Gap in Diagnosis of AMD

Disclosures New Methods in Diagnosing AMD Steven Ferrucci, OD, FAAO Chief, Sepulveda VA Professor, SCCO Speakers bureau/advisory board: Alcon Allergan Macula Risk VSP MacuLogix Reichert Technologies TradiDonal AMD Diagnosis TradiDonal Diagnosis Fundus exam q 6-12 mos HAG AMD leading cause of vision loss in padents> 65 TradiDonal diagnosis not working! HAG not sensidve enough Now that new treatments are available, early diagnosis is imperadve Large Unmet Need Prevalence of AMD 9.2 million Americans 7 out of every 100 adults over 40 years old 1 out of every 10 adults over 60 years old Prevalence of diabedc rednopathy 4.9 million Americans 3 out of every 100 adults over 40 years old Prevalence of glaucoma 2.7 million Americans 2 out of every 100 adults over 40 years old Klein et al. (2011) Arch Ophthalmology 129:75 Eye Disease Prevalence Group (2004) Arch Ophthalmology 122:532 Eye Disease Prevalence Group (2004) Arch Ophthalmology 122:552 2010 United States Census Gap in Diagnosis of AMD Current Treatment Up to 78% of AMD padents are unaware undl significant vision loss has already occurred Early AMD not adequately detected by current methods Normal Early/Dry AMD Late/Wet AMD Early AMD AREDS nutridonal supplements lower risk of progression by 25% Behavior modificadon Choroidal NeovascularizaDon LucenDs (ranibizumab) AvasDn (bevacizumab) off label Eylea (aflibercept) Olsen et al. (2004) Ophthalmology 111:250 Cervantes- Castañeda et al. (2008) Eye 22:777 1

New AMD Diagnosis New diagnosdc equipment being developed Earlier detecdon of disease AdaptDX FAF MSI Earlier detecdon of conversion from dry to wet AMD PHP: Home, Office OCT EvaluaDon of risk factors MPOD GeneDc TesDng Dark AdaptaDon Impairment Dark adaptadon is the transidon from day vision to night vision Dark adaptadon impairment is the clinical hallmark of early AMD. Cholesterol deposits responsible for drusen also impair dark adaptadon Owsley et al. (2001) Ophthalmology 108:1196 Jackson & Edwards (2008) J Ocular Biological Diseases & InformaDcs 1:7 Adapt DX Dark AdaptaDon in AMD Studies indicate dark adaptation is very sensitive for AMD diagnosis, more than other standard test Dark adaptation 85% sensitivity Snellen acuity 25% Contrast sensitivity 25% Photopic visual field 25% Scotopic visual field 20% Owsley et al. (2001) Ophthalmology 108:1196 AMD Disease Staging N=8 AdaptDx DiagnosDc Study N=9 N=5 MulDsite study N=6 N=5 N=1 Sample consisted of 127 AMD padents and 21 normal adults. All subjects in these subgroups failed to reach the recovery criteria within the 20 minute test duration. Dark adaptation time conservatively set at 20 minutes for comparison purposes. Clinical diagnosis confirmed by redna specialist grading fundus photographs Jackson & Edwards (2008) J Ocul Biol Dis Inform 1: 7 2

Rapid Dark AdaptaDon: Test Results PaDents classified as having AMD if dark adaptadon >6.5 minutes High SensiDvity: correctly idendfied 90.6% of confirmed AMD cases High Specificity: correctly idendfied 90.5% of confirmed normal cases AMD cases exhibit no rod recovery of dark adaptadon AdaptDx Advantages No preadaptadon required Protocols as rapid as 5 minutes Low padent burden Easy to operate CPT 92284 ($64 avg.) FDA 510K cleared (K100954) Glaucoma Successful Precedent Humphrey Perimeter Psychophysical test 5 minute dura>on $65 reimbursement (CPT 92083) Current eye care profit center AMD MacuLogix Psychophysical test 5 minute dura>on $65 reimbursement (CPT 92284) New, poten-ally larger eye care profit center AdaptDx Not currently FDA approved for AMD Approved as a dark adaptometer only 18 clinical studies and trials Over 1300 patients Commercially available early 2013 Decreased dark adaptation may precede clinical findings by as much as 4 years MacuLogix Principles of MulD- Spectral Imaging (MSI) RHA Optometrist s Gateway to the RPE FDA approved Health Canada approved European CE Mark obtained Technique used in remote sensing with applicadons in airborne and astronomical mapping to extract detailed info of distant views Approach which uses a moderate number of non overlapping discreet spectral bands, or slices, to highlight targeted features Offers spadal resoludon PLUS spectral informadon which is aids in localizadon/depth assessment ANNIDIS HEALTH SYSTEMS 17 3

Foresee PHP Preferential Hyperacuity Perimeter Uses Vernier acuity to detect changes for AMD before they can be seen with Amsler May be able to detect subtle progression in AMD to facilitate earlier referral and therefore treatment Distributed by Reichert Technologies The science Studies show that 80% of wet AMD patients arrive too late for useful treatment, after significant damage has already been done Often by time Amsler grid change is noted, VA is already reduced and lesion size is already to large Studies also show that lesion size is an important factor in successful treatment The science Studies also show what we probably knew: PHP had a greater sensitivity than the Amsler Grid in detecting AMD The PHP was superior to the Amsler Grid in detecting AMD related lesions in this cohort The test Easy operation Comfortable for patient Noninvasive Rapid threshold test ~ 5 min/ eye Automated results analysis Generates visual field map of disturbance patterns consistent with the progression of AMD Results Studies show that Foresee has good specificity/sensitivity for detection on CNVM Almost equal to FA, the gold standard May aid in earlier detection of dry to wet AMD sooner than current testing Out of 10 pts, 8 were detected earlier, 2 at same time Results Earlier detection may lead to earlier treatment and better results Also, may reduce number of referrals to retinal specialists for suspected CNVM as well as unnecessary FA 50-90% of pts referred to retina specialist did not have wet AMD 4

Types of Alerts Suspected Change Alert When a padent has a stadsdcally significant change compared to their personal threshold and the normadve database, the pracdce will be contacted to schedule a prompt appointment for an exam. The padent will also be nodfied. Can t Establish Baseline Alert (CEBL) When a padent is unable to establish a baseline, both the pracdce and padent will be nodfied. If padent is monocular, we will arrange to collect the device. Otherwise he/she will condnue monitoring the other eye. MPOD MacuScope TM Low MPOD has been shown to be risk factor for development of AMD in several studies High MPOD appears to be protecdve for AMD Measurement of MPOD may help stradfy risk factors for development of MPOD At least 2 commercially available instruments QuantifEYE TM by Zeavision Fundus Autofluorescence (FAF) Imaging Non-invasive technique which utilizes fluorescent properties of lipofuscin to study the health and viability of RPE/ photoreceptor complex 5

Fundus Autofluorescence (FAF) Imaging Optos Daytona In AMD, may help differentiate from similar entities FAF variation may precede retinal changes, and may be prognostic for those patients that will continue to develop vision loss Canon CX- 1 Hybrid Digital MydriaDc/Non- MydriaDc ReDnal Camera Color Red Free Cobalt FA FAF Heidelberg Spectralis with Blue Peak Cirrus Photo 800/ CZM Volk Pictor Hand help portable digital imaging system Can take both rednal and external photos Non- mydriadc Download as jpegs via USB 6

EyeQuick Digital Ophthalmoscope Camera Portable, wireless ReDnal and exterior photos Can transfer images via USB to computer or EMR Volk Digital Lenses Is AMD in our DNA? AMD is a genedc disease with known markers accoundng for at least 70% of the populadon atributable risk Other 30% is environmental/lifestyle Risk factors Non- modifiable: age, race, gender Modifiable: Smoking, increased BMI, poor diet/ nutridon, UV exposure Major genetic factors CFH Single most important genedc component CFH Y402H ARMS2/HTRA1 Second most important gene in AMD C3 Another component of the complement system ND2 Mitochondrial oxidadve phosphoryladon molecule Others Genetic Factors and Risk: More than additive! AMD GeneDc TesDng Former Smokers: 1.29x Current Smokers: 2.4X Non-Smoker and CFH,Y402H: 7.6X Current smoker and CFH,Y402H: 34X Macula Risk NXG IdenDfies AMD padents who may progress to vision loss within: 2 years 5 years 10 years Cheek Swab 7

Great Science - Key AMD genes Clinical Assessment + GeneDcs COL8A1 TIMP3 LIPC ARMS2 APOE CETP ABCA1 C3 C2 CFB CFI CFH Macula Risk NXG 12 genes CFH CFI CFB C2 C3 ARMS2 TIMP3 COL8A1 LIPC APOE CETP ABCA1 Complement Oxygen Metabolism Extracellular Matrix Cholesterol Metabolism Smoking BMI Age AMD status Complete set of Risk factors Non- GeneDc Factors 40% GeneDc Factors 60% Both required for highest accuracy 1. CFH 2. CFI 3. C2 4. CFB 5. C3 6. ARMS2 7. TIMP3* 8. COL8A1* 9. LIPC* 10. CETP* 11. ABCA1* 12. APOE Clinical ValidaDon March 2012 IOVS ProspecDve Assessment of GeneDc Effects on Progression to Different Stages of Age- Related Macular DegeneraDon Using MulDstate Markov Models Yi Yu, Robyn Reynolds, Bernard Rosner, Mark J. Daly, and Johanna M. Seddon InvesDgaDve Ophthalmology & Visual Science, March 2012, Vol. 53, No. 3 2560 Caucasians Average Follow up = 10.3 years 5 year predicdve power = 0.883 C StaDsDc Score 10 year predicdve power = 0.895 C StaDsDc Score SensiDvity & Specificity > 80% Macula Risk NXG Reimbursement for Insured PaDents ICD- 9 Codes 362.50 non- specific AMD 362.51 non- exudadve senile macular degeneradon 362.52 exudadve senile macular degeneradon 362.57 drusen PaDent Friendly Billing Policies PaDent Report Primary Eye Care Protocol Recommended pracdce protocol developed by the Macula Risk Optometry Advisory Board: L. Alexander, D. Cunningham, M. Dunbar, S. Ferrucci, J. Gerson, P. Karpecki, G. Morgan, D. Nelson, J. Rumpakis, J. Schaeffer, L. Semes, D. Shechtman, J. Sherman, K. Smick 8

Summary Knowledge of genetic risk is important Increased counseling for patients at high risk Know which pts need to be examined more frequently Sooner vitamin supplementation May have implications regarding treatment 37% higher risk of additional Lucentis injections if CFH Y402H CFH TT/TC treated with Avastin had increase in vision with 53.7 % improved vs. only 10.5% if CC genotype CATT study did not show relationship between genetic subtype and treatmnet Prevalence of Ocular Diseases Glaucoma 4.4 Million DiabeDc ReDnopathy 5.3 Million Dry AMD 15.0 Million For every 1 glaucoma pa-ent, there are 3 AMD pa-ents The Vision Problems in the U.S. Report, NEI, 2001 AMD: A Changing Environment When there was no effecdve therapy, the pracdce of following AMD with one annual exam followed by Amsler was acceptable Now there are breakthrough treatments that reduce loss of vision if detected early With great power, comes great responsibility Uncle Ben, Spiderman 9