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

Abstract

BackgroundBAY 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.ObjectivesTo assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.Patients/MethodsThis 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.ResultsBAY 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.ConclusionsThis 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.

Defining extended half‐life rFVIII—A critical review of the evidence

“…Following a single 50 IU/kg dose, the lower bound of the 90% CI for the AUC ratio of BAY 94‐9027 compared with Kogenate FS falls just outside the bioequivalence window, as shown in Figure . At a lower dose of 25 IU/kg, the lower bound of the 90% CI fell within the bioequivalence window; however, this dose is not comparable with doses used in the other studies in our review and is less representative of doses used in clinical practice . For BAY 81‐8937, the results from the LEOPOLD I study show that the 90% CIs for the AUC ratio compared with Kogenate FS in LEOPOLD I are almost completely within the bioequivalence window .…”

“…Established methods that have been applied to extend the half‐life of rFVIII include PEGylation—the chemical addition of a polyethylene glycol (PEG) to rFVIII—and Fc fusion—the covalent binding of rFVIII to the Fc domain of IgG 1 . A novel approach to improve rFVIII PK characteristics is the formation of a “single‐chain” by covalent binding of rFVIII heavy and light chains …”

“…In the case of rFVIII, 3 products (BAX 855, BAY 94‐9027 and N8‐GP) employ PEGylation, albeit with different size PEG molecules (Table ), to extend half‐life by disrupting interactions with the low‐density lipoprotein receptor‐related protein (LRP) 1. This protein is responsible for the physiological clearance of FVIII; interfering with this interaction may lead to reduced hepatic clearance of rFVIII …”

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

“…Notably, the mean half-life of ACE910 ranged between 28.3 and 34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours 1 ; rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [TG-based half-life] 13 ) and drugs recently approved or under development (#19 hours). 5,[21][22][23][24] Concizumab is a humanized anti-tissue factor pathway inhibitor antibody and is also subcutaneously available in humans. However, because of the target-mediated drug disposition of concizumab, its half-life is shorter than ACE910.…”

SHP656, a polysialylated recombinant factor VIII (PSA‐rFVIII): First‐in‐human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A

“…4 Traditional FVIII products typically require infusions three times weekly or every other day 5 ; newer preparations with extended halflives may permit less frequent infusion and therefore benefit patients and caregivers. [8][9][10][11] These approaches have resulted in approximately 1.4 to 1.5-fold extensions in half-life, 12 making twiceweekly prophylactic dosing a realistic option for many patients, as seen with ADYNOVATE® (rurioctocog alfa pegol; ADYNOVI™, Baxalta US Inc, a Takeda company) 10 and ELOCTATE ® (Fc-rFVIII; Antihemophilic [8][9][10][11] These approaches have resulted in approximately 1.4 to 1.5-fold extensions in half-life, 12 making twiceweekly prophylactic dosing a realistic option for many patients, as seen with ADYNOVATE® (rurioctocog alfa pegol; ADYNOVI™, Baxalta US Inc, a Takeda company) 10 and ELOCTATE ® (Fc-rFVIII; Antihemophilic…”