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General Description:

Efmoroctocog alfa, identified by CAS number 1270012-79-7, is a notable compound with significant therapeutic applications. Efmoroctocog alfa is a fully recombinant factor VIII-Fc fusion protein (rFVIIIFc) with an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products such as . It is an antihemorrhagic agent used in replacement therapy for patients with haemophilia A (congenital factor VIII deficiency). It is suitable for all age groups. Haemophilia A is a rare bleeding disorder associated with a slow clotting process caused by the deficiency of factor VIII. Patients with this disorder are more susceptible to recurrent bleeding episodes and excessive bleeding following minor traumatic injuries or surgical procedures . Prophylactic treatment may dramatically improve the management of severe haemophilia A in the future by reducing joint bleeding and other hemorrhages that cause chronic pain and disability to patients . Prophylaxis has also shown to reduce the formation of neutralizing anti-FVIII antibodies, or inhibitors . Factor VIII is a blood coagulant factor involved in the intrinsic pathway to form fibrin, or a blood clot. Efmoroctocog alfa is a first commercially available rFVIII-Fc fusion protein (rFVIIIFc) where the conjugated molecule of rFVIII to polyethylene glycol is covalently fused to the dimeric Fc domain of human immunoglobulin G1, a long-lived plasma protein . The B domain of factor VIII is deleted. In animal models of haemophilia, efmoroctocog alfa demonstrated an approximately two-fold longer t½ than commercially available rFVIII products . Other drug products with similar structure and function to Efmoroctocog alfa include , which is produced by recombinant DNA technology and is identical in sequence to endogenously produced Factor VIII, but does not contain the B-domain, which has no known biological function, and , which is purified endogenous Factor VIII from human pooled blood and contains both A- and B-subunits. It is commonly marketed as Elocta or Eloctate for intravenous injection. To date, no confirmed inhibitory autoantibodies were seen in previously treated patients included in clinical studies and treatment-emergent adverse events were generally consistent with those expected in the patient populations being studied . The extended half-life of efmoroctocog alfa provides several clinical benefits for patients, including reduced frequency of injections required and improved adherence to prophylaxis .

Indications:

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

Metabolism:

Efmoroctocog alfa undergoes metabolic processing primarily in: There are no detectable metabolites for efmoroctocog alfa. It is presumed to be metabolized via a same degradation pathway as endogenous factor VIII. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Efmoroctocog alfa are crucial for its therapeutic efficacy: Following a single intravenous dose of 50 IU/kg in previously-treated adult patients with severe haemophilia A, mean peak plasma concentrations (Cmax) ranged from 108 to 131 IU/dL. Mean area under the FVIII activity time curve (AUC/Dose) ranged from 47.5 to 51.2 IUxh/dL per IU/kg. Mean AUC/Dose in adolescent patients 12 to 18 years of age ranged from 38.2 to 40.8 IUxh/dL per IU/kg. Mean AUC/Dose in pediatric patients < 12 years of age ranged from 25.9 to 38.4 IUxh/dL per IU/kg . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Efmoroctocog alfa is an important consideration for its dosing schedule: Following a single intravenous dose of 50 IU/kg in previously-treated adult patients with severe haemophilia A, mean half life (t1/2) ranged from 19 to 20.9 h. Mean t1/2 in adolescent patients 12 to 18 years of age ranged from 16 to 17.5 h. Mean t1/2 in pediatric patients < 12 years of age ranged from 12.3 to 15.9 h . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Efmoroctocog alfa exhibits a strong affinity for binding with plasma proteins: Like endogenous factor VIII, efmoroctocog alfa binds to von Willebrand factor in the circulation. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Volume of Distribution:

Efmoroctocog alfa is distributed throughout the body with a volume of distribution of: Following a single intravenous dose of 50 IU/kg in previously-treated adult patients with severe haemophilia A, mean volume of distribution at steady state (Vss) ranged from 49.1 to 52.6 mL/kg. Mean Vss in adolescent patients 12 to 18 years of age ranged from 57.6 to 59.4mL/kg. Mean Vss in pediatric patients < 12 years of age ranged from 49.5 to 63.1 mL/kg . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Efmoroctocog alfa is a critical factor in determining its safe and effective dosage: Following a single intravenous dose of 50 IU/kg in previously-treated adult patients with severe haemophilia A, mean clearance (CL) rate ranged from 1.95 to 2.11 mL/h/kg. Mean CL in adolescent patients 12 to 18 years of age ranged from 2.45 to 2.62 mL/h/kg. Mean t1/2 in pediatric patients < 12 years of age ranged from 2.61 to 3.86 mL/h/kg . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Efmoroctocog alfa exerts its therapeutic effects through: In two multinational, open-label, noncomparative phase III trials involving previously treated pediatric and adult patients with severe haemophilia A, the clinical efficacy and safety of efmoroctocog alfa have been studied. The bleeding episodes were adequately controlled and bleeding rates were substantially reduced when efmoroctocog alfa has been used for individualized prophylaxis or treatment of bleeding . In adult patients receiving a single preoperative dose to maintain haemostasis during surgical procedures, the total dose on the day of surgery needed to maintain haemostasis ranged from 50.8 to 126.6 IU/kg . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Efmoroctocog alfa functions by: Factor VIII exists in a circulating protein complex consisting of two molecules via a non-covalent binding interaction; Factor VIII and von Willebrand factor. This complex remains inactive until the coagulation cascade is initiated, which activated factor VIII. Factor VIII is released from the protein complex upon activation and acts as a cofactor for factor IX-mediated conversion of factor X to activated factor X on phospholipid surfaces. Activated factor X is critical in converting prothrombin into thrombin and sequentially, thrombin converts fibrinogen to fibrin for the formation of a blood clot . Haemophilia A is a X-linked hereditary disorder of blood coagulation due to decreased levels of functional factor. The disorder can lead to various disabling complications including bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma . Efmoroctocog alfa is a recombinant fusion protein comprised of a single molecule of B-domain deleted human coagulation factor VIII covalently linked to the Fc domain of human immunoglobulin G1. It acts as a replacement therapy to increase the plasma levels of factor VIII, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies . Extended half-life of efmoroctocog alfa relative to endogenous factor VIII is explained by the Fc region binding to the neonatal Fc receptor expressed throughout life; the receptor is part of a naturally occurring pathway that protects immunoglobulins (and Fc fusion proteins) from lysosomal degradation by cycling them back into the circulation . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Efmoroctocog 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:

Efmoroctocog alfa is categorized under the following therapeutic classes: Hemostatics, Human Antihemophilic Factors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Efmoroctocog alfa include:

• Molecular Weight: 220000.0
• Molecular Formula: C9736H14863N2591O2855S78