Caplacizumab

Identification

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Name
Caplacizumab
Accession Number
DB06081
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Caplacizumab, firstly called ALX-0081, is a humanized single-variable-domain immunoglobulin consisting of two identical humanized building blocks genetically linked by a three-alanine linker. Caplacizumab was developed by Ablynx, a Sanofi company and FDA approved on February 6, 2019,6 and approved previously by the EU in October 2018 as a combination therapy with plasma exchange and immunosuppression.1

Protein structure
Db06081
Protein chemical formula
C1213H1891N357O380S10
Protein average weight
27880.0 Da
Sequences
>>Caplacizumab<<<
EVQLVESGGGLVQPGGSLRLSCAASGRTFSYNPMGWFRQAPGKGRELVAAISRTGGSTYY
PDSVEGRFTISRDNAKRMVYLQMNSLRAEDTAVYYCAAAGVRAEDGRVRTLPSEYTFWGQ
GTQVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTFSYNPMGWFRQAPGKGRELVA
AISRTGGSTYYPDSVEGRFTISRDNAKRMVYLQMNSLRAEDTAVYYCAAAGVRAEDGRVR
TLPSEYTFWGQGTQVTVSS
References:
  1. Cablivi (caplacizumab) EMA label [File]
Download FASTA Format
Synonyms
  • caplacizumab-yhdp
External IDs
ALX 0081 / ALX 0681 / ALX-0081
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CabliviKit11 mg/1mLIntravenous; SubcutaneousGenzyme Corporation2019-02-06Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
2R27AB6766
CAS number
915810-67-2

Pharmacology

Indication

Capacizumab is approved for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP) in conjunction with plasma exchange and immunosuppression in patients 18 years or older.1,6

aTTP is a rare autoimmune condition presented by a disruption of blood clotting order which is translated into systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia and organ ischemia. It is caused by the production of autoantibodies against ADAMTS-13 which is the protein in charge of cleaving the von-Wilebrand factor. The lack of this process produces the generation of ultra large von Wilebrand multimers that bind to platelets and form microthrombi and causing thromboembolic complications.3

Previously, capacizumab was under review for the prevention of thrombosis in high-risk patients with acute coronary syndrome undergoing percutaneous coronary intervention but this indication was withdrawn.1

Associated Conditions
Pharmacodynamics

In vitro studies have shown a caplacizumab-driven complete inhibition of platelet aggregation and in phase II clinical trials, it was shown to reduce the activity of the von Willebrand factor by 20% from treatment day 1 until treatment day 30. The level of von Willebrand factor in the plasma was also significantly reduced due to the clearance of the von Willebrand-caplacizumab complex.1

In phase III clinical trials, more than 50% of the tested individuals reached a platelet normal count. In these trials, it was observed as well a significant reduction in the incidence of aTTP1 as well as a significant reduction in the median time to response of about 39%.4 However, as caplacizumab does not target autoimmune response, relapses were observed after treatment discontinuation.2

The last clinical trial prior approval showed production of a platelet count of more than 150,000 per mcl after the cessation of plasma exchange therapy for 5 days as well as a reduction of patient recurrent thrombotic thrombocytopenic purpura and of disease-related death during treatment.6

Mechanism of action

Caplacizumab acts by targetting the A1 domain of the ultra-large von Willebrand factor which in order inhibits the interaction with the glycoprotein Ib-IX-V receptor in the platelets. Caplacizumab binds to von Willebrand factor with an affinity of 8.5 nM, thus it is very target specific.[5305] The blockage of the von Willebrand factor prevents the interaction between the von Willebrand factor and the platelets, hence, preventing platelet aggregation.1

TargetActionsOrganism
Uvon Willebrand factorNot AvailableHumans
Additional Data Available
Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

After intravenous administration of caplacizumab, the pharmacokinetic profile is non-linear and to follow a non-compartmental model as the pharmacokinetic profile of this drug is dependent on the expression of von Willebrand factor. After administration, caplacizumab is rapidly absorbed with a dose-dependent behavior. The peak concentration was reached after 6-7 hours1 and it presents a very high bioavailability reaching approximately 90%.9

The subcutaneous administration of a dose of 10 mg of caplacizumab produced a peak concentration of 528 ng/ml and an AUC of 7951 ng.h/ml.8

Volume of distribution

The reported volume of distribution of caplacizumab is 6.33 L.1

Protein binding

This antibody acts directly on plasma proteins and thus, this parameter is not significant for drug description.

Metabolism

Caplacizumab is 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 caplacizumab is divided between target-driven disposition which is driven by the binding to the von Willebrand factor and non-target disposition driven by the combination of catabolism and renal elimination.9

Half life

The reported half-life is reported to be in the range of 16-27 hours.9

Clearance

As the elimination is highly divided among hepatic, target-driven and renal elimination, the calculation of the clearance rate is not significant for drug description.

Toxicity

Cases of overdose are represented by an increased risk of bleeding and in these cases, external administration of von Willebrand factor concentrate should be done.Label

To this point, there have not been performed studies regarding the effect on fertility, genotoxicity, or carcinogenicity

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Caplacizumab is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Caplacizumab is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Caplacizumab is combined with 4-hydroxycoumarin.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of bleeding and hemorrhage can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Caplacizumab.
AbciximabThe risk or severity of bleeding can be increased when Caplacizumab is combined with Abciximab.
AbituzumabThe risk or severity of adverse effects can be increased when Caplacizumab is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Caplacizumab is combined with Abrilumab.
AceclofenacThe risk or severity of bleeding can be increased when Aceclofenac is combined with Caplacizumab.
AcemetacinThe risk or severity of bleeding can be increased when Acemetacin is combined with Caplacizumab.
AcenocoumarolThe risk or severity of bleeding can be increased when Caplacizumab is combined with Acenocoumarol.
Additional Data Available
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  • Action
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Food Interactions
Not Available

References

General References
  1. Duggan S: Caplacizumab: First Global Approval. Drugs. 2018 Oct;78(15):1639-1642. doi: 10.1007/s40265-018-0989-0. [PubMed:30298461]
  2. Coppo P, Cuker A, George JN: Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine. Res Pract Thromb Haemost. 2018 Nov 16;3(1):26-37. doi: 10.1002/rth2.12160. eCollection 2019 Jan. [PubMed:30656273]
  3. Peyvandi F, Scully M, Kremer Hovinga JA, Knobl P, Cataland S, De Beuf K, Callewaert F, De Winter H, Zeldin RK: Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2017 Jul;15(7):1448-1452. doi: 10.1111/jth.13716. Epub 2017 Jun 5. [PubMed:28445600]
  4. Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knobl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D: Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11;374(6):511-22. doi: 10.1056/NEJMoa1505533. [PubMed:26863353]
  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. FDA news [Link]
  7. Guide to Pharmacology [Link]
  8. Clinical trials [Link]
  9. Cablivi (caplacizumab) EMA label [File]
External Links
Wikipedia
Caplacizumab
ATC Codes
B01AX07 — Caplacizumab
FDA label
Download (1.21 MB)
MSDS
Download (92 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentNon ST Segment Elevation Myocardial Infarction (NSTEMI) / Stable Angina (Associated With High Risk PCI) / Unstable Angina Pectoris1
3Active Not RecruitingTreatmentAcquired Thrombotic Thrombocytopenic Purpura1
3CompletedTreatmentAcquired Thrombotic Thrombocytopenic Purpura1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
KitIntravenous; Subcutaneous11 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)61 ºC (Fab fragment)Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)
boiling point (°C)Fab fragment denaturates at 60 ºCArnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubilitySolubleAcqua E. Can Caplacizumab be a potential first drug therapy for Thrombotic Thrombocytopenic Purpura?.
isoelectric point 6.6 - 7.2 Jin, 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
Humans
Pharmacological action
Unknown
General Function
Protein n-terminus binding
Specific Function
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surf...
Gene Name
VWF
Uniprot ID
P04275
Uniprot Name
von Willebrand factor
Molecular Weight
309261.83 Da

Drug created on November 18, 2007 11:29 / Updated on May 01, 2019 10:01