Author(s): Alexander Solms, PhD, Bayer; Gili Kenet, MD, Sackler Faculty of Medicine, Chaim Sheba Medical Center; Heinz Delesen, Dipl.-Math, Bayer; Monika Maas Enriquez, MD, Bayer; Shadan Lalezari, MD, Chaim Sheba Medical Center

Research Category: Clinical Research/Clinical Trials

Description:

Objective:

Ideally, intra-individual differences in the pharmacokinetics (PK) properties of recombinant factor VIII (rFVIII) products should be compared in the same population using a crossover study design. In LEOPOLD I (NCT01029340), the PK profile of BAY 81-8973 (Kovaltry®; an unmodified, full-length rFVIII product manufactured using innovative technologies) was compared with that of rFVIII-FS (Kogenate®; a sucrose-formulated rFVIII product with the same amino acid sequence as BAY 81-8973) after a single 50 IU/kg infusion. A subset of these patients also participated in the PROTECT VIII trial (NCT01580293), in which the PK profile of BAY 94-9027 (Jivi®; a B-domain-deleted rFVIII product site-specifically PEGylated to extend its half-life) was assessed after a single 60 IU/kg infusion. Hence, this allows for an indirect intra-individual comparison of the PK of the three products.

Methods:

In this analysis, the PK profiles of rFVIII-FS, BAY 81-8973, and BAY 94-9027 were compared in 15 patients with severe hemophilia A who participated in both the LEOPOLD I and PROTECT VIII studies. The procedure for PK analysis was similar for both studies; although different reagents and analyzers were used to perform the one-stage assays in each study, validation results were similar between products and assays.

Summary:

In the analysis set, geometric mean half-lives using the one-stage assay were 12.4, 14.2 and 17.7 h for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively. Similar results were observed using both one-stage and chromogenic assays (chromogenic assay, geometric mean half-life: 12.1, 14.0 and 17.1 h for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively). Times to threshold concentration of 1 IU/dL after a single dose were predicted as 81.2, 93.5 and 119.7 h, respectively (using a population PK approach and a dose of 50 IU/kg), and the dose-normalized areas under the curve were 27.1, 32.5 and 66.8 h*kg/dL for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively.

Conclusions:

BAY 94-9027 demonstrated an extended half-life compared with both rFVIII-FS and BAY 81-8973, following a single infusion, in patients with severe hemophilia A. In conclusion, switching treatment from either rFVIII-FS or BAY 81-8973 to BAY 94-9027 is expected to provide improved protection from bleeds and/or allow for less frequent infusions. This is an encore abstract, previously included at the 13th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD 2020).