Eftrenonacog alfa API Manufacturers

General Description:

Eftrenonacog alfa, identified by CAS number 1270012-74-2, is a notable compound with significant therapeutic applications. 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) . 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 . 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 . When untreated, most patients die from bleeding complications before 25 years of age . 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 .

Indications:

This drug is primarily indicated for: Indicated for the treatment and prophylaxis of bleeding in patients of all age with haemophilia B (congenital factor IX deficiency). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Eftrenonacog alfa undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Eftrenonacog alfa are crucial for its therapeutic efficacy: 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 . The mean area under the FIX activity time curve (AUC) was 31.58 Uxh/dL per IU/kg . 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Eftrenonacog alfa is an important consideration for its dosing schedule: 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 . 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 . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Eftrenonacog alfa from the body primarily occurs through: Eftrenonacog alfa is expected to undergo renal clearance . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Eftrenonacog alfa is distributed throughout the body with a volume of distribution of: 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 . In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean Vss ranged from 289 to 365.1 mL/kg . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Eftrenonacog alfa is a critical factor in determining its safe and effective dosage: 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 . 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Eftrenonacog alfa exerts its therapeutic effects through: 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 . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Eftrenonacog alfa functions by: 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 . 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 . 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Eftrenonacog alfa belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Eftrenonacog alfa is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Biological Factors, Blood Coagulation Factors, Blood Proteins, Enzyme Precursors, Enzymes and Coenzymes, Globulins, Hemostatics, Immunoglobulin Constant Regions, Immunoglobulin Fragments, Immunoglobulins, Immunoproteins, Peptide Fragments, Peptides, Protein Precursors, Proteins, Recombinant Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Eftrenonacog alfa include:

• Molecular Weight: 98000.0