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Anti-VEGF “Other” uses 39th Annual All Gujarat Ophthalmology conf

Saturday 24th Sept 2011 Sep 24, 2011

11.45 am to 1.15 pm Hall C

Dr. Anand SudhalkarVadodara

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VEGF Generation: attempt at repair

•Hypoxia•Trauma

• Neovascularization

• Increased permeability

• Tissue regeneration, fibrosis

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The Research: Hypoxia & VEGF

• VEGF secreted in 24 hours• Peaked in 7 days• Decreased by 21 days• Returned to basal levels by 90 days after correction of

hypoxiaRef:• Vascular endothelial growth factor expression

and angiogenesis induced by chronic cerebral hypoperfusion in rat brain.

• Hai J, Li ST, Lin Q, Pan QG, Gao F, Ding MX.• Neurosurgery. 2003 Oct;53(4):963-70; discussion 970-2.

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The Research: TRAUMA & VEGF

• Starts within 4 hrs post injury• Max from 8hrs to 1 day post trauma.• Ref:• Neuroscience. 2003;122(4):853-67.• Early neutrophilic expression of vascular endothelial

growth factor after traumatic brain injury.• Chodobski A, Chung I, Koźniewska E, Ivanenko T,

Chang W, Harrington JF, Duncan JA, Szmydynger-Chodobska J.

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Anti VEGF,

Properties

• STOP New vessels formation

• Anti Inflammatory• Anti Tissue Growth

and healing

Applications

• Pterigium• Keratoplasty• Trabeculectomy• Granuloma

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Route of Administration

Injection: Intra Vit. Subconj Intracameral•Topical

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The Dosage

• Injection: 1.25mg (0.05cc)

• Topical: 25mg (1cc from inj) make upto • 4cc i.e. 6.25mg per cc• 1cc = 20 drops• 0.3125mg per drop• 1.25mg per 4 drops

•

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How long?

• 21 days to max one month• Decreased corneal NV was noted in 7 of 10 eyes, usually within

1 month of treatment. • Adverse effects generally appeared during the second month

of treatment.• The Effect of Topical Bevacizumab on

Corneal Neovascularization• ( Over a period of three months)

• Sang Woo Kim, MD,1 Byung Jin Ha, MD,1 Eung Kweon Kim, MD, PhD,1,2 Hungwon Tchah, MD,3Tae-im Kim, MD1,2doi:10.1016/j.ophtha.2008.02.013

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Is it Safe?

• Safety Profile of Topical VEGF Neutralization at the Cornea

• Bock F, Onderka J, Rummelt C, Dietrich T, Bachmann B, Kruse FE, ...Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.

• 2009 May;50(5):2095-102. Epub 2009 Jan 17.

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Conclusion

• Topical neutralization of VEGF-A at the corneal surface does not have significant side effects on normal corneal epithelial wound healing, normal corneal integrity, or normal nerve fiber density. Therefore, anti-VEGF eyedrops seem to be a relatively safe option to treat corneal neovascularization.

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Pterigium: Role of VEGF

• Decreased Pigment Epithelium-Derived Factor and Increased Vascular Endothelial Growth Factor Levels in Pterygia

• Jin, Ji MD; Guan, Ming PhD; Sima, Jing MD; Gao, Guoquan MD, PhD; Zhang, Mei MD; Liu, Zhuguo MD; Fant, James B.S.; Ma, Jian-xing MD, PhD

• Cornea:

• July 2003 - Volume 22 - Issue 5 - pp 473-477

• Basic Investigation

• Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)

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Pterigium

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Surgery: Excision with Hinged graft

Corneal dissectionSubconj tissue removalHinged Conj Graft

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From Day 4, Topical Bevacizumab started

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Day 14th

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Injection route for Pterigium

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Treatment of inflamed pterygia (Before surgery)or residual pterygial bed (after surgery)

A M MansourBr. J. Ophthalmol. 2009;93;864-865doi:10.1136/bjo.2008.155291

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The Injection DOSE

• subconjunctival• Ranibizumab -Lucentis• (0.1 ml or 1 mg)

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Inflamed Pterygia

Pterygium bed of the left eye displayselevated fibrovascular mass with a high count ofmicrovessels.Figure

One week after subconjunctivalranibizumab (0.1 ml or 1 mg), the pterygium bed appearsflattened with attenuation of conjunctival vessels. Thisappearance was unchanged 13 months after the injection.

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Residual Pterygium ( Post Excision)

The residual pterygium of the right eye was markedly injected following excision of the advancing edge of the pterygium at the end of phacoemulsification. Note the high count of conjunctival microvessels.

One week after subconjunctival bevacizumab (0.1 ml or 2.5 mg), the injection disappeared in the residual pterygium bed.

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Post KeratoplastyCorneal Vascularization

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Topical Avastin in Keratoplasty

Sang Woo Kim, MD,1 Byung Jin Ha, MD,1 Eung Kweon Kim, MD, PhD,1,2 Hungwon

Tchah, MD,3Tae-im Kim, MD1,2

Ophthalmology 2008;115:e33–e38 © 2008 by the American Academy of Ophthalmology.

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Design: Prospective, nonrandomized, masked observational case series.Participants: Ten eyes of 7 patients with corneal NV.

• Methods: Patients received topical bevacizumab (1.25%) twice daily. Ophthalmic evaluations included

• visual acuity, slit-lamp examination, and tonometry.• Main Outcome Measures: Corneal NV and changes in ophthalmic

evaluations.• Results: Decreased corneal NV was noted in 7 of 10 eyes, usually within 1

month of treatment. • Epitheliopathy (epithelial defect, epithelial erosion) was observed in 6 of

10 eyes, 1 resulting in corneal thinning. • Adverse effects generally appeared during the second month of treatment.• Conclusions: Topical application of bevacizumab was effective in reducing

corneal NV within the first month. However, by the second month there was an increased risk of adverse effects. Ophthalmology 2008;115:

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A. Before topical bevacizumab treatment. Note the corneal NV over the donor host junction in the right eye after penetrating keratoplasty. B, One month after topical bevacizumab treatment. Note the delayed progression of corneal NV.

A B

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Trabeculectomy

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Surgical ProcedureFornix based conj flapTriangular Scleral flapLamellar corneal dissectionEnter AcPunchClosure

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Anti VEGF: Desired Effect

•Reduce bleb congestion and fibrosis

•Work as an adjuvant?

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Topical Avastin started on Trab BlebPost op day 3

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Post op day 19

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Post Op day 40, Topical drops stopped

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Post Op day 110th

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Intracameral VEGF after trab • OSN SuperSite September 17, 2011 • Intracameral anti-VEGF injection associated with success in

trabeculectomy cases, study of 141 cases• Ingeborg Stalmans VIENNA, Austria — More glaucoma patients

achieved target IOP without medication or postoperative surgical interventions when receiving bevacizumab than a placebo group, a prospective study found.

• "A single intracameral inj. of bevacizumab at the end of trabeculectomy was associated with increased absolute success rates and reduced need for postoperative interventions," Ingeborg Stalmans, MD, PhD,

• In the study, absolute success was defined as "meeting the target IOP without IOP-lowering medication or postoperative surgical interventions," which excluded massage and suture adjustments.

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• The study found that 83% of all patients in the bevacizumab group achieved absolute success

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Sponsor: Wills Eye Information

provided by: Wills Eye

ClinicalTrials.gov Identifier: NCT00853073

Does Adding Bevacizumab Therapy in Glaucoma Surgery Improve the Success of Needle Bleb Revisions? (Avastin)

This study is ongoing, but not recruiting participants.

First Received on February 26, 2009. Last Updated on August 4, 2011 History of Changes

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Conclude

• Topical/ injectable Bevasizumab is effective in reducing vascularity post operatively in Pterigium and Trabeculectomies.

• The effect is long lasting even after stopping the topical drops after one month.

• There were no surface healing problems during one month treatment.

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Thank You

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The Inhibitory Effects of Bevacizumab Eye Drops on NGF Expression and Corneal Wound Healing in Rats•Eun Chul Kim1, •Weon Sun Lee2 and •Man Soo Kim1 + Author Affiliations•From the 1Department of Ophthalmology and Visual Science, and the 2Institute of Clinical Medicine Research, College of Medicine, Catholic University of Korea, Seoul, Korea. •Corresponding author: Man Soo Kim, Department of Ophthalmology, Seoul St. Mary's Hospital, 505 Ban-po Dong, Seocho-Ku, Seoul 137-040, Korea; mskim@catholic.ac.kr.

The bevacizumab group was treated with 5% bevacizumab and antibiotic 0.5% levofloxacin eye drops four times daily and the control group with antibiotic eye drops only

Topical

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Safety Profile of Topical VEGF Neutralization at the CorneaFrom the Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.

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Bevacizumab: Active Comparator subjects will receive 1.0mg (0.04cc of 25 mg/ml) subconjunctival bevacizumab either temporal or nasal to the bleb following bleb needling procedure in addition to 0.1 cc mitomycin C.Intervention: Drug: bevacizumab

Drug: bevacizumab 1.0mg (0.04 cc of 25 mg/ml subconjunctival bevacizumab following bleb needling procedureOther Name: Avastin

balanced salt solution: Placebo Comparator patients randomized to treatment B are given 0.04cc of balanced salt solution injected in identical fashion either temporal or nasal to the bleb following bleb needling procedure in addition to 0.1 cc mitomycin C.Intervention: Other: balanced salt solution

Other: balanced salt solution 0.04 cc of balanced salt solution injected to the bleb following bleb needling procedureOther Name: balanced salt solution

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Expression of Vascular Endothelial Growth Factor and Inducible Nitric Oxide Synthase in PterygiaLee, Do-Hyung M.D., Ph.D.; Cho, Hye Jin B.S.; Kim, Jong-Tak B.S.; Choi, Jun Sub B.S.; Joo, Choun-Ki M.D., Ph.D.

Cornea: October 2001 - Volume 20 - Issue 7 - pp 738-742

Basic Investigation

• VEGF and NO may play an important role in the development of pterygium and to identify VEGF and NO in the epithelium of pterygium. We hypothesize that environmental stress, such as ultraviolet irradiation and local inflammation stimulate the elaboration of NO and VEGF, resulting in the conjunctival fibrovascular ingrowth characteristic of pterygium.

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Decreased Pigment Epithelium-Derived Factor and Increased Vascular Endothelial Growth Factor Levels in Pterygia

Jin, Ji MD; Guan, Ming PhD; Sima, Jing MD; Gao, Guoquan MD, PhD; Zhang, Mei MD; Liu, Zhuguo MD; Fant, James B.S.; Ma, Jian-xing MD, PhD

Cornea: July 2003 - Volume 22 - Issue 5 - pp 473-477

Basic Investigation

• Pterygia exhibit significantly lower PEDF but higher VEGF levels than those in normal corneas and conjunctivae. The decreased PEDF level in pterygia may play a role in the formation and progression of pterygia.

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The Effect of Topical Bevacizumab onCorneal Neovascularization

Sang Woo Kim, MD,1 Byung Jin Ha, MD,1 Eung Kweon Kim, MD, PhD,1,2 Hungwon Tchah, MD,3Tae-im Kim, MD1,2

Ophthalmology 2008;115:e33–e38 © 2008

• Topical application of bevacizumab was effective in reducing corneal NV within the first month. (12.5mg bevacizumab with 1 mL normal saline

• However, by the second month there was an increased risk of adverse effects.

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Figure 3. The effect of topical bevacizumab in cases 6 and 7. Case 6 (A, B). A, Before topical bevacizumab treatment. Note that more than half of the cornea is covered with diffuse superficial and deep corneal neovascularization (NV). B, At 3 months after treatment. Note no significant changes. Case 7 (C, D). C, Before topical bevacizumab treatment. Vessels from the conjunctiva

crossed from the limbus towards the cornea 1 month after pterygiumresection. D, One month after topical bevacizumab treatment. Note no significant vascular change, but reduced corneal opacification .

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VEGF• The role of VEGF as a critical factor in the control of the growth of abnormal blood

vessels from the choroid directly attacks a central problem in this disease. The profound vascular permeability induced by VEGF is potentially of even greater importance in the treatment of established neovascular ARMD lesions, in which leakage of fluid from new vessels causes visual loss through retinal edema and exudation, subretinal fluid and hemorrhage. [7]

• Anti-VEGF aptamers are stable small RNA-like molecules that bind exclusively and with high affinity to the 165-kDa isoform of human VEGF [Figure - 1]. Pegaptanib sodium, an oligonucleotide known as an aptamer, binds and inhibits only the extracellular isoforms of VEGF that are at least 165 amino acids in length.

[9] Multiple biologically active forms of VEGF-A are generated by both alternative mRNA splicing and posttranslational modification (proteolytic cleavage), [10] and two of these forms (VEGF165 and VEGF121) have been detected in choroidal neovascular lesions. Pegaptanib (Macugen, Pfizer) can only bind and inhibit the larger VEGF165 isoform.

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Pegaptanib V/S Bevacizumab

• In contrast to pegaptanib, bevacizumab (Avastin; Genentech, South San Francisco) a full-length, humanized monoclonal antibody against VEGF and ranibizumab (Lucentis; Genentech, South San Francisco, California), a recombinant, humanized, monoclonal antibody antigen-binding fragment (Fab), bind and neutralize all the biologically active forms of VEGF.

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Bevacizumab• The similar VEGF binding properties of bevacizumab and

ranibizumab can be explained by their common molecular lineage. Both drugs are proteins that were genetically modified from the same murine monoclonal antibody against VEGF. The two proteins differ in their size and affinity for VEGF. Whereas bevacizumab is a humanized, murine full-length antibody with two binding sites for VEGF, ranibizumab is a humanized, murine antigen-binding fragment (Fab) with only a single affinity-matured binding site for VEGF. [

• Bevacizumab is currently approved as an intravenous treatment for metastatic colorectal cancer. There is anecdotal evidence that off-label use intravitreal bevacizumab improves short-term visual outcomes in patients with neovascular ARMD.

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VEGF-Trap(R1R2)• is a fusion protein that combines ligand-binding elements

taken from the extracellular domains of VEGFR-1 and VEGFR-2 fused to the Fc portion of IgG. This potent high-affinity VEGF blocker effectively suppresses tumor growth and vascularization in vivo , resulting in almost completely avascular tumors. Subcutaneous injections or a single intravitreous injection of VEGF-Trap(R1R2) strongly suppressed CNV in mice with laser-induced rupture of Bruch's membrane, and subretinal neovascularization in transgenic mice expressing VEGF in photoreceptor cells. [15]

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RNAi• is a double-stranded piece of interference RNA that is

taken up by chorioretinal cells, activating a protein that breaks down the antisense mRNA. Destruction of VEGF mRNA prevents the production of VEGF protein. The whole process is catalytic, so the RNAi may be a very potent and efficient blockade of VEGF. RNAi may have a long biologic half-life, indicating a much longer interval between intravitreal injections. Anti-VEGF RNAi for the treatment of CNV is currently being tested in clinical trials. [15]

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•]

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.

. Design:.

• Prospective, nonrandomized, masked observational case series

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Participants: Ten eyes of 7 patients with corneal NV.

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Intracameral: 141 case• The prospective, randomized, placebo-controlled, double-masked study looked at

the use of Avastin (bevacizumab, Genentech) for improved outcomes after trabeculectomy, including as an anti-scarring agent following surgery. The study included 141 patients with either primary open-angle glaucoma or normal tension glaucoma.

• Patients were divided into two groups, with 70 patients receiving bevacizumab and undergoing trabeculectomy and 71 patients receiving a placebo and undergoing trabeculectomy with mytomycin C.

• Follow-up was 6 months.• Bevacizumab 50 µl, 25 mg/mL was injected into the anterior chamber through

hydrated paracentesis.• The study found that 83% of all patients in the bevacizumab group achieved absolute

success, while 59% achieved absolute success in the placebo group.• "This was quite a striking difference, which was clearly statistically significant," she

said.• Disclosure: Dr. Stalmans has no relevant financial disclosures.