Octocog alfa Other names: Human plasma coagulation factor VIII concentrate

Octocog alfa (Full length recombinant human coagulation factor VIII (rDNA)) is a purified protein that has 2,332 amino acids. It is produced by recombinant DNA technology in baby hamster kidney cells (BHK) into which the human factor VIII gene has been introduced.

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 a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse 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, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

Pharmacodynamic effects

The activated partial thromboplastin time (aPTT) is prolonged in people with haemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with rFVIII normalizes the aPTT similar to that achieved with plasma-derived factor VIII.

The Pharmacokinetic (PK) profile of factor VIII was evaluated in PTPs with severe haemophilia A following 50 IU/kg in 21 subjects ≥18 years, 5 subjects ≥12 years and <18 years and 19 subjects <12 years of age.

A population PK model was developed based on all available factor VIII measurements (from dense PK sampling and all recovery samples) throughout the 3 clinical studies allowing calculation of PK parameters for subjects in the various studies. The table 4 below provides PK parameters based on the population PK model.

Table 4. PK parameters (geometric mean (%CV)) based on chromogenic assay*:

* Based on population PK estimates
** AUC calculated for a dose of 50 IU/kg

Repeated PK measurements after 6 to 12 months of prophylaxis treatment with factor VIII did not indicate any relevant changes in PK characteristics after long-term treatment.

In an international study involving 41 clinical laboratories, the performance of factor VIII in FVIII:C assays was evaluated and compared to a marketed full length rFVIII product. Consistent results were determined for both products. The FVIII:C can be measured in plasma with a one-stage coagulation assay as well as with a chromogenic assay using the routine methods of the laboratory.

The analysis of all recorded incremental recoveries in previously treated patients demonstrated a median rise of >2% (>2 IU/dL) per IU/kg body weight for factor VIII. This result is similar to the reported values for factor VIII derived from human plasma. There was no relevant change over the 6-12 months treatment period.

Table 5. Phase III incremental recovery results:

Non-clinical data reveal no special risk for humans based on safety pharmacology, in vitro genotoxicity, and short term repeat-dose toxicity studies. Repeat-dose toxicity studies longer than 5 days, reproductive toxicity studies, and carcinogenicity studies, have not been performed. Such studies are not considered meaningful due to the production of antibodies against the heterologous human protein in animals. Also factor VIII is an intrinsic protein and not known to cause any reproductive or carcinogenic effects.