Age-Related Macular Degeneration (AMD): Questions and Answers

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1 Age-Related Macular Degeneration (AMD): Questions and Answers Jacque L. Duncan, M.D. Professor Department of Ophthalmology UCSF 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), Normal AMD 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),

2 Age-Related Macular Degeneration AMD: Other Genetic Associations: 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 /HTRA1 on chromosome 10q26 CF2-FB, C3 Thornton et al., Eye 19 (2005), : 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 ABCA4 Fritzche L, et al. Nat Genet Apr;45(4):433-9, 439e1-2. doi: /ng 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 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 Grassmann et al., PLoS One 2012; 7(5):e37979 Perlee et al., Ophthalmology 2013, Ophthalmology Sep;120(9):

3 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 3

4 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: Sunness et al., AJO 2005; 140: Sunness et al., Ophthalmology 1997; 104: 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 My Doctor Says I Should Take Vitamins. Why? 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),

5 Percent with Advanced AMD Risk of Developing Advanced AMD Placebo Antioxidants Zinc Antioxidants+Zinc 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 Years Rein et al., Ophthalmology 114 (2007), 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! AREDS 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),

6 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 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: 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 crosssectional 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 6

7 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 7

8 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 8

9 Optical Coherence Tomography (OCT) Image resembles retinal histology Useful way to measure retinal thickness and structure quantitatively in living eyes 9

10 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 10

11 2000: Photodynamic Therapy (PDT) Low energy, long wavelength light activates lightsensitive 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 11

12 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 ETDRS letters Sham (n=238) MARINA Study: mean change in visual acuity over 2 years Ranibizumab 0.3 mg (n=238) Month Ranibizumab 0.5 mg (n=240) letter difference* 20.3 letter difference* *P< (Rounded values) Note: Vertical bars are ± one standard error of the mean. 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 12

13 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), 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= , P=0.04) Pneumonia, UTI, GI hemorrhage, nausea, vomiting CATT Research Group, NEJM (2011), 364:

14 Comparison of AMD Treatments Trial: CATT 2 year CATT results Single dose of ranibizumab costs 40x more than single dose of bevacizumab 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, NEJM (2011), 364: CATT Research Group, Ophthalmology (2012); 119: 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:

15 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? 15