Clinical Overview of Clinical Overview of Age-Related Macular DegenerationAge-Related Macular Degeneration

Victor H. Gonzalez, MDVictor H. Gonzalez, MD

Medical DirectorMedical DirectorValley Retina InstituteValley Retina Institute

McAllen, TXMcAllen, TX

Age-Related Macular DegenerationAge-Related Macular Degeneration

Affects patients ≥ 50 years of ageAffects patients ≥ 50 years of age Caucasian race, cigarette smoking, obesity, and Caucasian race, cigarette smoking, obesity, and

hypertension are significant risk factorshypertension are significant risk factors Condition marked by the appearance of drusen, an Condition marked by the appearance of drusen, an

accumulation of apparently undigested products of accumulation of apparently undigested products of retinal pigment epithelial cells under the basal lamina of retinal pigment epithelial cells under the basal lamina of Bruch's membraneBruch's membrane

Progressive deterioration of Bruch’s membrane, the Progressive deterioration of Bruch’s membrane, the retinal pigment epithelium, choriocapillaris, and outer retinal pigment epithelium, choriocapillaris, and outer retina in the macular arearetina in the macular area

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

Leading cause of severe vision loss in the developed Leading cause of severe vision loss in the developed countries countries – Marked byMarked by

Decreased visual acuity and contrast sensitivityDecreased visual acuity and contrast sensitivity Metamorphopsia and scotomaMetamorphopsia and scotoma

2 forms2 forms– Non-neovascular (dry)Non-neovascular (dry)– Neovascular (exudative, or “wet”) Neovascular (exudative, or “wet”)

90% of severe vision loss results from wet AMD90% of severe vision loss results from wet AMD

Vingerling JR. Epidemiol Rev. 1995;17:347.Hyman L. Age Related Macular Degeneration: Principles and Practice. New York: Raven Press; 1992;1-32.

Advanced AMD (choroidal neovascularization Advanced AMD (choroidal neovascularization or central GA) currently affects approximately or central GA) currently affects approximately 1.4 million people in the United States.1.4 million people in the United States.• ~ 8 million Americans at high risk for ~ 8 million Americans at high risk for

developing advanced AMDdeveloping advanced AMD• Potential increase in cases to 3 million by Potential increase in cases to 3 million by

year 2020year 2020

GA = Geographic atrophy.

Friedman DS, et al. Arch Ophthalmol. 2004;122:564-572.

Bressler NM, et al. Arch Ophthalmol. 2003:121:1621-1624.

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

Drusen and AMD—ProgressionDrusen and AMD—Progression

Exudative AMD

RPE & Sensory DetachmentDrusen

RPE Atrophy

Hemorrhagic Detachment

Fibrous Disciform Scar

Dry AMDRPE = retinal pigment epithelium.Jack J. Kanski, Jay Menon. Clinical Ophthalmology: A Systematic Approach. Elsevier Science; 2003.

How Is AMD Detected?How Is AMD Detected?

Clinical examClinical exam Visual function measurementVisual function measurement

– Visual acuityVisual acuity– Amsler gridAmsler grid– Contrast sensitivityContrast sensitivity

Diagnostic proceduresDiagnostic procedures– Fluorescein angiographyFluorescein angiography– Optical coherence Optical coherence

tomographytomography

1. http://images.google.com/images?q=Amsler+grid+%2B+AMD&ndsp=20&svnum=10&hl=en&lr=&client=firefox-a&rls=org.mozilla:en-US:official_s&start=0&sa=N 2. Image courtesy of Dr. V. Gonzalez, Valley Retina Institute P.A.

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Interventions to Slow ProgressionInterventions to Slow Progression

• AREDS formulationAREDS formulation– Vitamin C 500 mgVitamin C 500 mg– Vitamin E 400 IU (400 mg)Vitamin E 400 IU (400 mg)– Beta-carotene 15 mg (28640 IU vitamin A)Beta-carotene 15 mg (28640 IU vitamin A)– Zinc oxide 80 mgZinc oxide 80 mg– Cupric oxide 2 mgCupric oxide 2 mg

• Principal finding of studyPrincipal finding of study– Antioxidant vitamin/mineral (zinc) supplements modestly Antioxidant vitamin/mineral (zinc) supplements modestly

reduced risk of progression and reduced risk of progression and vision loss over 6 years vs placebovision loss over 6 years vs placebo

AREDS = Age-Related Eye Disease Study.AREDS Research Group. Arch Ophthalmol. 2001;119:1417.

AREDS SummaryAREDS Summary

Early AMDEarly AMD– No benefit from supplementsNo benefit from supplements

Intermediate AMD/monocular Intermediate AMD/monocular advanced AMDadvanced AMD– Antioxidants plus zinc or zinc Antioxidants plus zinc or zinc

alone significantly reduced the risk alone significantly reduced the risk of developing advanced AMDof developing advanced AMD

An estimated 300,000 Americans An estimated 300,000 Americans could avoid developing advanced could avoid developing advanced AMD over 5 years by taking AMD over 5 years by taking AREDS-type supplementsAREDS-type supplements

AREDS Research Group. Arch Ophthalmol. 2001;119:1417.

Less common than dry Less common than dry AMD, but more seriousAMD, but more serious

90% of severe vision loss 90% of severe vision loss results from wet AMDresults from wet AMD

Metamorphopsia is the initial Metamorphopsia is the initial symptom. Most lesions are symptom. Most lesions are not visible clinicallynot visible clinically

Wet AMDWet AMD

Hyman L. Age Related Macular Degeneration: Principles and Practice. New York: Raven Press; 1992.Image courtesy of Dr. V. Gonzalez, Valley Retina Institute P.A.

Treatments for Wet AMDTreatments for Wet AMD• Thermal laser coagulationThermal laser coagulation11

– MPS: Macular Photocoagulation StudyMPS: Macular Photocoagulation Study• Photodynamic therapy with verteporfinPhotodynamic therapy with verteporfin

– TAP: Treatment of Age-Related Macular Degeneration with TAP: Treatment of Age-Related Macular Degeneration with Photodynamic therapyPhotodynamic therapy22

– VIP: Verteporfin in Photodynamic therapyVIP: Verteporfin in Photodynamic therapy33

• Anti-VEGF therapiesAnti-VEGF therapies– Pegaptanib sodiumPegaptanib sodium

VISION: VEGF Inhibition Study in Ocular NeovascularizationVISION: VEGF Inhibition Study in Ocular Neovascularization44

– Ranibizumab (Lucentis)Ranibizumab (Lucentis) ANCHOR TrialANCHOR Trial55 MARINA Trial MARINA Trial66 FOCUS Trial FOCUS Trial77

– Bevacizumab (Off-label)Bevacizumab (Off-label)88

1. Macular Photocoagulation Study Group. Arch Ophthalmol. 1994;112:500. 2. (TAP) Study Group. Arch Ophthalmol. 1999; 117:1329. 3. VIP Study Group. Am J Ophthalmol. 2001;131:541. 4. Gonzales CR. Retina. 2005;25:815. 5. ANCHOR Study Group. Invest Ophthalmol Vis Sci. 2006;47:E-Abstract 2963. 6. MARINA Study Group. Invest Ophthalmol Vis Sci. 2006; 47:E-Abstract 2959. 7. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=9147. 8. http://www.fda.gov/CDER/foi/label/2004/125085lbl.pdf#search=%22Avastin%20package%20insert%22.

Laser PhotocoagulationLaser Photocoagulation

Obliterates choroidal neovascularization (CNV), Obliterates choroidal neovascularization (CNV), preventing further growth of fibrovascular tissuepreventing further growth of fibrovascular tissue

For some patients, it remains the 1st-line therapy for For some patients, it remains the 1st-line therapy for well demarcated extrafoveal/juxtafoveal CNV lesionswell demarcated extrafoveal/juxtafoveal CNV lesions

50% chance of recurrence within 2 years of treatment50% chance of recurrence within 2 years of treatment May damage surrounding tissueMay damage surrounding tissue

Macular Photocoagulation Study Group. Arch Ophthalmol. 1991;109:1220.Fine SL, et al. N Engl J Med. 2000;342:483.

Photodynamic Therapy with VerteporfinPhotodynamic Therapy with Verteporfin

Photodynamic therapyPhotodynamic therapy Rapid closure of vesselsRapid closure of vessels Intra- and extracellular infiltration of Intra- and extracellular infiltration of

inflammatory cellsinflammatory cells Increased edema in the short termIncreased edema in the short term Transient antiangiogenic effectsTransient antiangiogenic effects Upregulates vascular endothelial growth factorUpregulates vascular endothelial growth factor 90% of patients need retreatment at 3 months90% of patients need retreatment at 3 months

Schmidt-Erfurth U, et al. Invest Ophthalmol Vis Sci. 2002;43:830.

Photodynamic Therapy StudiesPhotodynamic Therapy Studies

TAP StudyTAP Study11

– Multicenter, double-blind, placebo-controlled, randomized, Multicenter, double-blind, placebo-controlled, randomized, clinical trial of verteporfin vs placeboclinical trial of verteporfin vs placebo

– AMD with classic subfoveal lesionsAMD with classic subfoveal lesions– Significant benefit with PDT therapy at 12 and 24 monthsSignificant benefit with PDT therapy at 12 and 24 months

VIP StudyVIP Study22

– Occult or minimally classicOccult or minimally classic– By month 24, verteporfin group was less likely to have By month 24, verteporfin group was less likely to have

moderate to severe vision lossmoderate to severe vision loss

TAP = Treatment of age-related macular degeneration with photodynamic therapy; PDT = photodynamic therapy; VIP = Verteporfin In photodynamic therapy

1. TAP Study Group. Arch Ophthalmol. 1999;117:1329.2. VIP Study Group. Am J Ophthalmol. 2001;131:541.

Vascular Endothelial Growth FactorVascular Endothelial Growth Factor11

• A protein that regulates angiogenesis (normal and A protein that regulates angiogenesis (normal and abnormal) abnormal)

• Member of a family of angiogenic and lymphangiogenic Member of a family of angiogenic and lymphangiogenic growth factorsgrowth factors

• Secreted by a variety of cells in response to Secreted by a variety of cells in response to hypoxia/ischemia and other signalshypoxia/ischemia and other signals

• Many strategies now target this factorMany strategies now target this factor22

– Interfering with pro-angiogenic growth factors, receptors, or Interfering with pro-angiogenic growth factors, receptors, or downstream signalingdownstream signaling

– Upregulating endogenous inhibitors, or administering Upregulating endogenous inhibitors, or administering exogenous inhibitorsexogenous inhibitors

– Directly targeting neovasculatureDirectly targeting neovasculature

1. Adamis AP, et al. Retina. 2005;25:111. 2. Witmer AN, et al. Prog Retin Eye Res. 2003;22:1.

PegaptanibPegaptanib—Anti-VEGF Aptamer—Anti-VEGF Aptamer

Selective VEGF inhibitionSelective VEGF inhibition Binds selectively to VEGFBinds selectively to VEGF165165

– Pathologic isoformPathologic isoform

Spares normal vasculatureSpares normal vasculature

Mechanisms of actionMechanisms of action

– AntiangiogenicAntiangiogenic22

– AntipermeableAntipermeable22

– AntiinflammatoryAntiinflammatory33

Pegaptanibbinds to VEGF165

VEGF = vascular endothelial growth factor1. http://www.revophth.com/index.asp?page=1_652.htm. 2. Ishida S, et al. J Exp Med. 2003;198:483.3. Carrasquillo KG , et al. Invest Ophthalmol Vis Sci. 2003;44(1):290.

Pegaptanib

1

VEGF Inhibition Study in Ocular VEGF Inhibition Study in Ocular Neovascularization (VISION)Neovascularization (VISION)

Two randomized controlled studies involving 1186 Two randomized controlled studies involving 1186 patients in 117 centers patients in 117 centers

Intravitreal injections every 6 weeks for 1 yearIntravitreal injections every 6 weeks for 1 year Primary endpoint: % of patients losing Primary endpoint: % of patients losing

<15 letters at 1 year<15 letters at 1 year Mean letters of visual acuity loss: 8 in pegaptanib-Mean letters of visual acuity loss: 8 in pegaptanib-

treated vs 15 in placebo at 1 yeartreated vs 15 in placebo at 1 year

Gragoudas ES. N Engl J Med. 2004;351:2805.

VISION StudyVISION Study

Primary efficacy endpoint: Primary efficacy endpoint: % of patients losing <15 letters at week 54% of patients losing <15 letters at week 54

Adapted with permission from Gragoudas ES. N Engl J Med. 2004;351:2805. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

0.3 mg0.3 mg 1 mg1 mg 3 mg3 mg ShamSham

N = 294N = 294 N = 300N = 300 N = 296N = 296 N = 296N = 296

< 15 letters< 15 letters 70%70% 71%71% 65%65% 55%55%

PP-value-value < .0001< .0001 .0003.0003 .0310.0310 ——

RanibizumabRanibizumab

Humanized fragment of a Humanized fragment of a monoclonal antibodymonoclonal antibody

Targets all isoforms of VEGFTargets all isoforms of VEGF 3 randomized clinical trials 3 randomized clinical trials

(ANCHOR, MARINA, and (ANCHOR, MARINA, and FOCUS)FOCUS)

Ranibizumab

Genentech, Inc. Data on file.

RanibizumabRanibizumabANCHOR TrialANCHOR Trial

423 patients with predominantly classic CNV randomized to423 patients with predominantly classic CNV randomized to– PDT/sham injection Q 3 mo for 2 yearsPDT/sham injection Q 3 mo for 2 years– Placebo PDT/0.3 mg ranibizumab injection once per Placebo PDT/0.3 mg ranibizumab injection once per

monthmonth– Placebo PDT/0.5 mg ranibizumab injection once per Placebo PDT/0.5 mg ranibizumab injection once per

monthmonth11

Primary endpoint: % of patients losing <15 letters Primary endpoint: % of patients losing <15 letters in 1 yearin 1 year11

Endpoint reached by 94% and 96% of patientsEndpoint reached by 94% and 96% of patients Vision improved in 36% – 40% of patientsVision improved in 36% – 40% of patients22

CNV = choroidal neovascularization; PDT = photodynamic therapy

1. Kaiser PK. Ophthalmology. 2005;9(1).2. http://www.clinicaltrials.gov/ct/show/NCT00061594?order=3.

RanibizumabRanibizumabMARINA TrialMARINA Trial

716 patients with minimally classic or occult lesions716 patients with minimally classic or occult lesions Patients randomized to monthly injections with 0.3 Patients randomized to monthly injections with 0.3

mg or 0.5 mg ranibizumab, or shammg or 0.5 mg ranibizumab, or sham Therapy found to improve vision in patients with Therapy found to improve vision in patients with

wet AMDwet AMD

Association for Research in Vision and Ophthalmology. ARVO2006. 2006.

MARINA Year 1 ResultsMARINA Year 1 Resultsand Conclusionsand Conclusions

95% of ranibizumab subjects lost <15 letters 95% of ranibizumab subjects lost <15 letters (vs 62% of sham)(vs 62% of sham)

25% – 34% of ranibizumab subjects gained 25% – 34% of ranibizumab subjects gained ≥≥15 letters 15 letters (vs 5% of sham)(vs 5% of sham)

First phase III clinical trial to show improvement in mean First phase III clinical trial to show improvement in mean visual acuityvisual acuity

No serious ocular side effectsNo serious ocular side effects No apparent systemic safety concernsNo apparent systemic safety concerns

Association for Research in Vision and Ophthalmology. ARVO2006. 2006.

Bevacizumab Bevacizumab (Off-Label)(Off-Label)

Recombinant humanized monoclonal antibody that Recombinant humanized monoclonal antibody that binds VEGFbinds VEGF

First anti-VEGF medication FDA approved as First anti-VEGF medication FDA approved as treatment for metastatic colorectal cancertreatment for metastatic colorectal cancer

Not approved for ophthalmic useNot approved for ophthalmic use Demonstrated efficacy in 2 case series (50 and 79 Demonstrated efficacy in 2 case series (50 and 79

patients)patients)1,21,2

1. Rich RM, et al. Retina. 2006;26:495.

2. Avery RL, et al. Ophthalmology. 2006;113:363.

AMD SummaryAMD Summary

AREDS formulation significantly reduces the risk of AREDS formulation significantly reduces the risk of progression from intermediate to advanced AMDprogression from intermediate to advanced AMD11

Pegaptanib sodium provides a safe treatment for all Pegaptanib sodium provides a safe treatment for all lesion compositionslesion compositions22

Recently approved ranibizumab is the first drug to Recently approved ranibizumab is the first drug to improve visual acuity in 30% – 40% of patientsimprove visual acuity in 30% – 40% of patients33

1. AREDS Research Group. AREDS report no. 8. Arch Ophthalmol. 2001;119:1417. 2. D’Amico DJ, et al. Clinical Trial Group. Ophthalmology. 2006;113:1001.3. Heier JS, et al. Ophthalmology. 2006;113:642.

Treatment SummaryTreatment Summary

Early data suggest that anti-VEGF treatment alone may not Early data suggest that anti-VEGF treatment alone may not be a long-term solutionbe a long-term solution

Numerous other antiangiogenic and/or anti- inflammatory Numerous other antiangiogenic and/or anti- inflammatory agents offer hope for the futureagents offer hope for the future

– – BevacizumabBevacizumab

– – Anecortave acetateAnecortave acetate

– – Triamcinolone acetonideTriamcinolone acetonide

– – VEGF trapVEGF trap

– – siRNAssiRNAs

– – Squalamine lactateSqualamine lactate

– – Kinase inhibitorsKinase inhibitors

– – AdPEDFAdPEDF

The Goals of Treating AMDThe Goals of Treating AMD

• To minimize loss of visual acuity and central visionTo minimize loss of visual acuity and central vision

• To preserve reading ability with/without visual aidsTo preserve reading ability with/without visual aids

• To optimize quality of lifeTo optimize quality of life

• To minimize adverse effects of treatment modalities To minimize adverse effects of treatment modalities

We look forward to the next decade of AMD We look forward to the next decade of AMD management, as investigations on management, as investigations on antiangiogenesis, inflammation, and other antiangiogenesis, inflammation, and other strategies continue. strategies continue.

Health-Related Quality of Life and Health-Related Quality of Life and Health Economics Associated with Health Economics Associated with

AMDAMD

Glenda S. Owens, RPh, MHA, CDMGlenda S. Owens, RPh, MHA, CDMVice PresidentVice President

Pharmacy ServicesPharmacy ServicesArcadian Health PlanArcadian Health PlanSan Dimas, CaliforniaSan Dimas, California

Burden of Age-Related Macular Degeneration Burden of Age-Related Macular Degeneration (AMD) and Visual Impairment(AMD) and Visual Impairment

AMD is the most common cause of severe, irreversible AMD is the most common cause of severe, irreversible vision lossvision loss

An estimated 200,000 new cases of wet AMD are An estimated 200,000 new cases of wet AMD are diagnosed each year in the United Statesdiagnosed each year in the United States

Without treatment, most patients rapidly progress to Without treatment, most patients rapidly progress to legal blindness (20/200) in less than 2 yearslegal blindness (20/200) in less than 2 years

The impact of visual impairment on direct and indirect The impact of visual impairment on direct and indirect costs and on patients’ health-related quality of life is costs and on patients’ health-related quality of life is significantsignificant

1. National Institutes of Health: National Eye Institute. Vision Problems in the U.S. 2002;20. Available at: http://catalog.nei.nih.gov/productcart/pc/viewPrd.asp?idcategory=43&idproduct=47. Accessed July 31, 2006.

2. Foundation of the American Academy of Ophthalmology. AMD: An Overview of the Disease. Available at: http://www.faao.org/what/AMD/Overview.cfm. Accessed July 31, 2006.

Impact of Visual Impairment on Annual Direct Impact of Visual Impairment on Annual Direct and Indirect Costsand Indirect Costs

In the United States, annual direct medical costs associated with In the United States, annual direct medical costs associated with visual impairment totaled $48.7 billion in 2003.visual impairment totaled $48.7 billion in 2003.11

When all indirect costs such as lost productivity are factored in, the When all indirect costs such as lost productivity are factored in, the total annual cost was $67.6 billion.total annual cost was $67.6 billion.11

Loss of vision among elderly women increases the risk of frequent Loss of vision among elderly women increases the risk of frequent falls.falls.22

In 2003 more than 1.8 million seniors age 65 years and older were In 2003 more than 1.8 million seniors age 65 years and older were treated in emergency departments for fall-related injuries and more treated in emergency departments for fall-related injuries and more than 421,000 were hospitalized.than 421,000 were hospitalized.33

1. NIH National Eye Institute Hu Analysis, available at: http://www.nei.nih.gov/eyedata/hu_estimates.asp#table2. 1. NIH National Eye Institute Hu Analysis, available at: http://www.nei.nih.gov/eyedata/hu_estimates.asp#table2. Accessed July 31, 2006.Accessed July 31, 2006.2. Coleman AL, et al. 2. Coleman AL, et al. OphthalmologyOphthalmology. 2004;111:857.. 2004;111:857.3. CDC.2005. Available at http://www.cdc.gov/ncipc/factsheets/falls.htm. Accessed July 31, 2006.3. CDC.2005. Available at http://www.cdc.gov/ncipc/factsheets/falls.htm. Accessed July 31, 2006.

Patient Reported Visual Function (PRVF) Patient Reported Visual Function (PRVF)

Importance of PRVFImportance of PRVF11

– Visual acuity (VA) is the standard visual measurement used in clinical trials. Visual acuity (VA) is the standard visual measurement used in clinical trials. However, VA does not equal visual function or However, VA does not equal visual function or the patient perspective of the the patient perspective of the impact of vision problems on function impact of vision problems on function

The National Eye Institute Visual Function Questionnaire The National Eye Institute Visual Function Questionnaire (NEI VFQ-25) is the measurement tool for self-reported visual function(NEI VFQ-25) is the measurement tool for self-reported visual function22

– Assesses vision-targeted functioningAssesses vision-targeted functioning Measures impact of vision problems on function for many common eye Measures impact of vision problems on function for many common eye

conditions conditions – Represents the patient perspective of the impact of vision problems on Represents the patient perspective of the impact of vision problems on

function with attention tofunction with attention to Near activitiesNear activities Distance activitiesDistance activities Vision-related dependencyVision-related dependency

1. Presented at ARVO. April 30–May 4, 2006, Fl.2. Mangione CM, et al. Arch Ophthalmol. 2001;119:1050

What Are Patient-Reported Outcomes What Are Patient-Reported Outcomes (PROs)?(PROs)?

Patient self-reported assessment of the impact of their health status on Patient self-reported assessment of the impact of their health status on – Quality of lifeQuality of life– Ability to functionAbility to function

PRO data are widely accepted in oncology, medicine, orthopedics, PRO data are widely accepted in oncology, medicine, orthopedics, rehabilitation, etcrehabilitation, etc

Use of PROs in ophthalmology reveal the patient’s belief about their level Use of PROs in ophthalmology reveal the patient’s belief about their level of visual function, which may not be reflective of their visual acuity (VA)of visual function, which may not be reflective of their visual acuity (VA)

VA is the standard visual measurement used in clinical trials; however, VA VA is the standard visual measurement used in clinical trials; however, VA does not equal visual functiondoes not equal visual function

PROs complement VA dataPROs complement VA data

These 2 patients have the same VA; however, visual function is markedly different

Visual Acuity Does Not Equal Visual FunctionVisual Acuity Does Not Equal Visual Function

Genentech Data on file. Reprinted with permission.

Despite normal VA, there is a temporary tilt in vision early after translocation surgery, but this tilt

is corrected by the second stage of the eye muscle surgery.

Visual Acuity Does Not Equal Visual FunctionVisual Acuity Does Not Equal Visual Function

Images of grandfather clocks © Copyright 2006, Duke University Eye Center. Reprinted with permission.

NEI VFQ-25NEI VFQ-25Administration and ScoringAdministration and Scoring

AdministrationAdministration– Most patients can complete the questionnaire in 10 Most patients can complete the questionnaire in 10

minutes minutes – Conducted in-person, by telephone interview, or it Conducted in-person, by telephone interview, or it

can be self-administeredcan be self-administered

Scoring system (overall and subscales)Scoring system (overall and subscales)– Scores range from 0 (worst) to 100 (best) for vision-Scores range from 0 (worst) to 100 (best) for vision-

related functionsrelated functions

Mangione CM, et al. Arch Ophthalmol. 2001;119:1050.

Subscale Number of Items Description of Items

General vision 1 • 6-level health rating item

General health 1 • 5-level health rating item

Near vision 6 • Reading normal newsprint• Seeing well up close• Finding objects on crowded shelf• Reading small print ( telephone book, Rx)• Figuring out whether bills are accurate• Shaving, hair styling, putting on makeup

Distance vision 6 • Going out to movies/plays/sports events• Going downstairs in dim light or at night• Reading street signs or names of stores

• Taking part in sports or active activities• Seeing and enjoying programs on tv• Recognizing people you know across a room

Vision-specific dependency

3 • Need much help from others• Stay home most of time• Rely too much on others’ word

NEI VFQ-25 SubscalesNEI VFQ-25 Subscales

Mangione CM, et al. Arch Ophthalmol. 2001;119:1050.

Subscale Number of Items Description of Items

Driving 3 • Difficulty driving in familiar places during the day• Difficulty driving in familiar places during the

night• Difficult conditions (ie, bad weather, rush hour)

Peripheral vision 1 • Noticing objects off to the side

Color vision 1 • Difficulty matching clothes

Ocular pain 2 • Amount pain• Amount time: pain

Vision-specific role difficulties

2 • Accomplish less• Limited in endurance

Vision-specific social function

2 • Seeing how people react• Visiting others

Vision-specific mental health

4 • Amount true of frustration• Amount true of embarrassment• Amount true of no control• Amount time of worry

NEI VFQ-25 SubscalesNEI VFQ-25 Subscales

Mangione CM, et al. Arch Ophthalmol. 2001;119:1050.

1. Miskala PH, et al. Arch Ophthalmol. 2004;122:758.2. Lindblad AS, Clemons TE. Arch Ophthalmol. 2005;123:1207.

How Do We Interpret Changes in the How Do We Interpret Changes in the NEI VFQ-25?NEI VFQ-25?

SST Report No. 1 SST Report No. 1 11

– A 3-line loss was associated with a 10-point decrease in the A 3-line loss was associated with a 10-point decrease in the NEI VFQ-25NEI VFQ-25

AREDS Report No. 14AREDS Report No. 1422

– Changes in NEI VFQ-25 overall and subscale scores of 10 Changes in NEI VFQ-25 overall and subscale scores of 10 points or more associated withpoints or more associated with

Clinically significant changes in vision (≥15 letter change)Clinically significant changes in vision (≥15 letter change) Progression to advanced AMD from intermediate stage of Progression to advanced AMD from intermediate stage of

AMDAMD

Improvement in Near ActivitiesImprovement in Near Activities

P values vs placebo: 0.3 mg—.0457 at month 1; .0045 at month 2; <.0001 at months 3, 6, 9, and 12.0.5 mg—.0413 at month 1; .0305 at month 2; <.0001 at months 3, 6, 9, and 12.

-12-10

-8-6-4-202468

1012

0 1 2 3 4 5 6 7 8 9 10 11 12

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Placebo (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)

Presented at ARVO. April 30–May 4, 2006, Fl.

Improvement in Distance ActivitiesImprovement in Distance Activities

-12-10-8-6-4-202468

1012

0 1 2 3 4 5 6 7 8 9 10 11 12

P values vs placebo:0.3 mg—.0067 at month 1; <.0001 at months 2, 3, 6, 9, and 12.0.5 mg—>.05 at month 1; .0127 at month 2; <.0001 at months 3, 6, 9, and 12.

MonthsMe

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Placebo (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)

Presented at ARVO. April 30–May 4, 2006, Fl.

Improvement in Vision-Specific Improvement in Vision-Specific DependencyDependency

-12-10-8-6-4-202468

1012

0 1 2 3 4 5 6 7 8 9 10 11 12

P values vs placebo: 0.3 mg—>.05 at month 1; .0094 at month 2; .0063 at month 3; .0051 at month 6; .0011 at month 9; .0004 at month 12. 0.5 mg—>.05 at month 1; <.0197 at month 2; .0012 at month 3; <.0001 at months 6, 9, and 12.

Months

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rePlacebo (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)

Presented at ARVO. April 30–May 4, 2006, Fl.

Ranibizumab-treated subjects reported improvements in Ranibizumab-treated subjects reported improvements in visual function in almost all VFQ subscales at month 12visual function in almost all VFQ subscales at month 12

Ranibizumab-treated subjects reported clinically Ranibizumab-treated subjects reported clinically meaningful improvements in the VFQ subscales most meaningful improvements in the VFQ subscales most important in AMDimportant in AMD– Near activitiesNear activities– Distance activitiesDistance activities– Vision-specific dependencyVision-specific dependency

MARINA PRVF ConclusionsMARINA PRVF Conclusions

Chang TS, et al. Presented at ARVO. April 30–May 4, 2006, Fl. (Poster 5252/B667)

Key Ocular Serious Adverse EventsKey Ocular Serious Adverse Events

*1 case reported as uveitis by investigator; †Same subject had 2 episodes each reported as uveitis, received systemic antibiotics once; ‡Same subject had 2 episodes.PDT = photodynamic therapy.

MARINA ANCHOR

Ranibizumab Ranibizumab

Placebo(n = 236)

0.3 mg (n = 238)

0.5 mg(n = 239)

PDT(n = 143)

0.3 mg(n = 137)

0.5 mg(n = 140)

Presumed endophthalmitis Culture positive Culture negative Culture not done

000

00

1 (0.4%)

02 (0.8%)*

0

000

000

1 (0.7%)0

1 (0.7%)†

Uveitis 0 2 (0.8%) 1 (0.4%)‡ 0 0 1 (0.7%)†

Rhegmatogenous retinal detachment 0 0 0 1(0.7%)‡ 1(0.7%) 0

Retinal tear 0 1 (0.4%) 1 (0.4%) 0 0 0

Vitreous hemorrhage 0 1 (0.4%) 1 (0.4%) 0 1 (0.7%) 0

Lens damage 0 0 1 (0.4%) 0 0 0

Presented at ARVO. April 30–May 4, 2006, FL.

Key Systemic Adverse EventsKey Systemic Adverse EventsMARINA ANCHOR

Ranibizumab Ranibizumab

Placebo(n = 236)

0.3 mg (n = 238)

0.5 mg(n = 239)

PDT(n = 143)

0.3 mg (n = 137)

0.5 mg(n = 140)

Hypertension (HTN)* 23 (9.7%) 20 (8.4%) 20 (8.4%) 12 (8.4%) 3 (2.2%) 9 (6.4%)

Mean change in SBP/DBP (mmHg) -2/-2 -1/-2 -4/-1 0/0.3 -2/-2 -2/1

Key arterialthromboembolic events

Myocardial infarction

1 (0.4%) 1 (0.4%) 1 (0.4%) 1 (0.7%) 1 (0.7%) 3 (2.1%)

Cerebrovascular accident 1 (0.4%) 1 (0.4%) 3 (1.3%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Death 0 1 (0.4%)† 2 (0.8%)‡ 2 (1.3%)§ 3 (2.2%)** 2 (1.4%)††

*No serious adverse events of HTN reported during year 1; †Myocardial infarction; ‡Small bowel infarct, chronic asthma/chronic obstructive pulmonary disease (COPD); §Cardiac arrest, COPD; **Cardiac arrest, respiratory arrest, viral syndrome; ††Cardiac failure, chronic heart failure.

Presented at ARVO. April 30–May 4, 2006, FL.

(n = 7545 total intravitreal injections)(n = 7545 total intravitreal injections)

Events n% per

Injection% per

Patient/y

Endophthalmitis* 12 0.16 0.1

Lens damage/cataract 5 0.07 0.1

Retinal detachment 6 0.08 0

VISION Study—VISION Study—SafetySafety

No apparent drug-related SAEsNo apparent drug-related SAEs Few injection-related SAEsFew injection-related SAEs

SAEs = serious adverse events.Adapted with permission from Gragoudas ES, et al. N Engl J Med. 2004;351:2805. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Do We See a Change in Vision-Do We See a Change in Vision-Related QOL in the MARINA Trial?Related QOL in the MARINA Trial?

17.7 letter difference*

17.0 letter difference*

*P < .0001 vs placebo

1 2 3 4 5 6 7 8 9 10 11 12

Month-10

-8

-6

-4

-2

0

2

4

6

8

10

No

. ET

DR

S L

ette

rs

-10.5

+6.5+7.2

12

Secondary Endpoint Secondary Endpoint Mean Change in Visual Acuity Over TimeMean Change in Visual Acuity Over Time

Placebo (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240)

Presented at ARVO. April 30–May 4, 2006, Fl.

Baseline = 0; P-values for combined 0.3 and 0.5 mg ranibizumab vs placebo.Error bars represent the 95% confidence interval of the mean.

-15

-10

-5

0

5

10

15

Overall visual

function

Nearactivities

Distance activities

Vision-specific

dependency

Improvement

Decline

(P < .0001)

(P < .0001) (P < .0001)(P < .0001)

Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)

Placebo (n = 238)V

FQ

sco

re

Mean Change in VFQ Score from Baseline at Mean Change in VFQ Score from Baseline at Month 12Month 12

Chang TS, et al. Presented at ARVO. April 30–May 4, 2006, Fl. (Poster 5252/B667)

Baseline = 0; P-values for combined 0.3 and 0.5 mg ranibizumab vs placebo.Error bars represent the 95% confidence interval of the mean.

Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)

Placebo (n = 238)

-15

-10

-5

0

5

10

15

Vision-specific social

function

Vision-specific mentalhealth

Vision-specific

role difficulties

General vision

Improvement

Decline

(P < .0001)

(P < .0001)

(P < .0001)

(P < .0001)

VF

Q 2

5 S

core

Mean Change in VFQ Score from Baseline at Mean Change in VFQ Score from Baseline at

Month 12Month 12

Presented at ARVO. April 30–May 4, 2006.

Baseline = 0; P-values for combined 0.3 and 0.5 mg ranibizumab vs placebo.Error bars represent the 95% confidence interval of the mean.

-15

-10

-5

0

5

10

15

DrivingGeneralhealth

Ocularpain

Color vision

Improvement

Decline

VF

Q 2

5 S

core

(P = .051)

(P = .260)(P < .0001) (P = .125)

Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240)

Placebo (n = 238)

Mean Change in VFQ Score from Baseline at Mean Change in VFQ Score from Baseline at Month 12Month 12

Presented at ARVO. April 30–May 4, 2006.

Health EconomicsHealth EconomicsCost to Society vs Benefits of TreatmentCost to Society vs Benefits of Treatment

Blindness has a significant impactBlindness has a significant impact– Annual medical expendituresAnnual medical expenditures– Indirect costs approximately 10 x direct costsIndirect costs approximately 10 x direct costs

Benefits of treatmentBenefits of treatment– Continuation or resumption of normal daily living activities, Continuation or resumption of normal daily living activities,

including drivingincluding driving– Avoid secondary medical problems, such as broken bones Avoid secondary medical problems, such as broken bones

due to fallsdue to falls– Minimal caregiver responsibilitiesMinimal caregiver responsibilities– Decreased likelihood of nursing home admissionDecreased likelihood of nursing home admission

Implications for the Implications for the Managed Care CommunityManaged Care Community

Stuart Levine, MD, MHAStuart Levine, MD, MHAAssistant Clinical Professor/Internal MedicineAssistant Clinical Professor/Internal Medicine

University of California, Los AngelesUniversity of California, Los AngelesDavid Geffen School of MedicineDavid Geffen School of Medicine

Chief Medical OfficerChief Medical OfficerProspect MedicalProspect Medical

Los Angeles, CaliforniaLos Angeles, California

Age-Related Macular Degeneration (AMD)Age-Related Macular Degeneration (AMD) Who Will Be Covered?Who Will Be Covered?

Medicare advantageMedicare advantage Medicare part DMedicare part D MedicaidMedicaid CommercialCommercial

– Pharmacy benefitPharmacy benefit– Medical benefitMedical benefit

AMDAMDPrioritiesPriorities

Is it a Is it a prioritypriority of the health plan? of the health plan?

Is it a Is it a prioritypriority of the physician community? of the physician community?

Is it a Is it a prioritypriority for patients? for patients?– Quality of lifeQuality of life– Ability to functionAbility to function

AMDAMD Cost of AMD on the Health PlanCost of AMD on the Health Plan

Direct costsDirect costs HospitalHospital PhysicianPhysician PharmacyPharmacy

Indirect costsIndirect costs DisabilityDisability Long-term careLong-term care Patient adherence for all illnessesPatient adherence for all illnesses Caregiver burdenCaregiver burden

AMDAMD Cost of AMD on the Health PlanCost of AMD on the Health Plan

AMDAMDPreventionPrevention

ZincZinc Vitamin C and EVitamin C and E Beta caroteneBeta carotene Cupric oxideCupric oxide

AMDAMDWhat Current Therapies Are Covered?What Current Therapies Are Covered?

Thermal laser coagulationThermal laser coagulation PDT with verteporfinPDT with verteporfin Anti-VEGFAnti-VEGF

– On-Label useOn-Label use Pegaptanib sodiumPegaptanib sodium RanibizumabRanibizumab

– Off-Label useOff-Label use Bevacizumab*Bevacizumab*

*Covered by Medicare in some states.

AMDAMDFuture TherapiesFuture Therapies

Efficacy Efficacy Medication vs placeboMedication vs placebo Head-to-head medication trialsHead-to-head medication trials CostCost Cost efficacy/medical cost offsetCost efficacy/medical cost offset PharmacoeconomicsPharmacoeconomics

How do you decide on future therapies?How do you decide on future therapies?

AMDAMDWhat Data Will Be Required?What Data Will Be Required?

Clinical Trials Must Demonstrate Efficacy of a Medication in Clinical Trials Must Demonstrate Efficacy of a Medication in Treatment of AMDTreatment of AMD

Types of trialsTypes of trials Length of trialsLength of trials Placebo controlledPlacebo controlled Head-to-headHead-to-head Numbers of patientsNumbers of patients Statistical significanceStatistical significance

AMDAMDPatient Population TargetedPatient Population Targeted

MedicareMedicare Medicaid age, blind, and disabledMedicaid age, blind, and disabled Dually eligible — Medicare - MedicaidDually eligible — Medicare - Medicaid

AMDAMDWill Occult AMD Be Covered?Will Occult AMD Be Covered?

Visual acuityVisual acuity DisabilityDisability

Cataract removal model of criteriaCataract removal model of criteria

At what degree of disease will the patient At what degree of disease will the patient be eligible for treatment?be eligible for treatment?