Take Home Messages. Age related Macular Degeneration. Summary. AMD Disease Management Gap. Lawrence J. Singerman, MD Retina Associates of Cleveland

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Advances in the Management of Neovascular Age related Macular Degeneration,FACS Clinical Professor of Ophthalmology Case Western Reserve University School of Medicine Cleveland, Ohio Professor of

and Ophthalmologists Early Diagnosis of AMD is Very Important We Have Made Enormous Progress in Managing AMD, Making Preservation of Vision Possible in 90% Summary AMD Disease Management Gap AMD is

Therapy MAY improve outcomes Macula Risk Testing 90% accurate AMD prognosis Optimized AREDS vitamins can prevent AMD progression Optimize your Treatment Plans (AREDS + Monitoring ) Dry AMD 2 /10

1 Advances in the Management of Neovascular Age related Macular Degeneration,FACS Clinical Professor of Ophthalmology Case Western Reserve University School of Medicine Cleveland, Ohio Professor of Clinical Ophthalmology Bascom Palmer Eye Institute Miami, Florida Take Home Messages AMD is the leading cause of Blindness over Age 60 in the USA Optimal Management of AMD is Challenging for Patients and Ophthalmologists Early Diagnosis of AMD is Very Important We Have Made Enormous Progress in Managing AMD, Making Preservation of Vision Possible in 90% Summary AMD Disease Management Gap AMD is increasing More than 30 million people More than half of Wet AMD patients are referred too late These patients never regain functional vision AREDS Supplements are a Standard of Care Genome Directed Therapy MAY improve outcomes Macula Risk Testing 90% accurate AMD prognosis Optimized AREDS vitamins can prevent AMD progression Optimize your Treatment Plans (AREDS + Monitoring ) Dry AMD 2 /10 Advanced AMD Half of all CNV are referred too late Boyer et al., Ophthalmology (2): Wong et al., Ophthalmology (1) : Visual Loss In Wet AMD role of new vessels Evolution of Therapy for Neovascular AMD photoreceptor degeneration Underlying Dry AMD leakage leakage thinning and functional loss neovascular complex neovascular complex Laser Thermal PDT Anti-VEGF Anti-VEGF, -PIGF Avastin Macugen Lucentis Eylea Fovista Anti- PDGF Anti- VEGF, -PDGF, -bfgf Squalamine distorts retinal anatomy evolves into a destructive scar In clinical trials Halt progression Improve vision 1

Previous RACI Macular Degeneration Studies (Wet, Dry, & Device) Alcon I Alcon II Alcon open label Eyetech 1000 Eyetech 1001 Eyetech 1004 Eyetech 1006 Eyetech 1009 Eyetech 1010 Eyetech 1011 Eyetech

Alcon IDEAA Genentech HORIZON Genentech SAILOR InSight Registry IMT VGT Registry AREDS II Denali Eyetech 1023 Fellow Eye Study Novartis Lucentis/PDT Pfizer Macugen Sirion Geographic Atrophy

2 Previous RACI Macular Degeneration Studies (Wet, Dry, & Device) Alcon I Alcon II Alcon open label Eyetech 1000 Eyetech 1001 Eyetech 1004 Eyetech 1006 Eyetech 1009 Eyetech 1010 Eyetech 1011 Eyetech 1012 FAME 4 FIHNESSE SST TAP TTT VALIO VAM VER Veritas VIP VisTA VFQ Validation MPS (15 yrs) Previous RACI Macular Degeneration Studies (Wet, Dry, & Device) Acuity 101 Acuity 201 CARE Alcon AART Alcon IDEAA Genentech HORIZON Genentech SAILOR InSight Registry IMT VGT Registry AREDS II Denali Eyetech 1023 Fellow Eye Study Novartis Lucentis/PDT Pfizer Macugen Sirion Geographic Atrophy Anti-Factor D Anti-Factor D phase 2 CATT Alcon GATE Eye drops for CNV Genentech HARBOR Ophthotech 1001 Ophthotech 3000 Mean Change in Visual Acuity Same Regimen for 2 years 15 letter Change from Baseline Same Regimen for 2 Years Monotherapy Anti-VEGF LIMITATIONS Majority of patients do not achieve significant visual gain Majority of patients do not achieve final visual acuity of 20/40 or better 25-30% lose vision 11 2

Long-term Anti-VEGF Therapy Suboptimal Visual Outcome PF 655 Quark/Pfizer Sirolimus Santen Everolimus Novartis Palomid 529 Paloma secure study Ophthalmology.

mtor inhibitor VEGF mtor inhibitor Blocks TORC1/TORC2 VEGF Trap Eye Regeneron/Bayer KH902 Kanghong Biotech AAV sflt01 Genzyme Endothelial cell membrane VEGF R1 VEGF R2 VA 20/200: 37% of patients

6 Letters Loss From baseline AL39324 Alcon Pazopanib GlaxoSmithKline AG013958 Pfizer Tyrosine kinase cascade Raf MEK ERK TG100801 Sanofi Aventis Gene Transcription Angiogenesis Block PDGF Block

11 GenVec OC 10X Combretastatin A4 OcuCure Oxigene Volociximab JSM6427 JNJ 26076713 Ophthotech Jerini Johnson & Johnson Compstatin (POT 4) scr1 Alcon/Potentia Avant Immunotherap.

Fovista (E10030) plus Lucentis (ranibizumab) had a 62% comparative benefit over Lucentis (ranibizumab) alone Phase 3 study under way Squalamine eye drop Inhibition of multiple angiogenesis factors,

3 Long-term Anti-VEGF Therapy Suboptimal Visual Outcome PF 655 Quark/Pfizer Sirolimus Santen Everolimus Novartis Palomid 529 Paloma secure study Ophthalmology Sep 25 Variable Treatment Regimen Blocks production of REDD1 Lucentis Genentech/Novartis Avastin Genentech Macugen OSI Eyetech AGN Allergan/Merck mtor inhibitor Blocks production of HIF 1 mtor inhibitor VEGF mtor inhibitor Blocks TORC1/TORC2 VEGF Trap Eye Regeneron/Bayer KH902 Kanghong Biotech AAV sflt01 Genzyme Endothelial cell membrane VEGF R1 VEGF R2 VA 20/200: 37% of patients Vatalanib Novartis P P Src P P Ras PKC412 Novartis seven up study ARVO 2012 Mean Change in VA Letter Score: 8.6 Letters Loss From baseline AL39324 Alcon Pazopanib GlaxoSmithKline AG Pfizer Tyrosine kinase cascade Raf MEK ERK TG Sanofi Aventis Gene Transcription Angiogenesis Block PDGF Block production of S1P Block nachr Produce PEDF Tubulin binding agents Block integrins Complement modulators Beyond the VEGF Pathway E Ophthotech isonep LPath ATG003 Comentis AdGVPEDF.11 GenVec OC 10X Combretastatin A4 OcuCure Oxigene Volociximab JSM6427 JNJ Ophthotech Jerini Johnson & Johnson Compstatin (POT 4) scr1 Alcon/Potentia Avant Immunotherap. Eculizumab ARC1905 JPE 1375 PMX53 Alexion Ophthotech Jerini Peptech Anti factor D rhcfhp Genentech Ophtherion Wet AMD Clinical Trials Fovista intravitreal injection Anti PDGF Phase 2b study results: Fovista (E10030) plus Lucentis (ranibizumab) had a 62% comparative benefit over Lucentis (ranibizumab) alone Phase 3 study under way Squalamine eye drop Inhibition of multiple angiogenesis factors, including VEGF, PDGF, and bfgf May reduce the number of intravitreal anti VEGF injections required Phase 2 study under way Fovista (1.5mg anti-pdgf) Combination Met the Pre-specified Primary Endpoint Squalamine Take Home Messages MEAN CHANGE VA (LETTERS) MEAN CHANGE IN VA (BASELINE TO Week 24) P = * 1.5MG FOVISTA + LUCENTIS 0.3MG FOVISTA + LUCENTIS LUCENTIS ITT LOCF Squalamine IV infusions were previously studied in humans with biologic effect demonstrated Squalamine eye drops achieve trough concentrations in the choroid well in excess of its threshold level to inhibit tissue angiogenesis Ongoing phase II clinical trial in wet AMD at 20+ centers with anticipated interim data in Q2/14, final data in Q4/14 Two ISTs underway in Proliferative Diabetic Retinopathy and RVO, with two additional ISTs in DME to be initiated soon *The Hochberg procedure 3

H 3 N + N H 2 + N H 2 H 3 C H O H 3 C CH 3 H 3 C CH 3 OH Squalamine Background Novel intracellular, anti angiogenic mechanism of action Potent inhibitor of VEGF, PDGF, and bfgf signaling through

4 Squalamine Structure Small molecule aminosterol which easily diffuses to post. segment First isolated from dogfish shark liver, now chemically synthesized The cationic charged nature enables it to bind to choroidal tissue, minimizing flushing into systemic circulation O O S O + H 3 N + N H 2 + N H 2 H 3 C H O H 3 C CH 3 H 3 C CH 3 OH Squalamine Background Novel intracellular, anti angiogenic mechanism of action Potent inhibitor of VEGF, PDGF, and bfgf signaling through chaperoning of the modulatory protein Calmodulin Endothelial Cell membrane bound Calmodulin is needed for the downstream angiogenesis signaling induced by these growth factors Control FITC (green fluorescence) labeled anti-calmodulin antibody Squalamine treated Awarded Fast Track designation for wet AMD by the FDA in May 2012 Phase II clinical trial underway for wet AMD Squalamine Does Not inhibit enos Previous Clinical Experience IV Previously studied using intravenous infusions 250+ patients with Wet AMD Safely tested in wet AMD at doses of up to 160mg per infusion Trial design: Weekly IV x 4 weeks, monthly IV thereafter Clinical Data in wet AMD trials Demonstrated biological effect Gains in visual acuity Strong maintenance of vision Positive effect in advanced, low vision wet AMD Intravenous Administration Challenges Suboptimal dosing due to rapid plasma clearance & short plasma half life Which eliminate ability to maintain posterior ocular therapeutic concentrations Right Drug, Wrong Delivery? IV results demonstrated clear activity even though dosed sub optimally IV dosing to achieve optimal posterior concentrations is not practical (>1 per week, long infusions) Could we formulate an eye drop with the ability to deliver drug optimally and achieve sustained inhibitory concentrations? Lack of commercial potential & enrollment difficulty of chronic IV infusions 4

posterior ocular tissues High potency Ability to inhibit multiple angiogenic growth factors Precedents for Topical Delivery to the Posterior Segment Many small molecule drugs do diffuse efficiently

5 Dosing Interval= QD 24 Hours, BID 12 Hours *=p value <.01 **=p value <.001 (values vs. day 1+Dosing Interval) Advances in the Management of Neovascular AMD Promising Properties of Topical Squalamine for Delivery & Treatment of Posterior Exudative Disease Long retention time in the posterior ocular tissues High potency Ability to inhibit multiple angiogenic growth factors Precedents for Topical Delivery to the Posterior Segment Many small molecule drugs do diffuse efficiently and have scleral penetration into the choroid There are over 50 reports of this in peer reviewed ophthalmological journals Topical Steroid eye drops have in fact been used in clinical practice for treating macular edema secondary to ocular surgeries Single dose Biodistribution in Rabbit Eyes Posterior Tissue Trough Levels Rapid uptake after single administration Significant residence time Trough levels well in excess of squalamine s threshold level to inhibit tissue angiogenesis Rapid uptake, more pronounced with higher frequency dosing Conclusions: Squalamine Eye Drops Sustained posterior sclera/choroid concentrations maintained above threshold therapeutic level Overcomes challenge of IV suboptimal dosing by noninvasively replenishing therapeutic concentrations Phase II Clinical Trial in Wet AMD Enrollment ongoing at 20+ US clinical sites Newly diagnosed wet AMD patients Duration: 9 month treatment period with interim analysis (50% completed) Randomized, double masked, placebo controlled study Safe to ocular tissues on long term administration MAY reduce the number of intravitreal injections of anti VEGF agents required and the complications of therapy for exudative AMD 5

Phase II Trial in Wet AMD Rescue treatment with Ranibizumab when specific OCT and VA parameters are met as per protocol Efficacy Endpoints 1 : Mean number of Ranibizumab injections 2 : Mean time to

6 Phase II Trial in Wet AMD Rescue treatment with Ranibizumab when specific OCT and VA parameters are met as per protocol Efficacy Endpoints 1 : Mean number of Ranibizumab injections 2 : Mean time to Ranibizumab retreatment 2 : VA gains, maintenance, and safety 60 patients per arm (120 total) Anticipated timelines Completion of enrollment Q Interim Data Q Final Data Q Potential Clinical Outcomes Adjunct to anti-vegf injections Single agent If significant group of patient don t require rescue anti-vegf treatment Ongoing Investigator Sponsored Trial (IST) OHR 003 Study Proliferative Diabetic Retinopathy (PDR) Monotherapy in 5 treatment naïve pts 6 month treatment period PI: Dr. Michael Elman Case Study data presented at the Macula Society Annual Meeting on February 19, 2014 Presentation entitled Regression of Retinal Neovascularization in PDR using Squalamine Lactate Eye Drops Ongoing Investigator Sponsored Trial (IST) Study OHR 004 Branch and Central Retinal Vein Occlusion (BRVO/CRVO) 20 Patients 10 BRVO, 10 CRVO 38 weeks of treatment, Ranibizumab rescue PI: Dr. John Wroblewski Planned New ISTs in 2014 Squalamine Eye Drops in Diabetic Macula Edema 30 Patients Randomized, masked, placebo controlled trial 24 wks treatment, with Squalamine Eye Drops Ranibizumab only for rescue therapy Investigators: Drs. David Boyer, Daniel Roth, Lawrence Singerman Planned New ISTs in 2014 Squalamine Eye Drops in DME Patients Subresponsive to Monthly Ranibizumab 20 Patients Randomized, masked, placebo controlled trial Monthly Ranibizumab in combination with Squalamine or placebo eye drops 24 week treatment duration PI: Dr. Glenn Stoller 6

Conclusions Squalamine IV infusions were previously studied in humans with biologic effect demonstrated Squalamine eye drops achieve trough levels well in excess of it s threshold level to inhibit

RVO, with two additional ISTs in DME to be initiated soon ForeseeHome Monitoring Process 1. Patient completes ForeseeHome test (3 minutes per eye) at home. 2.

If a statistically significant change in test scores is detected, Notal Vision promptly notifies both the doctor & patient to schedule an appointment for a comprehensive exam. 4.

net/patients/vision_testing Conclusions Combination treatment is likely to provide more favorable results in several aspects Eliminating VEGF and possibly causing true regression of CNV may reduce

7 Conclusions Squalamine IV infusions were previously studied in humans with biologic effect demonstrated Squalamine eye drops achieve trough levels well in excess of it s threshold level to inhibit tissue angiogenesis Ongoing phase II clinical trial in wet AMD at 20+ centers with anticipated interim data in Q2/14, final data in Q4/14 Two ISTs underway in Proliferative Diabetic Retinopathy and RVO, with two additional ISTs in DME to be initiated soon ForeseeHome Monitoring Process 1. Patient completes ForeseeHome test (3 minutes per eye) at home. 2. Test results are automatically transmitted to the Notal Vision Data Monitoring Center (DMC) via built in cellular modem or phone line. No computer or Internet is required by the patient. 3. If a statistically significant change in test scores is detected, Notal Vision promptly notifies both the doctor & patient to schedule an appointment for a comprehensive exam. 4. The doctor & patient can view results online through secure database at any time. Conclusions Combination treatment is likely to provide more favorable results in several aspects Eliminating VEGF and possibly causing true regression of CNV may reduce the risk of visual loss due to CNV May reduce # of injections, thereby reducing rate of complications The most significant complications of intravitreal injection (including endophthalmitis, RD, and cataract) relate directly to frequency of injection Reducing # of injections will also reduce overall cost of tx Conclusions Current Anti VEGF treatments Further research will maximize our options in treating AMD to minimize the devastating visual consequences of subfoveal CNV and advanced geographic atrophy However, we have already made dramatic progress in understanding and treating AMD, allowing us NOW to IMPROVE VISION in many cases that were untreatable just several years ago. This has made managing AMD much more gratifying for ophthalmology professionals and their patients 7

8 T H A N K Y O U f o r y o u r A t t e n t i o n 8

Management of Neovascular AMD

Kapusta AMD Part 1 Management of Neovascular AMD Dr. Michael A. Kapusta, MD, FRCSC Ophthalmologist in Chief Jewish General Hospital Vitreoretinal Surgeon 1 FINANCIAL DISCLOSURES Consulting honoraria Bayer,