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1.  The clinical utility of aflibercept for diabetic macular edema 
The treatment of center-involving diabetic macular edema (DME) has improved because of the proven efficacy of drugs that inhibit the effects of vascular endothelial growth factor (VEGF). The newest anti-VEGF drug, aflibercept, has recently been approved by the United States Food and Drug Administration for the treatment of center-involving DME and for diabetic retinopathy in eyes with DME. In the pivotal Phase III VISTA and VIVID trials, intravitreal aflibercept 2 mg injections every 4 or 8 weeks (after 5 monthly loading doses) produced superior gains in BCVA compared to laser/sham injections. In the Diabetic Retinopathy Clinical Research Network Protocol T trial, which featured monthly anti-VEGF monotherapy for 6 months, followed by monthly pro re nata anti-VEGF injections with laser rescue therapy from months 6 through 12, aflibercept 2 mg monthly was superior to bevacizumab 1.25 mg and ranibizumab 0.5 mg in eyes with BCVA of 20/50 or worse (aflibercept versus bevacizumab: P<0.001; aflibercept versus ranibizumab: P=0.003), but the three regimens were comparable for eyes with VA of 20/40 or better. Only in the 20/50 or worse subgroup did aflibercept achieve clinical superiority (>5 letter difference) to bevacizumab. Each treatment regimen led to significant macular thinning, with aflibercept being superior to bevacizumab in both visual acuity subgroups (P<0.001 for each), but it was not statistically superior to ranibizumab in either group. In diabetic patients, aflibercept has an excellent safety profile that does not appear to differ from laser/sham or other VEGF inhibitory drugs.
PMCID: PMC4583120  PMID: 26425104
aflibercept; bevacizumab; diabetic macular edema; ranibizumab; vascular endothelial growth factor
2.  Aflibercept 
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOL-FOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
PMCID: PMC3710732  PMID: 23444216
3.  Aflibercept in wet AMD: specific role and optimal use 
Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy.
This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used “older” anti-VEGF drugs.
For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English.
Results and conclusion
Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.
PMCID: PMC3749085  PMID: 23990705
aflibercept; AMD; neovascularization; VEGF; VEGF inhibition; VEGF-Trap eye
4.  Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration 
Choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF) has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA®), initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to illustrate the efficacy of aflibercept for managing treatment-naïve CNV, recalcitrant CNV, and CNV due to polypoidal choroidal vasculopathy. Safety profile, patient tolerability, and quality of life measures related to aflibercept are also provided. The evidence provided in this paper suggests aflibercept to be a promising agent that can be used to reduce the treatment burden of neovascular AMD.
PMCID: PMC4689264  PMID: 26719668
age-related macular degeneration; aflibercept; choroidal neovascularization; vascular endothelial growth factor; clinical trial
5.  Phase 1 Study of VEGF Trap (Aflibercept) Administered Subcutaneously to Patients with Advanced Solid Tumors 
To determine the maximum tolerated dose (MTD) or maximal administered dose (MAD) and pharmacokinetic and safety profiles of subcutaneously administered VEGF Trap (aflibercept), a novel anti-angiogenic agent.
Experimental Design
In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or bi-weekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.
Thirty-eight patients received at least one dose of aflibercept. MTD was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1600mcg/kg/week was the MAD. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3–4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to VEGF with a t1/2 of 18 days. No anti-aflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for more than 1 year.
Subcutaneous aflibercept was well-tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.
PMCID: PMC4211604  PMID: 20028764
angiogenesis; aflibercept; phase 1; VEGF inhibitors; cancer
6.  A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects 
Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.
Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1.
The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis–Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day−1 and 0.14 l day−1, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day−1 and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml−1. Interindividual variability of model parameters was moderate, ranging from 13.6% (Vmax) to 49.8% (Q).
The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.
PMCID: PMC3175510  PMID: 21575034
aflibercept; MONOLIX; population pharmacokinetics; target-mediated drug disposition; VEGF
7.  Effects of a Single Intravitreal Injection of Aflibercept and Ranibizumab on Glomeruli of Monkeys 
PLoS ONE  2014;9(11):e113701.
It is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.
The kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm.
Compared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased.
Surprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.
PMCID: PMC4240650  PMID: 25415380
8.  Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases 
Biologics in Therapy  2012;2(1):3.
In the western hemisphere, age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly. Currently approved therapies for AMD include argon laser, photodynamic therapy, and antivascular endothelial growth factor (VEGF) therapy. The index review discusses aflibercept (VEGF Trap-Eye) in the context of current anti-VEGF therapies for neovascular AMD and other retinal vascular diseases. It highlights important differences between VEGF Trap-Eye and currently used anti-VEGF therapies for neovascular AMD; and discusses the efficacy of these treatments utilizing information from landmark clinical trials.
A systematic search of literature was conducted on PubMed, Science Direct, and Scopus with no limitations of language or years of publication.
Preclinical studies have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules; and that it also binds to placental growth factor (PlGF). In clinical trials, VEGF Trap-Eye has been shown to be as effective in the treatment of neovascular AMD as other anti-VEGF therapies and possibly to have a longer duration of drug activity.
VEGF Trap-Eye has enhanced the treatment options currently available for the management of neovascular AMD. The comparable efficacy of VEGF Trap-Eye (to other anti-VEGF agents) coupled with its longer dosing interval may decrease the number of annual office visits for patients with AMD and their caregivers.
PMCID: PMC3873045  PMID: 24392297
Aflibercept; Age-related macular degeneration; Antivascular endothelial growth factor; Neovascular age-related macular degeneration; Vascular endothelial growth factor Trap-Eye
9.  Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases 
Biologics in Therapy  2012;2(1):3.
In the western hemisphere, age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly. Currently approved therapies for AMD include argon laser, photodynamic therapy, and antivascular endothelial growth factor (VEGF) therapy. The index review discusses aflibercept (VEGF Trap-Eye) in the context of current anti-VEGF therapies for neovascular AMD and other retinal vascular diseases. It highlights important differences between VEGF Trap-Eye and currently used anti-VEGF therapies for neovascular AMD; and discusses the efficacy of these treatments utilizing information from landmark clinical trials.
A systematic search of literature was conducted on PubMed, Science Direct, and Scopus with no limitations of language or years of publication.
Preclinical studies have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules; and that it also binds to placental growth factor (PlGF). In clinical trials, VEGF Trap-Eye has been shown to be as effective in the treatment of neovascular AMD as other anti-VEGF therapies and possibly to have a longer duration of drug activity.
VEGF Trap-Eye has enhanced the treatment options currently available for the management of neovascular AMD. The comparable efficacy of VEGF Trap-Eye (to other anti-VEGF agents) coupled with its longer dosing interval may decrease the number of annual office visits for patients with AMD and their caregivers.
PMCID: PMC3873045  PMID: 24392297
Aflibercept; Age-related macular degeneration; Antivascular endothelial growth factor; Neovascular age-related macular degeneration; Vascular endothelial growth factor Trap-Eye
10.  Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia 
The AAPS Journal  2013;15(3):662-673.
Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5–25 mg/kg) up to 3–7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0–16) and systemic bioluminescent imaging (days 0–28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration–time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h−1. This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.
PMCID: PMC3691438  PMID: 23550025
acute myeloid leukemia; aflibercept; doxorubicin; pharmacokinetics/pharmacodynamics; VEGF TRAP
11.  Aflibercept in wet age-related macular degeneration: a perspective review 
In the treatment of neovascular age-related macular degeneration (AMD), vascular endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications. Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models suggest this molecule may have a longer duration of action compared with current treatments. The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of patients who maintained or improved vision at 52 weeks compared with monthly injections of ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was approved by the FDA for the treatment of neovascular AMD on 18 November 2011.
PMCID: PMC3539286  PMID: 23342231
aflibercept; neovascular age-related macular degeneration; ranibizumab; vascular endothelial growth factor; wet age-related macular degeneration
12.  Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration 
Wet age-related macular degeneration (AMD) is the most common reason for vision loss in the United States. Many treatments, such as laser therapy and photodynamic therapies, have been used but their efficacy is limited. Emerging anti-vascular endothelial growth factor (VEGF) therapies are now considered the standard of care. Anti-VEGF agents inhibit angiogenesis in the eye by suppressing abnormal blood vessel growth, leading to vision improvement. Ranibizumab and bevacizumab are two examples of anti-VEGF drugs that have been approved; both showed promise based on the visual acuity scale. Aflibercept, another new therapy known to trap VEGF and inhibit multiple growth factors, is promising not only because it can be taken bimonthly based on year 1 of the VIEW trials, but it can also be extended, as demonstrated in year 2 of the VIEW trials. Based on a cost–effect analysis, aflibercept is comparable to other leading therapies. This is a review of relevant clinical trials that have proven the non-inferiority and safety of aflibercept compared to the standard of care and its unique role in the current management of wet AMD.
PMCID: PMC3595183  PMID: 23503202
aflibercept; VEGF; anti-VEGF; pegatanib; bevacizumab; ranibizumab; VIEW trials
13.  Aflibercept Treatment for Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy Refractory to Anti-vascular Endothelial Growth Factor 
To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab).
This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated.
BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 µm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 µm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 µm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV.
Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy.
PMCID: PMC4520865  PMID: 26240506
Aflibercept; Anti-vascular endothelial growth factor; Bevacizumab; Macular degeneration; Polypoidal choroidal vasculopathy
14.  Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab 
Angiogenesis  2012;15(2):171-185.
Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.
Electronic supplementary material
The online version of this article (doi:10.1007/s10456-011-9249-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3338918  PMID: 22302382
VEGF receptor; Aflibercept; Affinity; Age-related macular degeneration; Placental growth factor; Biomedicine; Cardiology; Biomedicine general; Ophthalmology; Cancer Research; Cell Biology; Oncology
15.  Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture 
The British Journal of Ophthalmology  2014;98(Suppl 1):i11-i16.
To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture.
Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death.
Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses.
At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses.
PMCID: PMC4033208  PMID: 24836865
Macula; Treatment Medical; Angiogenesis
16.  Compartment Model Predicts VEGF Secretion and Investigates the Effects of VEGF Trap in Tumor-Bearing Mice 
Frontiers in Oncology  2013;3:196.
Angiogenesis, the formation of new blood vessels from existing vasculature, is important in tumor growth and metastasis. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which has been targeted in numerous anti-angiogenic therapies aimed at inhibiting tumor angiogenesis. Systems biology approaches, including computational modeling, are useful for understanding this complex biological process and can aid in the development of novel and effective therapeutics that target the VEGF family of proteins and receptors. We have developed a computational model of VEGF transport and kinetics in the tumor-bearing mouse, which includes three-compartments: normal tissue, blood, and tumor. The model simulates human tumor xenografts and includes human (VEGF121 and VEGF165) and mouse (VEGF120 and VEGF164) isoforms. The model incorporates molecular interactions between these VEGF isoforms and receptors (VEGFR1 and VEGFR2), as well as co-receptors (NRP1 and NRP2). We also include important soluble factors: soluble VEGFR1 (sFlt-1) and α-2-macroglobulin. The model accounts for transport via macromolecular transendothelial permeability, lymphatic flow, and plasma clearance. We have fit the model to available in vivo experimental data on the plasma concentration of free VEGF Trap and VEGF Trap bound to mouse and human VEGF in order to estimate the rates at which parenchymal cells (myocytes and tumor cells) and endothelial cells secrete VEGF. Interestingly, the predicted tumor VEGF secretion rates are significantly lower (0.007–0.023 molecules/cell/s, depending on the tumor microenvironment) than most reported in vitro measurements (0.03–2.65 molecules/cell/s). The optimized model is used to investigate the interstitial and plasma VEGF concentrations and the effect of the VEGF-neutralizing agent, VEGF Trap (aflibercept). This work complements experimental studies performed in mice and provides a framework with which to examine the effects of anti-VEGF agents, aiding in the optimization of such anti-angiogenic therapeutics as well as analysis of clinical data. The model predictions also have implications for biomarker discovery with anti-angiogenic therapies.
PMCID: PMC3727077  PMID: 23908970
systems biology; mathematical model; computational model; angiogenesis; tumor xenograft model; anti-angiogenic therapy; cancer
17.  Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2009;28(2):207-214.
Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks.
Patients and Methods
Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability.
The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker.
IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
PMCID: PMC2815710  PMID: 19949018
18.  Treatment of Exudative Age-related Macular Degeneration: Focus on Aflibercept 
Drugs & Aging  2015;32(10):797-807.
A formulation of aflibercept for intravitreal injection (Eylea) is approved for the treatment of patients with exudative age-related macular degeneration (AMD). Aflibercept has a significantly higher affinity for Vascular endothelial growth factor (VEGF)-A compared with other monoclonal anti-VEGF antibodies. In addition to binding all VEGF-A isoforms, aflibercept also blocks other proangiogenic factors such as VEGF-B and placental growth factor. The VIEW 1 and 2 trials showed this drug achieves improved results in patients with exudative AMD similar to those obtained with monthly ranibizumab, using a bimonthly treatment regimen after a loading dose of three intravitreal injections, which translates to less use of healthcare resources. There is a subgroup of patients that present with persistent fluid after the loading dose that could benefit from monthly injections or personalized proactive treatment after the first year. In the second year of treatment, the Treat and Extend patterns can permit even more lengthening of the time between injections. More data are needed to confirm the optimal monitoring and retreatment dosing, to maintain long-term efficacy. Other preliminary data suggest that patients that do not respond to other anti-angiogenics and patients with special pathologies such as polypoidal choroidopathy or retinal angiomatous proliferation can improve upon switching to aflibercept. To date, the safety profile of aflibercept is excellent and is comparable to other anti-angiogenic treatments.
PMCID: PMC4607716  PMID: 26442858
19.  Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept 
Age-related macular degeneration (AMD) has become a major public health problem and a leading cause of blindness in industrialized nations. AMD results from the ageing eye’s inability to metabolize and dispose completely of photoreceptor outer segments and other waste products. As a result, lipids, particularly apolipoproteins, accumulate within Bruch’s membrane, leading to chronic ischemia and inflammation. The subsequent upregulation of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF), induces the growth of neovascular membranes from the choriocapillaris into the subretinal or subretinal pigment epithelium spaces. To counter this, intravitreally administered drugs (pegaptanib, bevacizumab, ranibizumab) that specifically target VEGF have become the standard treatment for exudative AMD. Aflibercept, a recently approved fusion protein, binds to all isoforms of both VEGF-A and placental growth factor with high affinity. Phase III trials showed that monthly or every other month injections of aflibercept prevent vision loss (fewer than 15 letters) in 95% of patients. Additionally, aflibercept injections every 4 or 8 weeks produce average vision gains of 6.9 letters to 10.9 letters, comparable with those achieved with monthly ranibizumab. After one year of regularly administered aflibercept injections, patients required an average of only 4.2 injections during the second year. Aflibercept promises to decrease the injection frequency required for many patients and appears to serve as an effective “salvage” therapy for patients who respond poorly to other anti-VEGF drugs.
PMCID: PMC3422153  PMID: 22973088
age-related macular degeneration; choroidal neovascularization; vascular endothelial growth factor; aflibercept; ranibizumab; bevacizumab; VEGF trap
20.  Retrospective Analysis of First-Line Anti-Vascular Endothelial Growth Factor Treatment Patterns in Wet Age-Related Macular Degeneration 
Advances in Therapy  2013;30(12):1111-1127.
This study compared the number of, and expenditures on, first-line intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections between patients who were treated with aflibercept or ranibizumab for wet age-related macular degeneration (AMD).
This was a retrospective cohort study based on U.S. administrative claims data. Selected patients had initiated first-line intravitreal anti-VEGF treatment with ranibizumab or aflibercept (index date) between November 18, 2011 and April 30, 2013, were aged ≥18 years on the index date, had 12 months of continuous insurance enrollment prior to the index date (baseline period), were diagnosed with wet AMD during the baseline period or on the index date, and had at least 6 or 12 months of follow-up enrollment after the index date without switching to a different anti-VEGF agent (follow-up periods). Outcomes measured within the 6 and 12 month follow-up periods included the number of, and healthcare expenditures on, intravitreal anti-VEGF injections. Multivariable regressions compared the outcomes between aflibercept and ranibizumab.
The 6 months analyses included 319 aflibercept patients and 1,054 ranibizumab patients (12 month analyses: 57 and 374, respectively). Over the first 6 months after the index date, neither the number of injections (aflibercept mean = 3.8 ± 1.6; ranibizumab mean = 3.9 ± 1.9) nor the expenditures on injections (aflibercept mean = $7 468 ± $4 211; ranibizumab mean = $7 816 ± $4 834) differed significantly between aflibercept patients and ranibizumab patients (in multivariable regression treating ranibizumab as reference: incidence rate ratio = 0.97, 95% confidence interval [CI] 0.91–1.03, P = 0.277; cost ratio = 0.96, 95% CI 0.89–1.04, P = 0.338). Differences were also insignificant in the 12 month analyses. The overall mean days between injections differed by only 1.8 (95% CI 1.3–2.3) days between the aflibercept patients and ranibizumab patients (42.4 and 40.6, respectively).
Aflibercept and ranibizumab were used at a similar frequency resulting in similar intravitreal anti-VEGF injection healthcare expenditures among wet AMD patients initiating first-line intravitreal anti-VEGF treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-013-0078-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3906738  PMID: 24310208
Anti-vascular endothelial growth factor; Healthcare expenditures; Healthcare utilization; Intravitreal; Ophthalmology; Retrospective wet age-related macular degeneration
21.  Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models 
Angiogenesis  2012;16(2):429-441.
Vascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult. These difficulties arise in part because the functional effects of VEGF inhibition on tumor vessels are still unclear. We therefore assessed rapid molecular, morphologic and functional vascular responses following treatment with aflibercept (also known as VEGF Trap or ziv-aflibercept in the United States) in preclinical tumor models with a range of responses to anti-VEGF therapy, including Colo205 human colorectal carcinoma (highly sensitive), C6 rat glioblastoma (moderately sensitive), and HT1080 human fibrosarcoma (resistant), and correlated these changes to long-term tumor growth inhibition. We found that an overall decrease in tumor vessel perfusion, assessed by dynamic contrast-enhanced ultrasound (DCE-US), and increases in tumor hypoxia correlated well with long-term tumor growth inhibition, whereas changes in vascular gene expression and microvessel density did not. Our findings support previous clinical studies showing that decreased tumor perfusion after anti-VEGF therapy (measured by DCE-US) correlated with response. Thus, measuring tumor perfusion changes shortly after treatment with VEGF inhibitors, or possibly other anti-angiogenic therapies, may be useful to predict treatment efficacy.
PMCID: PMC3595479  PMID: 23238831
VEGF blockade; Tumor perfusion; Tumor growth response; Preclinical model; Response biomarker
22.  Tumor surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy 
Cancer research  2011;71(22):7021-7028.
Anti-vascular therapy directed against VEGF or its receptors has been successful when administered at early stages of tumor vessel growth, but is less effective when administered later. Tumor blood vessels are heterogeneous, so vessel subpopulations may differ in their requirements for tumor cell-secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. Human cancers contain several distinct blood vessel types, including mother vessels (MV), glomeruloid microvascular proliferations (GMP), vascular malformations (VM), feeding arteries (FA) and draining veins (DV), all of which can be generated in mice in the absence of tumor cells using expression vectors for VEGF-A164. In this study, we investigated the sensitivity of each of these vessel types to anti-VEGF therapy with aflibercept ® (VEGF Trap), a potent inhibitor of VEGF-A164. Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A164 expressing adenovirus could prevent or regress tumor-free neovasculature, but it was progressively less effective if initiated at later times. Early-forming MVs and GMPs in which the lining endothelial cells expressed high levels of VEGFR-2 were highly susceptible to blockade by VEGF Trap. In contrast, late-forming VMs, FAs, and DVs that expressed low levels of VEGFR-2 were largely resistant. Together, our findings define the susceptibility of different blood vessel subtypes to anti-VEGF therapy, offering a possible explanation for the limited effectiveness of anti-VEGF-A/VEGFR treatment of human cancers, which are typically present for months to years before discovery and are largely populated by late-forming blood vessels.
PMCID: PMC3217088  PMID: 21937680
Angiogenesis; Arterio-venogenesis; Ad-VEGF-A164; VEGF; Aflibercept (VEGF Trap)
23.  Hemorrhagic Pseudoaneurysm in a Patient Receiving Aflibercept for Metastatic Thyroid Cancer 
Thyroid  2012;22(5):552-555.
Agents such as aflibercept, which target the angiogenic pathway, are of great interest as candidates for the management of metastatic differentiated thyroid cancer. Here, we report a patient who developed a hemorrhagic abdominal pseudoaneurysm shortly after being started on this drug.
Patient Findings
The patient was a 67-year-old woman being treated with single agent aflibercept (VEGF-Trap) for metastatic thyroid cancer. She had no history of intra-abdominal pathology or vascular disease but had been previously treated with sorafenib. Twelve days after receiving her second dose of aflibercept, she developed vague abdominal pain, which increased in severity and was accompanied by nausea and vomiting. Her symptoms progressed along with a decline in her hematocrit and signs of internal hemorrhaging. An angiogram identified an occluded celiac artery with increased collaterals and a bleeding pseudoaneurysm in the inferior pancreaticoduodenal artery. After the pseudoaneurysm was coiled, the patient stabilized.
Summary and Conclusions
Anti-angiogenic agents, usually well tolerated, can disrupt the delicate balance of normal endothelium, leading to hemorrhagic and thrombotic complications. The hemorrhage of aberrant vasculature should be included in the differential diagnosis in patients presenting with vague complaints while being treated with anti-angiogenic agents.
PMCID: PMC3338952  PMID: 22510046
24.  Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours 
British Journal of Cancer  2012;107(4):598-603.
This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.
Patients received intravenous aflibercept 4, 5, or 6 mg kg−1 with docetaxel and cisplatin (75 mg m−2 each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.
During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg−1). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg−1 and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.
Aflibercept 6 mg kg−1 with docetaxel and cisplatin 75 mg m−2 every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.
PMCID: PMC3419955  PMID: 22790797
aflibercept; VEGF trap; angiogenesis; anti-VEGF therapy
25.  The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC) 
OncoTargets and therapy  2012;5:59-65.
Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.
PMCID: PMC3345882  PMID: 22570554
chemotherapy; tumors; antiangiogenic

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