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Anti VEGF Therapy in Ophthalmology

Dr.Maharshi Maitra

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VEGFVascular Endothelial Growth Factor.It is an angiogenic factor responsible for growth

of new blood vessels (neovascularization).VEGF family includes VEGF-A, VEGF-B, VEGF-C,

VEGF-D, VEGF-E, placental growth factor.VEGF is responsible for many retinal diseases by

causing new vessels growth and by increasing leakage and causing retinal swelling.

At least six human VEGF-A isoforms of 121, 145, 165, 183, 189 and 206 amino acids are known to exist.

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Anti VEGF AgentsPegaptinib (Macugen) : It is an oligonucleotide

aptamer, which was the first anti-VEGF agent to be approved for use in neovascular AMD. Aptamers are nucleic acid ligands, which bind different targets such as proteins with high specificity and affinity.

Bevacizumab (Avastin) : Bevacizumab is a full-length recombinant humanized monoclonal antibody. It binds to and inhibits all isoforms of VEGF-A.

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Ranibizumab (Lucentis) : Ranibizumab is a recombinant, humanized antibody antigen-binding fragment (Fab) that binds and neutralizes all known active forms of VEGF-A.

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Mechanism of Action

The anti-VEGF agents block the VEGF molecules and decreases the abnormal and harmful new blood vessels formation and decreases the leakage and swelling of the retina. This leads to stabilization of vision and even improvement of vision in many cases.

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DosageRanibizumab is available in a 10mg/mL single

use vial and 0.05 mL (0.5mg) is given by intravitreal injection.

Ranibizumab should be refrigerated at 2° - 8° C and not frozen.

The intravitreal dosage of Bevacizumab is 1.25 mcg/0.05 cc.

Pegaptanib is administered in a 0.3 mg dose by intravitreal injection. It may be repeated once every six weeks.

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Indications

ARMD (Age-related macular degeneration)CNVM (Choroidal neovascular membrane)Severe Diabetic RetinopathyMacular OedemaVascular blocks (CRAO, CRVO)Neovascular GlaucomaVitreous Haemorrhage

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ARMD (Age-related macular degeneration)

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Choroidal/Sub-Retinal Neo-Vascular Membrane (CNVM/SRNVM)

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Severe Diabetic Macular Edema

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Macular edema due to Vascular Block of the retina

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Fundus and high-resolution OCT images of a patient with BRVO (a) before and (b) 2 months after treatment with ranibizumab showing resolution of bleedings and macular edema.

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Vitreous hemorrhage due to diabetic retinopathy or vascular block

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Technique of Intravitreal Injections

Anaesthesia : Subconjunctival 2% lidocaine at the injection site or with topical xylocaine jelly.

Lids and periocular area should be prepped with 5% povidone/iodine with a drop in the cul de sac.

The injection is most commonly given inferotemporally because of ease of access, 3.5- to 4-mm posterior to the limbus through pars plana.

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Visualization of the fundus via indirect ophthalmoscopy should then be performed to ensure that no complications have occurred.

Following the procedure, patients should use topical antibiotics for at least 3 days, and also 2 days prior to the procedure.

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ComplicationsForeign body sensationTearing(watering)PainRednessInjection-related complications such as Infectious endophthalmitisRetinal detachmentTraumatic cataract may occur with a frequency of

about 0.15 ± 0.05% after intravitreal injections.

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VEGF Trap

The VEGF Trap-Eye (Regeneron) is a recombinant fusion protein of portions of VEGF receptors 1 and 2, and the Fc region of human IgG which binds all VEGF-A isoforms.

It has higher affinity in comparison to other anti-VEGFs, including bevacizumab and ranibizumab.

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VEGF Trap-Eye has a longer half-life in the eye after intraocular injection and it binds other members of the VEGF family including placental growth factors 1 and 2, which have been shown to contribute to excessive vascular permeability.

This higher affinity may allow lower doses to be and to maintain a longer duration of action.

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Newer AgentsRNA interfering molecules : Bevasiranib is a

specific siRNA designed to decrease the level and activity of VEGF mRNA.

Rapamycin is a macrocyclic antibiotic produced by the bacterium Streptomyces hygroscopicus. The anti-angiogenic properties of rapamycin are associated with a decrease in VEGF production and a reduction in the response of vascular endothelial cells to stimulation by VEGF.

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Angiostatic steroids (Cortesenes) like anecortave acetate.

Tyrosine kinase inhibitors are also being tried as the VEGFRs are receptors of the tyrosine kinase receptor family.

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Studies

The FOCUS Study assessed the efficacy and adverse-events profile of a combined treatment with ranibizumab and verteporfin PDT in patients with predominantly classic CNV secondary to AMD during a 2-year, multicenter, randomized, single-masked, controlled study.

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The PIER Study evaluated the efficacy and safety of ranibizumab administered monthly for 3 months and then quarterly in patients with CNV secondary to AMD.

The VISION Study showed that patients receiving pegaptanib lost vision in a smaller rate than those treated with conventional care.

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MARINA Study

In the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) Study, 716 patients with either minimally classic or occult (with no classic lesions) CNV secondary to AMD were randomly assigned to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 or 0.5 mg) or sham injections.

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The benefit in VA was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in 5 patients (1.0%) and serious uveitis in 6 patients (1.3%) given ranibizumab.

The study showed that the intravitreal administration of ranibizumab during 2 years did prevent vision loss and improved mean VA and had low rates of serious adverse events.

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ANCHOR Study

The ANCHOR Study (published 2009) demonstrated that ranibizumab was superior to PDT with respect to VA and morphologic efficacy outcomes and that intravitreal treatment of predominantly classic CNV in AMD with ranibizumab had a low rate of serious ocular adverse events.

Ranibizumab provided greater clinical benefit than verteporfin PDT in patients with AMD with new-onset, predominantly classic CNV.

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PrONTO Study

The long-term efficacy of a variable-dosing regimen with ranibizumab was assessed in the ‘Prospective Optical Coherence Tomography Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with Intraocular Ranibizumab’ (PrONTO) Study, in which patients were followed for 2 years.

The study design was a 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab treatment based on OCT findings.

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In this open-label, prospective, single-center, uncontrolled clinical study, patients with AMD involving the central fovea and a central retinal thickness of 300 μm or more as measured by OCT received 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg).

At month 24, mean VA improved by 11.1 letters and the OCT-CRT decreased by 212 μm. VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months.