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The Latest And Greatest in the Management of Retinal Diseases

February 13, 2007

Santosh C. Patel, M.D.Retina Specialists Retinal Diseases

Majority of Blindness in Civilized WorldAMDDiabetic RetinopathyVein OcclusionsRetinal DetachmentsRetinitis PigmentosaMacular Dystrophies

Age-Related Macular Degeneration

Most significant advances in all of ophthalmology in past 2 yearsFinally, treatments that improve vision

Success is no longer defined as least letters lost

Research on AMD treatment will transfer into other vascular diseases (Diabetic Retinopathy and Vein Occlusions)

What Is AMD?

AMD is a degenerative retinal disease that can cause central vision loss and blindnessAMD is the leading cause of severe vision loss in people over 50 years of age in the western worldThere are 2 forms of AMD

Non-neovascular (dry) AMD Affects 80% to 90% of patients

Neovascular (wet) AMD Affects 10% to 20% of patients

Approximately 90% of vision loss results fromneovascular AMD

Risk Factors for AMDSeveral risk factors, other than age, havebeen suggested

Family historyGenderRace

SmokingGenetic factorsHigh cholesterolHypertension and cardiovascular diseaseLow intake of antioxidants/lutein

34.839.7

53.7

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2000 2010 2020

US

Popu

latio

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US Population ≥65 years1

Year

AMD Is an Increasing Concern as the Population Ages

As the population ages, more people are at risk of developing AMDBy 2020, up to 7.5 million people >65 years may suffer from AMD-related vision loss in developed countries2

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“Dry” Age Related Macular Degenerationtreatment

AREDS Antioxidants reduce the chance of visual loss from macular degenerationZinc supplementation also reduces the risk of visual lossThe combination of the two is even better

Lutein15-20 mg/day

Omega- 3- Fatty AcidsFish oil or 2 or more servings of fish

Estimate of Risk Reduction inDeveloping Any Advanced AMD*:

Intermediate AMD or Monocular Advanced AMD

Antioxidants ZincAntioxidants

+ Zinc

17% 21% 25%

Antioxidant and Zinc Therapy for Non-Neovascular AMD: Results From AREDS

RecommendationsFrom AREDS

Consider using supplement of antioxidants plus zinc for patients with intermediate AMD, monocular advanced AMD, or vision loss due to AMD in 1 eyePatients who do not meet these criteria but may have a family history or are believed to be at risk for developing AMD should

Maintain a diet rich in fruits and vegetablesSupplement their diet with a multivitaminUndergo periodic ophthalmic exams for the development of intermediate or advanced AMD

The Role of Luteinin Eye Health

A carotenoid found in fruits and vegetables

Antioxidant that protects cells from damage causedby free radicals

Upon consumption, lutein deposits into areas of the body most prone to free radical damage

One of the predominant antioxidants in the macula

The macula is susceptible to damage from blue light, which in turn may contribute to AMD

Lutein filters out blue light thereby preventing free radical damage in the eyes

The Role of Luteinin Eye Health (cont)

Some studies have suggested a possible linkbetween lutein and decreased risk of eye diseaseThe amount of lutein needed to provide a benefitis unknownFuture studies are needed to elucidate the effectsof lutein on AMD

AREDS II

Evaluating other micronutrients for AMDLutein 10 mgZeaxanthin 2 mgOmega-3 Fatty Acids (DHA/EPA)

Weekly servings of fishPurified Fish Oil

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AMD Damages the Macula

Retina

ChoroidSclera

RetinaChoroid

Sclera

Macula

Fovea

RPE

Bruch’s Membrane

Choriocapillaris

Figure courtesy of Novartis Pharmaceuticals Corporation.

Fundus photograph showing medium-sized drusen

(63–124 µm)1

Early AMD

Patients are usually asymptomatic and do not experience vision lossExamination reveals several small drusen or a few medium-sized drusenCan be followed yearlyAREDS Vitamins not proven to work

Fundus photographs showing numerous medium-sized drusen (left panel), and >1

large drusen (125 µm) [right panel]

Intermediate AMD

Examination reveals many medium-sized drusen or ≥1 large drusen Vision may be impairedAREDSAmsler Grid

Fundus photograph depictingcentral geographic atrophy

Advanced AMD: Non-Neovascular

Vision impairment ismore severeFollow fellow eye closely (every 3-4 months) if good vision

May have difficulty recognizing faces from distance

Examination revealsPresence of drusenDegeneration of RPE

Incidence of Neovascular AMD in Elderly Persons in the United States

Recent estimates were derived from random sample of Medicare beneficiaries aged 65 and older (N=1,041,009; between 1994 and 1998)1

Incidence based on diagnosis codes associated with AMD and CNV1

3-year incidence of AMD ≈9.4 to ≈11.4 per 10001

Estimates were consistent with the Beaver Dam and Framingham studies1,2

Photoreceptors

Choroid

RPE

Photos courtesy of Novartis Pharmaceuticals Corporation.

Progression of Neovascular AMD: Normal Retina

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Bruch’s membrane thickens (left panel)and drusen develop (right panel)

Bruch’sMembrane

Drusen

Photos courtesy of Novartis Pharmaceuticals Corporation.

Progression of Neovascular AMD: Development of Drusen

ChoroidalNeovascularLesion

Photos courtesy of Novartis Pharmaceuticals Corporation.

Progression of Neovascular AMD: Formation of New Vessels

New abnormal blood vessels proliferateand penetrate Bruch’s membrane

New blood vessels leak blood and fluid

Photos courtesy of Novartis Pharmaceuticals Corporation.

Progression of Neovascular AMD: Leakage of Fluid and Blood From

CNVVisudyne (Photodynamic Therapy)Kenalog (Triamcinolone)

Macugen (Pegaptanib)Lucentis (Ranibizumab)Avastin (Bevacizumab)

Retaane (Anecortave Acetate)VEGF TrapEvizon (Squalamine)

Current & Emerging Drug Therapy for Neovascular Macular Degeneration

Visudyne

In use since 2000Photosensitizing drugOnly available treatment for “wet” AMD until December 2004 (Macugen)

Circulating VisudyneComplexes With LDL1

Visudyne Accumulates inNeovascular Tissue, Which Is Rich in LDL Receptors2

Visudyne®: Selective Accumulation in CNV

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Step 1:Infusion

Step 2:Nonthermal

LaserApplication

Photos reprinted with permission from Novartis Pharmaceuticals Corporation.Visudyne® (verteporfin for injection) prescribing information. Novartis PharmaceuticalsCorporation; April 2003.

Visudyne® Administration:A 2-Step Process

Reactive Oxygen Products

Selective Occlusion of Abnormal Vessels3

Nonthermal Laser Activation of Visudyne

Endothelial Cell Damageand Thrombus Formation1

Visudyne®: Occlusion of CNV 1-3

2-Year Results in Predominantly Classic Lesions

*P<.004.†P<.001.Adapted with permission from Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol. 2002;120:1443-1454.

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Months After Study Enrollment

VA L

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ost F

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ean)

*

††

Visudyne (n=159)Placebo (n=83)

Visudyne Therapy Helps Slow the Rate of Vision Loss

0

VA = visual activity.Data on file, Novartis Pharmaceuticals Corporation.

VA After 5-Years’ Use of Visudyne®

in Eyes With Predominantly Classic Lesions

-30

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0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60Mea

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Time After Study Enrollment (months)

VisudynePlacebo

Sustained Benefit with Visudyne Therapy: VA

(n=121)

(n=134) (n=132)

(n=121) Patients originally assigned to placebo now receive Visudyne

(n=77)

(n=85)

PDT/Visudyne

Frequency of usage significantly decreased with introduction of Anti-VEGF agentsStill very good for Myopic Choroidal Neovascularization

Only approved treatment for Myopia

Triamcinolone (Kenalog)

Intraocular injection of 4 mg (0.1 mL)SpeculumBetadineInjected inferiorly (usually at 6 o’clock)

Anti-inflammatory and anti-VEGF propertiesUsed as monotherapy or in conjunction with PDT

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Triamcinolone (Risks)

Injection RisksEndophthalmitisTraumatic CataractRetinal DetachmentVitreous Hemorrhage

Steroid RisksCataractGlaucoma

Anti-VEGF

Vascular Endothelial Growth FactorNormal protein found in the blood systemVarious forms (different agents target different forms)AngiogenesisElevated levels help tumors/cancers growElevated levels help fuel

Choroidal neovascularization in AMDNeovascularization in Diabetic Retinopathy

Cause of Neovascular AMD in combination with aging changes of the retinaAll of the “new” drug therapies are aimed against VEGFTreatments take from our Oncology colleagues

Macugen (Pegaptanib)

Developed by Eyetech (Pfizer sponsored)Anti-VEGF Aptamer (Isoform 165)Chemically synthesized short strand of RNAFDA approved for all types of lesions (December 2004)Intravitreal injection every 6 weeks$1200/dose

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Macugen

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Baseline Week 54

Anatomical Data Support Clinical Results

Total lesion size and leak intensity were significantly less in Macugen-treated patients compared with usual care controls

Lucentis (Ranibizumab)

Developed by GenentechAntibody directed against VEGFBinds all isoforms of VEGF

Compared to Macugen which only targets isoform 165

Lucentis

FDA approval June 2006Intravitreal injection every 4 weeks90% of patients maintain or improve vision$2000/dose

Lucentis

Taken from Lucentis.com

Lucentis

ANCHORMARINASAILORFOCUSPIER

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Lucentis

PIER studymonthly injections every month for 3 monthsQuarterly injections from then onPatients did well compared to shamPatients did better with monthly injections than quarterly ones

Avastin

Systemic Anti- VEGF agent developed by GenentechFDA approved for metastatic colorectal cancer February 2004Phil Rosenfeld, MD PhD studied intravenous Avastin for AMD

Bascom Palmer’s 12 week results for 9 patientsSystemic infusion 2 weeks apart with total of 2- 3 treatmentsVision improved in 1 weekAt 3 months, average vision improved over 2 lines in both eyes

Avastin

May 2005 Rosenfeld thought about injecting Avastin into the eye

Genentech had thought Avastin’s molecule was too large to penetrate the retina

The drug worked better than any previous treatmentAvastin usage spread throughout the world

Avastin

Has been used for AMD >2 yearsA year before Lucentis was available

Excellent results (similar to Lucentis?)$75/doseNot FDA approved, but approved by MedicareIntravitreal injection every 4-6 weeks

Drawbacks of Anti-VEGF

Pan Anti-VEGF agents (Lucentis & Avastin) may have cardiovascular complicationsHistory of MI or Stroke in patientsMultiple injections may be cumulative systemicallyDifficult to determine Anti-VEGF complications in these patients

What is current treatment of AMD?

Lucentis or Avastin 1st

Which one is better?Cost comes into playPatients choice comes into play

Repeat at 4-6 weeks (usually necessary)Consider substituting Macugen

Current trials underway

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Lucentis vs. Avastin

FDA approved for AMD

Controlled trials with results and safety$2000/injection

Not FDA approved for AMD, but covered by MedicareLarge experience by retina specialists$75/injection

Lucentis vs. Avastin

Lucentis is smaller moleculeBetter penetration into retina?Cleared faster from blood stream so safer?

Retaane (Anecortave Acetate)

Developed by AlconSteroid with the glucocorticoid cleaved off

Prevents steroid associated IOP risesGiven as juxtascleral depot every 6 months

Anecortave Acetate

New trial under way for the prevention of “wet” AMDPatients must have one eye with “wet” AMD and other eye with “dry” AMD

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VEGF Trap

Regeneron PharmaceuticalsBlocks action of VEGFIntravitreal injection

Squalamine (Evizon)

Systemic Anti- VEGF agent developed by GenaeraPurified from tissue of dogfish sharkMOA is to interrupt and reverse angiogenic processFDA has granted Fast Track designation

Combination Therapy

Combining PDT with Anti-VEGF agentsCombining different Anti-VEGF agentsCombining PDT, Steroids & Anti-VEGF

Vascular Diseases

Diabetic RetinopathyBranch Retinal Vein OcclusionCentral Retinal Vein Occlusion

Diabetic Retinopathy

Macular EdemaNeovascularizationVitreous HemorrhageTractional Retinal Detachment

Diabetic Macular Edema

LaserIntraocular SteroidsAnti- VEGFSurgery

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Diabetic Macular Edemalaser treatment

Laser treatment is the “gold” standardLaser destroys the leaking microaneurysmsLaser also stimulates fluid resorption by the retinaHowever, laser is not effective in penetrating significantly edematous retina

Post laser fluorescein angiogram

OCT before and after laser photocoagulaton

Five months after laser photocoagulation for macular thickening

Intraocular Steroids

Intravitreal injection of 0.1 ml kenalogOften effective in reduction of retinal edema Effect may be transitoryOften used in combination with laser

Macular Edema Treated with Intraocular Kenalog

Intraocular Kenalogrisks

Endophthalmitis (usually non-infectious)Vitreous HemorrhageRetinal DetachmentCataract (most common)Glaucoma

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Macular Edema Steroid Implants

Dissolvable Dexamethasone ImplantClinical Trials-Office based

Macular Edema Steroid Implants

Long Acting Fluocinolone Implant

Surgically implanted

Diabetic Macular Edema

Anti-VEGF treatment for cases not responsive to steroids

Would eliminate cataract and glaucoma risks from steroidsCost an issue

Diabetic Macular Edema

Surgical OptionsVitreous Traction?OCT is a valuable toolVitrectomy

Proliferative RetinopathyProliferative Retinopathy

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Neovascularization of Iris from Diabetic Retinopathy

Treatment of Proliferative Retinopathy

Pan retinal photocoagulationTheory – Destroy ischemic retinaReduce proliferative factorsPossibly increase oxygen levels in the retinaCause atrophy of neovascular tissue

Treatment of Proliferative Retinopathy

Anti-VEGF agentMacugenAvastinLucentis

Used in cases refractory to laserCan be used pre-op in Diabetics

Tractional Retinal Detachment

More Severe Proliferative Retinopathy Tractional Retinal Detachment

treatment

Pars Plana VitrectomyMembrane PeelPanretinal Photocoagulation+/- Silicone Oil

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Branch Retinal Vein OcclusionBranch Retinal Vein Occlusion

macular edema

Same treatment strategy as in Diabetic macular edemaLaser treatment is “gold” standardNewer treatments include intraocular steroids and steroid implantsAnti-VEGF treatment

Current clinical trials underway

Central Retinal Vein Occlusion

Previous treatments included panretinal photocoagulation for neovascular glaucomaNewer treatments are aimed at visual improvement rather than prevention of glaucoma

Central Retinal Vein Occlusiontreatment

Intraocular steroids for treatment of macular edemaPRP for NeovascularizationAnti-VEGF treatment

Current clinical trials underwayMay help with both edema and prevention of neovascularization

Sutureless Surgery

25 gauge vitrectomy (23 gauge)Xenon light sourcesFaster recoveryNo suture irritationNo induced astigmatism from sutures

Xenon Light Sources

Halogen bulbs have been traditional light sourceBright, white, safe light for improved visibility in surgery UV-Blue wavelength filtering designed to reduce phototoxic effects IR wavelength filtering added to reduce heat effects

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High Speed Vitrectomy

Previous vitrectomy units had cut rates of 600 cpmLatest vitrectomy units have cut rates of 2500 cpm

Allows for less traction on retinaAllows surgeon to get closer to retinal surface without complications

25 Gauge Pars Plana Vitrectomy

Standard 20 GaugeConjunctival incisionsLarger incisionsSutures cause astigmatismLonger healing timeDelayed visual recoveryPatient discomfort

Sutureless 25 GaugeDoes not require conjunctival openingNo sutures requiredFaster recoveryNo induced astigmatismPatients much more comfortable

Retinal Tears/Detachments

Lattice DegenerationRetinal HolesRetinal TearsRetinal Detachments

Lattice Degeneration

Found in 8-10% of general populationRisk of RD low (0.1-0.7%)Risk of tear off lattice lesion 2.0%Atrophic Holes commonly found within lattice lesion

Retinal Tears/Holes

Horseshoe TearsVitreous tractionUsually symptomaticNeed to be treated with laser

Atrophic HolesOften asymptomaticCan lead to RD if holes within lattice lesionUsually not treated

Peripheral Retinal Tears/Holes/Lattice(When to Treat?)

Can observe without treatmentLattice and Holes in Pre-LASIK

Prophylactically treatAtrophic Holes in fellow eye of RD

Prophylactically treatLattice Degeneration in fellow eye of RD

Can observe without treatmentAsymptomatic Lattice Degeneration

Can observe without treatmentAsymptomatic Atrophic HolesCan observe without treatmentAsymptomatic Retinal Tear TreatAcute Symptomatic Retinal Tear

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Retinal Detachment Repair

Scleral BuckleVitrectomyPneumatic Retinopexy

Selective casesSuperior tears (between 10 and 2 o’clock)No other retinal pathology (lattice, holes, etc.)Cooperative patient

Pneumatic Retinopexy

Cryo or laser tearInjection of 0.3 cc gasLocal anesthesiaLess complicationsFaster RecoveryLess chance of cataract then vitrectomy

Choroidal Lesions

NeviMelanomasCHRPE

Choroidal Nevus

Present in 6% of Caucasian Population1 in 5000 Nevi will become MelanomasRisk Factors of Nevi becoming Melanomas

Thickness > 2 mm (Ultrasound)Subretinal fluidOrange Pigment (as compared to drusen)Symptoms of flashes, floaters, va lossMargin of tumor < 3 mm to optic disc

Nevus vs. Melanoma Treatment of Melanoma

First, systemic work up for metastasesTreatment of tumor

Transpupillary ThermotherapyPlaque RadiationCharge particle irradiationLocal resectionEnucleation

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Artificial Vision

Dual Chip System

Artificial Vision

Silicone Chip Intraocular Silicone Chip

Final Thoughts

Anti- VEGF May cure all (AMD, Diabetic Retinopathy, Vein Occlusions)May have drawbacks (Cardiovascular consequences, financial restrictions)

25 Gauge SurgeryFaster & BetterNow available at Baylor Plano

Imaging DevicesThe better we detect diseases, the faster we can treat (Optos, OCT, FA)