Introduction

• AMD is the leading cause of vision loss in Americans over the age of 60 • Advanced AMD is the leading cause of vision loss and irreversible blindness worldwide in those over the age of 50 • As many as 11 million Americans have some level of AMD UPDATE ON AMD 2021 – Expected to increase to nearly 22 million by 2050 • More than glaucoma (2.2 million) and DR (7.7 million) Steven Ferrucci, OD, FAAO COMBINED Chief, Optometry Sepulveda VA Professor, SCCO/MBKU 1 2

Introduction Dry AMD

• Exciting time to be interested in AMD • Currently mainstay treatment for Dry AMD revolves around prevention of progression through vitamins, nutrition and lifestyle • Many new treatments now available for AMD changes – Years ago, we had nothing at all to offer patients with AMD – Rheophoresis, Laser, did not prove effective – Smoking #1 modifiable risk factor for getting AMD as well as its • Current Treatments progression! • Potential Treatments • One study showed 90% of pts with AMD were not advised to quit smoking • Early detection of conversion from dry to wet may result in better • New Diagnostic Equipment treatment for patients

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AREDS AREDS 2

• First large scale study looking at nutrition and ocular health • AREDS 2: Enrollment ended June 2008 with ≈4200 patients followed • 3640 pts followed on average for 6.3 years for six years – Effect of lutein, zeaxanthin and omega 3 on AMD – Results released October 2001 – Effect of eliminating beta carotene on AMD • Results showed that 25% risk reduction to developing advanced – Effect of reducing zinc on AMD AMD in pts with intermediate (stage 3) AMD or worse – Effect of supplements on cataracts — 500 mg vitamin C — 400 IU vitamin E – Validate the AMD scale from original AREDS — 15 mg vitamin A (25,000 IU beta carotene) — 80 mg zinc • Results released May 5, 2013 — 2 mg copper

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1 “Wet” AMD AREDS2 Formulation • Neovascular “wet” AMD • Vitamin C (500 mg) – Mainstay of treatment consists of serial intravitreal injection of anti-VEGF agents

Anti-VEGF • Vitamin E (400 IU) Agents (Macugen®) (Lucentis® ) (Eylea® ) (Beovu® ) (Avastin® )

FDA approval 2004 2006 2011 2019 Not approved • Beta Carotene (15 mg) ANCHOR VIEW HAWK Pivotal studies VISION MARINA CATT 1 and 2 HARRIER • Lutein (10 mg)/Zeaxanthin (2 mg) IVAN – VEGF inhibitors have demonstrated improved visual and anatomic outcomes • Zinc (80 mg zinc oxide) compared with other therapies

VEGF = vascular endothelial growth factor. • Copper (2 mg cupric oxide) AAO. AMD preferred practice guidelines, 2019 (www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp). Kulkarni K, Prenner JL. Rev Ophthalmol. 1/13/2006. (www.reviewofophthalmology.com/article/an-update-on-macugen-trials). URLs accessed 5/30/2020. • Omega-3 fatty acids (DHA/EPA) 7 8

Anti-VEGF Agents Anti-VEGF Agents: Delivery and Dosage

• VEGF is a primary driver of blood vessel growth and leakage in AMD • Delivered intravitreally • Anti-VEGF agents block and neutralize VEGF – Results in decreased intra- and sub-retinal fluid • Dosing schedule and agent used varies – May also decrease risk of scar tissue formation • In general • Serious adverse effects (endophthalmitis) rare – Loading dose with 1 injection per month for 3 months, then inject based on FA, OCT, or other clinical findings • Less serious events (subconjunctival hemorrhage, vitreous hemorrhage, – Reduces patient burden while still delivering good results floaters) are also uncommon

, et al. Br J Ophthalmol. 2016;100:1623-1628. Kress B. Review of Optometry. 2019 (https://www.reviewofoptometry.com/article/antivegf-where-are-we-now). Accessed June 10, 2020. Treating Wet AMD with Anti-VEGF drugs. 2016 (https://www.reviewofophthalmology.com/article/treating-wet-amd-with-antivegf- drugs). Accessed June 10, 2020

Pongsachareonnont P, et al. Clin Ophthalmol. 2018;12:1877-1885. Yeo NJY, et al. Front Pharmacol. 2019;10:1363. Holz FG, et al. Br J Ophthalmol. 2016;100:1623-1628. American Society of Retina Specialists (ASRS). Intravitreal injections. (www.asrs.org/content/documents/fact-sheet-30-intravitreal-injections.pdf). Sukgen EA, et al. Int Ophthalmol. 2017;37:215-219. Living well with low vision. (https://lowvision.preventblindness.org/2013/06/25/betadine-and-eye-pain/). URLs accessed 5/30/2020.

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Anti-VEGF Agents: Outcomes Other Treatment Options

Lucentis1 Eylea2,3 Beovu4 Possible Not advised • Photodynamic therapy • Intravitreal steroids • • • ~30% gained at least 15 94% stable vision at 2 95% of patients (PDT) with as monotherapy years treated maintained letters by year 1 • Intravitreal steroids in • Radiation therapy acuity • Less fluid and greater • 34–41% gained 15 combination with PDT or • Electrical stimulation reduction in CST vs letters or more • 7.9–10.9 letters mean anti-VEGF agents • Macular aflibercept improvement of • • Average gain of 11.3 Laser photocoagulation translocation vision • At 1 year, half of subjects • letters at 1 year and Observation/suspension of therapy on 3-month dosing 10.7 letters at 2 years treatment

CST = central subfield thickness. AAO. AMD preferred practice guidelines, 2019 (www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp). 1. Brown DM, et al. Ophthalmology. 2009;116:57-65.e5. 2.Nguyen QD, et al. Invest Ophthalmol Vis Sci. 2011;52: abstract 3073. 3. Accessed 5/30/2020. Wong DT, et al. Retina. 2020;40:1010-1020. Giancipoli E, et al. J Ophthalmol. 2018:5612342. Veritti D, et al. Schmidt-Erfurth U, et al. Invest Ophthalmol Vis Sci. 2011;52:E-Abstract 1650. 4.Dugel PU, et al. Ophthalmology. 2020;127:72-84. Expert Rev Ophthalmol. 2010;5(5):681-688.

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2 Beovu update Is AMD Under diagnosed?

• In Feb, 2020, American Society of Retinal Specialists (ASRS) issued a • 25% of eyes deemed normal on DFE by eye care provider (both ODS warning reporting 14 cases of retinal vasculitis following injection of Beovu and MDs) had macular characteristics that indicated AMD – 11/14 were occlusive and resulted in vision loss – Of those, 30 % had level that would have been treatable with • In March, Novartis concluded that retinal vasculitis, retinal artery nutritional supplements – Eye care providers knew pts were being specifically screened for occlusion, or severe vision loss occurred in 8.75-10.08 out of 10,000 AMD injection • Another study showed that 79% pts with AMD were first diagnosed • Added to warning label with avg acuity of 20/50 from AMD! – Intraocular inflammation in 4% of pts – Artery occlusion in 1% • Advised to avoid if pts had h/o inflammation to any other anti-Vegf agent – BOTTOM LINE: WE ARE NOT DOING ENOUGH TO DETECT AMD!!!

Prevalence of undiagnosed Age-Related in Primary Eye Care Neely DC et al. JAMA ophthalmol 2017: 135(6): 57--575 13 14

Standard of Care Comparison: Two Multifactorial Diseases MacuLogix’s AdaptDx GLAUCOMA AMD • Dark adaptation is a sensitive marker for early AMD • The AdaptDx measures dark adaptation • Cup-to-Disc Ratio Drusen A rapid test of dark adaptation using the AdaptDx has been found to have a 90% sensitivity Structure for detecting dark adaptation impairment associated with AMD • Decreased dark adaptation may precede clinical findings of AMD by as much as 3 years • Dark adaptation is more sensitive than other tests such as Snellen acuity, contrast sensitivity, or visual fields which are about 25% sensitive.

Function Visual Field Dark Adaptation

Macular Pigment Optical Density (MPOD) Intraocular Pressure (IOP) Contrast Sensitivity Risk Corneal Thickness Genetic Testing Demographics and Family History Demographics, Family History, Lifestyle 15 15 16

Impaired Dark Adaptation is Earliest Biomarker of AMD AdaptDx Validated in Multi-Site Study sources: Owsley, C et al. Ophthalmology. 2016;123(2):344-351. sources: Jackson GR, et al. Invest Ophthalmol Vis Sci. 2014;55(3):1427-1431. High Sensitivity Correctly identified 90.6% RESEARCH SHOWS: of confirmed AMD cases Impaired dark adaptation Ouridentifies callsubclinical AMD High Specificity at least three ALSTAR Study Correctly identified to action 90.5% years before of confirmed normal cases it can be seen with imaging, Prospective Study of Subclinical AMD OCT or clinical exam. • Sample consisted of 325 adult's w/o clinically detectable AMD High Accuracy • At baseline, 24% of the subjects exhibited impaired dark adaptation 90.6% • AMD status determined at 3-year follow-up visit overall

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3 AdaptDx Advantages Successful Precedent Glaucoma AMD

• No preadaptation required • Protocols as rapid as 5 minutes • Low patient burden Humphrey Perimeter MacuLogix • Easy to operate •Psychophysical test •Psychophysical test • CPT 92284 ($64 avg.) •5 minute duration •5 minute duration •$65 reimbursement (CPT 92083) •$65 reimbursement (CPT 92284) • FDA 510K cleared •Current eye care profit center •New, potentially larger eye care (K100954) profit center

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Foresee Home At-risk Patients May Convert to Wet AMD at Any Point Between Follow-up Visits

Visit Visit 1 2

Converts Converts Converts after office between before office visit office visits visit

More likely Less likely to to lose vision lose vision

Reference: Rauch R, et al. Retina. 2012;32(7):1260-1264. 22 21 22

ForeseeHome® product overview AREDS2-HOME Study

Uses Preferential Intent to Treat (ITT) Hyperacuity ForeseeHome population results plus standard care arm Standard care arm Perimetry (PHP) 6,000+ actively 1520 testing patients 763 participants 757 participants participants

Medicare covered

51 CNV Mean follow up 1.4 yr ± 0.6 years 31 CNV events Mean VA at entry 20/25 Proven efficacy events with level 1 600+ active • Routine monitoring • evidence • Routine monitoring prescribers Patient symptoms • Patient symptoms • ForeseeHome

*Primary outcome: Change in BCVA from baseline to CNV detection

Reference: AREDS2-HOME Study Research Group. Ophthalmology. 2014;121(2):535-544. Reference: Data on File. 23 24 23 24

4 More patients who used ForeseeHome Patient Self-operated Home OCT provides high quality images Home OCT maintained ≥20/40 VA • Patient self-installed and self-operated P=.003 P=.005 P=.014 OCT device 94% 87% 91% • Monitoring of intra- and subretinal ≥20/40 ≥20/40 ≥20/40 fluid in between office visits 50% MORE • Provides cross sectional images of the 62% patients maintained 20/40 central 10 deg. (3 mm x 3 mm) of the ≥20/40 or better when using ForeseeHome vs standard of macula in patients with exudative AMD Heidelberg Spectralis (in-office device) care alone • 88 B-scans with dense 34 µm spacing ITT PP1 PP2 ensure high sensitivity of fluid N=18 N=40 N=32 N=29 detection Standard ForeseeHome arm • care Test takes approximately 10 sec. per 94% of patients maintained 20/40 at time of wet AMD diagnosis; eye Absolute visual acuity at time of wet AMD diagnosis is critical to visual acuity outcomes • Device uploads OCT data to cloud at year 1 Reference: AREDS2-HOME Study Research Group. Ophthalmology. 2014;121(2):535-544. 25 25 26

Home OCT Performance and Roadmap Role of Genetics in AMD

• US clinical trial demonstrated 90% of 196 elderly wet AMD patients with VA > • Risk 20/400 could self-operate and self-capture readable images following a 2-minute video tutorial (presented at ASRS 2019) • Progression •Human graders identified fluid with SENSITIVITY = 91.5% and SPECIFICITY = 97.0% for Notal Home OCT V2.5 when compared to • Treatment commercial OCT devices (presented at ASRS 2019) • Follow up protocol • Notal Vision’s patient-operated, AI-enabled Home OCT system was granted FDA Breakthrough Device Designation Status, and was selected to participate in FDA’s OCT Innovation Pilot Program •Notal Vision plans to bring first devices to patients’ homes in 2020 as part of clinical trials with a commercial launch in 2021

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Is AMD in our DNA? AMD is a Genetic Disease

• AMD is a genetic disease with known markers accounting for at least 70% of the population attributable risk • Other 30% is environmental/lifestyle • Risk factors – Non-modifiable: age, race, gender – Modifiable: Smoking, increased BMI, poor diet/nutrition, UV exposure Those with stronger genetic risk develop more advanced disease earlier in life.

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5 Genetic Factors and Risk: AMD Genetic Testing: Arctic DX More than additive! Macula Risk NXG Looks at 15 SNPs as well as • Former Smokers: 1.29x smoking, BMI, age and AMD status to determine AMD patients who • Current Smokers: 2.4X may progress to advanced AMD and vision loss in • Non-Smoker and CFH,Y402H: 7.6X • 2 years • Current smoker and CFH,Y420H: 34X • 5 years • 10 years Cheek Swab

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Patient Report AMD Risk Testing for a Full Spectrum of Patients

AMD Progression Risk Testing Lifetime AMD Risk Testing For people ≥55yo with or without AMD findings For people <55yo without AMD findings • Assesses a patient’s lifetime risk of developing advanced For people <55yo WITH AMD findings AMD (GA or CNV) allowing preventive lifestyle changes at • Assesses a patient’s risk of progression to advanced AMD younger age within 2, 5,10, 20 and 30 years • Delaying onset of disease with primary prevention • Delaying progression to advanced AMD with secondary including lifestyle modifications, supplementation (i.e. prevention including AREDS vitamins, increased nutrition) and nutritional intervention surveillance (home monitoring)

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Visible Genomics AMD Gene Panel Allele Gene SNP No. Variants AMD Risk Chromosome Pathway • Based on the latest in GG Lower Risk (Reference) AMD Genetics research ARMS2/HTRA1 Rs10490924 Immune/ GT Moderate Risk 10q26 (HtrA Serine Peptidase 1) (A69S) inflammatory • Clinically Proven and Clinically TT Higher Risk Actionable to be the most TT Highly Protective impactful variations on Rs1061170 (Y402H) CT Moderately Protective Complement AMD progression CC Higher Risk (Reference) • Combines both genetic CC Lower Risk (Reference) CFH Rs121913059 + non-genetic markers CT Moderate Risk 1q31 Complement (Complement Factor H) (R1210C) TT Higher Risk

AA Highly Protective Rs1410996 23andMe (IVS14) GA Moderately Protective Complement SNPs GG Higher Risk (Reference) GG Lower Risk (Reference) C3 Rs2230199 GC Moderate Risk 19p13 Complement (Complement Component 3) (R102G) CC Higher Risk

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6 Potential Therapies Potential Therapies

• Better Efficacy • Currently, there are ≈ 1822 studies evaluating AMD, both Wet and Dry – Better drug – Different Mechanism – www.clinicaltrials.gov ( March2021) • More than: • Reduced administration – glaucoma • Different delivery System – dry eye – Eye drops – diabetic eye disease – Oral • Exciting time to be involved, with many – Others possible therapies that may prove useful for our AMD patients

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Faricimab Faricimab

• Roche/Genetech • Avenue/Stairway • First bi-phasic antibody for intraocular use – Looked at 2 doses ( 6.0 and 1.5 mg) of Faricimab vs Lucentis • One arm: Vegf-A inhibitor – Good anatomic improvement and vision gains similar to Lucentis • Mean vision gains of 9.6 to 11.4, depending on dose and schedule • Other arm: Angiopoietin-2 (Ang-2)inhibitor – Faricimab 6.0 mg q 16 weeks had greatest gain (11.4) – growth factor that promotes vascular destabilization and and – TENAYA and LUCERNE inflammation • Phase III trial evaluating 6.0 mg of faricmab either every 8, 12, or 16 weeks vs • Dual inhibition of VEGF and Ang-2 have proven more effective Eylea every 6-8 weeks underway than inhibiting either target alone

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Port Delivery System Port delivery system

• Genentech looking at a Port Delivery System (PDS) • Archway Study • Placed through a scleral incision – Phase III. Results released July 2020 • Would release a constant influx of meds (Lucentis) rather than – Compared PDS with monthly Lucentis injection serial anti-VEGF injections – 98.4% of pts were able to go 6 mos without needing additional treatments • Refillable every 4-6 mos – Vision outcomes equivalent to receiving monthly Lucentis injections • Pts gained 0.2 letters at 36 and 40 weeks with PDS vs 0.5 with monthly Lucentis • Both arms achieved similar changes in retinal thickness from baseline – Generally well tolerated with a favorable benefit-risk profile

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7 Conclusion

• AMD Super prevalent! • AntiVEGF agents best treatment available for wet AMD • Vitamins and lifestyle changes for pts with dry AMD • Use new technology to take better care of your AMD pts! • Look out for new developments in treatments • Those involving fewer/no injections will ultimately prevail

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