamster kidney cell line used for BAY 81-8973 was developed by introducing the gene for human heat shock protein 70 into the rFVIII-FS cell line, a change that improved cell line robustness and productivity. Pathogen safety was enhanced by including a 20-nm filtration step, which can remove viruses, transmissible spongiform encephalopathy agents and potential protein aggregates. No human-or animal-derived proteins are added to the cell culture process, purification or final formulation. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of sialylation of N-linked glycans on the molecular surface. The innovative manufacturing techniques used for BAY 81-8973 yield an effective rFVIII product with a favourable safety profile for treatment of haemophilia A.

Defining extended half‐life rFVIII—A critical review of the evidence

“…Other new rFVIII products have been designed with different purposes other than to extend half‐life (Table ). For example, BAY 81‐8973 and Human‐cl rhFVIII have been manufactured, respectively, with the intent of reducing the potential for pathogen transmission and reducing immunogenicity (by avoiding hamster‐like epitopes by production in a human cell line) . Both have changes to the glycosylation of rFVIII compared to previous generation proteins (eg antihaemophilic factor [recombinant]: Kogenate FS), which can influence PK profile …”

Efficacy and safety of prophylaxis with BAY 81‐8973 in Chinese patients with severe haemophilia A enrolled in the LEOPOLD II trial

“…The efficacy and safety of BAY 81‐8973 were demonstrated in the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trial program, which enrolled children, adolescents, and adults with severe haemophilia A at sites worldwide . The efficacy of prophylaxis and superiority of prophylaxis over on‐demand treatment have been demonstrated in Chinese patients treated with sucrose‐formulated recombinant FVIII (rFVIII‐FS; Kogenate ® FS; Bayer), which has the same amino acid sequence as BAY 81‐8973 . To evaluate the efficacy and safety of BAY 81‐8973 specifically in Chinese patients with haemophilia A, we examined data from the LEOPOLD II trial, which enrolled 23 patients from China.…”

“…13,14 The efficacy of prophylaxis 9,16 and superiority of prophylaxis over on-demand treatment 17 have been demonstrated in Chinese patients treated with sucrose-formulated recombinant FVIII (rFVIII-FS; Kogenate ® FS; Bayer), which has the same amino acid sequence as BAY 81-8973. 18 To evaluate the efficacy and safety of BAY 81-8973 specifically in Chinese patients with haemophilia A, we examined data from the LEOPOLD II trial, which enrolled 23 patients from China. The subanalysis also explored whether treatment history in Chinese patients affected efficacy and safety.…”

Polysaccharide-based chromatographic adsorbents for virus purification and viral clearance

“…In addition to Nuwiq® [196], a wealth of antihemophilic FVIII products is currently available on the market, ranging from early plasma-derived to fourth-generation recombinant products [227]. MAb-based immunoaffinity chromatography (IAC) is a key purification step in most manufacturing processes of these commercial FVIII compounds [228,229], with chemical inactivation and NF devoted to viral clearance -like for mAb products. Nevertheless, a few studies have investigated the virus removal efficiency of the IAC step where a Seph matrix with an anti-FVIII mAb ligand was used as adsorbent: murine mAb (IgG) coupled to Nhydroxysuccinimide (NHS)-activated Seph 4FF [230] or Seph CL-2B [231], recombinantly produced anti-FVIII mAb (rF25) coupled to cyanogen bromide (CNBr)-activated Seph FF [217].…”