A Comparison of Efficacy Between Recombinant Activated Factor VII (ARYOSEVEN ^TM) and NOVOSEVEN® in Patients with Hereditary FVIII Deficiency with Inhibitor

Introduction: Concentrated factor VIII replacement therapy in severe hemophilia prevents disabling arthropathy, life-threatening bleeding, improves health related quality of life and increase life expectancy. Patients with neutralizing antibodies (inhibitors) did not respond to usual doses of FVIII and they need higher doses of FVIII or bypassing agents (eg. rFVIIa, FEIBA) to control bleeding. The aim of this study was to compare the efficacy of a new biosimilar recombinant factor VIIa (Aryoseven ™) with Novoseven® in controlling bleeding episodes in hemophilia A patients with inhibitors.

Methods: A randomized double blind clinical trial study was conducted in eight comprehensive hemophilia care centers in Iran. We randomized 66 male patients in two groups, with 4 consecutive block randomization when bleeding occurred. All patients entered the study with only one bleed. Informed consent signed by all patients or their parents. Group A (31 patients, 47%) received Aryoseven ™ and group B (35 patients, 53%) received Novoseven®. rFVIIa dosage was 90 -120 μg/kg intravenously every 2 hours.

Results: During the study 66 patients (All male) were enrolled in two arms. The mean age was 20.5±10.9 years. Comparison of baseline data between the two showed no significant difference. The distributions of these variables were similar between the two groups. Other factors, such as vital signs, coagulation tests, liver, renal function tests, and blood count were not significantly different between the two groups. Median plasma level of FVII clotting activity (FVII: C) in group A and B was 103.8±38.4 IU/ dl and 98.6±26.7 IU/dl before injection respectively. Median plasma level of FVIII inhibitor in group A and B was 15.0 BU (IQR: 8.8-58.0) and 19.0 BU (IQR: 11.0-31.0). The average time from onset of bleeding to start treatment were 1246± 1104 and 2301 ± 1693 minutes (p = 0.311) in group A and B respectively.

This study results showed that increased levels of factor VII were comparable between two groups after rFVIIa injection. A comparison of the Kavakli global response scores after injection and the treatment success rate in terms of achieving to score 6 or higher showed that both groups were comparable in treatment success rates. The global treatment response rate was 96.8% in group A and 91.4% in group B. Administration of either Aryoseven™ or Novoseven® had comparable effect on controlling pain and joint mobility. Reported side effects were minor (headache, nausea, and rash) and occurred in similar frequency.

Discussion: The present study showed increased FVII levels and clinical efficacy in the control of the bleeding episodes in Hemophilia A patients with inhibitor for both drugs. Some similarities exist between our findings and the previous clinical trials designed for Novoseven®. In other studies, the treatment success rate by using the global response scoring system has been 70% -86% by different rFVIIa dosage regimen, in our study was above 90% in both treatment groups. In most studies, it was reported more than 90% achieving to cessation of bleeding at 9 hours after first injection of rFVIIa as response time which was also similar to our study.

Conclusion: This study showed non-inferiority of Aryoseven ™ compared to Novoseven® in cessation of bleeding episodes in hemophilia A patients with inhibitor. There was no evidence of significant difference between the efficacy and safety of two drugs. There were no clinically meaningful differences between the biosimilar product and the original product in terms of the safety, purity, and efficacy. Biosimilar rFVIIa is effective in treatment of acute joint bleeding in patients with inhibitor in comparison to Novoseven®.