Identification

Summary

Eftrenonacog alfa is a recombinant Factor IX used to treat and prevent bleeding in hemophilia B.

Brand Names
Alprolix
Generic Name
Eftrenonacog alfa
DrugBank Accession Number
DB11608
Background

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.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
Protein Chemical Formula
Not Available
Protein Average Weight
98000.0 Da (Approximate)
Sequences
Not Available
Synonyms
  • Coagulation factor IX recombinant immunoglubulin g1 fusion protein
  • Eftrenonacog alfa
  • Recombinant human coagulation factor IX, FC Fusion protein

Pharmacology

Indication

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

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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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.

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.

Adverse Effects
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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.

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
AbciximabThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Abciximab.
AcenocoumarolThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Acenocoumarol.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Eftrenonacog alfa.
AducanumabThe risk or severity of adverse effects can be increased when Eftrenonacog alfa is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Eftrenonacog alfa.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Eftrenonacog alfa.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Eftrenonacog alfa.
AlteplaseThe therapeutic efficacy of Eftrenonacog alfa can be decreased when used in combination with Alteplase.
Aminocaproic acidThe risk or severity of adverse effects can be increased when Aminocaproic acid is combined with Eftrenonacog alfa.
AmivantamabThe risk or severity of adverse effects can be increased when Eftrenonacog alfa is combined with Amivantamab.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AlprolixKit3000 [iU]/5mLIntravenousBiogen Inc.2014-05-052020-12-31US flag
AlprolixKit500 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2014-05-05Not applicableUS flag
AlprolixKit500 [iU]/5mLIntravenousBiogen Inc.2014-05-052021-04-30US flag
AlprolixInjection, powder, for solution1000 IUIntravenousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2021-01-12Not applicableEU flag
AlprolixKit; Powder, for solution4000 unit / vialIntravenousSanofi AventisNot applicableNot applicableCanada flag
AlprolixKit; Powder, for solution3000 unit / vialIntravenousSanofi Aventis2016-01-15Not applicableCanada flag
AlprolixKit4000 [iU]/5mLIntravenousBiogen Inc.2016-10-282020-10-31US flag
AlprolixKit2000 [iU]/5mLIntravenousBioverativ Therapeutics Inc.2014-05-05Not applicableUS flag
AlprolixInjection, powder, for solution3000 IUIntravenousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2021-01-12Not applicableEU flag
AlprolixKit2000 [iU]/5mLIntravenousBiogen Inc.2014-05-052020-11-30US flag

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
Affected organisms
Not Available

Chemical Identifiers

UNII
02E00T2QDE
CAS number
1270012-74-2

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. [Article]
  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. [Article]
  3. FDA Approved Drug Products: ALPROLIX [coagulation factor IX (recombinant), Fc fusion protein], lyophilized powder for solution, for intravenous injection [Link]
PubChem Substance
347911218
RxNav
1535944
Wikipedia
Factor_IX

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHemophilia B2
3CompletedTreatmentSevere Hemophilia B1
1CompletedTreatmentCongenital Hematological Disorder / Hemophilia B1
1CompletedTreatmentHemophilia B1
0CompletedTreatmentHemophilia / Menstrual Flow Excessive1
Not AvailableActive Not RecruitingNot AvailableHemophilia B1
Not AvailableCompletedNot AvailableHemophilia1
Not AvailableCompletedNot AvailableHemophilia As / Hemophilia B1
Not AvailableCompletedNot AvailableHemophilia B1
Not AvailableTerminatedNot AvailableHemophilia As / Hemophilia B1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available

Drug created at June 24, 2016 19:21 / Updated at May 22, 2022 04:54