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Age-Related Macular Degeneration (AMD):

Questions and Answers

Jacque L. Duncan, M.D.Professor

Department of OphthalmologyUCSF

What is AMD? Leading Cause of Severe Vision Loss

among people over 50 in U.S.

9 million cases in U.S.

Prevalence increasing as population ages

Population >60 will double by 2030

Number with advanced AMD will increase 50% by 2020

Eye Diseases Prevalence Research Group, Arch Ophthalmol 122 (2004), 564-572

AMDNormal Who Gets AMD?

Risk Factors: Age > 65 years Female White Race Light Iris Pigmentation Family History of AMD Cigarette Smoking: pooled studies show

>4x risk Wet AMD

Thornton et al., Eye 19 (2005), 935-944

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Age-Related Macular Degeneration

Risk Factors: Age greater than age 65 years

Female Gender

Family History of AMD

Light Iris Pigmentation

Cigarette Smoking: pooled studies show >4x risk CNV

Hyperopia

Hypertension, hypercholesterolemia, cardiac disease

Genetic Background: heritability up to 71%

CFH: Tyr402His on chromosome 1q

Loc 387715/HTRA1 on chromosome 10q26

CF2-FB, C3Thornton et al., Eye 19 (2005), 935-944

AMD: Other Genetic Associations:

2008: C3

2010: CFI/PLAG12A

SYN3/TIMP3

CETP

LIPC

2011: VEGFA

COL10A1

2013: 7 novel genes plus ABCA4 revisited: COL8A1/FILIPIL

IER3/DDRI

SLC16A8

COL15A1/TGFBR1

RAD51B

ADAMTS9

B3/ALTL

ABCA4Fritzche L, et al. Nat Genet. 2013 Apr;45(4):433-9, 439e1-2.

doi: 10.1038/ng.2578. Epub 2013 Mar 3.

How can genetics help me?

Genetic profiling: Higher genetic risk score present in patients with

younger onset of AMD <75 yo: mean GRS 1.87 vs >75 mean GRS 1.45

Combining genotype with phenotype significantly better predicts risk of progression to late AMD than phenotype alone

Better understanding of mechanisms may lead to new therapies

Grassmann et al., PLoS One 2012; 7(5):e37979

Perlee et al., Ophthalmology 2013, Ophthalmology. 2013 Sep;120(9):1880-92.

How can the doctor tell I have AMD?

Early Changes: Dry AMD

Drusen Yellow Deposits Under Retina

Low and High Risk: Size

Characteristics: hard, soft, confluent

Pigment Changes

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Normal Retina Early Dry AMD: Drusen

Does AMD always cause blindness?

No!

Most people with AMD do NOT develop blindness

But it is so common that the 20-30% of people with AMD who do lose vision is a lot of people

My doctor says I have Dry AMD, and I can’t see well…..

Late Dry AMD: Geographic Atrophy (GA) Progressive loss of the blood vessels and cells

under the retina and the vision cells they supply

Affects 3.5% >75, 22% > 90 years old Early: Regions of Vision Loss around the

Center Gradual central vision loss Often spares very center until late

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Geographic Atrophy (GA)How Does GA Affect Vision?

Significant cause of moderate and severe central vision loss

Patients with good central vision can have severe problems with vision (reading difficulty, fluctuating vision, limited night vision)

Sunness et al., Ophthalmology 1996; 103: 1458-66Sunness et al., AJO 2005; 140: 1085-93Sunness et al., Ophthalmology 1997; 104: 1677-91

I have Dry AMD. What can I do about it?

There is no effective treatment or cure for Dry AMD right now

Clinical trials are under way (more about that later in this talk)

Prevention is key! Quit Smoking Vitamin Supplements

Age Related Eye Disease Study (AREDS) Double-masked, placebo-controlled, multicenter,

randomized clinical trial

3,640 patients, followed at least 5 years (average 6.3 years)

Randomly assigned to high doses of:1. Antioxidants

• Vit C 500mg, Vit E 400 IU, -carotene 15mg

2. Zinc = 80mg Zn oxide + 2mg cupric oxide

3. Antioxidants + Zinc

4. Placebo

AREDS Research Group, Arch Ophthalmol 119 (2001), 1417-36

My Doctor Says I Should Take Vitamins. Why?

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Risk of Developing Advanced AMD

PlaceboAntioxidantsZincAntioxidants+Zinc

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Public Health Impact

AREDS: estimated up to 300,000 cases of advanced AMD could be prevented in the US over 5 years with use of AREDS supplements

Rein et al., Ophthalmology 114 (2007), 1319-1326

Age Related Eye Disease Study (AREDS) Recommend: All people > 55 years old

should have dilated eye examinations every year If patients have medium to high-risk AMD in

either eye, or advanced AMD in 1 eye:

Consider supplemental vitamin C, E, zinc+copper

Add -carotene if not a smoker

Quit smoking if a smoker!

AREDS2 4203 patients studied for a median of 5 years;

randomized to receive AREDS formulation PLUS: Lutein 10 mg + zeaxanthin 2 mg

DHA (350 mg) + EPA (650 mg)

Lutein + Zeaxanthin AND DHA + EPA

Placebo: AREDS pill, some without beta carotene or low zinc (25 mg)

1940 eyes developed advanced AMD Lutein 10 mg + zeaxanthin 2 mg: 29%

DHA (350 mg) + EPA (650 mg): 31%

Lutein + Zeaxanthin AND DHA + EPA: 30%

Placebo: 31%

More lung cancer in beta carotene group, mostly among former smokers(91%) (2% vs 0.9%, P=0.04)

AREDS Research Group, JAMA 309 (2013), 2005-15

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Stem Cell Therapy for AMD ACT study at UCLA in Phase I/II trial

Human ES derived RPE cells

12 GA Pts; Dose escalation 50,000-200,000 cells injected in subretinal

space

Va 20/400 or worse in treated eye; 20/400 or better in contralateral eye

Case report in Lancet showed safety

Schwartz et al, Lancet 2012; 379: 713-20

Complement in AMD

Complement factor D antibody (lampalizumab) Phase II clinical trial (MAHALO) 20% reduction in GA progression compared to

sham when injected intravitreally each month

44% reduction in GA in patients with CFI biomarker

In 2014: Genetic testing not yet impacting AMD patient management, but maybe soon…

Studying the Macula: OCT Non-invasive method of creating cross-

sectional images in vivo Like ultrasound:

Instead of differences in acoustic backscattering, OCT uses differences in reflectivity of light to image different tissues

High resolution: 3-10mm Necessary to image retinal structures

No contact with eye required Ideally suited to imaging ocular structures

OCT: Cross-sectional image resembles histology

Useful way to measure retinal structure quantitatively in vivo

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OCT: Drusen in AMD

OCT: Geographic Atrophy What is Wet AMD?

10% of patients, 90% of severe vision loss

Choroidal Neovascularization (CNV)

New Blood Vessels Grow Under Retina

Vision is lost due to Bleeding, Damage to Retina, Scar Tissue (Disciform Scar)

Causes abrupt loss of central vision Straight lines may look wavy

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Wet AMD Wet AMD: Disciform Scar

How can the doctor tell if I have Wet AMD? Fluorescein Angiogram: test to look at

blood vessels supplying retina

OCT: test to measure retinal thickness, blood under retina

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Optical Coherence Tomography (OCT)

Image resembles retinal histology Useful way to measure retinal thickness and

structure quantitatively in living eyes

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Treatments for Wet AMD (CNV)

1990s: Laser Treatment

About half of treated eyes lost six or more lines of vision over 5 years

New vessels came back in many, if not most, patients over 5 years

Immediate blind spot where laser was delivered

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2000: Photodynamic Therapy (PDT)

Low energy, long wavelength light activates light-sensitive dye to selectively close new vessels

Less damage to retina over the vessels than traditional laser

Risk of severe sunburn if all skin isn’t protected for 2-3 days after treatment

Repeat treatment every 3 months for the 1st year, then every 3-4 months for the 2nd Average = 5.4 treatments per patient over 2 y

Vision does not improve in most patients

2005: Anti-VEGF Therapies

Vascular Endothelial Growth Factor: protein that causes new vessels to grow

Treatments to block VEGF: Pegaptanib (Macugen)

Bevacizumab (Avastin)

Ranibizumab (Lucentis)

What is Macugen (Pegaptanib)?

Aptamer: inactivates one form of VEGF (protein that causes new vessels to grow)

Phase III study: 70% of patients lost less than 3 lines of vision (vs. about 50% of placebo)

FDA-approved January 2005

Injection into the eye required every 6 weeks

Vision does not improve in most patients

What is Avastin (Bevacizumab)? Full-length antibody: binds to all forms of

VEGF FDA-approved for cancer patients

Off-label use: small amounts injected into the eye as often as every month

No randomized clinical trials, but case series show vision improvement in nearly all patients

Vision Improvement, versus less vision loss seen with PDT and Macugen

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What is Lucentis (Ranibizumab)? Fragment of antibody: binds to all forms of

VEGF

Phase III Randomized clinical trials show vision improvement in 95% patients maintained up to 2 years

Lucentis is injected into the eye every month

Patients gain vision; contrast to less loss of vision seen with laser, PDT and Macugen

FDA approved 6/06

21.4 letter difference*

20.3 letter difference*

+7.2

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Month-15

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+5.4+6.6

MARINA Study:mean change in visual acuity over 2 years

Note: Vertical bars are ± one standard error of the mean.

*P<0.0001(Rounded values)

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

How often will I need Lucentis shots, and for how long? Well-designed trials show vision

improvement with injections every month.

Can we treat less often and still get good vision?

Pier: RCT

PrONTO: Prospective Case Series

PIER Study Phase 3b, controlled, randomized trial

Reduced injection schedule 3 monthly injections, then injections every 3

months After an initial increase in vision (during monthly

dosing), vision declines with quarterly dosing to baseline at month 12

90% retained baseline acuity at 12 months, but not the vision improvement seen with monthly doses

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PrONTO Study: Prospective OCT imaging of pts with

Neovascular AMD Treated with intra-Ocular ranibizumab

Lucentis every month for 3 months, then exam every month for 1 year

Treat if vision drops > 5 letters, OCT thickness increases >100um, new blood or new CNV

Mean vision improved by 9.3 letters at 12 months; improved by > 15 letters in 35%

Patients needed an average of 5.6 injections

Fung et al., Am J Ophthalmol 143 (2007), 566-583

Many Different Treatment Regimens… Monthly

“Treat-and-observe”: regular treatment until the macula is mostly free of exudation, then treat only for signs of recurrence.

“Treat-and-extend”: regular monthly treatment until the macula is dry, then treatment continues at gradually increasing intervals injections are administered whether there appears

to be active CNV or not.

Goal: cautiously extend the time between injections as far apart as tolerated as long as there are no signs of recurrence.

Anti-VEGF Therapies for CNV: Lucentis: best designed studies, best chance of

maintaining or gaining vision

Very expensive

Avastin (same drug, larger protein approved for cancer therapy) for much lower cost, but off-label, produced by compounding pharmacies: increased risk of infection

BOTH carry slight risk of retinal detachment, infection, glaucoma, cataract, and possible increased risk of stroke with Lucentis

Comparison of AMD Treatments Trial: CATT

1208 patients, multicenter RCT of CNV Pts randomized to receive ranibizumab or bevacizumab

every month or as needed with monthly exams Primary outcome: change in visual acuity at 1 year No significant difference

8.0 vs 8.5 letters gained monthly 5.6 vs 6.8 letters gained as needed

Slightly greater risk of adverse events with bevacizumab (RR=1.29, 95% CI=1.01-1.66, P=0.04) Pneumonia, UTI, GI hemorrhage, nausea, vomiting

CATT Research Group, NEJM (2011), 364: 1897-908

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Comparison of AMD Treatments Trial: CATT

Single dose of ranibizumab costs 40x more than single dose of bevacizumab

CATT Research Group, NEJM (2011), 364: 1897-908

2 year CATT results

Avastin and Lucentis both associated with similar mean gain in visual acuity

13.9% (Avastin as needed) vs 45.5% (Lucentis months) fluid free at 2 years

Treatment as needed resulted in less gain of acuity with both drugs

No difference in risk of death or arteriothrombotic events

CATT Research Group, Ophthalmology (2012); 119: 1388-1398

Increased Infection Risk with Avastin? Bevacizumab: not FDA-approved

for intraocular injection

New York Times report 8/30/11: At least 16 people in Florida and

Tennessee “blinded” by Avastin injections

Endophthalmitis due to strep viridans

Traced to single lot of Avastin and single compounding pharmacy in Hollywood, Florida

VEGF-Trap: Aflibercept (Eylea) Fusion protein with VEGF binding

receptors: binds VEGF and PIGF 2 mg/ 0.5 ml Inject every month for 3 months, then every

2 months FDA-approved in 11/2011 Sometimes works for people who don’t

respond to ranibizumab/bevacizumab

Browning et al, AJO 2012; 154: 222-6

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Conclusions No cure for AMD

Anti-VEGF therapies: Stop growth, but may need to be injected into the eye every month indefinitely………..

Prevent development of vision loss in the first place with AREDS and STOP SMOKING!

Research into reasons for vision loss continues…

Questions?