Lonoctocog alfa

Lonoctocog alfa is a recombinant human protein that replaces the missing coagulation factor VIII needed for effective hemostasis. Lonoctocog alfa is a single polypeptide chain with a truncated B-domain that allows for a covalent bridge to link the factor VIII heavy and light chains. Lonoctocog alfa has demonstrated a higher VWF affinity relative to full-length rFVIII. VWF stabilizes factor VIII and protects it from degradation. Activated lonoctocog alfa has an amino acid sequence identical to endogenous FVIIIa.

Pharmacodynamic effects

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation. 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 factor VIII and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as 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.

Adult population

The pharmacokinetics (PK) of lonoctocog alfa was evaluated in 81 previously treated adult subjects who had been diagnosed with severe haemophilia A with <1% factor VIII and with age from 18-60 years old, following an intravenous injection of 50 IU/kg. The PK parameters were based on plasma factor VIII activity measured by the chromogenic substrate assay. The PK profile obtained 3 to 6 months after the initial PK assessment was comparable with the PK profile obtained after the first dose.

Pharmacokinetic Parameters following a Single Injection of 50 IU/kg of lonoctocog alfa – Chromogenic Substrate Assay:

IR = incremental recovery recorded at 30 minutes after injection; C_max = maximum concentration, AUC_0-inf = area under the factor VIII activity time curve extrapolated to infinity; t_1/2 = half-life; MRT = mean residence time; CL = body weight adjusted clearance with N=80; V_ss = body weight adjusted volume of distribution at steady-state. IR and C_max were baseline corrected while the remaining parameters were not baseline corrected with N=81.

Paediatric population

The pharmacokinetics (PK) of lonoctocog alfa were evaluated in 10 previously treated adolescents (12 to <18 years of age) and 39 previously treated children (0 to <12 years of age) following an intravenous injection of a single dose of 50 IU/kg. All patients had been diagnosed with severe haemophilia A with <1% factor VIII.

The PK parameters were based on plasma factor VIII activity measured by the chromogenic substrate assay.

Comparison of Pharmacokinetic Parameters by Age Category following a Single Injection of 50 IU/kg of lonoctocog alfa – Chromogenic Assay:

IR = incremental recovery recorded at 30 minutes after injection for subjects 12 to <18 years and at 60 minutes after injection for subjects 1 to <12 years; C_max = maximum concentration, AUC = area under the factor VIII activity time curve extrapolated to infinity; t_1/2 = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state. IR and C_max were baseline corrected while the remaining parameters were not baseline corrected.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity studies, local tolerability and thrombogenicity assessments.