Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1290U)

• DTT Name: Coagulation factor VIII (F8)
• Synonyms: Procoagulant component; F8C; Antihemophilic factor; AHF
• Gene Name: F8
• DTT Type: Successful target; [1]
• UniProt ID: FA8_HUMAN
• TTD ID: T14602
• Sequence:
  MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFN
  TSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAV
  GVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSH
  VDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRD
  AASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNH
  RQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNE
  EAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLA
  PDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTL
  LIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGP
  TKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDE
  NRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILS
  IGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRG
  MTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNSRHPSTRQKQFNATTI
  PENDIEKTDPWFAHRTPMPKIQNVSSSDLLMLLRQSPTPHGLSLSDLQEAKYETFSDDPS
  PGAIDSNNSLSEMTHFRPQLHHSGDMVFTPESGLQLRLNEKLGTTAATELKKLDFKVSST
  SNNLISTIPSDNLAAGTDNTSSLGPPSMPVHYDSQLDTTLFGKKSSPLTESGGPLSLSEE
  NNDSKLLESGLMNSQESSWGKNVSSTESGRLFKGKRAHGPALLTKDNALFKVSISLLKTN
  KTSNNSATNRKTHIDGPSLLIENSPSVWQNILESDTEFKKVTPLIHDRMLMDKNATALRL
  NHMSNKTTSSKNMEMVQQKKEGPIPPDAQNPDMSFFKMLFLPESARWIQRTHGKNSLNSG
  QGPSPKQLVSLGPEKSVEGQNFLSEKNKVVVGKGEFTKDVGLKEMVFPSSRNLFLTNLDN
  LHENNTHNQEKKIQEEIEKKETLIQENVVLPQIHTVTGTKNFMKNLFLLSTRQNVEGSYD
  GAYAPVLQDFRSLNDSTNRTKKHTAHFSKKGEEENLEGLGNQTKQIVEKYACTTRISPNT
  SQQNFVTQRSKRALKQFRLPLEETELEKRIIVDDTSTQWSKNMKHLTPSTLTQIDYNEKE
  KGAITQSPLSDCLTRSHSIPQANRSPLPIAKVSSFPSIRPIYLTRVLFQDNSSHLPAASY
  RKKDSGVQESSHFLQGAKKNNLSLAILTLEMTGDQREVGSLGTSATNSVTYKKVENTVLP
  KPDLPKTSGKVELLPKVHIYQKDLFPTETSNGSPGHLDLVEGSLLQGTEGAIKWNEANRP
  GKVPFLRVATESSAKTPSKLLDPLAWDNHYGTQIPKEEWKSQEKSPEKTAFKKKDTILSL
  NACESNHAIAAINEGQNKPEIEVTWAKQGRTERLCSQNPPVLKRHQREITRTTLQSDQEE
  IDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNR
  AQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASR
  PYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDV
  DLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRA
  PCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGH
  VFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKC
  QTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMII
  HGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFN
  PPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFA
  TWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFL
  ISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRM
  EVLGCEAQDLY
• Function: Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  COPII (Coat Protein 2) Mediated Vesicle Transport (R-HSA-204005)
  Cargo concentration in the ER (R-HSA-5694530)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Drotrecogin alfa	DM59JCN	Cerebrovascular ischaemia	8B1Z	Approved	[1]
Efanesoctocog alfa	DM2CKIJ	Haemophilia A	3B10.0	Approved	[2]
Eloctate	DMRCX8K	Haemophilia A	3B10.0	Approved	[3]
Factor 8	DMAB6PM	Hemophilia	3B10.0	Approved	[4]

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SK-NBP601	DMUY09W	Hemophilia	3B10.0	Preregistration	[5]
BAY 94-9027	DM09M3H	Hemophilia	3B10.0	Phase 3	[6]
Milademetan	DMPVDQ3	Liposarcoma	2B59	Phase 3	[7]
N8-GP	DMY60DT	Factor VIII deficiency	3B10	Phase 3	[8]
OBI-1	DMENDP6	Factor VIII deficiency	3B10	Phase 3	[9]
PF-07055480	DMWPA4L	Haemophilia A	3B10.0	Phase 3	[10]
Plasma derived factor VIII PEGylated liposomal	DM1RWMY	Factor VIII deficiency	3B10	Phase 3	[4]
Recombinant von Willebrand factor/recombinant Factor VIII complex	DM7JFDO	Von willebrand disease	3B12	Phase 3	[11]
Turoctocog alfa	DMPBJ8W	Haemophilia A	3B10.0	Phase 3	[12]
Valoctocogene roxaparvovec	DMMKE2H	Haemophilia A	3B10.0	Phase 3	[13]
BAY 794980	DMA75FG	Discovery agent	N.A.	Phase 2	[14]
TB-402	DM4I6XK	Atrial fibrillation	BC81.3	Phase 2	[4]
BAY2599023	DMUK1K1	Haemophilia A	3B10.0	Phase 1/2	[15]
SPK-8011	DM8K7CN	Haemophilia A	3B10.0	Phase 1/2	[16]
SPK-8016	DMCP8F3	Haemophilia A	3B10.0	Phase 1/2	[16]
TAK-754	DMH6GLU	Haemophilia A	3B10.0	Phase 1/2	[17]

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Factor VIII-XTEN	DM1AYVU	Hemophilia	3B10.0	Investigative	[4]
Full-length Factor VIII molecule	DM4M91Z	Hemophilia	3B10.0	Investigative	[4]
GPG-290	DMRJ5OD	Angina pectoris	BA40	Investigative	[4]
Human recombinant factor VIII	DMG1BYH	Factor VIII deficiency	3B10	Investigative	[4]
IATX-FVIII	DM8U4HE	Factor VIII deficiency	3B10	Investigative	[4]
LA-N8	DMLGK27	Factor VIII deficiency	3B10	Investigative	[4]
LG-888	DM1W8Y0	Factor VIII deficiency	3B10	Investigative	[4]
LG-889	DMIHDEB	Factor VIII deficiency	3B10	Investigative	[4]
Long-acting factor VIII	DMZUSJD	Coagulation defect	3B10.0	Investigative	[4]
Simoctocog alfa	DM3LDFB	Discovery agent	N.A.	Investigative	[18]
SMaRT FVIII	DMGJTL3	Hemophilia	3B10.0	Investigative	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Neonatal sepsis	1G41	Whole blood	1.08E-22	0.89	1.82

References

• [1] Protein C in critical illness. Am J Health Syst Pharm. 2009 Jun 15;66(12):1089-96.
• [2] Efanesoctocog alfa for hemophilia A: results from a phase 1 repeat-dose study. Blood Adv. 2022 Feb 22;6(4):1089-1094.
• [3] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2607).
• [5] Clinical pipeline report, company report or official report of SK Chemicals.
• [6] Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost. 2014 Apr;12(4):488-96.
• [7] A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021 Oct 7;138(14):1258-1268.
• [8] Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost. 2013 Apr;11(4):670-8.
• [9] Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia. 2015 Mar;21(2):162-70.
• [10] Clinical pipeline report, company report or official report of Pfizer.
• [11] 6 Factor VIII Concentrates, Factor VIII/von Willebrand Factor Concentrates, Factor IX Concentrates, Activated Prothrombin Complex Concentrates. Transfus Med Hemother. 2009 December; 36(6): 409-418.
• [12] The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight ), in patients with hemophilia A. J Thromb Haemost. 2015 Mar;13(3):370-9.
• [13] Clinical pipeline report, company report or official report of BioMarin Pharmaceutical.
• [14] Efficacy and safety of prophylaxis with once-weekly BAY 79-4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients. A randomised, active-controlled, double-blind study. Thromb Haemost. 2012 Nov;108(5):913-22.
• [15] ClinicalTrials.gov (NCT03588299) A Phase 1/2 Open-label Safety and Dose-finding Study of BAY2599023 (DTX201), an Adeno-associated Virus (AAV) hu37-mediated Gene Transfer of B-domain Deleted Human Factor VIII, in Adults With Severe Hemophilia A. U.S.National Institutes of Health.
• [16] Clinical pipeline report, company report or official report of Spark Therapeutics.
• [17] A reprieve from hemophilia A, but for how long? Nat Biotechnol. 2020 Oct;38(10):1107-1109.
• [18] A new recombinant factor VIII: from genetics to clinical use