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| Primary information |
|---|
| ID | 13418 |
| Therapeutic ID | Th1402 |
| Protein Name | Eftrenonacog alfa |
| Sequence | NA
|
| Molecular Weight | 98000 |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | 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 [FDA Label]. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean t1/2 ranged from 66.49 to 82.22 hours [FDA Label]. |
| Description | 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) [A31556]. 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. Hemophilia B is a blood disorder with an incidence of approximately once every 30,000 male births in all populations and ethnic groups [A31557]. 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 [FDA Label]. When untreated, most patients die from bleeding complications before 25 years of age [A31557]. 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 2014 and later approved by the EMA in May 2016. Eftrenonacog alfa treatment demonstrated good tolerability with no reports of inhibitor development in clinical studies [A31556]. |
| Indication/Disease | Indicated for the treatment and prophylaxis of bleeding in patients of all age with haemophilia B (congenital factor IX deficiency). |
| Pharmacodynamics | 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 [A31556]. 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 [A31556]. |
| Mechanism of Action | The coagulation protein factor IX (FIX) is a vitamin K-dependent coagulation factor and one of the critical serine proteases involved in the coagulation cascade. Upon activation by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway, factor IX, in combination with factor VIII, activates factor X. Activated factor X mediates the conversion of prothrombin to thrombin which sequentially leads to thrombin converting fibrinogen into fibrin. A blood clot is then formed [FDA Label]. With a mutation in the gene encoding the coagulation protein factor IX (FIX), patients with hemophilia B have factor IX deficiency and are at high risk for recurrent bleeding episodes. Eftrenonacog alfa is composed of a single molecule of recombinant FIX (rFIX) covalently fused to the dimeric Fc domain of immunoglobulin (Ig) G1 (rFIXFc). It serves as a replacement therapy to increase the plasma levels of factor IX thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies [FDA Label]. The Fc region of human immunoglobulin G1 binds with the neonatal Fc receptor which is expressed throughout life as part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life. The binding of eftrenonacog alfa to the neonatal Fc receptor delays degradation and recycles the fusion protein back into circulation for increased plasma half life and prolonged therapeutic action [FDA Label, A31557]. |
| Toxicity | 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 [FDA Label]. |
| Metabolism | The 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. |
| Absorption | 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 [FDA Label]. The mean area under the FIX activity time curve (AUC) was 31.58 Uxh/dL per IU/kg [FDA Label]. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean AUC ranged from 22.71 to 29.50 Uxh/dL per IU/kg [FDA 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 [FDA Label]. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean Vss ranged from 289 to 365.1 mL/kg [FDA Label]. |
| Clearance | 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 [FDA Label]. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, mean CL ranged from 3.390 to 4.365 mL/h/kg [FDA Label]. |
| Categories | Enzymes and Coenzymes |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | NA |
| Brand Name | Alprolix |
| Company | Bioverativ Therapeutics Inc. |
| Brand Description | Bioverativ Therapeutics Inc. |
| Prescribed For | Intravenous |
| Chemical Name | 4000 [iU]/5mL |
| Formulation | ALPROLIX™ is contraindicated in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients |
| Physical Appearance | headache, numbness and tingling sensation in the mouth, dizziness, changes in the sense of taste, breath odor, fatigue, injection site pain, heart palpitations, difficulty urinating, and low blood pressure (hypotension). |
| Route of Administration | Alprolix is an injectable medicine that is used to help control and prevent bleeding in people with hemophilia B. Hemophilia B is also called congenital Factor IX deficiency. Your healthcare provider may give you Alprolix when you have surgery. |
| Recommended Dosage | Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] is a recombinant DNA derived, coagulation Factor IX concentrate indicated in adults and children with hemophilia B (congenital Factor IX deficiency) to control and prevent bleeding episodes, for perioperative management, and for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Alprolix is not indicated for induction of immune tolerance in patients with hemophilia B. |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |