Recombinant Factor VIIa (Eptacog Alfa)

Recombinant factor VIIa (NovoSeven®; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries.

Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 µg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

Recombinant factor VIIa is a recombinant protein, similar in structure to coagulation factor VIIa derived from human plasma, but manufactured without using material of human origin. It has effects on both tissue factor-dependent and -independent coagulation. In particular, at pharmacologic concentrations, its main effect is to enhance thrombin generation on the surface of activated platelets, even in the absence of factors VIII and IX, which are deficient in patients with congenital hemophilia A and B, respectively. The thrombin induced by recombinant factor VIIa enhances platelet activation, fibrin formation, and inhibition of fibrinolysis. The effects of recombinant factor VIIa are localized to the site of vascular injury and it does not appear to enhance systemic activation of coagulation. Thrombotic events have been reported rarely. Antibodies to recombinant factor VIIa generally do not develop in patients with hemophilia, although there have been a few reports in patients with factor VII deficiency.

Following a single intravenous dose of recombinant factor VIIa in patients with hemophilia, the area under the plasma concentration-time curve generally increased in a dose-dependent fashion. Volume of distribution at steady state, clearance, elimination half-life, and mean residence time were generally independent of dose in patients with hemophilia. Values for clearance were higher in pediatrie patients than in adults with hemophilia, and were also higher in patients with factor VII deficiency than in adults with hemophilia.

In addition to a number of small controlled trials, therapeutic efficacy data for recombinant factor VIIa come from noncomparative studies, and compassionate- or emergency-use programs. The most widely used dosage in these studies was 90 µ-g/kg every 2–4 hours in patients with congenital hemophilia with inhibitors, acquired hemophilia or Glanzmann thrombasthenia, and 15–30 µ-g/kg in patients with congenital factor VII deficiency. Hemostatic efficacy was generally evaluated using a global assessment by the patient or the physician.

Recombinant factor VIIa was effective at controlling mild to moderate bleeding episodes in patients with congenital hemophilia with inhibitors during home treatment in noncomparative studies, with efficacy rates of up to 93% after ≈2 doses. Early treatment was more likely to be associated with a successful outcome than late treatment.

In double-blind or open-label comparative trials in hemophilia patients with inhibitors experiencing hemarth-roses, the effectiveness of a single dose of recombinant factor VIIa 270 µg/kg was similar to that of a standard regimen of 90 µg/kg every 3 hours. A single 270 µg/kg dose achieved successful hemostasis in >90% of patients with mild to moderate bleeding episodes after 9 hours without the need for additional hemostatic medication.

Two open-label, crossover studies compared recombinant factor VIIa with aPCC in hemophilia patients with inhibitors. One study failed to demonstrate equivalency between the two treatments, possibly due to inadequate patient/bleed numbers. In the other study, patient-assessed treatment response did not differ significantly between recombinant factor VIIa (single dose of 270 µg/kg or standard regimen of three doses of 90 µg/kg at 3-hour intervals) and aPCC 75 U/kg; however, fewer patients required ‘rescue’ therapy with additional hemostatic agents after a single 270 µ-g/kg dose of recombinant factor VIIa than after aPCC.

Based on data largely from the compassionate-use program, recombinant factor VIIa was effective in the treatment of major nonsurgical bleeds (e.g. life- or limb-threatening bleeds), and at producing and maintaining hemostasis during surgery, in patients with hemophilia with inhibitors. In a double-blind controlled trial in hemophilia patients with inhibitors undergoing surgical procedures, satisfactory hemostasis was achieved in 13 out of 14 patients (93%) treated with a standard regimen of recombinant factor VIIa.

Data from a limited number of patients with acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia (mostly from the compassionate-use programs or patient registries) indicated that recombinant factor VIIa was also effective at treating surgical and nonsurgical bleeding in these patient groups. Efficacy rates were generally consistent with those seen in patients with congenital hemophilia.

Recombinant factor VIIa is generally well tolerated and adverse events do not appear to be dose-related. Non-serious adverse events include nausea, fever, injection-site pain, skin rash and increased values for ALT, alkaline phosphatase and lactate dehydrogenase. The overall incidence of serious adverse events with recombinant factor VIIa is <1%. Serious events have included thrombotic events (e.g. myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation); however, they have generally occurred in patients with predisposing risk factors or in patients without hemophilia being treated for non-approved conditions. Recombinant factor VIIa has no risk for transmission of human pathogens, is not immunogenic, and does not induce an anamnestic response in patients with inhibitors.

On-demand treatment with recombinant factor VIIa was associated with improvements in health-related quality of life relative to plasma-derived agents in a cost-utility study in hemophilia patients with inhibitors. Modelled cost analyses in this patient population found that on-demand treatment of mild to moderate bleeds with recombinant factor VIIa was cost neutral or cost saving relative to aPCC. Modelled cost analyses also showed that orthopedic surgery using recombinant factor VIIa to maintain hemostasis was generally cost saving over the medium to long term relative to not having surgery. Modelled analyses were performed from the healthcare payer perspective.