BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review

Johnny N Mahlangu, Sanjay P Ahuja, Jerzy Windyga, Nikki Church, Anita Shah, Lawrence Schwartz, Johnny N Mahlangu, Sanjay P Ahuja, Jerzy Windyga, Nikki Church, Anita Shah, Lawrence Schwartz

Abstract

BAY 81-8973 (Kovaltry®) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate® FS/KOGENATE®, Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens. BAY 81-8973 was extensively studied in the LEOPOLD clinical development program, which enrolled participants of all age groups (children, adolescents, and adults) with severe hemophilia A. The pharmacokinetic profile of BAY 81-8973 was shown to be noninferior to, and for some variables more favorable than, rFVIII-FS and another commercial full-length rFVIII product. BAY 81-8973 was shown to be efficacious when used for prophylaxis, on-demand treatment, and perioperative hemostasis. The efficacious prophylaxis dose of BAY 81-8973 was approximately 20-40 IU/kg given two or three times per week, which achieved low annualized bleeding rates. Either the one-stage or the chromogenic assay provides accurate measurements for postinfusion monitoring of BAY 81-8973 levels, with no product-specific calibration standard needed. The incidence of treatment-related adverse events was ⩽7% across all LEOPOLD studies, and no previously treated patient developed anti-BAY 81-8973 inhibitors in the completed primary studies.

Keywords: BAY 81-8973; Kovaltry; hemophilia A; pharmacokinetics; prophylaxis; recombinant factor VIII.

Conflict of interest statement

Conflict of interest statement: Dr. Mahlangu has received research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche; is a member of the scientific advisory committees of Amgen, Baxalta, Biogen, CSL Behring, Novo Nordisk, and Roche; and is on the speakers bureaus of Amgen, Bayer, Biogen, Biotest, and CSL Behring. Dr. Ahuja is a member of the advisory boards of Bayer, Baxalta, and Biogen, and has been on the speakers bureaus of Biogen, Grifols, and Novo Nordisk. Dr. Windyga received honoraria or research grants from Bayer, Baxalta, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi. Dr. Church and Dr. Shah are employees of Bayer. Mr. Schwartz was a Bayer employee at the time this manuscript was originally submitted.

Figures

Figure 1.
Figure 1.
Glycan structures in BAY 81-8973 and rFVIII-FS. rFVIII-FS, recombinant factor VIII formulated with sucrose.
Figure 2.
Figure 2.
Summary of study designs for LEOPOLD clinical trial program.– CS/ADJ, chromogenic substrate assay/labeled potency adjusted by a predefined factor to mimic results obtained with the one-stage assay; CS/EP, chromogenic substrate assay per European Pharmacopoeia; ED, exposure day; PTP, previously treated patient; PUP, previously untreated patient; rFVIII-FS, recombinant factor VIII formulated with sucrose. *Dose/infusion and dosing frequency selected by investigator within range. †Dose/infusion selected by investigator within range.

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