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

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

Contraindications & Blackbox Warnings

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Pharmacodynamics

The equilibrium dissociation constants (K_D) 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

Target	Actions	Organism
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) C_max 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 C_maxof 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.

Drug	Interaction
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Alendronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Alendronic acid.
Clodronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Clodronic acid.
Etidronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Etidronic acid.
Ibandronate	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Ibandronate.
Pamidronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Pamidronic acid.
Risedronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Risedronic acid.
Tiludronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Tiludronic acid.
Zoledronic acid	The risk or severity of jaw osteonecrosis and anti-angiogenesis can be increased when Aflibercept is combined with Zoledronic acid.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Eylea	Injection, solution	40 mg/1mL	Intravitreal	Regeneron Pharmaceuticals, Inc.	2011-11-21	Not applicable
Eylea	Injection, solution	40 mg/ml	Intravitreal	Bayer Ag	2016-09-08	Not applicable
Eylea	Solution	2 mg / 0.05 mL	Intravitreal	Bayer	2020-11-17	Not applicable
Eylea	Solution	2 mg / 0.05 mL	Intravitreal	Bayer	2013-12-23	Not applicable
Eylea	Injection, solution	40 mg/ml	Intravitreal	Bayer Ag	2016-09-08	Not applicable
Eylea Hd	Injection, solution	8 mg/0.07mL	Intravitreal	Regeneron Pharmaceuticals, Inc	2023-08-18	Not applicable
Eylea Hd	Injection, solution	8 mg/0.07mL	Intravitreal	Regeneron Pharmaceuticals, Inc	2023-08-18	Not applicable
Zaltrap	Injection, solution, concentrate	25 mg/ml	Intravenous	SANOFI WINTHROP INDUSTRIE	2016-09-08	Not applicable
Zaltrap	Solution, concentrate	100 mg/4mL	Intravenous	sanofi-aventis U.S. LLC	2012-08-03	Not applicable
Zaltrap	Injection, solution, concentrate	25 mg/ml	Intravenous	SANOFI WINTHROP INDUSTRIE	2016-09-08	Not applicable

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. [Article]
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]
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]
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]
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]
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]
FDA Approved Drug Products: EYLEA (aflibercept) injection for intravitreal use (February 2023) [Link]
FDA Approved Drug Products: ZALTRAP (ziv-aflibercept) injection for intravenous use (June 2020) [Link]
FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]
Aflibercept MSDS [Link]
ZALTRAP® (ZIV-AFLIBERCEPT) APPROVED IN THE EU FOR PATIENTS WITH PREVIOUSLY TREATED METASTATIC COLORECTAL CANCER [Link]
U.S. FDA APPROVES ZALTRAP® (ZIV-AFLIBERCEPT) AFTER PRIORITY REVIEW FOR PREVIOUSLY TREATED METASTATIC COLORECTAL CANCER [Link]
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]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Diabetic Macular Edema (DME)	4
4	Active Not Recruiting	Treatment	Diabetic Retinopathy (DR)	1
4	Completed	Other	Wet Macular Degeneration	1
4	Completed	Prevention	Diabetic Macular Edema (DME)	1
4	Completed	Treatment	Age - Related Macular Degeneration (AMD)	5
4	Completed	Treatment	Age - Related Macular Degeneration (AMD) / Polypoidal Choroidal Vasculopathy (PCV)	1
4	Completed	Treatment	AMD (With Persistent or Recurrent Fluid Despite Monthly Intravitreal Anti-VEGF Therapy)	1
4	Completed	Treatment	Anti Vascular Endothelial Growth Factor / Macular Degeneration	1
4	Completed	Treatment	Branch Retinal Vein Occlusion / Central Retinal Vein Occlusion (CRVO) / Diabetic Macular Edema (DME) / Retinal Vein Occlusion	1
4	Completed	Treatment	Central Retinal Vein Occlusion (CRVO)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravitreal
Injection, solution	Intravitreal	40 mg/1mL
Solution	Intravitreal	2 mg / 0.05 mL
Injection, solution	Intravitreal	40 mg/ml
Injection, solution	Intravitreal
Injection, solution	Intravitreal	8 mg/0.07mL
Injection, solution	Intravitreal	2.0 mg/50mcl
Solution	Intraocular	2 mg
Solution	Intraocular	11.120 mg
Injection	Intravenous
Injection, solution, concentrate	Intravenous	25 mg/1ml
Injection, solution, concentrate	Intravenous	25 mg/ml
Injection, solution, concentrate	Intravenous; Parenteral	25 MG/ML
Solution	Intravenous	100 mg / 4 mL
Solution	Intravenous	200 mg / 8 mL
Solution, concentrate	Intravenous	100 mg/4mL
Solution, concentrate	Intravenous	200 mg/8mL
Injection	Parenteral	100 mg/4ml
Injection	Parenteral
Injection, solution, concentrate	Intravenous	200 mg/8ml
Injection, solution, concentrate	Intravenous
Solution	Intravenous	25.0 mg/ml
Solution	Ophthalmic	40 mg/1ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
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

Properties

State

Liquid

Experimental Properties

Property	Value	Source
water solubility	>100 mg/mL	L47920

Targets

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Details1. Vascular endothelial growth factor A

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

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]
FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]

Details2. Placenta growth factor

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

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]
FDA Approved Drug Products: EYLEA® HD (aflibercept) injection, for intravitreal use (August 2023) [Link]

Details3. Vascular endothelial growth factor B

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

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 September 25, 2023 04:25

Aflibercept

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References

References