Aflibercept

Identification

Name

Aflibercept

Accession Number

DB08885

Description

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors fused with the Fc region of human immunoglobulin gamma 1 (IgG1). Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa). It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa. All five putative N-glycosylation sites on each polypeptide chain predicted by the primary sequence can be occupied with carbohydrate and exhibit some degree of chain heterogeneity, including heterogeneity in terminal sialic acid residues, except at the single unsialylated site associated with the Fc domain. Aflibercept, as an ophthalmic agent, is used in the treatment of macular edema following Central Retinal Vein Occlusion (CRVO) and neovascular Age-Related Macular Degeneration (AMD). Ziv-aflibercept, under the brand name Zaltrap, was developed as an injection for treatment of metastatic colorectal cancer. FDA approved in November 18, 2011 and EMA approved in November 2012.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Fusion proteins

Protein Chemical Formula

C₄₃₁₈H₆₇₈₈N₁₁₆₄O₁₃₀₄S₃₂

Protein Average Weight

115000.0 Da (with glycosylation)

Sequences

> Protein sequence for aflibercept
SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS
RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL
VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ
GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR
TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPG

Download FASTA Format

Synonyms

Aflibercept
Aflibercept (genetical recombination)
Ziv-aflibercept

External IDs

AVE 0005
AVE 005
AVE-0005
AVE0005
Bay 86-5321
BAY-865321
Bay86-5321

Pharmacology

Indication

The opthalmic agent is used for the treatment of neovascular (wet) age-related mascular degeneration (AMD) and macular edema following central retinal vein occulsion (CRVO). The systemic injection, known as ziv-aflibercept, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is for the treatment of metastatic colorectal cancer that is resistant to or progressed following treatment with oxaliplatin.

Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Compared to other anti-VEGF drugs like bevacizumab and ranibizumab, aflibercept has a higher binding affinity to VEGF-A (Kd = 0.5 pM).

Mechanism of action

Ablibercept is a recombinant fusion protein that acts as a decoy receptor for the ligands, vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). It prevents these ligands to binding to endothelial receptors, VEGFR-1 and VEGFR-2, to suppress neovascularization and decrease vascular permeability. This ultimately will slow vision loss or the progression of metastatic colorectal cancer.

Target	Actions	Organism
AVascular endothelial growth factor A	binder	Humans
APlacenta growth factor	binder	Humans
AVascular endothelial growth factor B	binder	Humans

Absorption

In patients with wet AMD and CRVO, the mean peak plasma concentration (Cmax) was 0.02 mcg/mL and 0.05 mcg/mL respectively. These concentrations were reached in 1 to 3 days. Aflibercept did not accumulate when administered as repeated doses intravitreally every 4 weeks.

Volume of distribution

After intravenous injection of aflibercept, the volume of distribution is 6 L.

Protein binding

Not Available

Metabolism

Because aflibercept is a protein, it is expected to be broken down via proteolysis into smaller peptides and amino acids. The cytochrome P450 enzyme system is not involved in the metabolism of aflibercept.

Route of elimination

Via kidney and liver

Half-life

Intravitreal half-life= 7.13 days in humans; Terminal elimination half-life of free aflibercept in plasma was 5 to 6 days after IV injection of 2 - 4 mg/kg dose.

Clearance

When cancer patients were given 2-9 mg/kg every 2 or 3 week; 1 hour IV infusion of aflibercept the typical estimated clearances were as follows: CL of free aflibercept (CLf) = 0.88 L/day; CL of bound aflibercept (CLf) = 0.19 L/day; Patients clear free aflibercept faster if they had low albumin or high alkaline phosphatase levels.

Adverse Effects

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Toxicity

For all intravitreal VEGF inhibitors, there is increased risk of stroke and myocardial infarction. An increase in intraocular pressure may also occur. When used intravenously, most common adverse reactions were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: Not Available

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Eylea	Solution	40 mg	Intravitreal	Bayer	2020-11-17	Not applicable
Eylea	Injection, solution	40 mg/ml	Intravitreal	Bayer Ag	2012-11-22	Not applicable
Eylea	Solution	40 mg	Intravitreal	Bayer	2013-12-23	Not applicable
Eylea	Injection, solution	40 mg/1mL	Intravitreal	Regeneron Pharmaceuticals, Inc.	2011-11-21	Not applicable
Eylea	Injection, solution	40 mg/ml	Intravitreal	Bayer Ag	2012-11-22	Not applicable
Zaltrap	Injection, solution, concentrate	25 mg/ml	Intravenous	Sanofi Aventis Groupe	2016-09-08	Not applicable
Zaltrap	Solution	200 mg	Intravenous	Sanofi Aventis	2014-05-08	2020-07-13
Zaltrap	Solution, concentrate	200 mg/8mL	Intravenous	sanofi-aventis U.S. LLC	2012-08-03	Not applicable
Zaltrap	Injection, solution, concentrate	25 mg/ml	Intravenous	Sanofi Aventis Groupe	2016-09-08	Not applicable
Zaltrap	Solution	100 mg	Intravenous	Sanofi Aventis	2014-05-08	2020-07-13

Additional Data Available

Application Number

Available for Purchase

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

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Product Code

Available for Purchase

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

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Chemical Identifiers

UNII: 15C2VL427D
CAS number: 862111-32-8

References

General References

Freund KB, Mrejen S, Gallego-Pinazo R: An update on the pharmacotherapy of neovascular age-related macular degeneration. Expert Opin Pharmacother. 2013 Jun;14(8):1017-28. doi: 10.1517/14656566.2013.787410. Epub 2013 Apr 8. [PubMed:23560774]
Thai HT, Veyrat-Follet C, Mentre F, Comets E: Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Jul;72(1):167-80. doi: 10.1007/s00280-013-2182-1. Epub 2013 May 15. [PubMed:23673444]

External Links

KEGG Drug: D09574
PubChem Substance: 347910379
RxNav: 1232150
ChEMBL: CHEMBL1742982
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Aflibercept

AHFS Codes

10:00.00 — Antineoplastic Agents
52:92.00 — EENT Drugs, Miscellaneous

FDA label

Download (325 KB)

MSDS

Download (91.1 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Other	Wet Macular Degeneration	1
4	Active Not Recruiting	Treatment	Age Related Macular Degeneration (ARMD) / Age-Related Macular Degeneration (ARMD) / Polypoidal Choroidal Vasculopathy (PCV)	1
4	Active Not Recruiting	Treatment	Diabetic Macular Edema (DME)	2
4	Active Not Recruiting	Treatment	Diabetic Retinopathy (DR)	1
4	Completed	Basic Science	Neovascular Age-Related Macular Degeneration	1
4	Completed	Prevention	Diabetic Macular Edema (DME)	1
4	Completed	Treatment	Age - Related Macular Degeneration (AMD)	1
4	Completed	Treatment	Age Related Macular Degeneration (ARMD) / Age-Related Macular Degeneration (ARMD)	2
4	Completed	Treatment	Age-Related Macular Degeneration (ARMD)	2
4	Completed	Treatment	AMD (With Persistent or Recurrent Fluid Despite Monthly Intravitreal Anti-VEGF Therapy)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravitreal	40 MG/ML
Injection, solution	Intravitreal	40 mg/1mL
Injection, solution	Intravitreal	40 mg/ml
Solution	Intravitreal	40 mg
Solution	Intraocular	2 mg
Injection	Intravenous	25 MG/ML
Injection, solution, concentrate	Intravenous	100 mg/4mL
Injection, solution, concentrate	Intravenous	25 mg/ml
Injection, solution, concentrate	Intravenous; Parenteral	25 MG/ML
Solution	Intravenous	100 mg
Solution	Intravenous	200 mg
Solution, concentrate	Intravenous	100 mg/4mL
Solution, concentrate	Intravenous	200 mg/8mL
Injection	Intravenous	100 mg/4ml
Injection, solution, concentrate	Intravenous	200 mg/8ml
Injection, solution	Intravitreal	1.75 mg/0.07mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
Unlock Additional Data
US7306799	No	2007-12-11	2020-05-23
US7531173	No	2009-05-12	2026-02-02
US7374758	No	2008-05-20	2020-05-23
US7608261	No	2009-10-27	2027-06-14
US7070959	No	2006-07-04	2020-05-23
US7374757	No	2008-05-20	2020-05-23

Additional Data Available

Filed On

Available for Purchase

The date on which a patent was filed with the relevant government.

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Properties

State

Liquid

Experimental Properties

Property	Value	Source
water solubility	>100 mg/mL	MSDS

Targets

Details1. Vascular endothelial growth factor A

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Binder

General Function: Vascular endothelial growth factor receptor binding
Specific Function: Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of...
Gene Name: VEGFA
Uniprot ID: P15692
Uniprot Name: Vascular endothelial growth factor A
Molecular Weight: 27042.205 Da

References

Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [PubMed:22813448]

Details2. Placenta growth factor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Binder

General Function: Heparin binding
Specific Function: Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1/VEGFR-1. Isoform PlGF-2 binds NRP1/neuropilin-1 and NR...
Gene Name: PGF
Uniprot ID: P49763
Uniprot Name: Placenta growth factor
Molecular Weight: 24788.45 Da

References

Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [PubMed:22813448]

Details3. Vascular endothelial growth factor B

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Binder

General Function: Vascular endothelial growth factor receptor 1 binding
Specific Function: Growth factor for endothelial cells. VEGF-B167 binds heparin and neuropilin-1 whereas the binding to neuropilin-1 of VEGF-B186 is regulated by proteolysis.
Gene Name: VEGFB
Uniprot ID: P49765
Uniprot Name: Vascular endothelial growth factor B
Molecular Weight: 21601.56 Da

References

Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [PubMed:22813448]