Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTFEZ5Q)

• DTT Name: Coagulation factor IX (F9)
• Synonyms: Plasma thromboplastin component; PTC protein; Factor IX; Christmas factor
• Gene Name: F9
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: FA9_HUMAN
• TTD ID: T83369
• EC Number: EC 3.4.21.22
• Sequence:
  MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNL
  ERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCP
  FGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGR
  VSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPW
  QVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRII
  PHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVF
  HKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVE
  GTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT
• 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, phospholipids, and factor VIIIa.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Gamma-carboxylation of protein precursors (R-HSA-159740)
  Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus (R-HSA-159763)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  Extrinsic Pathway of Fibrin Clot Formation (R-HSA-140834)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Emicizumab	DM0AQ83	Factor VIII deficiency	3B10	Approved	[2]
Recombinant Factor IX	DMY7ESM	Bleeding disorder	GA20-GA21	Approved	[1]

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMT-061	DMSO02K	Haemophilia B	3B11.0	Phase 3	[3]
CSL-654	DMZJGVL	Factor IX deficiency	3B11	Phase 3	[4]
Fidanacogene elaparvovec	DMFZ81T	Haemophilia B	3B11.0	Phase 3	[5]
Mim8	DMX33ZR	Haemophilia A	3B10.0	Phase 3	[6]
RG6013	DMER75Y	Haemophilia A	3B10.0	Phase 3	[7]
TTP889	DMCQARM	Blood forming organ disorder	JB64.1	Phase 2	[8]
AMT-060	DM7RNKM	Factor IX deficiency	3B11	Phase 1/2	[9]
SB-FIX	DMUP52Y	Haemophilia B	3B11.0	Phase 1/2	[10]
AAV2-hFIX16	DMIDEKB	Factor IX deficiency	3B11	Phase 1	[11]
N9-GP	DM3IT6R	Factor IX deficiency	3B11	Phase 1	[12]
RG6512	DM8104I	Haemophilia A	3B10.0	Phase 1	[13]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RB-006	DMAINU1	Coronary artery disease	BA80	Discontinued in Phase 3	[14]
Trenonacog alfa	DM7RNPJ	Discovery agent	N.A.	Discontinued in Phase 3	[15]
SB 249417	DM2C0LN	Sepsis	1G40-1G41	Discontinued in Phase 1	[16]
Draculin	DMX4KIT	Thrombosis	DB61-GB90	Terminated	[17]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-Benzyloxybenzo[b]thiophene-2-carboxamidine	DM0T1NZ	Discovery agent	N.A.	Investigative	[18]
4-iodobenzo[b]thiophene 2-carboxamidine	DMXAEGF	N. A.	N. A.	Investigative	[18]
4-Phenyl-benzo[b]thiophene-2-carboxamidine	DMLZSH1	Discovery agent	N.A.	Investigative	[18]
5-Benzyloxy-benzo[b]thiophene-2-carboxamidine	DM8WB96	Discovery agent	N.A.	Investigative	[18]
6-Benzyloxybenzo[b]thiophene-2-carboxamidine	DMARP3M	Discovery agent	N.A.	Investigative	[18]
BNP-FIX	DMJY1KR	Factor IX deficiency	3B11	Investigative	[19]
F-9TG	DMYWERO	Factor IX deficiency	3B11	Investigative	[19]
Factor IX-XTEN	DMSQ3I9	Hemophilia	3B10.0	Investigative	[19]
Gamma-Carboxy-Glutamic Acid	DMZMCT0	Discovery agent	N.A.	Investigative	[20]
MG-1104	DMHR1GX	Factor IX deficiency	3B11	Investigative	[19]
MOD-3012	DMLYVQB	Factor IX deficiency	3B11	Investigative	[19]
PMID20121197C57	DMM49JO	Discovery agent	N.A.	Investigative	[21]
RAZAXABAN	DMPML15	Discovery agent	N.A.	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Neonatal sepsis	1G41	Whole blood	3.59E-01	-0.02	-0.12
Coronary artery disease	BA80-BA8Z	Peripheral blood	5.69E-01	-0.13	-0.45

References

• [1] BAX326 (RIXUBIS): a novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B. Ther Adv Hematol. 2014 Oct;5(5):168-80.
• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [3] Clinical pipeline report, company report or official report of uniQure.
• [4] Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012 September 20; 120(12): 2405-2411.
• [5] Factor IX assay discrepancies in the setting of liver gene therapy using a hyperfunctional variant factor IX-Padua. J Thromb Haemost. 2021 May;19(5):1212-1218.
• [6] ClinicalTrials.gov (NCT05878938) Open-label Safety Study in Adults and Adolescents With Haemophilia A With and Without FVIII Inhibitors Switching Directly From Emicizumab Prophylaxis to NNC0365-3769 (Mim8) Prophylaxis. U.S.National Institutes of Health.
• [7] Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost. 2014 Feb;12(2):206-13.
• [8] Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost. 2008 Mar;6(3):457-63.
• [9] Phase I/II clinical trial of AMT-060 for treating hemophilia B. uniQure N.V.
• [10] ClinicalTrials.gov (NCT02695160) Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects With Severe Hemophilia B. U.S. National Institutes of Health.
• [11] Assessing the potential for AAV vector genotoxicity in a murine model. Correction in: Blood. 2011 June 16; 117(24): 6739.
• [12] Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011 Sep 8;118(10):2695-701.
• [13] Clinical pipeline report, company report or official report of Roche
• [14] In-vitro evaluation of anti-factor IXa aptamer on thrombin generation, clotting time, and viscoelastometry. Thromb Haemost. 2009 May;101(5):827-33.
• [15] Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.Haemophilia.2012 Nov;18(6):881-7.
• [16] Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clin Pharmacol Ther. 2002 Apr;71(4):235-45.
• [17] Expression of biological activity of draculin, the anticoagulant factor from vampire bat saliva, is strictly dependent on the appropriate glycosylation of the native molecule. Biochim Biophys Acta. 1998 Oct 23;1425(2):291-9.
• [18] Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis. J Med Chem. 2010 Feb 25;53(4):1465-72.
• [19] 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: 2364).
• [20] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [21] Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors. J Med Chem. 2010 Feb 25;53(4):1473-82.
• [22] Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1795-8.