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

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.

Tailoring haemophilia A prophylaxis with BAY 81-8973: A case series

“…Second, its characteristics are further enhanced by the presence in the cells of the gene for human heat shock protein 70 (HPS70), which is essential for proper protein folding and increases FVIII expression. Data from comparative studies have confirmed PK parameters for BAY 89-8173 to be non-inferior toand for some PK variables significantly better thanthose for rFVIII-FS and another commercial unmodified rFVIII (antihemophilic factor (recombinant) plasma/albumin-free method, rAHF-PFM, Advate ® ) in terms of higher AUC, prolonged t1/2 and mean residence time (MRT) after IV injection, and slower clearance [8 The safety and efficacy of BAY 81-8973 have been extensively studied in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) international clinical development program [20,21,22,23], encompassing three separate trial segments in patients affected by severe HA: LEOPOLD I (part A: PK profile; part B: safety and efficacy in prophylaxis; part C: hemostasis during surgery and extension), LEOPOLD II (randomization to: on demand, low and high dose prophylaxis) and LEOPOLD KIDS (part A: PK profile, safety and efficacy in prophylaxis in previously treated patients; part B: PK profile, safety and efficacy in prophylaxis in previously untreated patients and extension) [22,23].…”

“…Moreover, it is known that concentrates with a higher von Willenbrand factor (VWF) content are associated to lower inhibitor development . Although BAY 81-8973 does not contain VWF, the molecule's characteristics (consistent glycosylation and sulfation of 6 tyrosine sites, which make it more similar to endogenous FVIII) increase its affinity for the patient's VWF compared to other rFVIII, which may prevent inhibitor development [8].…”

“…Current guidelines for the management of patients with severe HA recommend prophylaxis with intravenous (IV) administration of FVIII concentrates in order to prevent spontaneous hemarthroses, preserve healthy joints, reduce the incidence of hemophilic arthropathy and improve QoL [3][4][5][6][7][8]. In patients with severe hemophilia, the success of prophylaxis depends on the maintenance of values of FVIII above the threshold of 1 IU/dL, based on early observations that patients with moderate HA rarely bleed and experience chronic 4 arthropathy [9].…”

“…The LEOPOLD I and II enrolled over 120 adolescent and adult patients with HA (12 to 65, mean age 30 years) featuring a compromised and difficult to manage joint status, most with target joints (71% Leopold I and 89.9% Leopold II). Of note, in these two clinical trials BAY 81-8973 demonstrated to effectively prevent bleeding episodes with both a twiceweekly and three-times-weekly dosing prophylactic regimen [8,20,23].…”