Identification

Name
Turoctocog alfa
Accession Number
DB09109
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
Description

Turoctocog alfa is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII.[1] It was developped by Novo Nordisk and FDA approved in October 16, 2013.[6]

Protein structure
Db09109
Protein chemical formula
C7480H11379N1999O2194S68
Protein average weight
166000.0 Da (Without post-translational modifications)
Sequences
>>Heavy chain<<<
ATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFN
IAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQ
REKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCR
EGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNR
SLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLL
MDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRF
DDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIG
RKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGI
TDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNME
RDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAG
VQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKH
KMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYE
DSYEDISAYLLSKNNAIEPRSFSQNSRHPSQNPPVLKRHQR
>>Light chain<<<
EITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWD
YGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVE
DNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKD
EFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKS
WYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMG
SNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHA
GMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPF
SWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFG
NVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDA
QITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGV
KSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRI
HPQSWVHQIALRMEVLGCEAQDLY
Download FASTA Format
Synonyms
Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NovoeightInjection, powder, for solution1500 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
NovoeightInjection, powder, for solution500 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
NovoeightInjection, powder, for solution3000 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
NovoeightInjection, powder, for solution250 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
NovoeightInjection, powder, for solution2000 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
NovoeightInjection, powder, for solution1000 IUIntravenousNovo Nordisk2013-11-13Not applicableEu
ZonovateKit; Powder, for solution3000 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
ZonovateKit; Powder, for solution1500 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
ZonovateKit; Powder, for solution500 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
ZonovateKit; Powder, for solution1000 unitIntravenousNovo Nordisk2018-03-23Not applicableCanada
Categories
UNII
969NZA3X9T
CAS number
1192451-26-5

Pharmacology

Indication

Turoctocog alfa is indicated for the treatment and prophylaxis of bleedings in patients presenting hemophilia A.[7] The treatment with turoctocog alfa is related with its use to control bleeding episodes or as a perioperative management.[8] Hemophilia A is a hereditary hemorrhagic disorder generated by the congenital deficit of the coagulation factor VIII. This disease is manifested as excessive spontaneous or trauma-driven bleeding. The coagulation factor VIII is a robust initiator of thrombin which is later required for the generation of fibrin to form a platelet plug and its gene is expressed in the X chromosome.[2]

Associated Conditions
Pharmacodynamics

After turoctocog alfa administration, it has been reported a significant improvement in hemostasis. This effect was observed by the amelioration on whole blood clotting time.[3] In clinical trials, there were no reports of development of factor VIII inhibitors and even 90% of the ocurred bleeds were resolved with 1 or 2 infusions of turoctocog alfa. There are no reports of treatment failure.[9] In vitro studies confirmed the ability of turoctocog alfa to improve clot formation and clot stability. All these studies prove that turoctocog alfa is fully functional and its activity is similar to the one showed by other recombinant factor VIII products.[10]

Mechanism of action

The B domain is known to perform the function of restrict the expression of the endogenous coagulation factor VIII but it has no direct relationship to the function of this factor. In normal conditions during hemostasis, the coagulation factor VIII will be activated by specific thrombin cleavages producing A1, A2 and A3-C1-C2 fragments of activated factor VIII (Factor VIIIa) which will form a complex with the factor IXa and activate the factor X leading to a stable haemostatic plug.[1] Turoctocog contains all function-related domains with a considerably easier intact expression of the protein in mammalian cells by truncating the B domain.[4] This recombinant structure allows it to replace the missing factor VIII and restore hemostasis.[7]

TargetActionsOrganism
ACoagulation factor IX
activator
Humans
ACoagulation factor X
activator
Humans
AProthrombin
binder
Humans
Absorption

In pre-clinical studies, the absorption half-life was reported wot be 5.4 hours.[3] The absorption profile varies depending on the age of the patient where the AUC is 9.92, 11.09 and 15.26 IU hour/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively. The Cmax according to the different age groups is 1, 1.07 and 1.226 IU/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively.[9]

Volume of distribution

In pre-clinical studies, turoctocog distribution was studied based on a two model compartment and it resulted in 59 ml/kg in the central compartment and 13 ml/kg in the peripheral compartment. It also presented an inter-compartmental flow of 0.66 ml/hour kg.[3]

Protein binding

Because turoctocog alfa is a recombinant protein, there has been not enough studies of protein binding.[10]

Metabolism

Turoctocog alfa is expected to be cleaved by proteolysis into small individual aminoacids that constitute them after receptor mediated cell endocytosis.[10]

Route of elimination

After intravenous administration of turoctocog alfa, the time for complete elimination of the blood plasma is of 50-55 hours. Due to the fact that this drug is a 166 kDa, it is thought that it will be eliminated by tissue mechanisms such as receptor mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion.[10]

Half life

In pre-clinical studies, turoctocog half-life was reported to be 16 hours.[3] In knockout mice there are reports of half-life of 7-8 hours.[10]

Clearance

In pre-clinical studies, turoctocog clearance was reported to be 6.5 ml/hour kg.[3]

Toxicity

In preclinical safety studies, there was a change in reported systolic pressure after 2-weeks of multiple dosing.[9] Thrombus formation, cardiovascular, neurological or respiratory effects are not expected to be a safety concern.[10]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with 4-hydroxycoumarin.
AbciximabThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Abciximab.
AcenocoumarolThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Acenocoumarol.
Acetylsalicylic acidThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Acetylsalicylic acid.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Turoctocog alfa.
AlteplaseThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Alteplase.
AmediplaseThe therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Amediplase.
Aminocaproic AcidAminocaproic Acid may increase the thrombogenic activities of Turoctocog alfa.
Food Interactions
Not Available

References

General References
  1. Ezban M, Vad K, Kjalke M: Turoctocog alfa (NovoEight(R))--from design to clinical proof of concept. Eur J Haematol. 2014 Nov;93(5):369-76. doi: 10.1111/ejh.12366. Epub 2014 May 28. [PubMed:24797664]
  2. Salen P, Babiker HM: Hemophilia A . [PubMed:29261993]
  3. Agerso H, Stennicke HR, Pelzer H, Olsen EN, Merricks EP, Defriess NA, Nichols TC, Ezban M: Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia. 2012 Nov;18(6):941-7. doi: 10.1111/j.1365-2516.2012.02896.x. Epub 2012 Jul 20. [PubMed:22812621]
  4. Ahmadian H, Hansen EB, Faber JH, Sejergaard L, Karlsson J, Bolt G, Hansen JJ, Thim L: Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule. Blood Coagul Fibrinolysis. 2016 Jul;27(5):568-75. doi: 10.1097/MBC.0000000000000477. [PubMed:26761578]
  5. Takedani H, Hirose J: Turoctocog alfa: an evidence-based review of its potential in the treatment of hemophilia A. Drug Des Devel Ther. 2015 Mar 24;9:1767-72. doi: 10.2147/DDDT.S57967. eCollection 2015. [PubMed:25848213]
  6. FiercePharma [Link]
  7. EMA Reports [Link]
  8. NovoNordisk [Link]
  9. EU Reports [Link]
  10. Australian report [Link]
External Links
PubChem Substance
347910410
Wikipedia
Turoctocog_alfa
AHFS Codes
  • 20:28.16 — Hemostatics
MSDS
Download (269 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCongenital Hematological Disorder / Hemophilia A5
2Active Not RecruitingTreatmentHemophilia A / Hemostasis1
3CompletedTreatmentCongenital Hematological Disorder / Hemophilia A5
3RecruitingTreatmentHemophilia A1
4RecruitingTreatmentCongenital Hematological Disorder / Hemophilia A1
Not AvailableEnrolling by InvitationNot AvailableCongenital Hematological Disorder / Hemophilia A3
Not AvailableRecruitingNot AvailableHemophilia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous1000 IU
Injection, powder, for solutionIntravenous1500 IU
Injection, powder, for solutionIntravenous2000 IU
Injection, powder, for solutionIntravenous250 IU
Injection, powder, for solutionIntravenous3000 IU
Injection, powder, for solutionIntravenous500 IU
Kit; powder, for solutionIntravenous1000 unit
Kit; powder, for solutionIntravenous1500 unit
Kit; powder, for solutionIntravenous2000 unit
Kit; powder, for solutionIntravenous250 unit
Kit; powder, for solutionIntravenous3000 unit
Kit; powder, for solutionIntravenous500 unit
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
water solubilitySolubleNovoNordisk monograph
isoelectric pointIt does not posses a distinct valueNovoNordisk monograph

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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
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. Ezban M, Vad K, Kjalke M: Turoctocog alfa (NovoEight(R))--from design to clinical proof of concept. Eur J Haematol. 2014 Nov;93(5):369-76. doi: 10.1111/ejh.12366. Epub 2014 May 28. [PubMed:24797664]
  2. Ahmadian H, Hansen EB, Faber JH, Sejergaard L, Karlsson J, Bolt G, Hansen JJ, Thim L: Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule. Blood Coagul Fibrinolysis. 2016 Jul;27(5):568-75. doi: 10.1097/MBC.0000000000000477. [PubMed:26761578]
  3. EMA Reports [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
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. Ezban M, Vad K, Kjalke M: Turoctocog alfa (NovoEight(R))--from design to clinical proof of concept. Eur J Haematol. 2014 Nov;93(5):369-76. doi: 10.1111/ejh.12366. Epub 2014 May 28. [PubMed:24797664]
  2. Ahmadian H, Hansen EB, Faber JH, Sejergaard L, Karlsson J, Bolt G, Hansen JJ, Thim L: Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule. Blood Coagul Fibrinolysis. 2016 Jul;27(5):568-75. doi: 10.1097/MBC.0000000000000477. [PubMed:26761578]
  3. EMA Reports [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Australian report [Link]

Drug created on September 17, 2015 15:07 / Updated on January 15, 2019 15:20