Eftrenonacog alfa

Identification

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Name
Eftrenonacog alfa
Accession Number
DB11608
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
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) 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.

Hemophilia 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 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 1.

Protein chemical formula
Not Available
Protein average weight
98000.0 Da (Approximate)
Sequences
Not Available
Synonyms
  • Coagulation factor IX recombinant immunoglubulin g1 fusion protein
  • Recombinant human coagulation factor IX, FC Fusion protein
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlprolixKit4000 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2016-10-28Not applicableUs
AlprolixKit500 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2014-05-05Not applicableUs
AlprolixKit1000 [iU]/5mLIntravenousBiogen2014-05-05Not applicableUs
AlprolixKit; Powder, for solution250 unitIntravenousBioverativ Canada IncNot applicableNot applicableCanada
AlprolixKit250 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2016-02-18Not applicableUs
AlprolixKit4000 [iU]/5mLIntravenousBiogen2016-10-28Not applicableUs
AlprolixKit500 [iU]/5mLIntravenousBiogen2014-05-05Not applicableUs
AlprolixKit; Powder, for solution3000 unitIntravenousBioverativ Canada Inc2016-01-15Not applicableCanada
AlprolixKit3000 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2014-05-05Not applicableUs
AlprolixKit250 [iU]/5mLIntravenousBiogen2016-02-18Not applicableUs
Additional Data Available
  • Application Number
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  • Product Code
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Categories
UNII
02E00T2QDE
CAS number
1270012-74-2

Pharmacology

Indication

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

Associated Conditions
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 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.

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 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 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 Label,2.

Additional Data Available
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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 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 to 29.50 Uxh/dL per IU/kg Label.

Volume of distribution

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 to 365.1 mL/kg Label.

Protein binding
Not Available
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.

Route of elimination

Eftrenonacog alfa is expected to undergo renal clearance 2.

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 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 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 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 Label.

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 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.
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with 4-hydroxycoumarin.
AbciximabThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Abciximab.
AbituzumabThe risk or severity of adverse effects can be increased when Eftrenonacog alfa is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Eftrenonacog alfa is combined with Abrilumab.
AcenocoumarolThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Acenocoumarol.
Acetylsalicylic acidThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Acetylsalicylic acid.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Eftrenonacog alfa.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Eftrenonacog alfa.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Hoy SM: Eftrenonacog Alfa: A Review in Haemophilia B. Drugs. 2017 Jul;77(11):1235-1246. doi: 10.1007/s40265-017-0778-1. [PubMed:28646426]
  2. Miguelino MG, Powell JS: Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B. Patient Prefer Adherence. 2014 Aug 8;8:1073-83. doi: 10.2147/PPA.S54951. eCollection 2014. [PubMed:25143713]
External Links
PubChem Substance
347911218
AHFS Codes
  • 20:28.16 — Hemostatics
FDA label
Download (448 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentHemophilia / Menstrual Flow Excessive1
1CompletedTreatmentCongenital Hematological Disorder / Haemophilia B1
1CompletedTreatmentHereditary factor IX deficiency1
3CompletedTreatmentHereditary factor IX deficiency2
3CompletedTreatmentSevere Hemophilia B1
Not AvailableNot Yet RecruitingNot AvailableHereditary factor IX deficiency1
Not AvailableRecruitingNot AvailableHaemophilia B1
Not AvailableRecruitingNot AvailableHaemophilia B / Hemophilia A1
Not AvailableRecruitingNot AvailableHemophilia1
Not AvailableTerminatedNot AvailableHemophilia A / Hereditary factor IX deficiency1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
KitIntravenous1000 [iU]/5mL
KitIntravenous2000 [iU]/5mL
KitIntravenous250 [iU]/5mL
KitIntravenous3000 [iU]/5mL
KitIntravenous4000 [iU]/5mL
KitIntravenous500 [iU]/5mL
Kit; powder, for solutionIntravenous1000 unit
Kit; powder, for solutionIntravenous2000 unit
Kit; powder, for solutionIntravenous250 unit
Kit; powder, for solutionIntravenous3000 unit
Kit; powder, for solutionIntravenous4000 unit
Kit; powder, for solutionIntravenous500 unit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Drug created on June 24, 2016 13:21 / Updated on September 19, 2019 03:17