Efanesoctocog alfa

Efanesoctocog alfa is replacement factor VIII therapy. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of functional factor VIII:C and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

Efanesoctocog alfa or recombinant coagulation Factor VIII Fc-Von Willebrand Factor-XTEN is a recombinant fusion protein that temporarily replaces the missing coagulation Factor VIII needed for effective haemostasis.

Efanesoctocog alfa is a FVIII protein that is designed not to bind endogenous VWF in order to overcome the half-life limit imposed by FVIII-VWF interactions. The D’D3 domain of VWF is the region that interacts with FVIII. Appending the D’D3 domain of VWF to a rFVIII-Fc fusion protein provides protection and stability to FVIII and prevents FVIII interaction with endogenous VWF, thus overcoming the limitation on FVIII half-life imposed by VWF clearance.

The Fc region of human immunoglobulin G1 (IgG1) binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by recycling them back into circulation and thus prolonging the plasma half-life of the fusion protein. Efanesoctocog alfa contains 2 XTEN polypeptides, which further increase its pharmacokinetics (PK). The natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN polypeptide, inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN is inserted in between the D’D3 domain and Fc.

The pharmacokinetics (PK) of efanesoctocog alfa were evaluated in the Phase 3 studies XTEND-1 and XTEND-Kids, enrolling 159 adults and adolescents, and 74 children <12 years old, respectively, receiving weekly intravenous injections of 50 IU/kg. Among children <12 years old, 37 subjects had efanesoctocog alfa single dose PK profiles available.

Efanesoctocog alfa has demonstrated a half-life that is about 4-fold longer compared to standard half-life factor VIII products and about 2.5- to 3-fold longer compared to extended half-life factor VIII products. PK parameters following a single dose of efanesoctocog alfa are presented in Table 1. The PK parameters were based on plasma factor VIII activity measured by the aPTT-based one-stage clotting assay. After a single dose of 50 IU/kg, efanesoctocog alfa exhibited high sustained factor VIII activity with prolonged half-life across age cohorts. There was a trend of increasing AUC, and decreasing clearance, with increasing age in the paediatric cohorts. The PK profile at steady state (week 26) was comparable with the PK profile obtained after the first dose.

Table 1. Pharmacokinetic parameters following a single dose of efanesoctocog alfa by age (one-stage clotting assay using Actin-FSL):

^a Calculation based on 128 profiles.
^b N=17
AUC_0-tau = area under the activity-time curve over the dosing interval, CL = clearance, MRT = mean residence time, SD = standard deviation, t_½z = terminal half-life, Vss = volume of distribution at steady state, C_max = maximum activity

In XTEND-1, efanesoctocog alfa at steady state maintained normal to near normal (>40 IU/dL) factor VIII activity for a mean (SD) of 4.1 (0.7) days with once weekly prophylaxis in adults. The factor VIII activity over 10 IU/dL was maintained in 83.5% of adults and adolescent subjects throughout the study. In children <12 years, weekly efanesoctocog alfa at steady state maintained normal to near normal (>40 IU/dL) factor VIII activity for 2 to 3 days and >10 IU/dL factor VIII activity for approximately 7 days (see Table 2).

Table 2. Pharmacokinetic parameters at steady state of efanesoctocog alfa by age (one-stage clotting assay using Actin-FSL):

^a Steady state peak, trough and incremental recovery were computed using available measurements at week 52/end of study PK sampling visit.
^b Time to factor VIII activity was predicted using a population PK model for paediatric patients.
^c Time to factor VIII activity was predicted using a population PK model for adult patients.
Peak = 15 min post dose at steady state, Trough = predose factor VIII activity value at steady state, SD = standard deviation

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies in rats and monkeys (including measurements of safety pharmacology) and an in vitro haemocompatibility study. Studies to investigate genotoxicity, carcinogenicity toxicity to reproduction or embryo-foetal development have not been conducted.