Preclinical pharmacokinetics and biodistribution of subcutaneously administered glycoPEGylated recombinant factor VIII (N8‐GP) and development of a human pharmacokinetic prediction model

Essentials

• N8‐GP is an extended half‐life recombinant factor VIII (FVIII) for the treatment of hemophilia A.
• Subcutaneous (SC) FVIII dosing might reduce the treatment burden of prophylaxis.
• SC N8‐GP has a favorable PK profile in animal models and disappears from skin injection sites.
• Combined animal (SC) and clinical (IV) data suggest that daily SC dosing may provide prophylaxis.

Summary

Background

N8‐GP is an extended half‐life recombinant factor VIII (FVIII) for the treatment of hemophilia A. Subcutaneous administration of FVIII may reduce the treatment burden of prophylaxis; however, standard FVIII products have low bioavailability after subcutaneous dosing in animals.

Objective

To evaluate the pharmacokinetics, effectiveness and local distribution of subcutaneously administered N8‐GP in preclinical models and predict the human pharmacokinetic (PK) profile.

Methods

The pharmacokinetics of subcutaneously administered N8‐GP were evaluated in FVIII knockout (F8‐KO) mice and cynomolgus monkeys; a human PK prediction model in hemophilia A patients was developed. The hemostatic effect was evaluated in a tail vein bleeding model in F8‐KO mice. The injection‐site distribution and absorption of subcutaneously administered N8‐GP were assessed in F8‐KO mice by the use of temporal fluorescence imaging and immunohistochemistry.

Results

Subcutaneously administered N8‐GP had a bioavailability, a first‐order absorption rate and a half‐life, respectively, of 24%, 0.094 h^?1 and 14 h in F8‐KO mice, and 26%, 0.33 h^?1 and 15 h in cynomolgus monkeys. A dose‐dependent effect of subcutaneously administered N8‐GP on blood loss was observed in mice. A minimal amount of N8‐GP was detected at the injection site 48–72 h after single or multiple dose(s) in F8‐KO mice. Subcutaneously administered N8‐GP was localized to the skin around the injection site, with time‐dependent disappearance from the depot. PK modeling predicted that subcutaneously administered N8‐GP at a daily dose of 12.5 IU kg^?1 will provide FVIII trough levels of 2.5–10% in 95% of patients with severe hemophilia A.

Conclusions

Subcutaneously administered N8‐GP may provide effective hemophilia A prophylaxis. A phase I clinical trial is underway to investigate this possibility.