ANTI VEGF IN OPHTHALMOLOGY

ANTI VEGF IN OPHTHALMOLOGYPRESENTER: DR. SIDDHARTH GAUTAMDR.PAVITRA PATEL

INTRODUCTIONVEGF means Vascular Endothelial Growth Factor, which is responsible for growth of blood vessels.

Besides having a role in normal vascular growth, VEGF is also responsible for many retinal diseases by causing new vessels growth and by increasing leakage and thus causing retinal swelling.

VEGF PROPERTIES:

Stimulates angiogenesisPotent inducer of vascular permeabilityPro-inflammatory

VEGF was first identified, purified, and cloned in 1989.

PROCESS OF ANGIOGENESISInductionVasodilation and increased permeability of pre-existing vesselsActivated endothelial cells release proteases to degrade matrixEndothelial cells proliferate and migrateProliferating cells adhere to one another

ResolutionDifferentiation and maturation of blood vessels

ANGIOGENIC FACTORS

VEGF

HISTORY OF VEGF

CLASSIFICATION OF VEGFArchetypal member of the VEGF family is VEGF A.

Other members are Placental growth factor (PGF), VEGF B, VEGF C, and VEGF D.

A new member of VEGF Related family encoded by viruses (VEGF E)In the venom of some snakes (VEGF F ) have also been discovered.

FUNCTIONSTYPE OF VEGFFUNCTIONSVEGF AAngiogenesisIncreases migration of endothelial cellsIncreases mitosis of endothelial cellsIncreases matrix metalloproteinase activityCreation of blood vessel lumenCreates fenestrationChemotactic for macrophages and granulocytes Vasodilation ( Indirectly by NO release )VEGF BEmbryonic angiogenesis (myocardial tissue to be specific )

TYPE OF VEGFFUNCTIONSVEGF C LymphangiogenesisVEGF DDevelopment of lymphatic vasculature surrounding lung bronchioles.Placental Growth Factor (PGF)VasculogenesisAngiogenesis during ischemiaInflammationWound healing andCancer

The human isoforms are 121, 145, 165, 189, & 206.The isoform number refers to the number of amino acids contained in the mature, secreted protein.

CLINICAL SIGNIFICANCE

VEGF A plays a role in the disease pathology of the wet form Age related macular degeneration,which is the leading cause of blindness for the elderly of the industrialized world.

The vascular pathology is similar to diabetic retinopathy with some differences in neovascularization.

VEGF D levels are significantly elevated in patients with Angiosarcoma.

Patients suffering from pulmonary emphysema have decreased levels of VEGF in the pulmonary arteries.

In kidneys, increased expression of VEGF A in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.

VEGF alternatives can be predictive of early onset pre-eclampsia.

ROLE OF VEGF IN HEALTHY EYEHigh concentrations are seen in RPE.

May be important for choriocapillary survival.

Neuroprotective role.

Two major prevalent isoforms in retina are VEGF121(120) & VEGF165(164).

VEGF RECEPTORSVEGF initiates endothelial cell proliferation when it binds to a member of VEGF receptor (VEGFR) family, a group of highly homologous receptors with intracellular tyrosine kinase domain that includes :

VEGFR1(FLT1)VEGFR2(KDR)VEGFR3(FLT4)

ANTI-VEGFThe anti-VEGF agents block the VEGF molecules and thus benefit the patients by decreasing the abnormal and harmful new blood vessels formation and by decreasing the leakage and swelling of the retina.

This leads to stabilization of vision and even improvement in vision in many cases.

ANTI VEGF DRUGSMonoclonal antibodyBevacizumab (Avastin)Antibody derivativeRanibizumab (Lucentis)AptamerPegaptanib (Macugen)Oral small molecules(Inhibit tyrosine kinases)LapatinibSunitinibSorafenibFusion proteinsVEGF Trap-eye (aflibercept)Miscellaneous siRNA-Bevasiranib, adPEDF

COMMON INDICATIONS OF ANTI-VEGF USE

OTHER INDICATIONSPOSTERIOR SEGMENTANTERIOR SEGMENTROP1. Iris neovascularization2. EALES diseaseBefore Keratoplasty to reduce to reduce corneal neovascularizationRefractory post surgical CME3. Pterygium4. COATS disease4. Trabeculectomy (to modulate wound healing)

USE IN ROP:

Bevacizumab was claimed as a wonder drug for all stage 3 + ROP.However, results revealed that safety was still an issue.Choroidal rupture has been reported with injection of bevacizumab.Adverse influence on the development of choroidal vessels.

USE IN EALES DISEASE:

Recent articles have suggested intraocular bevacizumab as a new form of treatment in neovascular eales disease or as a possible adjunctive treatment to vitreoretinal surgery for the management of eales disease with tractional retinal detachment.However, this treatment has a legacy of serious complications like secondary rhegmatogenous retinal detachment, within a week of receiving intravitreal bevacizumab.Combination therapy of laser treatment and intraocular bevacizumab was effective in improving and stabilizing the vision.

USE IN PTERYGIUM:

VEGF have been detected in pterygium.There is marked elevation of VEGF in pterygia in comparison to normal conjunctival samples.

Subconjunctival bevacizumab is used in recurrent pterygium.

Topical bevacizumab is used in the treatment of corneal neovascular vessels, higher concentration has adverse effects.

Therefore, duration of treatment may well determine the safety of topical bevacizumab.

ANTI-VEGF FOR EYE DISEASESBEVACIZUMAB: AVASTINRecombinant humanizedmonoclonal antibodythat blocks angiogenesis by inhibitingVEGF-A

It received its first approval in 2004, for combination use with standardchemotherapy for metastaticcolon cancer It has since been approved for use in Certain lung cancers, Renal cancers, Ovarian cancersGlioblastoma multiforme of the brain

Not yet approved by FDA-Off label use in Ophthalmology.

Rosenfield et al were the first ones to describe & publish the off label use of intravitreal Bevacizumab in 2005.

MECHANISM OF ACTION:

USE IN EYE DISEASE:Successfully used to inhibit VEGF and slow the progress of Age-related macular degeneration(AMD) &diabetic retinopathyOff-label useas anintravitreal agentin the treatment of proliferative (neovascular) eye diseases Particularly forChoroidal neovascular membrane(CNV) in AMD.

Although not currently approved by the FDA for such use, the injection of 1.25-2.5mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity.

Many retina specialists have noted impressive results in the setting of:CNVProliferative diabetic retinopathyNeovascular glaucomaDiabetic macular edemaRetinopathy of prematurityMacular edema secondary to retinal vein occlusions.

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ADMINISTRATION AND DOSAGE:

Bevacizumab is typically given by transconjunctival intravitreal injections into the posterior segment.

Intravitreal injections for retinal pathologies are typically administered at 4-6 week intervals, although this varies widely based on disease and response. DOSE: Typical dose is 1.25mg in 0.05ml in adults, and half that dose in babies.

COMBINATION THERAPY:

Photodynamic TherapyAnti PDGFIntravitreal TriamcinoloneTriple TherapyRadiation

BENEFITS:Reduces frequency of injectionsReduces recurrence

PHARMACOKINETICS:

AbsorptionTime to reach steady state is predicted to be 100 days.

EliminationEstimated half-life is approximately 20 days.

DRUG INTERACTIONS:Irinotecan/5fluorouracil/leucovorinIncidence of epistaxis and GI hemorrhage, minor gum bleeding, vaginal hemorrhage increasesLive vaccinesCoadministration of live vaccines may result in a reduced immune responsePaclitaxelDecreased paclitaxel exposure when given in combination with bevacizumabSunitinibCoadministration of Bevacizumab and sunitinib has been reported to cause unexpected severe toxicity (eg, microangiopathic hemolytic anemia)

BENEFITS:

High efficacyLonger half life upto 20 days & thus fewer injectionsLack of preservativeHigher safety dose Retinal toxicity occurs at dosage > 3.5mgLower costWide availability

ADVERSE REACTIONS:

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PEGAPTANIB: MACUGEN

Pegylated Aptamer

Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic medicine for the treatment of neovascular WET AMD.

Discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals.

Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

MECHANISM OF ACTION:

Two primary pathological processes responsible for vision loss associated with neovascular AMD.

ADMINISTRATION AND DOSAGE:

Administered in a 0.3mg dose once every six weeks byintravitrealinjection.

Marketed as a pre-filled syringe.

CONTRAINDICATED in patients with ocular or periocular infections.

PHARMACOKINETICS: (Not adequately studied in humans)

AbsorptionVery slow systemic absorptionOccurs within 1 to 4 days after 0.3 mg monocular dose.

Metabolism & ExcretionBy Endo & Exonucleases excreted by kidney.

DRUG INTERACTIONS:Not affected by Cytochrome P450 system.

RANIBIZUMAB: LUCENTIS

Lucentis is an monoclonal antibody fragment( Fab) developed from the identical parent antibody as Avastin.

Lucentis was approved for neovascular AMD in the U.S. in 2006, and is authorized for multiple ocular conditions in Australia, Canada, and Europe.

It has a licensed indication for use in DME in Australia, Canada and Europe.

MECHANISM OF ACTION:

Much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A.

Anti-angiogenic property.

Unlike the full length antibody, it penetrates the ILM and can gain access to the sub retinal space.

ADMINISTRATION AND DOSAGE:

Available as Injection, intravitreal 10 mg/mLDose: 0.5 mg/0.05 ml once every month

PHARMACOKINETICS:

Vitreous t1/2 = 3 days (animals) 9 days (humans)

Serum concentrations upto 2000x lower than in the vitreous.

Reduction in Ranibizumab clearance in renal impairment is considered clinically insignificant & dose adjustment is not expected to be needed.

DRUG INTERACTIONS: Have not been studied.

SAFETY PROFILE:

Serious ocular adverse events in 2 year MARINA study for ranibizumab 0.5 mg:Endophthalmitis 1.3% Uveitis 1.3% .Retinal tear 0.4%Lens damage 0.4%

Serious ocular adverse events in 1 year ANCHOR study for ranibizumab 0.5 mg :

Endophthalmitis 1.4 % Uveitis 0.7%

There was no increase in systemic adverse effects such as HTN, arterial thromboembolism in either study.

DIFFERENCEBEVACIZUMAB (AVASTIN)RANIBIZUMAB(LUCENTIS)Full sized antibodyAntibody fragment148 kilodaltons48 kilodaltonsHalf life-20 daysHalf life- 3 daysClearance is slowClearance 100 folds fasterLong action & less dosage140 times higher affinityCosts lessCostly

AFLIBERCEPT: EYLEA (NEW DRUG)

Recombinant fusion proteinconsisting of VEGF-binding portions from the extracellular domains of human VEGFreceptors1 and 2, that are fused to the Fc portion of the human IgG1immunoglobulin.

INDICATIONS FOR USE:

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

Recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters).

Administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months).

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

Recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters).

Administered by intravitreal injection once every 4 weeks.

CONTRAINDICATIONS:

Contraindicated in patients with infections or activeinflammationsof or near the eye

AFLIBERCEPT is moving through clinical trials for further intraocular and systemic indications.

HOW TO GIVE INTRAVITREAL INJECTION?Injection volumeAn injection volume of 0.05 mL is most commonly used.

Maximum safe volume to inject without preinjection paracentesis is believed to be 0.1 mL to 0.2 mL.

Larger injection volumes are uncommon, with two exceptions: the injection of gas for pneumatic retinopexy and the injection of multiple intravitreal agents in one session.

Needle selection

Needle size varies according to the substance injected, with 27-gauge needles often used for crystalline substances such as triamcinolone acetonide and 30-gauge needles commonly used for the anti-VEGF agents ranibizumab, bevacizumab, and aflibercept.

Studies suggest that smaller, sharper needles require less force for penetration and result in less drug reflux.

Needle length between 0.5 and 0.62 inches (12.7 to 15.75 mm) is recommended, as longer needles may increase risk of retinal injury if the patient accidentally moves forward during the procedure.

Injection site

The patient should be instructed to direct his or her gaze away from the site of needle entry.

The injection is placed 3 to 3.5 mm posterior to the limbus for an aphakic or pseudophakic eye, and 3.5 to 4 mm posterior to the limbus for a phakic eye.

Injection in the inferotemporal quadrant is common, although any quadrant may be used.

Injection technique

Some guidelines suggest pulling the conjunctiva over the injection site with forceps or a sterile cotton swab to create a steplike entry path.

While this approach may, in theory, decrease reflux and risk of infection, a straight injection path is most commonly employed.

After the sclera is penetrated, the needle is advanced toward the center of the globe and the solution is gently injected into the midvitreous cavity.

The needle is removed, and a sterile cotton swab is immediately placed over the injection site to prevent reflux.

IOP and CRA perfusion is assessed.

Topical Antibiotic is administered for one week.

CONTRA-INDICATIONS OF ANTI-VEGF1. Fibrovascular proliferation threatening the macula2. Active ocular or periocular inflammation3. Known hypersensitivity to drugs 4. Uncontrolled hypertension5. Cardiovascular disease6. Pregnancy and lactation7. Pre pubescent children

PEGAPTANIBRANIBIZUMABBEVACIZUMABTRADE NAMEMacugenLucentisAvastinCOMPOUNDAptamerAntibody fragmentFull humanized monoclonal antibodyVEGF BINDING PROPERTYVEGF-A165SelectiveVEGF-A all forms(1 binding site)VEGF-A all forms(2 binding site)VITREOUS t1/24 Days3 Days (Rabbits)9 Days (Humans)5.6 Days21 Days (Systemic)DOSE0.3 mg in 90 ul1/6 weeks0.5 mg in 0.05 ml1/month1.25 mg in 0.05 ml1/3 monthsCOSTRs 47,000/syringeRs 56,000/vialRs 37,000/vialADVANTAGESLow immunogenicitySelective actionMore prospective safety & efficacy dataCost effectiveLong actingDISADVANTAGESCostCVS RisksCostHTN,CVS RisksRebound macular edema