NAV

Efanesoctocog alfa

Identification

Summary

Efanesoctocog alfa is a recombinant DNA-derived, Factor VIII concentrate indicated for routine prophylaxis, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding in patients with hemophilia A.

Brand Names
Altuviiio
Generic Name
Efanesoctocog alfa
DrugBank Accession Number
DB16662
Background

Efanesoctocog alfa (BIVV001) is a recombinant factor VIII (FVIII) analogue fusion protein used for the routine prophylaxis, perioperative management of bleeding and on-demand treatment and control of bleeding episodes in patients with hemophilia A.6 The use of FVIII replacement products is beneficial in patients with hemophilia A; however, their quality of life can be affected due to frequent doses.1 Efanesoctocog alfa was designed to have an extended half-life, and to surpass the half-life ceiling to which other forms of recombinant FVIII are subjected due to their association with von Willebrand factor (VWF). Endogenous VWF protects FVIII from degradation but also sets a half-life of approximately 15 to 19 h. To extend the half-life of FVIII, efanesoctocog alfa is fused to dimeric Fc, a D'D3 domain of VWF, and two XTEN polypeptides.1,2

In February 2023, efanesoctocog alfa was approved by the FDA as a new class of factor VIII therapy for hemophilia A.6,7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors / Fusion proteins
Protein Chemical Formula
Not Available
Protein Average Weight
312000.0 Da (approximate)
Sequences
>BddFVIII-Fc chain
ATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFN
IAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQ
REKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCR
EGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNR
SLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLL
MDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRF
DDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIG
RKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGI
TDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNME
RDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAG
VQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKH
KMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYE
DSYEDISAYLLSKNNAIEPRSFSQNGTSESATPESGPGSEPATSGSETPGTSESATPESG
PGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESG
PGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSA
PGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSET
PGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESG
PGTSTEPSEGSAPASSEITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQ
KKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGEL
NEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNET
KTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVT
VQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGL
VMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSK
AGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLAR
LHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKW
QTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLN
SCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQV
DFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTP
VVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLYDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPG
>vWF fragment-FVIII a2-Fc chain
SLSCRPPMVKLVCPADNLRAEGLECTKTCQNYDLECMSMGCVSGCLCPPGMVRHENRCVA
LERCPCFHQGKEYAPGETVKIGCNTCVCRDRKWNCTDHVCDATCSTIGMAHYLTFDGLKY
LFPGECQYVLVQDYCGSNPGTFRILVGNKGCSHPSVKCKKRVTILVEGGEIELFDGEVNV
KRPMKDETHFEVVESGRYIILLLGKALSVVWDRHLSISVVLKQTYQEKVCGLCGNFDGIQ
NNDLTSSNLQVEEDPVDFGNSWKVSSQCADTRKVPLDSSPATCHNNIMKQTMVDSSCRIL
TSDVFQDCNKLVDPEPYLDVCIYDTCSCESIGDCAAFCDTIAAYAHVCAQHGKVVTWRTA
TLCPQSCEERNLRENGYEAEWRYNSCAPACQVTCQHPEPLACPVQCVEGCHAHCPPGKIL
DELLQTCVDPEDCPVCEVAGRRFASGKKVTLNPSDPEHCQICHCDVVNLTCEACQEPGTS
ESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTS
TEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSP
AGSPTSTEEGSPAGSPTSTEEGASSDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE
VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP
REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
References:
  1. WHO: International Nonproprietary Names for Pharmaceutical Substances (INN) [Link]
Download FASTA Format
Synonyms
  • Antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl
External IDs
  • BIVV- 001
  • BIVV001
  • rFVIIIFc-VWF-XTEN

Pharmacology

Indication

Efanesoctocog alfa is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding.6

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

The efficacy of efanesoctocog alfa is comparable to that of recombinant factor VIII (FVIII). Both promote fibrin clot formation and injury‐induced platelet accumulation and have a similar hemostatic potential.3 The use of 50 IU/kg of efanesoctocog alfa once a week resulted in FVIII levels associated with a low risk of bleeding.6

Efanesoctocog alfa has an acceptable side-effect profile and is usually well tolerated.4,5 However, patients treated with efanesoctocog alfa may present allergic-type hypersensitivity reactions, including anaphylaxis. Also, the formation of FVIII neutralizing antibodies is possible following the administration of efanesoctocog alfa.6

Mechanism of action

Efanesoctocog alfa is a recombinant factor VIII (FVIII) analogue fusion protein that temporarily replaces the missing coagulation FVIII needed for effective hemostasis.6 It is formed by a single recombinant FVIII protein fused to dimeric Fc, a D'D3 domain of von Willebrand factor (VWF), and two XTEN polypeptides, and was designed to have an extended half-life.1

In plasma, most FVIII circulates in a complex with VWF, which protects FVIII from degradation and extends its half-life. However, it also sets a half-life ceiling of approximately 15 to 19 h.2 Linking the D'D3 domain of VWF to the recombinant FVIII-Fc fusion protein provides protection and stability to FVIII and prevents FVIII interaction with endogenous VWF. The lysosomal degradation of efanesoctocog alfa is delayed thanks to the Fc region of human immunoglobulin G1 (IgG1) that binds to the neonatal Fc receptor (FcRn), and the XTEN polypeptides alter the hydrodynamic radius of the fusion protein and reduce clearance and degradation rates.6 Altogether, these modifications lead to a 3- to 4-fold increase in FVIII half-life.2,6

Hemophilia A is a genetic disorder caused by missing or defective FVIII. The use of efanesoctocog alfa in patients with hemophilia A increases FVIII plasma levels, temporarily correcting coagulation deficiency.6

TargetActionsOrganism
UCoagulation factor IX
binder
Humans
UCoagulation factor X
binder
Humans
ULow-density lipoprotein receptor-related protein 2
binder
Humans
UBasement membrane-specific heparan sulfate proteoglycan core protein
binder
Humans
Absorption

Efanesoctocog alfa administered as a single intravenous injection of 50 IU/kg had an AUC of 6710 IU⋅h/dL in children between 1 and 6 years old, 7190 IU⋅h/dL in children between 6 and 12 years old, 8350 IU⋅h/dL in adolescents between 12 and 18 years old, and 9850 IU⋅h/dL in adults. In all groups, a single dose of 50 IU/kg of efanesoctocog alfa led to high sustained FVIII activity and a prolonged half-life. As age increased, there was a tendency of higher AUC values; however, this effect was not clinically significant. Sex, race (White, Asian), VWF antigen activity, hematocrit level, blood type, HCV status, or HIV status did not have a clinically significant effect on efanesoctocog alfa either. At steady state (week 26), the pharmacokinetic profile of efanesoctocog alfa was comparable to the one obtained after the first dose.6

Volume of distribution

Efanesoctocog alfa administered as a single intravenous injection of 50 IU/kg had a volume of distribution at steady-state of 38.0 mL/kg in children between 1 and 6 years old, 38.1 mL/kg in children between 6 and 12 years old, 34.9 mL/kg in adolescents between 12 and 18 years old, and 31.0 mL/kg in adults.6

Protein binding

Not Available

Metabolism

As a fusion protein, efanesoctocog alfa is expected to be metabolized by proteases throughout the body.

Route of elimination

Not Available

Half-life

Efanesoctocog alfa administered as a single intravenous injection of 50 IU/kg had a terminal half-life of 39.9 h in children between 1 and 6 years old, 42.4 h in children between 6 and 12 years old, 44.6 h in adolescents between 12 and 18 years old, and 48.2 h in adults.6

Clearance

Efanesoctocog alfa administered as a single intravenous injection of 50 IU/kg had a clearance of 0.74 mL/h/kg in children between 1 and 6 years old, 0.681 mL/h/kg in children between 6 and 12 years old, 0.582 mL/h/kg in adolescents between 12 and 18 years old, and 0.493 mL/h/kg in adults.6

Adverse Effects
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Toxicity

Toxicity information regarding efanesoctocog alfa is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hypersensitivity, including anaphylaxis.6 Symptomatic and supportive measures are recommended. The carcinogenicity, mutagenicity or effects on fertility of efanesoctocog alfa have not been evaluated.6

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
No interactions found.

Products

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International/Other Brands
Altuviiio (Bioverativ Therapeutics)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AltuviiioKit; Powder, for solution3000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS flag
AltuviiioKit; Powder, for solution500 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS flag
AltuviiioKit; Powder, for solution2000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS flag
AltuviiioKit; Powder, for solution250 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS flag
AltuviiioKit; Powder, for solution4000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS flag
AltuviiioKit; Powder, for solution1000 [iU]/3mLIntravenousBioverativ Therapeutics Inc.2023-02-22Not applicableUS 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
  • Humans and other mammals

Chemical Identifiers

UNII
WH7BHQ0RB4
CAS number
2252477-42-0

References

General References
  1. Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, Fruebis J, Benson CC: BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020 Sep 10;383(11):1018-1027. doi: 10.1056/NEJMoa2002699. [Article]
  2. Seth Chhabra E, Liu T, Kulman J, Patarroyo-White S, Yang B, Lu Q, Drager D, Moore N, Liu J, Holthaus AM, Sommer JM, Ismail A, Rabinovich D, Liu Z, van der Flier A, Goodman A, Furcht C, Tie M, Carlage T, Mauldin R, Dobrowsky TM, Liu Z, Mercury O, Zhu L, Mei B, Schellenberger V, Jiang H, Pierce GF, Salas J, Peters R: BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood. 2020 Apr 23;135(17):1484-1496. doi: 10.1182/blood.2019001292. [Article]
  3. Demers M, Aleman MM, Kistanova E, Peters R, Salas J, Seth Chhabra E: Efanesoctocog alfa elicits functional clot formation that is indistinguishable to that of recombinant factor VIII. J Thromb Haemost. 2022 Jul;20(7):1674-1683. doi: 10.1111/jth.15741. Epub 2022 May 22. [Article]
  4. von Drygalski A, Chowdary P, Kulkarni R, Susen S, Konkle BA, Oldenburg J, Matino D, Klamroth R, Weyand AC, Jimenez-Yuste V, Nogami K, Poloskey S, Winding B, Willemze A, Knobe K: Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A. N Engl J Med. 2023 Jan 26;388(4):310-318. doi: 10.1056/NEJMoa2209226. [Article]
  5. Lissitchkov T, Willemze A, Katragadda S, Rice K, Poloskey S, Benson C: Efanesoctocog alfa for hemophilia A: results from a phase 1 repeat-dose study. Blood Adv. 2022 Feb 22;6(4):1089-1094. doi: 10.1182/bloodadvances.2021006119. [Article]
  6. FDA Approved Drug Products: ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] lyophilized powder for solution, for intravenous use (February 2023) [Link]
  7. Globe News Wire: FDA approves once-weekly ALTUVIIIO, a new class of factor VIII therapy for hemophilia A that offers significant bleed protection [Link]
RxNav
2631083

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentHemophilia A1
3CompletedTreatmentHemophilia A1
1CompletedOtherVon Willebrand's Disease1
1CompletedTreatmentHemophilia A1
1, 2CompletedOtherHemophilia A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Kit; powder, for solutionIntravenous1000 [iU]/3mL
Kit; powder, for solutionIntravenous2000 [iU]/3mL
Kit; powder, for solutionIntravenous250 [iU]/3mL
Kit; powder, for solutionIntravenous3000 [iU]/3mL
Kit; powder, for solutionIntravenous4000 [iU]/3mL
Kit; powder, for solutionIntravenous500 [iU]/3mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Details1. Coagulation factor IX
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Binder of endogenous factor VIII.
General Function
Serine-type endopeptidase activity
Specific Function
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholi...
Gene Name
F9
Uniprot ID
P00740
Uniprot Name
Coagulation factor IX
Molecular Weight
51778.11 Da
References
  1. Saenko EL, Ananyeva NM, Tuddenham EG, Kemball-Cook G: Factor VIII - novel insights into form and function. Br J Haematol. 2002 Nov;119(2):323-31. doi: 10.1046/j.1365-2141.2002.03793.x. [Article]
Details2. Coagulation factor X
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Binder of endogenous factor VIII.
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Saenko EL, Ananyeva NM, Tuddenham EG, Kemball-Cook G: Factor VIII - novel insights into form and function. Br J Haematol. 2002 Nov;119(2):323-31. doi: 10.1046/j.1365-2141.2002.03793.x. [Article]
Details3. Low-density lipoprotein receptor-related protein 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Binder of endogenous factor VIII.
General Function
Calcium ion binding
Specific Function
Acts together with cubilin to mediate HDL endocytosis (By similarity). May participate in regulation of parathyroid-hormone and para-thyroid-hormone-related protein release.
Gene Name
LRP2
Uniprot ID
P98164
Uniprot Name
Low-density lipoprotein receptor-related protein 2
Molecular Weight
521952.77 Da
References
  1. Saenko EL, Ananyeva NM, Tuddenham EG, Kemball-Cook G: Factor VIII - novel insights into form and function. Br J Haematol. 2002 Nov;119(2):323-31. doi: 10.1046/j.1365-2141.2002.03793.x. [Article]
  2. Pisal DS, Balu-Iyer SV: Phospholipid binding improves plasma survival of factor VIII. Thromb Haemost. 2010 Nov;104(5):1073-5. doi: 10.1160/TH10-06-0422. Epub 2010 Sep 13. [Article]
Details4. Basement membrane-specific heparan sulfate proteoglycan core protein
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Curator comments
Binder of endogenous factor VIII.
General Function
Protein c-terminus binding
Specific Function
Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which i...
Gene Name
HSPG2
Uniprot ID
P98160
Uniprot Name
Basement membrane-specific heparan sulfate proteoglycan core protein
Molecular Weight
468826.45 Da
References
  1. Saenko EL, Ananyeva NM, Tuddenham EG, Kemball-Cook G: Factor VIII - novel insights into form and function. Br J Haematol. 2002 Nov;119(2):323-31. doi: 10.1046/j.1365-2141.2002.03793.x. [Article]

Drug created at March 26, 2021 02:43 / Updated at March 01, 2023 18:29