Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers

Abstract

Summary Background Development of neutralizing antibodies remains the most problematic complication in treating congenital hemophilia. Control and prevention of bleeding events in such patients with recombinant factor VIIa (rFVIIa) is limited by the short half‐life of the available product. Here, we report on the pharmacokinetics and safety of a novel, recombinant fusion protein linking coagulation FVIIa with albumin (rVIIa‐FP) in a first‐in‐human study in healthy male subjects. Methods Forty healthy male subjects between 18 and 35 years of age were included and dosed in five consecutive cohorts. In each cohort, six subjects were randomized to a single dose of rVIIa‐FP (140, 300, 500, 750, or 1000 μg kg−1) and two to placebo. All subjects received anticoagulation with an oral vitamin K antagonist to reach an international normalized ratio between 2 and 3 prior to dosing with rVIIa‐FP/placebo. Dosing with oral vitamin K antagonist was continued at a fixed dose for 6 days after injection of rFVIIa. Results and Conclusions Tolerance of rVIIa‐FP was good at all dose levels. No serious adverse events were observed. None of the subjects developed anti‐drug antibodies. The maximum baseline‐corrected mean (SD) FVIIa plasma activity increased in a dose‐proportional manner. Across the dose range, the median half‐life was consistent, ranging from 6.1 to 9.7 h. At the highest dose of 1000 μg kg−1, the median FVIIa activity‐based half‐life was 8.5 h. Clearance ranged from 7.62 to 12.74 mL h−1 kg−1. Compared with the commercially available rFVIIa product, rVIIa‐FP had a reduced clearance resulting in an approximately 3‐ to 4‐fold increase in half‐life.

Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa‐FP)

“…Furthermore, rVIIa‐FP had a reduced mean CL (i.e. 7.62 mL h −1 kg −1 at 1000 μg kg −1 ), resulting in an approximately 3‐ to 4‐fold increase in t ½ compared with rFVIIa . In two clinical studies conducted in healthy human volunteers, rFVIIa (5–320 μg kg −1 ) had a mean t ½ (determined measuring FVII clotting activity) between 2.43 and 2.45 h and CL rates ranging between 31 and 35 mL h −1 kg −1 .…”

The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery

“…Another example is recombinant FVIIa (NovoSeven ® ) with a half-life of only 2.4 hours in humans [253]. After fusion to the Nterminal end of human albumin, separated with a flexible glycine serine linker, the half-life increases up to 4-fold , and the fusion is now in clinical trials for treatment of haemophilia [251][252][253][254][255]. This strategy has also been chosen for coagulation factor IX [248][249][250].…”

“…Examples include hirudin [256], CD4 [258], insulin [260], growth hormone [259], granulocyte colony stimulating factor [244],  and  interferons [245][246][247], thioredoxin [266,267], coagulation factors [248][249][250][251][252][253][254][255] and antibody fragments [204,[261][262][263]268]. An illustrating example is recombinant interferon 2b used for treatment of chronic hepatitis C with only a half-life of 4 hours in humans, however, upon genetic fusion to human albumin the half-life increases by 35-fold to 141 hours [246].…”

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

“…A new FVIII agent for replacement therapy, recombinant B‐domain deleted porcine FVIII (OBI‐1), demonstrated efficacy and safety for the treatment of bleeding episodes in patients with acquired haemophilia A in phase II/III studies and in patients with congenital haemophilia A in a phase II study . A recombinant fusion protein linking rFVIIa with albumin (rVIIa‐FP), a new bypassing agent in clinical development with extended half‐life, showed good tolerability in 40 healthy males in a phase I study …”