ALPROLIX

Eftrenonacog alfa is a long-acting recombinant fusion protein used in the treatment of hemophilia B. It is comprised of a single molecule of human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 via recombinant DNA technology in a human embryonic kidney cell line (HEK293H) 1.

The presence of the

Fc domain extends the terminal half-life which confers clinical benefits of prolonged therapeutic efficacy, less frequent intravenous injections for patient convenience and improved adherence to prophylaxis.

B is a blood disorder with an incidence of approximately once every 30,000 male births in all populations and ethnic groups 2.

It is an

X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), leading to decreased levels of endogenous factor IX and increased susceptibility to recurrent bleeding episodes caused spontaneously or as a result of accidental or surgical trauma Label.

When untreated, most patients die from bleeding complications before 25 years of age 2.

Eftrenonacog alfa acts as a replacement therapy to restore the levels of factor IX and allow normal hemostasis.

Eftrenonacog alfa was developed and marketed as Alprolix for intravenous injection by Biogen.

It was first approved by the FDA in March and later approved by the EMA in May 2016.

Eftrenonacog alfa treatment demonstrated good tolerability with no reports of inhibitor development in clinical studies 1.

Indicated for the treatment and prophylaxis of bleeding in patients of all age with haemophilia B (congenital factor IX deficiency).

In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, eftrenonacog alfa prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens.

The extension of those studies demonstrated effectiveness in the treatment of bleeding episodes and when used in the perioperative setting in all age groups 1.

In animal models, a single intravenous dose of eftrenonacog alfa displayed half values approximately three.

• to four-fold longer than those seen with recombinant FIX 1.

Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean peak plasma concentration (Cmax) was 46.10 IU/dL Label.

The mean area under the

FIX activity time curve (AUC) was 31.58 Uxh/dL per IU/kg Label.

In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean AUC ranged from 22.71-29.50 Uxh/dL per IU/kg Label.

Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean volume of distribution at steady-state (Vss) was 303.4 mL/kg Label.

In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean Vss ranged from 289-365.1 mL/kg Label.

Fc domain of eftrenonacog alfa is expected to undergo lysosomal degradation while the remaining recombinant FIX (rFIX) portion is expected to be metabolized by the same pathway as endogenous factor IX.

Eftrenonacog alfa is expected to undergo renal clearance 2.

Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean terminal half life (t1/2) was 77.6 hours Label.

In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean t1/2 ranged from 66.49-82.22 hours Label.

Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean clearance (CL) was 3.17 mL/h/kg Label.

In pediatric and adolescent patients (< 18 years of age) receiving the same dose, mean CL ranged from 3.390-4.365 mL/h/kg Label.

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Based on findings from a rabbit thrombogenicity test and rat or monkey repeated-dose toxicity studies, eftrenonacog alfa displays no special hazards for humans.

Studies to investigate the genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development have not been conducted.

Eftrenonacog alfa has shown to cross the placenta in small amounts according to a mouse placental transfer study Label.