Pharmacokinetic properties of BAY 81‐8973, a full‐length recombinant factor VIII

Abstract

Introduction BAY 81‐8973 is a full‐length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose‐formulated recombinant FVIII (rFVIII‐FS) but is produced with advanced manufacturing technologies. Aim To analyse the pharmacokinetics (PK) of BAY 81‐8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. Methods The LEOPOLD trials enrolled patients with severe haemophilia A aged 12–65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one‐stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50‐IU kg−1 dose of BAY 81‐8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non‐Asian). Results Pharmacokinetic assessments in the LEOPOLD I trial showed non‐inferiority of BAY 81‐8973 vs. rFVIII‐FS. The PK of BAY 81‐8973 were comparable after single and multiple dosing. Age‐based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. Conclusions Results of the LEOPOLD trials show that the BAY 81‐8973 pharmacokinetic profile is non‐inferior to rFVIII‐FS. Similar BAY 81‐8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups.

Efficacy and safety of BAY 81‐8973, a full‐length recombinant factor VIII: results from the LEOPOLD I trial

“…BAY 81-8973 has glycans shifted to higher branched structures and a shift towards higher sialylation. These slight changes in glycan structures may contribute to the improved pharmacokinetic (PK) profile of BAY 81-8973 vs. rFVIII-FS, as described previously [6].…”

“…Part A was a phase I study to assess the PK non-inferiority of BAY 81-8973 to rFVIII-FS [6]; part B was a phase III study to assess efficacy, safety and tolerability of prophylactic treatment with BAY 81-8973 (with an optional 12-month extension phase); and part C was an efficacy and safety study in patients undergoing major surgery. All patients provided written informed consent.…”

“…) was non-inferior to rFVIII-FS [6]. BAY 81-8973 had a longer half-life compared with Annualized bleeding rate.…”

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

“…In clinical trials, the pharmacokinetic profile of BAY 81-8973 was noninferior to that of rFVIII-FS, and for some variables, BAY 81-8973 showed more favourable pharmacokinetics [18]. Compared with rFVIII-FS, BAY 81-8973 had a longer half-life, higher area under the curve, longer mean residence time and slower clearance [18].…”

“…The manufacturing process used for BAY 81-8973 results in an rFVIII product of enhanced purity with a consistently high degree of sialylation of N-linked glycans on the molecular surface, a posttranslational modification step that is important to the half-life of some mammalian proteins [5,18,19]. The BAY 81-8973 molecule has been characterized in detail.…”