Efmoroctocog alfa

Identification

Name
Efmoroctocog alfa
Accession Number
DB11607
Description

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 Moroctocog alfa1. 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 1. 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 1,2. Prophylaxis has also shown to reduce the formation of neutralizing anti-FVIII antibodies, or inhibitors 2.

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 Label. 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 1.

Other drug products with similar structure and function to Efmoroctocog alfa include Moroctocog alfa, 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 Antihemophilic factor human, 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 1. The extended half-life of efmoroctocog alfa provides several clinical benefits for patients, including reduced frequency of injections required and improved adherence to prophylaxis 1.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors / Fusion proteins / Peptides
Protein Chemical Formula
C9736H14863N2591O2855S78
Protein Average Weight
220000.0 Da (Apparent, B-domain deleted)
Sequences
Not Available
Synonyms
  • Antihemophilic Factor (Recombinant BDD), FC Fusion Protein
  • Antihemophilic factor (recombinant, FC fusion protein)
  • Coagulation factor VIII recombinant immunoglubulin g1 fusion protein

Pharmacology

Indication

Indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency) Label.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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 Label. 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 Label.

Mechanism of action

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 Label.

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 Label. 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 Label.

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 Label,1.

TargetActionsOrganism
Avon Willebrand factor
binding
Humans
Absorption

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 Label.

Volume of distribution

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 Label.

Protein binding

Like endogenous factor VIII, efmoroctocog alfa binds to von Willebrand factor in the circulation.

Metabolism

There are no detectable metabolites for efmoroctocog alfa. It is presumed to be metabolized via a same degradation pathway as endogenous factor VIII.

Route of elimination
Not Available
Half-life

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 Label.

Clearance

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 Label.

Adverse Effects
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Toxicity

Based on the findings from acute and repeated dose toxicity studies, efmoroctocog alfa displays no special hazard for humans. Studies to assess the genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development of efmoroctocog alfa have not been conducted. In a placental transfer study, efmoroctocog alfa has been shown to cross the placenta in small amounts in mice Label.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EloctateKit5000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2017-09-06Not applicableUS flag
EloctateKit5000 [iU]/3mLIntravenousBiogen Inc.2014-07-142019-09-30US flag
EloctateKit2000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2017-09-06Not applicableUS flag
EloctateKit3000 [iU]/3mLIntravenousBiogen Inc.2014-07-142019-09-30US flag
EloctateKit750 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2017-09-06Not applicableUS flag
EloctateKit1000 [iU]/3mLIntravenousBiogen Inc.2014-07-142020-04-30US flag
EloctateKit; Powder, for solutionIntravenousSanofi Aventis2016-01-15Not applicableCanada flag
EloctateKit250 [iU]/3mLIntravenousBiogen Inc.2014-07-142019-04-30US flag
EloctateKit; Powder, for solutionIntravenousSanofi Aventis2016-01-15Not applicableCanada flag
EloctateKit4000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2017-09-06Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
7PCM518YLR
CAS number
1270012-79-7

References

General References
  1. Frampton JE: Efmoroctocog Alfa: A Review in Haemophilia A. Drugs. 2016 Sep;76(13):1281-1291. doi: 10.1007/s40265-016-0622-z. [PubMed:27487799]
  2. Tiede A: Half-life extended factor VIII for the treatment of hemophilia A. J Thromb Haemost. 2015 Jun;13 Suppl 1:S176-9. doi: 10.1111/jth.12929. [PubMed:26149020]
  3. FDA Approved Drug Products: Eloctate (Antihemophilic Factor (Recombinant), Fc Fusion Protein) powder for intravenous injection [Link]
PubChem Substance
347911217
RxNav
1543095
AHFS Codes
  • 20:28.16 — Hemostatics
FDA label
Download (557 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentHemophilia A With Inhibitors1
4CompletedTreatmentHemophilia A1
3CompletedOtherSevere Hemophilia A1
3CompletedTreatmentHemophilia A3
3Not Yet RecruitingPreventionHemophilia A Without Inhibitor1
3Not Yet RecruitingTreatmentHemophilia A With Inhibitors1
3WithdrawnTreatmentSevere Hemophilia A1
2TerminatedTreatmentHemophilia1
1CompletedTreatmentSevere Hemophilia A1
0CompletedTreatmentHemophilia / Menstrual Flow Excessive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
KitIntravenous1000 [iU]/3mL
KitIntravenous1500 [iU]/3mL
KitIntravenous2000 [iU]/3mL
KitIntravenous250 [iU]/3mL
KitIntravenous3000 [iU]/3mL
KitIntravenous4000 [iU]/3mL
KitIntravenous500 [iU]/3mL
KitIntravenous5000 [iU]/3mL
KitIntravenous6000 [iU]/3mL
KitIntravenous750 [iU]/3mL
Kit; powder, for solutionIntravenous
Injection, powder, lyophilized, for solutionIntravenous1000 IU
Injection, powder, lyophilized, for solutionIntravenous250 IU
Injection, powder, lyophilized, for solutionIntravenous500 IU
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binding
General Function
Protein n-terminus binding
Specific Function
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surf...
Gene Name
VWF
Uniprot ID
P04275
Uniprot Name
von Willebrand factor
Molecular Weight
309261.83 Da

Drug created on June 24, 2016 13:15 / Updated on November 27, 2020 08:19

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