A Generic Version of rFVIIa Is Bioequivalent to the Branded Version of rFVIIa

Introduction: Recombinant activated factor VIIa (rFVIIa) (Novoseven) was first approved by European Medicine Agency for treatment of patients with auto and allo-antibodies against factor VIII and IX. Additionally bleeding disorders hemophilia with inhibitors, acquired hemophiliacs, congenital factor VII deficiency, Glanzmann Thrombasthenia, von Willebrand disease, immune thrombocytopenia and massive bleeding due to trauma and surgery. A generic version of factor VIIa namely Aryoseven is available in south-east Asian countries and used as a pro-hemostatic agent. Aryoseven is produced by utilizing baby hamster kidney cells expressing single chain form which is converted into factor VIIa during the manufacturing process. The molecular characteristics of Aryoseven are comparable to Novoseven. This study is focused on the comparison of several batches of currently available Novoseven and multiple batches of Aryoseven in standardized laboratory methods to demonstrate the equivalence.

Materials and Methods: Four batches of Novoseven were obtain from commercial vendors. Four batches of Aryoseven were made available by UGA (Munich, Germany). These agents were reconstituted in sterile saline to obtain a working concentration of 100 mcg/ml to test their coagulant activity. Normal plasma samples, factor VII deficient plasma samples, plasma samples from various patient groups including liver disease and those on oral anticoagulant drugs were used to measure the effect of FVIIa on their clotting profile. Thrombin generation studies were carried out using the fluorogenic substrate method. The levels of FVIIa in various batches of both generic and branded versions of FVIIa were measured utilizing ELISA methods. The procoagulant actions of both types of FVIIa were also studied using thrombin generation marker measurements including F1.2 and TAT in various plasma systems. All result are compiled and tabulated as group means and applicable statistical method were used to compare the two groups of drugs.

Results: In the normal human pool studies supplementation of Novoseven and Aryoseven produced marginal reduction in the aPTT, both agents produced almost identical effects in the elevated aPTT plasma samples (40-60 seconds) supplementation of both agents showed comparable reduction on the aPTT in a concentration range of 0-10 mcg/ml. Both agents produced similar reduction of aPTT in heparinized plasma at 0-10 mcg/ml. In the PT assays at concentrations < 1 mcg/ml both Novoseven and Aryoseven produced marked correction of elevated PT samples including orally anti coagulated patient samples. Both agents produced slight reduction in PT assay of the normal plasma. These results are compiled in Table 1. In the thrombin generation assays both the Novoseven and Aryoseven produced comparable generation of thrombin in a concentration range 0-10 mcg/ml, no differences were noted between the two agents. Such parameters as the peak thrombin, area under the curve (AUC) and lag time were comparable. The two FVIIa preparations also produced comparable effects in the plasma samples with elevated PT and aPTT. The FVII antigen levels was comparable in both preparations. Thrombin generation markers such as F1.2 and TAT were generated at equivalent level by both agents in normal and pathologic plasma samples.

Conclusion: These studies demonstrate that the two versions of FVIIa are comparable. Furthermore, these results warrant additional validation in animal models and clinical trials.

No relevant conflicts of interest to declare.