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Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

Coyle TE, Reding MT, Lin JC, Michaels LA, Shah A, Powell J - J. Thromb. Haemost. (2014)

Bottom Line: A 168-h PK study was performed after the first and last BAY 94-9027 doses.BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS).BAY 94-9027 was well tolerated, and no immunogenicity was observed.

View Article: PubMed Central - PubMed

ABSTRACT

Background: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia.

Objectives: To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.

Patients/methods: This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.

Results: BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.

Conclusions: This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

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Concentration–time curves of chromogenic factor VIII activity for a single dose of sucrose-formulated recombinant FVIII (rFVIII-FS) given at (A) 25 IU kg−1 and (B) 50 IU kg−1, and after single and multiple doses of BAY 94-9027 given at (A) 25 IU kg−1 and (B) 60 IU kg−1. The data shown are mean ± 90% confidence interval.
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fig03: Concentration–time curves of chromogenic factor VIII activity for a single dose of sucrose-formulated recombinant FVIII (rFVIII-FS) given at (A) 25 IU kg−1 and (B) 50 IU kg−1, and after single and multiple doses of BAY 94-9027 given at (A) 25 IU kg−1 and (B) 60 IU kg−1. The data shown are mean ± 90% confidence interval.

Mentions: PK parameters are shown in Table2. Infusion of a single dose of BAY 94-9027 at 25 IU kg−1 or 60 IU kg−1 yielded similar Cmax values as similar doses of rFVIII-FS. Dose-proportional increases in plasma concentrations were seen between BAY 94-9027 doses (Fig.3). The Cmax of BAY 94-9027 was not substantially changed after multiple doses. There was a slight increase in concentration following multiple doses of 25 IU kg−1 BAY 94-9027 twice weekly as compared with rFVIII-FS, and there was no further change in concentration following multiple doses of 60 IU kg−1 once weekly. The AUC was greater following infusion of a single dose of BAY 94-9027 than with rFVIII-FS, and the mean half-life of BAY 94-9027 following a single 25-IU kg−1 or 60-IU kg−1 dose was 18.4 h (range, 13.7–28.1 h) vs. 13.0 h (range, 8.4–18.7 h) for rFVIII-FS following a single dose. All subjects with data for the single dose of rFVIII-FS and the last dose of BAY 94-9027 (n = 13) showed an increase in half-life when given BAY 94-9027 as compared with rFVIII-FS (Fig.4). The half-life of BAY 94-9027 was 18.7 h (range, 12.1–30.0 h) when averaged across the two cohorts and across single-dose and multiple-dose data, and was significantly longer than that of rFVIII-FS (P < 0.0001). PK parameters of BAY 94-9027 were similar after single and multiple doses. VWF levels at baseline were similar between groups, but there was a tendency for there to be a longer BAY 94-9027 half-life among subjects with higher VWF levels (Fig.5).


Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

Coyle TE, Reding MT, Lin JC, Michaels LA, Shah A, Powell J - J. Thromb. Haemost. (2014)

Concentration–time curves of chromogenic factor VIII activity for a single dose of sucrose-formulated recombinant FVIII (rFVIII-FS) given at (A) 25 IU kg−1 and (B) 50 IU kg−1, and after single and multiple doses of BAY 94-9027 given at (A) 25 IU kg−1 and (B) 60 IU kg−1. The data shown are mean ± 90% confidence interval.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265842&req=5

fig03: Concentration–time curves of chromogenic factor VIII activity for a single dose of sucrose-formulated recombinant FVIII (rFVIII-FS) given at (A) 25 IU kg−1 and (B) 50 IU kg−1, and after single and multiple doses of BAY 94-9027 given at (A) 25 IU kg−1 and (B) 60 IU kg−1. The data shown are mean ± 90% confidence interval.
Mentions: PK parameters are shown in Table2. Infusion of a single dose of BAY 94-9027 at 25 IU kg−1 or 60 IU kg−1 yielded similar Cmax values as similar doses of rFVIII-FS. Dose-proportional increases in plasma concentrations were seen between BAY 94-9027 doses (Fig.3). The Cmax of BAY 94-9027 was not substantially changed after multiple doses. There was a slight increase in concentration following multiple doses of 25 IU kg−1 BAY 94-9027 twice weekly as compared with rFVIII-FS, and there was no further change in concentration following multiple doses of 60 IU kg−1 once weekly. The AUC was greater following infusion of a single dose of BAY 94-9027 than with rFVIII-FS, and the mean half-life of BAY 94-9027 following a single 25-IU kg−1 or 60-IU kg−1 dose was 18.4 h (range, 13.7–28.1 h) vs. 13.0 h (range, 8.4–18.7 h) for rFVIII-FS following a single dose. All subjects with data for the single dose of rFVIII-FS and the last dose of BAY 94-9027 (n = 13) showed an increase in half-life when given BAY 94-9027 as compared with rFVIII-FS (Fig.4). The half-life of BAY 94-9027 was 18.7 h (range, 12.1–30.0 h) when averaged across the two cohorts and across single-dose and multiple-dose data, and was significantly longer than that of rFVIII-FS (P < 0.0001). PK parameters of BAY 94-9027 were similar after single and multiple doses. VWF levels at baseline were similar between groups, but there was a tendency for there to be a longer BAY 94-9027 half-life among subjects with higher VWF levels (Fig.5).

Bottom Line: A 168-h PK study was performed after the first and last BAY 94-9027 doses.BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS).BAY 94-9027 was well tolerated, and no immunogenicity was observed.

View Article: PubMed Central - PubMed

ABSTRACT

Background: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia.

Objectives: To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.

Patients/methods: This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.

Results: BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.

Conclusions: This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Show MeSH
Related in: MedlinePlus