Pharmacokinetic and Dynamic of Subcutaneously Administered FVIII by Novel vWF Fragments in a Hemophilia A Mouse Model

Conventional treatment of hemophilia A (HA) encompasses repetitive intravenous (IV) injections of coagulation factor VIII (FVIII). Subcutaneous (SC) route of administration results in very low FVIII bioavailability, caused by adhesive properties of FVIII leading to enhanced proteolysis and clearance. To overcome this problem, and chaperone FVIII into the circulation after SC administration, two von Willebrand Factor (vWF) fragments were tested. Here, we present the molecular design and preclinical properties of two candidate molecules, OCTA12 and OCTA13. Both are dimerized fragments, OCTA12 containing the D’D3 domain only, OCTA13 consisting of a D’D3- A1-A2-A3 fragment. Biacore studies demonstrated binding of both fragments to recombinant FVIII (rFVIII, simoctocog alfa, Nuwiq, Octapharma) and blocking FVIII binding to phospholipids. Pharmacokinetics (PK) were evaluated in F8−/− mice after a single dose, IV or SC, of rFVIII alone or in complex with OCTA12 or OCTA13 in a 1:6.2 molar ratio. rFVIII alone was not absorbed after SC administration. Addition of OCTA12 or OCTA13 resulted in detectable FVIII activity in plasma, reaching a maximum at 6 hours (h) after injection, followed by a slow decline in FVIII activity over 48 h. OCTA12 appeared more efficient than OCTA13 leading to FVIII bioavailability of 18.5 and 7.2%, respectively. Both fragments did not significantly change PK of rFVIII after a single IV dose. Efficacy profile of FVIII and OCTA12 SC was determined in F8−/− mouse demonstrating comparable hemostatic efficacy of FVIII:OCTA12 SC 9 h post-injection to IV administered FVIII 2 h after treatment. In conclusion, recombinant vWF supported FVIII delivery through the SC space into the vascular circulation increasing bioavailability of rFVIII up to 18% in HA mouse model. Efficacy study showed nearly normalized hemostasis especially at 9 h post-injection and prolonged FVIII efficacy. OCTA12 (now termed SUBQ-8) is a promising candidate for future clinical studies aiming to establish that SC FVIII may be an efficacious and less burdensome prophylactic treatment for HA.