Aflibercept

Identification

Summary

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor used to treat Neovascular (Wet) Age-Related Macular Degeneration (AMD), various types of macular edema and diabetic retinopathy, and metastatic colorectal cancer

Brand Names
Eylea, Zaltrap
Generic Name
Aflibercept
DrugBank Accession Number
DB08885
Background

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors, VEGFR1 and VEGFR2, fused with the Fc region of human immunoglobulin gamma 1 (IgG1).3 Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa).4 It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa.9 All five putative N-glycosylation sites on each polypeptide chain predicted by the primary sequence can be occupied with carbohydrates 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.5,6 Due to the 2 fused VEGFR, aflibercept has a higher affinity to the cognate ligands than the endogenous individual receptor. However, it lacks the intracellular structure to propagate subsequent signal transduction, thus essentially sequestering the ligands to prevent activation of VEGFR.3,9

Ziv-aflibercept, under the brand name Zaltrap, was developed as an intravenous injection for the treatment of metastatic colorectal cancer, and it was approved by the FDA and EMA in August 2012 and February 2013, respectively.11,12 The intravitreal formulation, under the brand name EYELEA, was approved by the FDA for the treatment of retinopathy of prematurity in preterm infants in February 2023 and for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy in August 2023.13 An aflibercept biosimilar, Yesafili, was approved for use in the EU in September 2023.14

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Fusion proteins
Protein Chemical Formula
C4318H6788N1164O1304S32
Protein Average Weight
115000.0 Da (with glycosylation, constituting an additional 15% of the total molecular mass)
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 macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), and retinopathy of prematurity (ROP).7

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.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofBranch retinal vein occlusion with macular edema••••••••••••••••••••
Treatment ofCentral retinal vein occlusion with macular edema••••••••••••••••••••
Management ofDiabetic macular edema•••••••••••••••••••••
Treatment ofDiabetic macular edema (dme)••••••••••••••••••••
Management ofDiabetic retinopathy•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The equilibrium dissociation constants (KD) for aflibercept for various human receptors are as follow: 0.5 pM for VEGF-A165, 0.36 pM for VEGF-A121, 1.92 pM for VEGF-B, and 39 pM for PlGF-2.8

The effect of 6 mg per kg intravenous aflibercept every three weeks on QTc interval was evaluated in 87 patients with solid tumors in a randomized, placebo-controlled study. No large changes in the mean QT interval from baseline (i.e., greater than 20 ms as corrected for placebo) based on the Fridericia correction method were detected in the study. However, a small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded due to the limitations of the study design.8

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.8,9

TargetActionsOrganism
AVascular endothelial growth factor A
inhibitor
binder
Humans
APlacenta growth factor
inhibitor
binder
Humans
AVascular endothelial growth factor B
inhibitor
binder
Humans
Absorption

Following unilateral intravitreal administration of 8 mg aflibercept, the mean (SD) Cmax of free aflibercept in plasma was 0.30 (0.27) mg/L, and the median time to maximal concentration in plasma was 2.9 days. The accumulation of free aflibercept in plasma following three initial monthly intravitreal doses was minimal (mean accumulation ratio 1.2); subsequently, no further accumulation was observed.9

In patients with wet age-related macular degeneration (AMD), retinopathy of prematurity (RVO), and diabetic macular edema (DME), the mean Cmaxof free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days following intravitreal administration of 2 mg per eye.7 The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients.7

Volume of distribution

The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept is approximately 7 L.9

Protein binding

No information is available on the protein binding of aflibercept.

Metabolism

Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis.9

Route of elimination

Not Available

Half-life

For the intravitreal formulation, the half-life was estimated to be 7.13 days.3 For the intravenous formulation, following a dose of 4 mg per kg every two weeks administered intravenously, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4-7 days).8

Clearance

Following an hour of intravenous infusion of 2 to 9 mg/kg every 2 or 3 week in cancer patients, the clearances of free and bound aflibercept were estimated to be 0.88 L/day and 0.14 L/day respectively.2 Healthy subjects have a similar clearance of free aflibercept but slightly faster clearance of bound aflibercept (0.19 L/day).2 Patients with a low albumin or high alkaline phosphatase levels also typically exhibit faster clearance of free aflibercept.2

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.9

Adequate and well-controlled studies with aflibercept have not been conducted in pregnant women. Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations. A fetal No Observed Adverse Effect Level (NOAEL) was not identified. At the lowest dose shown to produce adverse embryofetal effects, systemic exposure (based on AUC for free aflibercept) was approximately 0.9 -fold of the population pharmacokinetic estimated exposure in humans after an intravitreal dose of 8 mg.9

Animal reproduction studies are not always predictive of human response, and it is not known whether EYLEA HD can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for aflibercept, treatment with aflibercept may pose a risk to human embryofetal development. Aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.9

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.9

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. All changes were reversible within 20 weeks after cessation of treatment. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free aflibercept that was 91 times higher than the population pharmacokinetic estimated systemic exposure in humans after an intravitreal dose of 8 mg.9

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.
DrugInteraction
Alendronic acidThe risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Alendronic acid.
Clodronic acidThe risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Clodronic acid.
Etidronic acidThe risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Etidronic acid.
IbandronateThe risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Ibandronate.
Pamidronic acidThe risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Pamidronic acid.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EyleaInjection, solution40 mg/mlIntravitrealBayer Ag2016-09-08Not applicableEU flag
EyleaInjection, solution40 mg/mlIntravitrealBayer Ag2016-09-08Not applicableEU flag
EyleaSolution2 mg / 0.05 mLIntravitrealBayer2020-11-17Not applicableCanada flag
EyleaSolution2 mg / 0.05 mLIntravitrealBayer2013-12-23Not applicableCanada flag
EyleaInjection, solution40 mg/1mLIntravitrealRegeneron Pharmaceuticals, Inc.2011-11-21Not applicableUS flag

Categories

ATC Codes
S01LA05 — AfliberceptL01XX44 — Aflibercept
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
15C2VL427D
CAS number
862111-32-8

References

General References
  1. 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. [Article]
  2. 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. [Article]
  3. Sophie R, Akhtar A, Sepah YJ, Ibrahim M, Bittencourt M, Do DV, Nguyen QD: Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases. Biol Ther. 2012 May 29;2(1):3. doi: 10.1007/s13554-012-0003-4. eCollection 2012. [Article]
  4. Moreno MR, Tabitha TS, Nirmal J, Radhakrishnan K, Yee CH, Lim S, Venkatraman S, Agrawal R: Study of stability and biophysical characterization of ranibizumab and aflibercept. Eur J Pharm Biopharm. 2016 Nov;108:156-167. doi: 10.1016/j.ejpb.2016.09.003. Epub 2016 Sep 8. [Article]
  5. Lee JY, Choi JW, Hwang S, Hahm SH, Ahn YH: Site-Specific Glycan Microheterogeneity Evaluation of Aflibercept Fusion Protein by Glycopeptide-Based LC-MSMS Mapping. Int J Mol Sci. 2022 Oct 5;23(19):11807. doi: 10.3390/ijms231911807. [Article]
  6. Shen Z, Wang Y, Xu H, Zhang Q, Sha C, Sun B, Li Q: Analytical comparability assessment on glycosylation of ziv-aflibercept and the biosimilar candidate. Int J Biol Macromol. 2021 Jun 1;180:494-509. doi: 10.1016/j.ijbiomac.2021.03.020. Epub 2021 Mar 6. [Article]
  7. FDA Approved Drug Products: EYLEA (aflibercept) injection for intravitreal use (February 2023) [Link]
  8. FDA Approved Drug Products: ZALTRAP (ziv-aflibercept) injection for intravenous use (June 2020) [Link]
  9. FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]
  10. Aflibercept MSDS [Link]
  11. ZALTRAP® (ZIV-AFLIBERCEPT) APPROVED IN THE EU FOR PATIENTS WITH PREVIOUSLY TREATED METASTATIC COLORECTAL CANCER [Link]
  12. U.S. FDA APPROVES ZALTRAP® (ZIV-AFLIBERCEPT) AFTER PRIORITY REVIEW FOR PREVIOUSLY TREATED METASTATIC COLORECTAL CANCER [Link]
  13. EYLEA HD (AFLIBERCEPT) INJECTION 8 MG APPROVED BY FDA FOR TREATMENT OF WET AGE-RELATED MACULAR DEGENERATION (WAMD), DIABETIC MACULAR EDEMA (DME) AND DIABETIC RETINOPATHY (DR) [Link]
  14. AJMC Center for Biosimilars: European Commission Approves First Aflibercept Biosimilar [Link]
KEGG Drug
D09574
PubChem Substance
347910379
RxNav
1232150
ChEMBL
CHEMBL1742982
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aflibercept
MSDS
Download (91.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentDiabetic Macular Edema (DME)4
4Active Not RecruitingTreatmentDiabetic Retinopathy (DR)1
4Active Not RecruitingTreatmentNeovascular Age-Related Macular Degeneration (nAMD)1
4CompletedOtherWet Macular Degeneration1
4CompletedPreventionDiabetic Macular Edema (DME)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravitreal
Injection, solutionIntravitreal114.3 mg/ml
Injection, solutionIntravitreal40 mg/1mL
SolutionIntravitreal2 mg / 0.05 mL
Injection, solutionIntravitreal40 mg/ml
Injection, solutionIntravitreal
Injection, solutionIntravitreal8 mg/0.07mL
Injection, solutionIntravitreal2.0 mg/50mcl
SolutionIntraocular2 mg
SolutionIntraocular11.120 mg
InjectionIntravenous
Injection, solution, concentrateIntravenous25 mg/1ml
Injection, solution, concentrateIntravenous25 mg/ml
Injection, solution, concentrateIntravenous; Parenteral25 MG/ML
SolutionIntravenous100 mg / 4 mL
SolutionIntravenous200 mg / 8 mL
Solution, concentrateIntravenous100 mg/4mL
Solution, concentrateIntravenous200 mg/8mL
InjectionParenteral100 mg/4ml
InjectionParenteral
Injection, solution, concentrateIntravenous200 mg/8ml
Injection, solution, concentrateIntravenous
SolutionIntravenous25.0 mg/ml
SolutionIntravenous25.000 mg
SolutionOphthalmic40 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7306799No2007-12-112020-05-23US flag
US7531173No2009-05-122026-02-02US flag
US7374758No2008-05-202020-05-23US flag
US7608261No2009-10-272027-06-14US flag
US7070959No2006-07-042020-05-23US flag
US7374757No2008-05-202020-05-23US flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
water solubility>100 mg/mLL47920

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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
  1. 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. [Article]
  2. FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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
  1. 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. [Article]
  2. FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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
  1. 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. [Article]

Drug created at May 24, 2013 21:16 / Updated at April 13, 2024 19:42