About OJO | Search | Ahead of print | Current Issue | Archives | Author Instructions | Reviewer Guidelines | Online submissionLogin 
Oman Journal of Ophthalmology Oman Journal of Ophthalmology
  Editorial Board | Subscribe | Advertise | Contact
https://www.omanophthalmicsociety.org/ Users Online: 2039  Wide layoutNarrow layoutFull screen layout Home Print this page  Email this page Small font size Default font size Increase font size


 
 Table of Contents    
REVIEW ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 3  |  Page : 112-115  

Vascular endothelial growth factor trap-eye and trap technology: Aflibercept from bench to bedside


Department of Surgery, Division of Ophthalmology, Security Forces Hospital, Riyadh 11481, Saudi Arabia

Date of Web Publication11-Oct-2014

Correspondence Address:
Ali M Al-Halafi
Department of Surgery, Division of Ophthalmology, Security Forces Hospital, PO BoŚ 3643, Riyadh 11481
Saudi Arabia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-620X.142591

Rights and Permissions
   Abstract 

Anti-vascular endothelial growth factor (VEGF) currently used to treat eye diseases have included monoclonal antibodies, antibody fragments, and an aptamer. A different method of achieving VEGF blockade in retinal diseases includes the concept of a cytokine trap. Cytokine traps technology are being evaluated for the treatment of various diseases that are driven by excessive cytokine levels. Traps consist of two extracellular cytokine receptor domains fused together to form a human immunoglobulin G (IgG). Aflibercept/VEGF trap-eye (VTE) is a soluble fusion protein, which combines ligand-binding elements taken from the extracellular components of VEGF receptors 1 and 2 fused to the Fc portion of IgG. This protein contains all human amino acid sequences, which minimizes the potential for immunogenicity in human patients. This review presents the latest data on VTE in regard to the pharmacokinetics, dosage and safety, preclinical and clinical experiences. Method of the literature search: A systematic search of the literature was conducted on PubMed, Scopus, and Google Scholar with no limitation on language or year of publication databases. It was oriented to articles published for VTE in preclinical and clinical studies and was focused on the pharmacokinetics, dosage and safety of VTE.

Keywords: Aflibercept (EYLEA® ), anti-vascular endothelial growth factor agents, diabetic macular edema, neovascular age-related macular degeneration, vascular endothelial growth factor trap-eye


How to cite this article:
Al-Halafi AM. Vascular endothelial growth factor trap-eye and trap technology: Aflibercept from bench to bedside. Oman J Ophthalmol 2014;7:112-5

How to cite this URL:
Al-Halafi AM. Vascular endothelial growth factor trap-eye and trap technology: Aflibercept from bench to bedside. Oman J Ophthalmol [serial online] 2014 [cited 2020 Feb 19];7:112-5. Available from: http://www.ojoonline.org/text.asp?2014/7/3/112/142591


   Introduction Top


Angiogenesis is important for several physiological processes, including embryonic and postnatal development, reproductive functions, and wound healing. [1] A different endogenous inhibitors of angiogenesis have been identified, including endostatin, tumstatin, and vasostatin. [2] However, despite such complexity, vascular endothelial growth factor (VEGF)-A appears to be necessary for growth of blood vessels in a variety of normal and pathological circumstances. [3],[4],[5],[6] The VEGF family consists of five related glycoproteins, VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF). [7],[8] VEGF has two main receptors in normal biological systems: VEGF receptors (VEGFR) 1 and VEGFR2. VEGFR2 mediates most of the endothelial cell proliferating activity of VEGF, [9],[10] whereas VEGFR1 has other activities of VEGF, such as its chemo-attractant properties. [10] Both receptors are important for the angiogenic-promoting properties of VEGF.

VEGF-A is responsible for vascular permeability, which is critical for normal physiological processes such as wound healing, but can potentially increase leakage in pathological diseases, such as neovascular age-related macular degeneration (AMD). [9],[10] VEGF-A promotes the survival of hematopoietic stem cells; the migration of these cells appears to be promoted via interactions with VEGFR1. [10] It has been suggested VEGF-A is a significant factor for the recruitment of monocytes and macrophages in an inflammatory neovascularization. [11] Despite the fact that the role of VEGF-B in angiogenesis is not entirely understood, there is proof that it may be involved in inflammatory angiogenesis in various disease states, and may also modulate endothelial proliferation and vessel growth. [12] VEGF-C and VEGF-D have a role in the development of the lymphatic system. [10] In human tumors, over expression of VEGF has been frequently observed. [13] Definitely, increased VEGF expression was established to correlate frequently with tumor progression, recurrence, and survival. [14],[15] VEGF trap-eye (VTE) made by fusing DNA sequences encoding the second immunoglobulin (Ig) domain of human VEGFR1 to the third Ig domain of human VEGFR2, is fused to the constant region of human IgG, which serves to create a homodimer of the fusion protein. [16] The VTE forms a stable and inert complex with VEGF. [17] It also binds its receptors as homo- or heterodimers. [9] The trap binds VEGF very tightly and prevents it from activating its cell surface receptor. In contrast, anti-VEGF antibodies bind in a manner that allows the VEGF dimer to interact further with other molecules. VTE forms inert complexes with VEGF that minimizes the potential for VEGF-trap to interact with more than one VEGF-trap molecule. [17]

This review presents the latest data on VTE in regard to the pharmacokinetics, dosage and safety, preclinical and clinical experiences.

Method of the literature search

A systematic search of the literature was conducted on PubMed, Scopus, and Google Scholar with no limitation on language or year of publication databases. It was oriented to articles published for VTE in preclinical and clinical studies and was focused on the pharmacokinetics, dosage and safety of VTE.


   Pharmacokinetics Top


The pharmacokinetics and posterior segment distribution of intravitreal VTE were studied in rabbits. [18] Maximum vitreous concentrations of free VTE were about 500 μg/ml 0.25-6 h following the 500-μg injection, and vitreous elimination half-life was approximately 4.5 days. In This model, VTE was found in both retina and choroid, from which it was eliminated with a similar half-life. Ten days after the injection, maximal plasma total VTE levels were 1.6 μg/ml. At week 4, vitreous free VTE was 10-fold greater than levels of excess bound VTE. Therefore, ocular VEGF production would likely be totally suppressed for >6 weeks following an intravitreal injection based on these results. [18] It also shows an extended half-life, allowing for long-term blockade. [19] Experimental studies with intravitreal injections display that VTE should penetrate all layers of the retina (molecular weight∼110,000) with the least possible systemic exposure. [20] In diabetic rats, an intravitreal injection of VTE was distributed to all retinal layers, with minimal systemic exposure. [21] A recent study showed that the binding activity for the monoclonal antibody ranibizumab would be fairly close to that of the anti-VEGF monoclonal antibody bevacizumab, implying that VTE should have more extended binding activity than anti-VEGF monoclonal antibody. [22] This study hypothesizes that VTE should have more durable effects than currently available VEGF blockers, which would likely result in longer intervals between doses. VTE theoretically binds VEGF more tightly than native receptors or monoclonal antibodies, which suggests that a much lower dose of VTE may be used versus anti-VEGF monoclonal antibodies. [16] VTE blocks all VEGF-A isoforms and PlGF. [11],[16],[19] It also blocks all isoforms of VEGF-B. [23] Consistent with this comprehensive receptor-blocking effect, VTE was shown in vitro to block several biological effects of VEGF, including potent blockade of the activation of VEGFR by VEGF and also complete blockade of VEGFR2-induced phosphorylation in cultured human umbilical vein endothelial cells. [16]


   Dosage and Safety Top


VTE/Aflibercept (EYLEA® -Regeneron Pharmaceuticals, Inc., Tarrytown, New York, NY, USA and Bayer Healthcare Pharmaceuticals, Berlin, Germany) is a novel 115-kDa anti-VEGF agent. It is available in a single-use vial which contains 0.05 mL of VTE (40 mg/mL in 10 mmol/L sodium phosphate, 40 mmol/L sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2). [24] Up to date, VTE is only available for intravitreal injection. No systemic effects have been reported in any phase I, phase II, or phase III trials with intravitreal administration of doses of up to 4 mg (<0.06 mg/kg; 0.057 mg/kg). [25],[26]

A number of articles have been reporting a significant increase in systemic adverse effects in patients treated with intravitreal VEGF blocker agents. [27] The Committee for Medicinal Products for Human Use showed an increase in cerebrovascular events with VTE. [28] In contrast, the VTE: Investigation of Efficacy and Safety in Wet (VIEW) 1 and VIEW 2 studies stated "there was a similar overall incidence of systemic (nonocular) adverse events, serious systemic adverse events." [29]


   Drug Actions Top


Preclinical

Preclinical animal studies have determined the efficacy of VTE in several models of neovascularization in the eye, including the suppression of choroidal neovascular membrane (CNV) in mice and suppression of VEGF-induced breakdown of the blood-retinal barrier. Subcutaneous injections of a single intravitreal injection of VTE markedly inhibited CNV in mice with laser-induced rupture of Bruch's membrane. [30] Subcutaneous injection of VTE also significantly suppressed subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. [30] In a mouse model of suture-induced inflammatory corneal neovascularization, VTE have been shown to block angiogenesis. [11] It also prevents the development of grade 4 CNV lesions in primates and strongly reduced proliferative activities of the retina to laser injury in adult cynomolgus monkeys. [31] Every 4 weeks intravitreal VTE injection was also demonstrated to be safe in cynomolgus monkeys after 13 weeks of administration. [32]

Julien et al. [33] studied the different effects of intravitreal injections of ranibizumab and VTE on retinal and choroidal tissues of monkey eyes. Four cynomolgus monkeys were intravitreally injected with 0.5 mg of ranibizumab and another four with 2 mg of VTE, and they concluded that the ranibizumab permeated the retina through intercellular spaces, whereas VTE was taken up by neuronal and retinal pigment epithelium (RPE) cells. VTE induced protein complex formation and more hemolysis in the choriocapillaris, leading to individual RPE cell death. The clinical significance and relation of these findings to the Fc domain or to other characteristics of VTE remain to be investigated.

Clinical

Neovascular age-related macular degeneration

VTE is currently being evaluated for two eye diseases: Neovascular (wet) AMD and diabetic macular edema (DME). VTE has undergone phase I and II clinical trials in wet AMD, and is presently in phase III clinical testing. The phase I study, known as Clinical Evaluation of Anti-angiogenesis in the Retina Intravitreal Trial (CLEAR-IT) 1, consisted of two parts. It was designed to evaluate the safety, tolerability, and biological effects of intravitreal VTE in patients with neovascular AMD. Overall, in the CLEAR-IT 1, part 1 and part 2 studies, intravitreal injection of up to 4 mg of VTE was well-tolerated with no ocular inflammation seen. [34],[35] CLEAR-IT 2 was designed based upon the phase I study results showing clinically meaningful improvement in visual acuity (VA) with single doses of 0.5, 2.0, and 4.0 mg and sustained clinical activity beyond 1 month. At the analysis of CLEAR-IT 2 study, the most common adverse events were those typically associated with intravitreal injections and appeared to be related to the injection procedure. There was no relationship between VTE dose and the occurrence of any particular ocular adverse event. No adverse consequences of increased intraocular pressure were reported. [35] In the phase I and II studies, intravitreal injections of VTE caused no drug-related systemic adverse effects. [34],[35] In the phase II AMD study, there were no drug-related serious adverse events and no systemic adverse events were mentioned by the investigators as being related to study drug administration. [36] Phase III based upon the preliminary phase II study results which indicated that doses of 0.5 and 2 mg monthly produced substantial gains in VA and a single 2-mg dose had a sustained improvement in VA when compared to 2 mg monthly for at least 8 weeks, the phase III program was designed to evaluate these dosing schedules when compared to the standard dosing schedule for ranibizumab 0.5 mg monthly. Two identical, noninferiority phase III studies are currently under way to evaluate VTE for wet AMD, known as VIEW 1 and VIEW 2. Both will compare VTE with the monoclonal antibody fragment ranibizumab using a noninferiority design. Both are randomized, double-masked, active-controlled, efficacy and safety studies with a primary endpoint of the proportion of patients treated with VTE who maintains vision at the end of 1 year, compared to ranibizumab patients. [24] In VIEW 1 and VIEW 2 were considered, continued monthly VTE achieved superior outcomes compared with every 8-week dosing. [37] In the treatment-naive eyes included in the VIEW 1 and VIEW 2 trials, VTE and ranibizumab treatment resulted in clinically equivalent visual outcomes. [30] VTE treatment for patients with exudative AMD, who were incomplete responders to multiple ranibizumab injections (TURF trial) which published by Wykoff et al. [38] employed every other month dosing after the first 3-monthly doses, but was designed to permit pro re nata (PRN) dosing at the intervening months, supporting the observation that VTE does not maintain maximal retinal deturgescence for 2 months in many patients and indicative of the refractory exudative nature of the study eyes. In TURF trial, 72% eyes required retreatment at both PRN visits, and 79% PRN retreatments were required. Furthermore, VTE 2.0 mg treatment maintained mean VA improvements previously achieved with high-dose 2.0-mg ranibizumab injections in recalcitrant wet AMD patients and significant anatomic improvement and was required monthly in most patients.

Diabetic macular edema

The initial phase I study of VTE in DME, CLEAR-IT DME, was an exploratory study of the safety, tolerability and biological effect of a single intravitreal administration of 4 mg VTE in patients with DME at two centers involving five patients. [25] According to the study, the maximum change from baseline in key outcome measures at 6 weeks included reductions in center retinal thickness, with a mean reduction of −115.4 μm and a median reduction of −118 μm (P < 0.03). Macular volume was reduced by a mean of −1 μm 3 and a median of −0.6 μm 3 (P < 0.04). The Early Treatment Diabetic Retinopathy Study best corrected VA (BCVA) letters improved by a mean of 6.8 and a median of 9 (P < 0.03) and no serious ocular adverse events were reported. [25] Based on the results of a phase I study, a 52 weeks, multicenter, randomized, double-masked, active-controlled phase II clinical trial was conducted. The primary aim of the DME and VTE: Investigation of Clinical Impact (DA VINCI) study was to assess the safety and efficacy of intravitreal VTE in comparison with focal/grid laser photocoagulation in patients with DME. The primary end point results of the DA VINCI study (week 24) revealed that treatment with intravitreal VTE produced a statistically significant improvement in VA when compared with macular laser treatment. It also showed that VTE was well-tolerated, and its ocular adverse events were consistent with those seen with other intravitreal anti-VEGF agents. The DA VINCI study group has also published the results of different doses and dosing regimens of VTE with laser photocoagulation in eyes with DME after 52 weeks. Assessment of the changes in BCVA and mean changes in CRT at 24 and 52 weeks revealed that significant gains in BCVA from baseline, achieved at week 24, were maintained or improved at week 52 in all VTE groups. [39]


   Conclusion Top


VTE presents a potential exciting new addition to the current VEGF antagonists available for the treatment of retinal vascular diseases such as neovascular AMD and DME. Results from clinical trials with VTE have been favorable and comparable to other anti-VEGF agents. Due to its longer half-life, VTE may also decrease the frequency of injections for retinal vascular diseases patients. These results could be attributed to the stronger and prolonged binding of VTE to the VEGF-A receptor compared to other available antagonists.

 
   References Top

1.
Folkman J, Klagsbrun M. Angiogenic factors. Science 1987;235:442-7.  Back to cited text no. 1
[PUBMED]    
2.
Sund M, Hamano Y, Sugimoto H, Sudhakar A, Soubasakos M, Yerramalla U, et al. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc Natl Acad Sci U S A 2005;102:2934-9.  Back to cited text no. 2
    
3.
Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795-803.  Back to cited text no. 3
[PUBMED]    
4.
Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature 2005;438:937-45.  Back to cited text no. 4
    
5.
Ellis LM, Hicklin DJ. VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer 2008;8:579-91.  Back to cited text no. 5
    
6.
Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358:2039-49.  Back to cited text no. 6
[PUBMED]    
7.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76.  Back to cited text no. 7
    
8.
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439-42.  Back to cited text no. 8
    
9.
Breen EC. VEGF in biological control. J Cell Biochem 2007;102:1358-67.  Back to cited text no. 9
[PUBMED]    
10.
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol 2006;7:359-71.  Back to cited text no. 10
    
11.
Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004;113:1040-50.  Back to cited text no. 11
    
12.
Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: Review. Blood Cells Mol Dis 2007;38:258-68.  Back to cited text no. 12
    
13.
Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368-80.  Back to cited text no. 13
[PUBMED]    
14.
Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207-25.  Back to cited text no. 14
    
15.
Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007;109:1478-86.  Back to cited text no. 15
    
16.
Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393-8.  Back to cited text no. 16
    
17.
Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, et al. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A 2007;104:18363-70.  Back to cited text no. 17
    
18.
Furfine E, Coppi A, Koehler-Stec EM, et al. Pharmacokinetics and ocular tissue penetration of VEGF trap after intravitreal injections in rabbits. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO), April 30-May 4; Fort Lauderdale, FL; 2006.  Back to cited text no. 18
    
19.
Rudge JS, Thurston G, Davis S, Papadopoulos N, Gale N, Wiegand SJ, et al. VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene-based discovery of the next generation of angiogenesis targets. Cold Spring Harb Symp Quant Biol 2005;70:411-8.  Back to cited text no. 19
    
20.
Pieramici DJ, Rabena MD. Anti-VEGF therapy: Comparison of current and future agents. Eye (Lond) 2008;22:1330-6.  Back to cited text no. 20
    
21.
Cao J, Song H, Renard RA, et al. Systemic or intravitreal administration of VEGF trap suppresses vascular leak and leukostasis in the retinas of diabetic rat. Invest Ophthalmol Vis Sci 2006;47:E-abstract 1745.  Back to cited text no. 21
    
22.
Stewart MW. Predicted biologic activity of intravitreal bevacizumab. Retina 2007;27:1196-200.  Back to cited text no. 22
[PUBMED]    
23.
VEGF TRAP-EYE (aflibercept ophthalmic solution) Ophthalmologic Drugs Advisory Committee, June 17, 2011, Regeneron Pharmaceuticals, Inc.  Back to cited text no. 23
    
24.
EYLEA-Aflibercept injection, solution. Regeneron Pharmaceuticals, Inc. Available from: http//www.dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=67921 [Last accessed on 2014 Feb 11].  Back to cited text no. 24
    
25.
Do DV, Nguyen QD, Shah SM, Browning DJ, Haller JA, Chu K, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009;93:144-9.  Back to cited text no. 25
    
26.
Thai HT, Veyrat-Follet C, Vivier N, Dubruc C, Sanderink G, Mentré F, et al. A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects. Br J Clin Pharmacol 2011;72:402-14.  Back to cited text no. 26
    
27.
Gillies MC, Wong TY. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2007;356:748-9.  Back to cited text no. 27
[PUBMED]    
28.
European Medicines Agency. 2012 Assessment Report: Eylea (Aflibercept). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002392/WC500135744.pdf. [Last accessed on 2012 Dec 10].  Back to cited text no. 28
    
29.
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48.  Back to cited text no. 29
[PUBMED]    
30.
Saishin Y, Saishin Y, Takahashi K, Lima e Silva R, Hylton D, Rudge JS, et al. VEGF-TRAP (R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier. J Cell Physiol 2003;195:241-8.  Back to cited text no. 30
[PUBMED]    
31.
Wiegand SJ, Zimmer E, Nork TM, et al. VEGF trap both prevents experimental choroidal neovascularization and causes regression of established lesions in non-human primates. Invest Ophthalmol Vis Sci 2005;46:E-abstract 1411.  Back to cited text no. 31
    
32.
Zimmer E, Christian BJ, Miller PE. Safety evaluation of intravitreal administration of VEGF trap in cynomolgus monkeys for 13 weeks. Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO), April 30-May 4; Fort Lauderdale, FL; 2006.  Back to cited text no. 32
    
33.
Julien S, Biesemeier A, Taubitz T, Schraermeyer U. Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol 2014;98:813-25.  Back to cited text no. 33
    
34.
Nguyen QD, Hariprasad S, Browning DJ, et al. Interim resultsfrom a phase 1, safety, tolerability, and bioactivity study of intravitreal VEGF trap in patients with neovascular age-related macular degeneration: The CLEAR-IT 1 study. Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), May 6-10; Fort Lauderdale, FL: 2007.  Back to cited text no. 34
    
35.
Nguyen QD, Shah SM, Browning DJ, et al. Results of a phase I, do see scalation, safety, tolerability, and bioactivity study of intravitreous VEGF trap in patients with neovascular age-related macular degeneration. Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), April 30-May 4; Fort Lauderdale, FL; 2006.  Back to cited text no. 35
    
36.
Benz MS, Nguyen QD, Chu K, et al. Interim results of the phase II, randomized, controlled dose-and interval-ranging study of repeated intravitreal VEGF trap administration in patients with neovascular age-related macular degeneration (AMD). Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), May 6-10; Fort Lauderdale, FL; 2007.  Back to cited text no. 36
    
37.
Jaffe G. The Effect of Early, Persistent Fluid on Subsequent Visual Acuity in the VIEW 1 and VIEW 2 Studies of Neovascular AMD. Canada: American Society of Retina Specialists Toronto; August 25 th , 2013.  Back to cited text no. 37
    
38.
Wykoff CC, Brown DM, Maldonado ME, Croft DE. Aflibercept treatment for patients with exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections (TURF trial). Br J Ophthalmol 2014;98:951-5.  Back to cited text no. 38
[PUBMED]    
39.
Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65.  Back to cited text no. 39
    




 

Top
   
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Pharmacokinetics
   Dosage and Safety
   Drug Actions
   Conclusion
    References

 Article Access Statistics
    Viewed2746    
    Printed69    
    Emailed0    
    PDF Downloaded618    
    Comments [Add]    

Recommend this journal