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John M Teare,1 David S Kates,1 Anita Shah,2 Stephen Garger1 1Biological Development, Bayer US LLC Pharmaceuticals, Berkeley, CA, USA; 2Pharmacokinetics Pharmacodynamics Hematology, Bayer US LLC Pharmaceuticals, Whippany, NJ, USA Background: BAY 81–8973 (Kovaltry) is an unmodified full-length recombinant factor VIII (rFVIII) for treatment of hemophilia A. The BAY 81–8973 manufacturing process results in a product of enhanced purity with a consistently high degree of branching and sialylation of N-linked glycans. This study evaluated whether a relationship exists between N-linked glycosylation patterns of BAY 81–8973 and two other rFVIII (sucrose-formulated rFVIII [rFVIII-FS; Kogenate FS]) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM; Advate) and their pharmacokinetic (PK) characteristics.Materials and methods: N-linked glycans or terminal carbohydrates were enzymatically removed from immobilized BAY 81–8973, rFVIII-FS, and rAHF-PFM proteins and analyzed using high-performance liquid chromatography to determine the percentage of individual N-linked glycan structures and degree of sialylation of each structure. PK data were available from two separate phase 1 crossover studies in which the PK profile of BAY 81–8973 was compared with that of rFVIII-FS (n=26) and rAHF-PFM (n=18) in patients with severe hemophilia A who received a single 50 IU/kg dose of each product.Results: BAY 81–8973 and rFVIII-FS had increased N-linked glycan branching with higher levels of sialylation compared with rAHF-PFM. Levels of trisialylated glycans were 29.0% for BAY 81–8973 vs 11.5% for rFVIII-FS and 4.8%–5.5% for rAHF-PFM; tetrasialylated glycans were 12.0% vs 2.8% and 0.6%, respectively. Degree of sialylation was 96% for BAY 81–8973, 94% for rFVIII-FS, and 78%–81% for rAHF-PFM. Based on chromogenic assay results from the single-dose phase 1 PK studies, BAY 81–8973 half-life was 15% longer than that for rFVIII-FS and 16% longer than rAHF-PFM.Conclusion: Increased N-glycan branching and sialylation were seen for BAY 81–8973 vs rFVIII-FS and rAHF-PFM. Improved PK for BAY 81–8973 relative to rFVIII-FS and rAHF-PFM as seen in single-dose crossover PK studies might be related to this greater level of branching and sialylation, which can prolong the time BAY 81–8973 remains in the circulation. Keywords: clearance, glycan structure, glycosylation, half-life |
