Identification

Name
Emicizumab
Accession Number
DB13923
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Emicizumab is a humanized recombinant monoclonal antibody that mimics the function of the coagulation Factor VIII and it has the capacity to bind simultaneously to activated Factor IX and Factor X. The ability of Emicizumab to bind to all these three different factors allows it to overcome immunogenicity and unstable hemostatic efficacy produced by previous Factor VII agents. Emicizumab was originated as an improved form of hBS23 and it was approved on November 16, 2017.[1, 8] It was created by Chugai Pharmaceuticals Co. Ltd. and co-developed with Roche and Genentech.[7]

Protein structure
Db13923
Protein chemical formula
C6434-H9940-N1724-O2047-S45
Protein average weight
145637.0 Da
Sequences
>>>Emicizumab heavy chain 1<<<<
QVQLVESGGGLVQPGGSLRLSCAASGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYY
RREVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRTGREYGGGWYFDYWGQGTLVT
VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGG
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQKE
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
QEGNVFSCSVMHEALHNRYTQKSLSLSP
>>>Emicizumab heavy chain 2<<<<
QVQLVQSGSELKKPGASVKVSCKASGYTFTDNNMDWVRQAPGQGLEWMGDINTRSGGSIY
NEEFQDRVIMTVDKSTDTAYMELSSLRSEDTATYHCARRKSYGYYLDEWGEGTLVTVSSA
STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQYNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQEGN
VFSCSVMHEALHNHYTQESLSLSP
>>>Emicizumab light chain<<<<
DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPD
RFSGSRYGTDFTLTISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG [Link]
Download FASTA Format
Synonyms
  • emicizumab-kxwh
External IDs
ACE 910 / ACE-910 / ACE910
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
HemlibraInjection, solution150 mg/1mLSubcutaneousGenentech, Inc.2017-11-16Not applicableUs
HemlibraInjection, solution30 mg/1mLSubcutaneousGenentech, Inc.2017-11-16Not applicableUs
HemlibraInjection, solution150 mg/1mLSubcutaneousGenentech, Inc.2017-11-16Not applicableUs
HemlibraInjection, solution150 mg/1mLSubcutaneousGenentech, Inc.2017-11-16Not applicableUs
Categories
UNII
7NL2E3F6K3
CAS number
1610943-06-0

Pharmacology

Indication

The main function of Emicizumab is the prevention of bleeding episodes. Thus, Emicizumab is approved for the routine prophylaxis to prevent or reduce the frequency of bleeding episodes of adult and pediatric patients with hemophilia A with or without Factor VIII inhibitors.[11]

Hemophilia A is a deficiency of coagulation Factor VIII which causes a serious bleeding disorder. The standard treatment is done with the administration of recombinant or serum-deriver Factor VIII which induces the formation of anti-factor VIII alloantibodies (Factor VIII inhibitors) and renders the standard treatment ineffective.[2]

Associated Conditions
Pharmacodynamics

Emicizumab mimics the function of coagulation factor VIII, therefore it binds to the activated form of Factor IX (Factor IXa). This binding forms a complex that will later bind to the X factor of the coagulation factor. [4] The ability of Emicizumab to interact with both factors (Factor IXa and Factor X) activates the coagulation cascade that will subsequently lead to the segmentation of fibrinogen into fibrin and the formation of blood clots.[3] The effect of Emicizumab is translated into the restoration of the blood coagulation process and, therefore, in the reduction of hemorrhagic episodes.[8] The activity of emicizumab can also produce changes in activated clotting time (ACT), activated partial thromboplastin time (aPTT) and one-step Factor VIII activity. [10] In addition, the unique bispecific structure of Emicizumab prevents the formation of Factor VIII inhibitors or their effect. [2]

In the first clinical trials, emicizumab was tried on previously treated adult and pediatric patients of hemophilia A with FVIII inhibitors. In this trials, the annualized bleeding rate requiring treatment with coagulation factors was reduced by 87% when compared to untreated patients.[12]

Those clinical trials were followed by a second round on previously treated patients of severe hemophilia A without FVIII inhibitors. In this trial, the annualized bleed rate was reduced by 96% when compared to untreated patients.[12]

Mechanism of action

Emicizumab exerts its action by performing the function of the coagulation Factor VIII without presenting a structural homology.[9] It presents a dual specificity which allows it to bind to both the Factor IXa and Factor X, performing the required bridging activity for the launch of the coagulation cascade.[2]

TargetActionsOrganism
ACoagulation factor IX
cofactor
Human
ACoagulation factor X
activator
Human
Absorption

Subcutaneous administration of Emicizumab presents a very high bioavailability ranging from 80.4% to 93.1% when administered subcutaneously in a dose of 1 mg/kg.[6] In clinical trials, at the same dose, Emicizumab presented a linear exposure which concentration peaked 1-2 weeks after administration and presented a profile framed by a Cmax of 5.92 mcg/ml and an AUC of 304 mcg day/ml.[1]

After subcutaneous administration, the absorption half-life was 1.7 days and the pharmacokinetic profile seemed to be shared when the medication was administered in the abdomen, upper arm, and thigh.[13]

Volume of distribution

The apparent volume of distribution is 11.4 L when administered subcutaneously and there are reports indicating that this value can increase with increasing body weight.[6] When emicizumab is administered intravenously, the volume of distribution at steady state is 106 ml/kg.[13]

Protein binding

As emicizumab is a monoclonal antibody acting on the bloodstream, the determination of protein binding studies is not required.

Metabolism

Emicizumab is a monoclonal antibody and thus, it is thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling. Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis.[5]

Route of elimination

The elimination of Emicizumab was monophasic in clinical trials.[1]

Half life

Emcicizumab presents a long half-life ranging from 27.8 to 34.4 days.[Label]

Clearance

The apparent clearance is 0.24 L/day when administered in multiple subcutaneous injections and there are reports indicating that this value can increase with increasing body weight.[6]

Toxicity

The administration of Emicizumab has reported cases of microangiopathy and thrombotic events with concomitant use of activated prothrombin complex concentrate at doses higher of 100 U/kg/24 hours. There are also reports of injection site reaction, headaches and arthralgia.[10]

Genotoxicity and carcinogenicity studies have not been performed as it is not expected that emicizumab can have any interaction with DNA, or chromosomal material.[13]

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Emicizumab can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Emicizumab can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Emicizumab can be decreased when used in combination with 4-hydroxycoumarin.
AbciximabThe therapeutic efficacy of Emicizumab can be decreased when used in combination with Abciximab.
AbituzumabThe risk or severity of adverse effects can be increased when Abituzumab is combined with Emicizumab.
AcenocoumarolThe therapeutic efficacy of Emicizumab can be decreased when used in combination with Acenocoumarol.
Acetylsalicylic acidThe therapeutic efficacy of Emicizumab can be decreased when used in combination with Acetylsalicylic acid.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Emicizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Emicizumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Emicizumab.
Food Interactions
Not Available

References

General References
  1. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, Shima M: A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016 Mar 31;127(13):1633-41. doi: 10.1182/blood-2015-06-650226. Epub 2015 Dec 1. [PubMed:26626991]
  2. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Fukazawa N, Yoneyama K, Yoshida H, Nogami K: Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med. 2016 May 26;374(21):2044-53. doi: 10.1056/NEJMoa1511769. [PubMed:27223146]
  3. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  4. Nogami K: Bispecific antibody mimicking factor VIII. Thromb Res. 2016 May;141 Suppl 2:S34-5. doi: 10.1016/S0049-3848(16)30361-9. [PubMed:27207420]
  5. Tabrizi MA, Tseng CM, Roskos LK: Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006 Jan;11(1-2):81-8. doi: 10.1016/S1359-6446(05)03638-X. [PubMed:16478695]
  6. Yoneyama K, Schmitt C, Kotani N, Levy GG, Kasai R, Iida S, Shima M, Kawanishi T: A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A. Clin Pharmacokinet. 2018 Sep;57(9):1123-1134. doi: 10.1007/s40262-017-0616-3. [PubMed:29214439]
  7. Roche news [Link]
  8. Bussiness wire [Link]
  9. Roche study [Link]
  10. Genentech professionals information [Link]
  11. FDA news [Link]
  12. FDA news [Link]
  13. Hemlibra (Emicizumab) EMA label [File]
External Links
Wikipedia
Emicizumab
FDA label
Download (592 KB)
MSDS
Download (1.25 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers / Hemophilia A1
3Active Not RecruitingPreventionHemophilia A1
3Active Not RecruitingTreatmentHemophilia A3
3RecruitingPreventionHemophilia A1
3RecruitingTreatmentHemophilia A1
4RecruitingTreatmentHemophilia A1
Not AvailableAvailableNot AvailableHemophilia A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous150 mg/1mL
Injection, solutionSubcutaneous30 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)78ºC Ji-Hee, et al. Front Immunol, 7:394 (2016)
boiling point (°C)Fab and Fc domains denaturates at 60 and 70 ºC respectivelyArnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubility50 mg/mlHuman IgG purified. Product Information
isoelectric point6.6 - 7.2Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

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
Human
Pharmacological action
Yes
Actions
Cofactor
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. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, Shima M: A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016 Mar 31;127(13):1633-41. doi: 10.1182/blood-2015-06-650226. Epub 2015 Dec 1. [PubMed:26626991]
  2. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Fukazawa N, Yoneyama K, Yoshida H, Nogami K: Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med. 2016 May 26;374(21):2044-53. doi: 10.1056/NEJMoa1511769. [PubMed:27223146]
  3. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  4. Nogami K: Bispecific antibody mimicking factor VIII. Thromb Res. 2016 May;141 Suppl 2:S34-5. doi: 10.1016/S0049-3848(16)30361-9. [PubMed:27207420]
Kind
Protein
Organism
Human
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. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, Shima M: A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016 Mar 31;127(13):1633-41. doi: 10.1182/blood-2015-06-650226. Epub 2015 Dec 1. [PubMed:26626991]
  2. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Fukazawa N, Yoneyama K, Yoshida H, Nogami K: Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med. 2016 May 26;374(21):2044-53. doi: 10.1056/NEJMoa1511769. [PubMed:27223146]
  3. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  4. Nogami K: Bispecific antibody mimicking factor VIII. Thromb Res. 2016 May;141 Suppl 2:S34-5. doi: 10.1016/S0049-3848(16)30361-9. [PubMed:27207420]

Drug created on November 16, 2017 11:12 / Updated on November 02, 2018 07:47