Prolonged half-life of glycoPEGylated rFVIIa variants compared to native rFVIIa

Abstract Introduction Bleeding episodes in haemophilia patients with inhibitors are primarily treated with by-passing agents such as recombinant activated FVII (rFVIIa). Prophylactic treatment with rFVIIa has been shown to significantly reduce the number of bleeding episodes as compared to conventional on-demand haemostatic therapy, and a reduced dosing frequency could present an improved treatment option in inhibitor patients. Materials and methods A series of glycoPEGylated rFVIIa derivatives (5-40 K PEG) has been produced and their effect and pharmocokinetics have been investigated in several animal species. Results The glycoPEGylated rFVIIa derivatives exhibit significant prolongation of half-life in mice, dogs and pigs as measured by rFVIIa clot activity. The clearance of rFVIIa, rFVIIa-5 K PEG, rFVIIa-10 K PEG, rFVIIa-20 K PEG and rFVIIa-40 K PEG in minipigs were estimated to 59, 27, 22, 8.7 and 3.1 ml/h/kg, respectively. Across species a reduction in clearance as a function of the size of the attached PEG was observed. By allometric scaling, the compiled pharmacokinetics predicts a human half-life for rFVIIa-10 K PEG and rFVIIa-40 K PEG of approximately 7 and 12 h, respectively. The rFVIIa-10 K PEG and rFVIIa-40 K PEG are efficacious in stopping a bleed in the haemophilia A mouse tail-bleeding model after intravenous administration. Conclusions GlycoPEGylation of rFVIIa significantly increases the rFVIIa exposure in three animal models, glycoPEGylated rFVIIa compounds are effective in vivo and thus, represents a potential prophylactic treatment option for patients with inhibitors.