A randomized, double‐blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulation

Abstract

Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven) and a new rFVIIa formulation (VII25) stable at up to 25 degrees C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 microg kg(-1), in a randomized order 2-3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89-0.96), within the predefined bioequivalence range (0.80-1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25 degrees C. VII25's 'user-friendly' formulation removes the inconvenience of storing/transporting at 2-8 degrees C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained.

Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa

“…Factor VII activity over time was nearly identical with the 2 formulations (Figure 2A),48 and the 90% confidence intervals for difference in the primary end point of area under the curve was 0.93, well within the 0.8 to 1.25 definition of bioequivalence. Coagulation parameters, including levels of prothrombin fragment F 1+2 (Figure 2B)48 and D dimer (Figure 2C),48 activated partial thromboplastin time at 30 minutes postdose, and prothrombin time at 5 hours and 24 hours postdose, were also similar with the 2 formulations. Mean pharmacokinetic profiles were similar for the 2 formulations and are summarized in Table 2 48.…”

“…Pharmacokinetic and pharmacodynamic equivalence of rFVIIa-RT with original rFVIIa was demonstrated in a randomized, double-blind, 2-way crossover study in healthy volunteers 48. Factor VII activity over time was nearly identical with the 2 formulations (Figure 2A),48 and the 90% confidence intervals for difference in the primary end point of area under the curve was 0.93, well within the 0.8 to 1.25 definition of bioequivalence.…”

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

“…This linear PK profile enables accurate prediction of plasma ACE910 concentration according to dose. Notably, the mean half-life of ACE910 ranged between 28.3 and 34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours 1 ; rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [TG-based half-life] 13 ) and drugs recently approved or under development (#19 hours). 5,[21][22][23][24] Concizumab is a humanized anti-tissue factor pathway inhibitor antibody and is also subcutaneously available in humans.…”

“…1 Patients who develop FVIII inhibitors are treated with bypassing agents, including recombinant activated factor VII (rFVIIa) 7 or activated prothrombin complex concentrate (aPCC). 8 Frequent intravenous administration of these agents is required because of their unstable hemostatic efficacy caused by short half-lives (rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [thrombin generation (TG)-based half-life] 13 ). New treatments with more convenient administration routes, lower administration frequency, and less immunogenicity against coagulation factors are needed.…”

Recombinant Activated Factor VII: Mechanisms of Action and Current Indications

“…Pharmacokinetic bioequivalence between the currently available formulation and this new room-temperature-stable rFVIIa has been demonstrated. 37 No serious adverse events were reported. The portability of room-temperature-stable rFVIIa increases convenience and allows immediate access to treatment without the need to return home or go to the hospital, 38 which may help to avoid the adverse consequences of delayed infusion.…”