Rurioctocog alfa pegol

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 haemophilic 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 a X-chromosomal 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 results 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.

Rurioctocog alfa pegol, is a pegylated recombinant human factor VIII with an extended half-life. Rurioctocog alfa pegol is a covalent conjugate of octocog alfa consisting of 2,332 amino acids with polyethylene glycol (PEG) reagent (MW 20 kDa). The therapeutic activity of rurioctocog alfa pegol is derived from octocog alfa, which is produced by recombinant DNA technology from a Chinese hamster ovary cell line. Octocog alfa is then covalently conjugated with the PEG reagent. The PEG moiety is conjugated to octocog alfa to increase the plasma half-life.

The pharmacokinetics (PK) of rurioctocog alfa pegol were evaluated in a crossover study with octocog alfa in 26 subjects (18 adults and 8 adolescents) and in 22 subjects (16 adults and 6 adolescents) after 6 months of treatment with rurioctocog alfa pegol. Plasma factor VIII activity was measured by the one stage clotting assay and chromogenic assay.

Rurioctocog alfa pegol has an extended half-life of 1.4 to 1.5-fold compared to recombinant human coagulation factor VIII (octocog alfa) in the adolescent and adult population, as determined based on one stage clotting and chromogenic assays, respectively. An increase in AUC and a decrease in clearance as compared to the parent molecule, octocog alfa, were also observed. Incremental recovery was comparable with both products. The change in PK parameters was similar in both the adult and adolescent populations and between one-stage clotting and chromogenic substrate assays.

Paediatric pharmacokinetics

Pharmacokinetic parameters calculated from 39 subjects less than 18 years of age (intent-to-treat analysis) are available for 14 children (2 to less than 6 years), 17 older children (6 to less than 12 years) and 8 adolescent subjects (12 to <18 years of age). The half-life extension in the paediatric population was 1.3 to 1.5 fold using both the one stage clotting and chromogenic assays.

The mean clearance (based on body weight) of rurioctocog alfa pegol was higher and the mean half-life was lower in children less than 12 years of age than adults.

A higher dose may be required in children less than 12 years of age.

Pharmacokinetic parameters using the chromogenic assay (Arithmetic mean ± SD):

Abbreviations: C_max: maximum observed activity; AUC: area under the curve; MRT: mean residence time; CL: clearance; V_ss: body weight adjusted volume of distribution at steady-state,
^a Individual PK with 12 post-infusion samples.
^b Population PK model with 3 post-infusion samples based on randomized drawing schedule.
^c NA, Not applicable, as Incremental Recovery and C_max in children were determined by individual PK. Results for Incremental Recovery and C_max determined by individual PK in parenthesis.
^d The clearance value of 12.18 ml/(kg·h) for subject 122001 in age group 12 to < 18 years was not included in the analysis of clearance.

In the repeat dose toxicity study in Cynomologous monkey, two animals showed vacuolation in the kidney in the mid dose group (350IU/kg). The vacuolations did not recover after 2 weeks. The human relevance of kidney vacuolation observed in the preclinical study is unknown.

Nonclinical data are limited to 1 month exposure and no studies in juvenile animals were conducted with rurioctocog alfa pegol. Thus it was not possible to conclude on the potential risks of PEG accumulation in various tissues/organs relevant for chronic use of rurioctocog alfa pegol in the paediatric population. No studies on genotoxicity, carcinogenicity or reproductive toxicity have been performed with rurioctocog alfa pegol.