“Beyond Anti-VEGF-A for Retinal Diseases”

“Beyond anti-VEGF-A for Retinal Diseases”

New York City, KOL Forum, November 6 2018 Megan Baldwin PhD, CEO & Managing Director NEOVASCULAR AMD CURRENT TREATMENT PARADIGMS AND UNMET NEEDS

ARSHAD M. KHANANI MD,MA MANAGING PARTNER, DIRECTOR OF CLINICAL RESEARCH, DIRECTOR OF FEL LOWSHIP SIERRA EYE ASSOCIATES CLINICAL ASSOCIATE PROFESSOR UNIVERSITY OF NEVADA - RENO OBJECTIVES

▪ PRACTICE SETTING

▪ STANDARD OF CARE DOSING STRATEGIES

▪ CLINICAL TRIALS DATA HIGHLIGHTING UNMET NEEDS

▪ NEW TREATMENTS ON THE HORIZON PRACTICE SETTING

▪ PRIVATE OFFICE BASED PRACTICE

▪ MULTISPECIALTY WITH 2 RETINAL PHYSICIANS

▪ 55 EMPLOYEES TOTAL

▪ 7 TECHNICIANS, 3 RESEARCH COORDINATORS

▪ 15-20 ACTIVE CLINICAL TRIALS

▪ 70 PATIENTS A DAY ON AVERAGE

▪ APPROXIMATELY 500 INJECTIONS A MONTH ANGIOGENESIS IN AGE-RELATED MACULAR DEGENERATION COMPLEX CASCADE OF EVENTS

VEGF

Vascular Endothelial Growth Factor

Tube formation + remodeling Endothelial cell activation

Basement membrane degradation Endothelial cell proliferation, migration

Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48; Davis GE, et al. Circ Res. 2005;97(11):1093-107. CURRENT PARADIGM – BLOCK VEGF-A

VEGF

Vascular Endothelial Growth Factor

Tube formation + remodeling Endothelial cell activation

Basement membrane Endothelial cell proliferation, degradation migration

Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48; Davis GE, et al. Circ Res. 2005;97(11):1093-107. CURRENT ANTI-VEGF-A THERAPIES FOR nAMD

▪ ANTI-VEGF-A THERAPY HAS REVOLUTIONIZED THE MANAGEMENT OF nAMD IN THE PAST 10-15 YEARS

▪ THREE MOLECULES CURRENTLY USED: ▪ RANIBIZUMAB (LUCENTIS) ▪ BEVACIZUMAB (AVASTIN) ▪ AFLIBERCEPT (EYLEA) ANTI-VEGF-A DOSING STRATEGIES USED IN CLINICAL TRIALS TO OPTIMIZE OUTCOMES AND MANAGE nAMD DISEASE

MONTHLY - ANCHOR - MARINA - CATT - HARBOR

PRN TREAT AND - SAILOR EXTEND - CATT - LUCAS - HARBOR - TREX - ALTAIR CONTINUOUS FIXED MONTHLY DOSING: VISUAL ACUITY FROM BASELINE THROUGH MONTH 24

MARINA1 MONTHS MONTHS ANCHOR2

VIEW 1 and 23

1. Rosenfeld PJ et al. N Engl J Med. 2006;355:1419-1431. 2. Brown DM et al. N Engl J Med. 2006;355:1432-1444. 3. Heier JS et al. Ophthalmology. 2012;119:2537-2548. CONTINUOUS MONTHLY DOSING

WHY DO IT? ▪ EVIDENCE OF IMPROVING VISION ▪ MAINTAIN VISION AND RETINAL DRYING ▪ AVOIDS UNDER-TREATMENT

WHY NOT DO IT? ▪ NOT INDIVIDUALIZED ▪ nAMD IS HETEROGENEOUS ▪ VARIABLE NATURAL HISTORY AND TREATMENT RESPONSE ▪ MANY PATIENTS DO WELL WITHOUT MONTHLY TREATMENT ▪ VEGF-A SUPPRESSION VARIES BETWEEN PATIENTS ▪ RESULTS BEYOND 2 YEARS LARGELY UNKNOWN CONSEQUENCES OF OVERTREATMENT

▪ EXPENSE: DIRECT AND INDIRECT COSTS

▪ INCONVENIENCE: FREQUENT VISITS

▪ INCREASED RISK (CUMULATIVE) ▪ INFECTION ▪ SUSTAINED IOP ELEVATION/GLAUCOMA INDIVIDUALIZED ANTI-VEGF TREATMENT WHY? HOW? GOALS

AVOID OVERTREATMENT SUPPRESS CNV PRN (AS NEEDED) GROWTH, EXUDATION

SAFER FREQUENT OCT MORE TREAT-AND-EXTEND IMAGING WITH “ZERO TOLERANCE” COST-EFFECTIVE PRN DOSING IN HARBOR

DISTRIBUTION OF THE NUMBER OF RANIBIZUMAB INJECTIONS OVER 2 YEARS

Ho AC, Busbee BG, Regillo CD, et al. Ophthalmology. 2014;121(11):2181-2192. UNDERTREATMENT COMPROMISES VISUAL ACUITY

POSITIVE CORRELATION OF VA GAINS AND NUMBER OF MANY PATIENTS RECEIVE FEWER INJECTIONS ANTI-VEGF-A INJECTIONS OVER 12 MONTHS IN REAL-WORLD VS CLINICAL STUDIES

US medical claims database: Patients received a mean of only 4.6 and 6.9 injections of bevacizumab & ranibizumab over 12 mo, respectively

Hussain RM et al. Ophthalmic Surg Lasers Imaging Retina. 2017;48:780-784. PRO RE NATA (PRN) DOSING

PATIENTS RECEIVE:

▪ A SERIES OF MONTHLY LOADING INJECTIONS OF ANTI -VEGF THERAPY

▪ REGULAR OFFICE VISITS FOR ASSESSMENT OF VISUAL ACUITY

▪ ANATOMIC MEASURES BASED ON OCT, FA OR OTHER IMAGING MODALITIES POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN

▪ ALLOWS FOR RECURRENCE OF NEOVASCULAR LEAKAGE AND GROWTH

▪ MULTIPLE RECURRENCES LEADS TO PROGRESSION OF DISEASE

▪ POORER LONG-TERM VISUAL OUTCOMES IN SOME PATIENTS

Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1. TREAT-AND-EXTEND DOSING: WHAT IS IT?

▪ SERIES OF LOADING ANTI-VEGF INJECTIONS, (TYPICALLY 4-WK INTERVALS), WITH VA AND ANATOMIC ASSESSMENT

▪ WHEN CRITERIA INDICATING NO DISEASE ACTIVITY ARE MET, PATIENTS RECEIVE AN INJECTION; TREATMENT INTERVAL IS EXTENDED, USUALLY BY 2 WEEKS AT A TIME, UNTIL MAXIMUM INTERVAL OF 12 –16 WEEKS IS REACHED

▪ IF CNV LESIONS ARE REACTIVATED, TREATMENT INTERVAL IS REDUCED

Spaide R. Am J Ophthalmol. 2007;144:679-680 BENEFITS OF TREAT-AND-EXTEND DOSING

▪ CONTINUOUS (PROACTIVE) ▪ MINIMIZES RECURRENCES/SETBACKS

▪ VARIABLE (INDIVIDUALIZED) ▪ MINIMIZES OVERTREATMENT ▪ MINIMIZES TREATMENT BURDEN ▪ MAXIMIZES SAFETY

▪ COST-EFFECTIVE ▪ MINIMIZES DRUG USE, TESTING, AND OFFICE

Spaide R. Am J Ophthalmol. 2007;144:679-680 CURRENT UNMET NEEDS IN nAMD NEOVASCULAR AMD ANTI-VEGF A BLOCKADE

15 10 20/63 5

0 20/100 0 6 12 18 24 +25 -5

-10 Mean Changei in ETDRS BCVA ETDRS in Changei Mean

-15

-20 Months ANCHOR, MARINA, HARBOR, CATT, VIEW1/2

Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48 NEOVASCULAR AMD – SHORTCOMINGS OF VEGF-A BLOCKADE 20/20 35 >70% VA REMAINS TO BE GAINED 25

20/100 5

0 6 12 18 24

-5 Mean Changei in ETDRS BCVA ETDRS in Changei Mean -15 #1 EFFICACY -25 MONTHS

#2 Durability X 8

20/40 ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE FIXED OR PRN DOSING

ANCHOR, MARINA, HARBOR, CATT, VIEW1/2 Injections 15 Mean = 10.2 Range = 6.6-12.3

11.3 MARINA 0.5 mg

10 ANCHOR (0.5 mg)

HARBOR 0.5 mg Monthly

Mean = 8.4 CATT Ranibizumab Monthly

HARBOR 0.5 mg PRN 5 5.9 CATT Bevacizumab Monthly CATT Ranibizumab PRN

Mean Change in ETDRS BCVA ETDRS in Change Mean CATT Bevacizumab PRN

VIEW1 (0.5q4)

VIEW1 (2q8) 0 VIEW1 (2q4) 0 3 6 9 12 VIEW2 (0.5q4) Months VIEW2 (2q8)

Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. VIEW2 (2q4) Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48 ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE TREAT & EXTEND DOSING

LUCAS, TREND, TREX-AMD

15 Injections Mean = 8.9 Range = 8.0-10.1

10 10.5 Mean = 8.6

6.6

5 Mean Changei in ETDRS BCVA ETDRS in Changei Mean

LUCAS Ranibizumab 0 LUCAS Bevacizumab 0 3 6 9 12 TREND Months TREX AMD

Berg K, et al. Ophthalmology. 2015 Jan;122(1):146-52; Silva R, et al. Ophthalmology. 2018 Jan;125(1):57-65; Wykoff CC, et al. Ophthalmology. 2015 Dec;122(12):2514-22. REAL-WORLD DATA: MAJORITY OF nAMD PATIENTS LIKELY UNDERTREATED 1ST YEAR OF MANAGEMENT

≈73% ≤ 5 injections LUMINOUS

19.6 20

15 13.5 12.2 11.7 9.5 10 8.5 7.4 5.9 5.1 Proportion of patients (%) patients of Proportion 5 2.9 2.1 1.0 0.5 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (n=250) (n=287) (n=661) (n=412) (n=455) (n=396) (n=322) (n=199) (n=173) (n=97) (n=72) (n=35) (n=17) (n=2) (n=1)

Number of ranibizumab injections up to Month 12

Holz FG, et al. Presented at: EURetina 2017; September 7-10, 2017; Barcelona, Spain. KEY POINTS & ISSUES WITH CURRENT ANTI-VEGF-A THERAPY

▪ UPPER LIMIT FOR VA ~9 LETTERS FOR nAMD ▪ IMPROVEMENTS IN VA APPEAR DEPENDENT UPON ▪ NUMBER OF INTRAVITREAL INJECTIONS ▪ CLOSE MANAGEMENT OF ANATOMICAL CHANGES

▪ AVOID UNDERTREATMENT ▪ UNDER-TREATMENT IS COMMON AND PROHIBITS PATIENTS FROM ACHIEVING EXPECTED VA GAINS ▪ “MORE IS BETTER” BUT MAY COME AT A PRICE IN nAMD WHICH IS A CHRONIC DISEASE

▪ POSSIBILITY TO INDIVIDUALIZE TREATMENT WITH PRN OR TAE ▪ >12 WEEK TREATMENT INTERVAL POSSIBLE IN ~25-50% OF PATIENTS

▪ NEW TREATMENT MODALITIES INCLUDING COMBINATION THERAPY ARE NEEDED TO IMPROVE VISION AND/OR DURABILITY OF RESPONSE ▪ VEGF-A JUST ONE MOLECULAR PATHWAY IN THE PATHOGENESIS OF nAMD

Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1. ADDITIONAL ANTI-VEGF AGENTS DUAL-TARGETING BROLUCIZUMAB & ABICIPAR FARICIMAB INTO THE (RG7716) FUTURE

VEGF-C/D BLOCKADE: OPT-302

MOONSHOTS C/D

C/D Extra-Cellular

- -

Domains 1-3 DRUG DELIVERY VEGF ▪ GENE THERAPY VEGF hVEGFR-3 APPROACHES ▪ STEM CELLS ▪ DROPS ▪ PILLS

hIgG1 Fc COMPARISON OF CURRENT VS EMERGING ANTI-VEGF-A AGENTS

Bevacizumaba Ranibizumab Aflibercept Brolucizumabb Abicipar pegolb Monoclonal Single-chain Designed ankyrin Full antibody VEGFR-1/2-Fc Format humanized antibody fragment repeat protein (IgG1) fusion protein antibody fragment (scFv) (DARPin)1

Molecular structure

Molecular weight 149 kDa 48 kDa 115 kDa 26 kDa 34 kDa Clinical dose 1.25 mg 0.5 mg 2.0 mg 6.0 mg 2.0 mg for nAMD (unlicensed use)

aOff-label; not FDA-approved for any ocular indications bUnder investigation for treatment of nAMD 1. Molecular Partners. www.molecularpartners.com/our-products/abicipar/. Accessed 7/17/18. BROLUCIZUMAB: PHASE 3 STUDY DESIGN

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018. BROLUCIZUMAB WAS NON-INFERIOR TO AFLIBERCEPT

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018 BROLUCIZUMAB ACHIEVED SUPERIOR REDUCTIONS IN CENTRAL SUBFIELD THICKNESS (CST) AT WEEKS 16, 48 and 96.

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018 Abicipar Pegol: Phase 3 CEDAR and SEQUOIA Study Design

▪ RANDOMIZED, TRIPLE-MASKED TRIALS ▪ CEDAR: N=939 ▪ SEQUOIA: N=946 ▪ TWO DOSES ABICIPAR PEGOL 2 MG Q8WK VS ABICIPAR PEGOL 2 MG Q12WK VS RANIBIZUMAB 0.5 MG Q4WK THROUGH 96 WK ▪ PRIMARY OUTCOME: BCVA CHANGE FROM BASELINE

Week BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 2Q8 2Q12 RQ4

Abicipar pegol 2 mg PRIMARY ENDPOINT n = (1:1:1) Ranibizumab 0.5 mg 900 Sham treatme No treatment

1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02462928. 2. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT02462486. CEDAR PRIMARY ENDPOINT: STABLE VISION AT WK 52 ABICIPAR Q8WK AND Q12WK NONINFERIOR TO RBZ Q4WK

RBZ, ranibizumab Allergan. 7/19/18. www.allergan.com/investors/events-presentations/events/abicipar-cedar-and-sequoia-topline-phase-3-clinica.aspx. Accessed 7/22/18. INCIDENCE OF INTRAOCULAR INFLAMMATION EVENTS

SEQUOIA STUDY CEDAR STUDY Intraocular Inflammation Events 100% 90% 80% 70% 60% 50% 40% 30% 15.7% 15.3% 20% 15.1% 15.4% 10% 0.6% 0.0% 0% Abicipar Q8 Abicipar Q12 Ranibizumab Q4 Intraocular Inflammation Events

Allergan. 7/19/18. www.allergan.com/investors/events-presentations/events/abicipar-cedar-and-sequoia-topline-phase-3-clinica.aspx. Accessed 7/22/18. PORT DELIVERY SYSTEM WITH RANIBIZUMAB (PDS): HOW DOES IT WORK?1

▪ NONBIODEGRADABLE REFILLABLE PORT PLACED BENEATH THE CONJUNCTIVA

▪ RESERVOIR REFILLED VIA SUBCONJUNCTIVAL OPENING USING CUSTOM REFILL NEEDLE

▪ PROVIDES CONSTANT LEVELS OF RANIBIZUMAB

1. Barakat MR et al. Retinal Physician. 10/1/15. www.retinalphysician.com/issues/2015/october-2015/new-developments-for-the-treatment-of-exudative-an#ref17. Accessed 6/7/18. 2. Helzner J. Retinal Physician. 1/18/17. www.retinalphysician.com/issues/2017/january-2017/genentech-acquires-developer-of-sustained-release. Accessed 6/15/18. FARICIMAB OVERVIEW: FIRST BISPECIFIC ANTIBODY DESIGNED FOR INTRAOCULAR USE

• ANG-2 IS A KEY DRIVER OF ANGIOGENESIS • UPREGULATION OF ANG-2 (OBSERVED IN NAMD) LEADS TO DECREASED TIE2 ACTIVATION • SUBSEQUENT VASCULAR LEAKAGE AND NEOVASCULARIZATION Regula JT et al. EMBO Mol Med. 2016;8:1265-1288. AVENUE:PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL

STUDY TREATMENT FINAL VISIT

6.0 MG FARICIMAB TOTAL N = 273 PATIENTS* 1.5 MG FARICIMAB • AGE ≥50 YEARS 0.5 MG • TREATMENT-NAÏVE NAMD R RANIBIZUMAB • SUBFOVEAL CNV LESION PRIMARY • BCVA 20/40–20/320 (73–24 ENDPOINT ETDRS LETTERS) SHAM

0 4 8 12 16 20 24 28 32 36 TIME, WEEKS

Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States. AVENUE: MEAN CHANGE IN BCVA FROM BASELINE TO WEEK 36

+ 9.1 letters 10 + 7.6 letters + 7.2 letters + 6.0 letters 5

+ 5.9 letters

Baseline, ETDRS Letters ETDRS Baseline, Adjusted Mean BCVA Change From From Change BCVA Mean Adjusted 0 0 4 8 12 16 20 24 28 32 36 Time, Weeks

6.0 mg faricimab 6.0 mg faricimab 1.5 mg faricimab 0.5 mg ranibizumab Q4W/ 0.5 mg ranibizumab Q4W Q4W/Q8W Q4W 6.0 mg faricimab Q4W Q4W LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE BCVA CHANGE FROM BASELINE, ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT02484690). Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States. AVENUE: MEAN CHANGE IN CST FROM BASELINE TO WEEK 36

-100 – 147 μm – 156 μm – 172 μm – 175 μm -200

– 185 μm

From Baseline, µm Baseline, From Adjusted Mean CST Change Change CST Mean Adjusted

-300 0 4 8 12 16 20 24 28 32 36 Time, Weeks

6.0 mg faricimab 6.0 mg faricimab 1.5 mg faricimab 0.5 mg ranibizumab Q4W/ 0.5 mg ranibizumab Q4W Q4W/Q8W Q4W 6.0 mg faricimab Q4W Q4W

LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE CST CHANGE FROM BASELINE. ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT02484690). CST = CENTRAL SUBFIELD THICKNESS. Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States. . STAIRWAY: PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL

Study Treatment Final Visit

Total N = 76 patients* Q16W dosing

• Age ≥50 years R Active disease at Week 24† • Treatment-naïve nAMD Q12W dosing • Subfoveal CNV lesions • BCVA 20/40–20/320 (73–24 ETDRS letters) Q4W dosing

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time, Weeks 6.0 mg faricimab 0.5 mg ranibizumab Prespecified disease Primary endpoint assessment at Week 24 Sham

Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States. BCVA OUTCOMES WITH Q16W AND Q12W FARICIMAB WERE COMPARABLE TO Q4W RANIBIZUMAB

▪ NEOVASCULAR AMD MANAGEMENT HAS EVOLVED GREATLY

▪ CURRENT MANAGEMENT ▪ INDIVIDUALIZED MONOTHERAPY ▪ SHORT-ACTING DIRECT PAN-VEGF-A INHIBITORS ▪ INDUCTION F/B INDEFINITE, FREQUENT MAINTENANCE RX ▪ LACK OF SUSTAINED VISION GAINS OVER TIME IN PRACTICE

▪ FUTURE MANAGEMENT: EFFICACY AND DURABILITY ▪ OTHER VEGF-A BLOCKERS (BROLUCIZUMAB AND ABICIPAR) ▪ SUSTAINED DELIVERY OF VEGF-A INHIBITORS (PDS) ▪ TARGETS IN ADDITION TO VEGF-A BLOCKADE ▪ VEGF-C AND VEGF-D (OPT-302) ▪ VEGF-A AND ANG-2 (FARICIMAB) “Beyond anti-VEGF-A for Retinal Diseases”

New York City, KOL Forum, November 6 2018 Megan Baldwin PhD, CEO & Managing Director Beyond Anti-VEGF-A for Diabetic Macular Edema

Rishi P. Singh, MD Staff Physician, Cole Eye Institute Associate Professor of Ophthalmology Medical Director, Clinical Systems Cleveland Clinic, Cleveland Ohio

Cole Eye Institute Financial Disclosures

● Consultant For Regeneron, Genentech, Shire, Zeiss, Optos, Allergan

● Sponsored Researched – Apellis, Genentech/Roche, Regeneron, Alcon/Novartis

Cole Eye Institute How Common Is Diabetes?

Age-adjusted Prevalence of Diagnosed Diabetes in US Adults1,2

<4.5% 4.5%‒5.9% 6.0%‒7.4% 7.5%‒8.9% ≥9.0%

1994 1998 2003 2008 2015

1. Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/statistics/slides/maps_diabetes_trends.pptx. Accessed March 5, 2018. 2. Centers for Disease Control and Prevention. http://gis.cdc.gov/grasp/diabetes/DiabetesAtlas.html. Accessed March 5, 2018. Cole Eye Institute Future Prevalence Projections Of Diabetes

Percent of Total Population With Diabetes (Diagnosed and Undiagnosed)

7%-8% 9%-11% 12%-14% 15%-17% 18%-20%

20202020 2025 2030

Rowley et al. Popul Health Manag. 2017;20:6. Cole Eye Institute Diabetes Is Associated With Serious Comorbidities

Diabetic retinopathy1

28.5% in patients aged ≥40 Stroke4 ≈13.6% have diabetic 11.5 per 1000 persons with diabetes macular edema (DME)2

Ischemic Heart Disease4 Diabetic nephropathy3 18.3 per 1000 persons with diabetes 29.9% in diabetic patients

Diabetic neuropathy1 60%-70% in diabetic patients

1. Centers for Disease Control and Prevention. 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed June 11, 2018. 2. Varma, et al. 2012 Joint Meeting of the American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology; November 10-13, 2012; Chicago, IL. Poster PO252. 3. United States Renal Data System. 2012 atlas of CKD and ESRD. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012. http://www.usrds.org/atlas.aspx. Accessed February 7, 2013. 4. Centers for Disease Control and Prevention. 2017 National Diabetes Statistics Report. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed July 10, 2018. Cole Eye Institute Chronic Hyperglycemia Initiates a Number of Inter-related Pathways that Lead to DME

Inflammation ↑ AGEs ↑ ROS Microvascular damage Leukostasis ↑ ICAM Pericyte loss PKC activation Endothelial damage ↑ Nitric oxide DME ↑ Polyols ↑ Eicosanoids

VEGF overexpression

AGEs = advanced glycation end-products ICAM = intercellular adhesion molecule PKC = protein kinase C; ROS = reactive oxygen species Boyer DS, et al. Ther Adv Endocrinol Metab. 2013;4(6):151-169. Cole Eye Institute Current Approved and Off-label Therapies for Diabetic Macular Edema

● Approved Treatments ● Unapproved Treatments

● Anti-VEGF ● Anti-VEGF

● Lucentis – ● Avastin – Genentech/Roche Genentech/Roche

● Eylea – Regeneron ● Steroid

● Steroid ● Triamcinolone

● Ozurdex – Allergan ● Triescence - Alcon

● Iluvein – Alimera

Cole Eye Institute Why we need additional treatments

• Post hoc analysis demonstrate not all patients respond to treatment • Persistent retreatment of patients • We currently only address two pathways in DME with intermittent treatment

Cole Eye Institute Anti-VEGF-A has limited efficacy

≥15-LETTER BCVA NUMBER OF CLINICAL TRIAL TREATMENT DOSAGE(S) UNDER STUDY INCREASE AT 1 YEAR PATIENTS (%) 0.3 mg 125 45% RISE ranibizumab 0.5 mg 125 39% 0.3 mg Even when treatment 125 34% RIDE ranibizumab 0.5 mgregimens are optimized under 127 46% ranibizumab + 0.5 mg ranibizumabclinical trial conditions, 187 30% DRCR prompt laser + focal / grid lasermeaningful 3-10 days after visualfirst IVTacuity PROTOCOL I ranibizumab + 0.5 mg ranibizumab increases are only achieved 188 28% deferred laser + focal / grid laser ≥24 weeks after first IVT by 30% to 45% of DME BOLT bevacizumab 1.25 mg 42 12% patients 2 mg every 4 weeks 154 42% VISTA* aflibercept 2 mg every 8 weeks* 151 31% 2 mg every 4 weeks 136 32% VIVID* aflibercept 2 mg every 8 weeks* 135 33%

*2 mg every 8 weeks after initial loading period of 2 mg every 4 weeks for first 5 doses.

Elman MJ, Aiello LP, Beck RW, et al. Ophthalmology. 2010;117(6):1064-1077; Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Ophthalmology. 2014;121(11):2247-2254. Cole Eye Institute Michaelides M, Kaines A, Hamilton RD, et al. Ophthalmology. 2010;117(6):1078-1086; Nguyen QD, Brown DM, Marcus DM, et al. Ophthalmology. 2012;119(4):789-801. Patients With DME Can Be Categorized Based on Types of Response to Anti-VEGF-A Treatment

From the DRCR.net trial of ranibizumab and laser for patients with DME

Type of Early and Early but Slow and No Response Consistent Inconsistent Variable Response Improvement* at 16 Weeks ✓ ✓ ✗ ✗ Improvement* at 32 Weeks and/or 1 Year ✓ ✓✗ ✓✗ ✗

% of Patients 49.6% 14.9% 12.5% 22.9% = 50.4% n=143/288 n=43/288 n=36/288 n=66/288

Non responders

* OCT thickness decreased ≥20% from baseline. Bressler SB, et al. Arch Ophthalmol. 2012.

Cole Eye Institute We Know Very Quickly Whether or Not Patients Will Respond to Anti-VEGF-A

20 16.5 15.2 13.8 15

10 6.9 8.2 8.2 p<0.001 5 2.8 3.0

-0.3 BCVA Change from Baseline BCVA -5 BL 12 16 20 24 28 32 36 40 44 48 52 . .. … 68 . .. … 84 . .. … …. 104 . .. 120 . .. 136 ...... … . …. 156 … … Weeks

<5 letters 5-9 letters ≥10 letters at 12w (N=135) at 12w (N=79) at 12w (N=126)

Am J Ophthalmol. 2016 Dec;172:72-79. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Gonzalez VH, Campbell J, Holekamp NM, Kiss S, Loewenstein A, Augustin AJ, Ma J, Ho AC, Patel V, Whitcup SM, Dugel PU. Cole Eye Institute Targets for future DME treatment

● A better Anti-VEGF-A molecule/Steroid Molecule ● eg. Brolucizumab, DARPin

● Sustained delivery of anti-VEGF-A ● eg Port Delivery System

● A new mechanism of action ● PlGF Inhibition • THR-317 (Thrombogenics) ● Ang2/Tie2 Pathway • RG7716 (Roche/Genentech) • AKB-9778 (Aerpio) ● Targeting Integrin • Luminate (Allegro) ● VEGF-C/D inhibition • OPT-302 (Opthea)

Cole Eye Institute Anti-PLGF: THR-317 (Thrombogenics)

PlGF expression is elevated in hypoxic human RPE cells in vitro PGF is elevated in aqueous humour in PlGF is elevated in aqueous humour in patients with DME and PDR patients with DME and PDR

Vitreous PlGF and VEGF-A are elevated 100 3x and 1.8x respectively in patients with ** active PDR compared to quiescent PDR 80

/mL) 60

Phase 1/2: 49 patients, including anti- pg VEGF-A naïve patients as well as sub- 40

optimal anti-VEGF-A responders *** PGF ( PGF 20

30% of the anti-VEGF-A treatment naïve Not detected study subjects treated with THR-317 in 0 the 8mg group showed a > or equal to 15 Control DME PDR letter gain from baseline at Day 90 versus 5.3 % in the 4mg group

Phase 2 clinical study by Q2 2018

Ando R et al. Acta Ophthalmol 2014; 92 (3): e245–e246; Mitamura Y et al. Diabetes Care 2002; 25 (12): 2352; Miyamoto N et al. Diabetologia 2007; 50 (2): 461–470; Martinsson-Niskanen et al; 2011 Clinical Therapeutics 33:1142-1149 Cole Eye Institute Ang-2 Being Investigated In Two Studies

● Boulevard

● Phase 2 – Roche/Genentech – Bispecific molecule with both Ang-2 and anti- VEGF-A (RG7716)

● Ruby

● Phase 2 – Bayer/Regeneron – Co-formulation of Ang-2 and aflibercept

● Did not meet the primary endpoint of superiority of co-formulated compound versus aflibercept

Cole Eye Institute Faricimab (RG7716) Molecular Structure

Cole Eye Institute BOULEVARD Trial

Cole Eye Institute Secondary endpoints from the BOULEVARD Study

Cole Eye Institute Activating the Tie-2 Receptor Pathway - Aerpio

● Tie‐2 is a key control axis for retinal vascular stability

● Inhibiting HPTPβ removes “the brake” on Tie‐2, activating it and affecting the vascular stability

● AKB‐9778 is a potent, specific inhibitor of HPTPβ

Cole Eye Institute TIME-2 tested AKB-9778 alone and in combination with Lucentis

56-day observation period, with LUCENTIS® treatment allowed as 15 mg AKB-9778 subcutaneous BID needed 3 SHAM injections q4

15 mg AKB-9778 subcutaneous BID 3 doses intravitreal LUCENTIS (0.3 mg) q4 N=144 R 1:1:1 PLACEBO subcutaneous BID 3 doses intravitreal LUCENTIS (0.3 mg) q4

STUDY VISITS

Intravitreal LUCENTIS injection 65 Sham injection Cole Eye Institute AKB-9778 + Lucentis significantly reduced retinal thickness compared to Lucentis alone,

Change in CST from Baseline to Month 3

6 10 0 -10 -8 -10

-30

-50

AKB-9778 (N=46) -70 Lucentis (N=47) -91 -90 AKB-9778 + Lucentis (N=48) -102 -110 -110 -106 -130 p = 0.008 -150

CST Reduction (µm) Reduction CST -146 -164 -170 Baseline Month 1 Month2 Month 3

66 Cole Eye Institute Integrin Inhibition for DME: Allegro - Risuteganib

Cole Eye Institute Del Mar Phase 2b With Risuteganib (Luminate)

Phase 2b – Stage 1: Monotherapy vs Avastin with 6-month follow-up (n=136)

Goal

Drug Safety Dose Ranging Durability Efficacy vs anti-VEGF-A

Phase 2b – Stage 2: Avastin pretreatment vs combination therapy with 5-month follow-up (n=80)

Goal

Increase efficacy by clearing out pre- existing VEGF-A load

Cole Eye Institute Phase 2b DEL MAR Stage 1: Primary and Secondary Endpoints Were Met (n=136)

Primary Endpoint Secondary Endpoint Mean BCVA non-inferiority at study week 20 (≤3 letters) Mean OCT CMT non-inferiority at study week 20 (≤30µ)

NO LUMINATE DOSING NO LUMINATE DOSING

Cole Eye Institute Conclusions

● Still unmet need in the treatment of diabetic macular edema

● Multiple promising avenues are being studied

● Hopefully combinations of the current drugs and drugs in the pipeline will improve the quality of vision for our patients with DME

Cole Eye Institute “Beyond anti-VEGF-A for Retinal Diseases”

New York City, KOL Forum, November 6 2018 Megan Baldwin PhD, CEO & Managing Director Targeting a More Complete Blockade of VEGF: Results from the Phase 1b/2a Trial of OPT-302 (anti-VEGF-C/D “Trap”) and Ranibizumab in Neovascular AMD

Nathan Steinle, MD California Retina Consultants Financial Disclosures

Consultant for: • Alimera Sciences, Genentech, Regeneron, Regenerative Patch Technologies

Speaker for: • Genentech, Notal Vision, Regeneron

Research Funding: • Genentech, Zeiss VEGF-A Inhibition Upregulates VEGF-C/D

Ranibizumab Aflibercept Bevacizumab

Neovascular AMD Patients2 VEGF-C VEGF-B VEGF-A OPT-302 PlGF VEGF-D 10.00 OPT-302 (anti-VEGF-C/-D): 8.91 9.00 • Inhibits angiogenesis & 8.00 vascular leakage 6.91 • Overcomes escape mechanism /ml) 66% pg 7.00

VEGFR-1 VEGFR-2 VEGFR-3 to VEGF-A suppression (

C - 6.00 5.37

VEGF 5.00

4.00 Humor 3.00

2.00 Aqueous Aqueous 1.00

0.00 Baseline 1m 2m

Angiogenesis Angiogenesis Bevacizumab Bevacizumab Vascular Permeability Lymphangiogenesis

Pathway blocked Ligand Ig-like domain Kinase domain by OPT-302

ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144 OPT-302 a Novel ‘Trap’ Inhibitor of VEGF-C/D

OPT-302 Inhibition of CNV in Rodent Model of AMD • OPT-302 Control OPT-302 • A ‘trap’ molecule that binds & neutralises the activity of VEGF-C/-D, blocking their activation of receptors VEGFR- 70% 2 and VEGFR-3 78% 91% • Potent inhibitor of VEGF-C (~5pM) and VEGF-D (~0.5 nM)

Aflibercept OPT-302 + Aflibercept * C/D

C/D Extra-Cellular Domains 1-3

- -

hVEGFR-3

VEGF VEGF

* Pairwise comparison: OPT-302 vs Aflibercept + OPT-302 (p<0.02) hIgG1 Fc Aflibercept vs Aflibercept + OPT-302 (p<0.05)

Combined inhibition of VEGF-A (Aflibercept) and VEGF-C/-D (OPT-302) is more effective than inhibition of VEGF-A alone OPT-302 Phase 1b/2a First-in-Human Study in nAMD Patients (n=51)

Part 1: Dose-escalation Part 2: Dose-expansion (Open-label) (Randomised 3:1)

OPT-302 (2 mg) OPT-302 (2 mg) Monotherapy* Monotherapy* IVT Q4W x 3 IVT Q4W x 3, n=8 pts

Cohort 4

OPT-302 (2 mg) + OPT-302 (2 mg) Ranibizumab (0.5 mg) + Ranibizumab (0.5 mg)

IVT Q4W x 3 IVT Q4W x 3, n=23 pts

up atWeek up 24

- up to weektoup 12 Cohort 3 - OPT-302 (1 mg) +

Ranibizumab (0.5 mg) Follow

IVT Q4W x 3 window DLT Day 28 Primary Analysis after allafterAnalysis Primary

Cohort 2 weeks 12 complete subjects OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) Longtermfollow IVT Q4W x 3

Cohort 1

• Comprises of 4 treatment cohorts of 5 subjects each *Access to rescue anti-VEGF-A Tx ClinTrials Identifier NCT 02543229 Treatment Groups

Wet AMD Patients N=51

OPT-302 + ranibizumab OPT-302 Combination Therapy Monotherapy N=38 N=13

Treatment Prior-Treated Treatment Prior-Treated Naïve with anti-VEGF-A Naïve with anti-VEGF-A N=18 N=20 N=7 N=6

• Mean Age: 77.4 years • 32/51 (63%) female and 19 (37%) were male • 49% treatment-naive • 51% were difficult to treat patients who were heavily pre-treated and sub-responsive to prior anti-VEGF-A therapy • Mean number prior anti-VEGF-A injections = 17 • Lesions: 73% Occult, 23% Minimally Classic, 4% Predominantly Classic OPT-302 ± Ranibizumab Safety Results in nAMD

• OPT-302  ranibizumab administered by IVT injection (Baseline, Week 4, Week 8) • No missed doses, safety experience with ~150 intravitreal (ocular) injections of OPT-302

• OPT-302 intravitreal doses up to 2 mg ± ranibizumab 0.5 mg • No dose limiting toxicities (MTD not reached) • No study drug related serious adverse events or systemic AEs • AEs primarily related to IVT injection procedure (Mild/moderate, manageable) • Two patients (3.9%) had treatment-related AEs of Grade 1/Mild anterior chamber inflammation / anterior uveitis in the low and mid-dose combination groups • No OPT-302 related AEs observed in high dose (2mg) combination or monotherapy patients (n=41) • No clinically significant changes in IOP, ECG’s, blood pressure, vitals • No evidence of OPT-302-related immunogenicity • OPT-302 was generally safe and well tolerated ± with ranibizumab Summary of Adverse Events Reported in ≥ 5% of all Subjects

OPT-302 (0.3 mg) + RBZ OPT-302 (1 mg) + RBZ OPT-302 (2 mg) + RBZ OPT-302 (2 mg) Total Number of (0.5 mg) (0.5 mg) (0.5 mg) Monotherapy Subjects (n=5) (n=5) (n=28) (n=13) (N=51)

Total pts with at least one AE 5 4 22 9 40 (79%)

Total pts with at least 1 Ocular AE 5 4 18 8 35 (69%) Ocular AEs Conjunctival Haemorrhage 4 3 9 4 20 (39%) Punctate Keratitis 1 2 6 2 11 (22%) Eye pain 2 2 5 2 11 (22%) Retinal haemorrhage 1 - 1 2 4 (8%) Eye irritation - 1 2 - 3 (6%) Ocular discomfort 1 - 2 - 3 (6%) Vitreous floaters - 1 - 2 3 (6%)

Total pts with at least 1 Non-Ocular AE 3 3 13 4 23 (45%) Non-Ocular AEs Nasopharyngitis 1 - 1 1 3 (6%) OPT-302 Serum Pharmacokinetic Profile (± Ranibizumab)

Mean OPT-302 serum concentrations

100.0 OPT-302 Monotherapy (2 mg) • Non-compartmental OPT-302 PK analysis indicated: • low systemic exposure Combination OPT-302 (2 mg) + • a half-life of 8 ± 2 days Ranibizumab (0.5 mg) • mean Cmax of ~21 ng/mL at ~31 hours post IVT injection at a dose of 2 mg • no accumulation • no influence from ranibizumab on the PK profile. 10.0

Intravitreal OPT-302 (2 mg) Cmax Tmax AUC0–last T1/2

302 Serum Concentrations (ng/mL) ConcentrationsSerum 302  - (± 0.5 mg ranibizumab) (ng/mL) (hours) (ng h/mL) (days) Mean ± SD 21.1 ± 17.3 31 ± 24 2760 ± 1110 8 ± 2 (n) (n = 41) (n = 41) (n = 30) (n = 10)

Mean (+SD) OPT (+SD) Mean 1.0 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336

Time (hours) Intravitreal OPT-302 (2 mg) monotherapy

Change in mean Best Corrected Visual Acuity from Baseline to week 12

• OPT-302 monotherapy at 2 mg to assess biological activity in absence of standard of care

+5.6 letters • Anti-VEGF-A (ranibizumab) rescue therapy criteria: • <10% decrease in CST and ≥ 5 letter loss of BCVA +4.4 letters • 7/13 (56%) patients (4 treatment-naïve, 3 prior treated) did not require ‘rescue’ therapy through week 12 + 2.8 letters • 5/13 (38%) patients received one rescue injection to week 12 • 1 pt (8%) had 2 rescue injections to week 12 • Mean time to rescue therapy was 58 days

OPT-302 Monotherapy Patients: n = 13 (wk 4, 8), 12 (wk 12); Mean Baseline VA = 55.7 Letters OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness

Change in mean BCVA Change in mean Central Subfield Thickness

15 Time (weeks) Naïve pts (n=18) Prior treated pts (n=20) 0 2 4 6 8 10 12 0

-20 +10.8 letters 10 -40 -54 µM -60

-80 5 + 4.9 letters -100

-119 µM

Change from baseline in CST (µM) CST baseline in from Change -120

-140 Naïve pts (n=18) Change from Change baselinefrom in Visual Acuity (ETDRS Letters) 0 Prior treated pts (n=20) -160 0 4 8 12 Time (weeks) Treatment Naïve Patients: Prior-Treated Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg) n = 20 (wk 4, 8), 19 (wk 12); OPT-302 (0.3-2.0 mg) + ranbizumab (0.5 mg) Mean Baseline VA = 56.5 Letters Mean Baseline VA = 64.5 Letters OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness

Reduction in CNV size on FA % Patients with absent CNV on FA

9 60 7.71 8 50 %

7 50 ) 2 6 40 5 27.8 %

4 3.74 30 CNV Size (mm Size CNV 3 20 2.03 2

1 FA on CNV Absent with Patients % 10 5.6 %* 0 0 Baseline Week 4 Week 12 Baseline Week 4 Week 12 OPT-302 + Ranibizumab OPT-302 + Ranibizumab

Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg); * Absent on FA, present on OCT Case Study Naïve Patient (Occult): OPT-302 + Ranibizumab

Baseline Week 4 Week 12

VA: 53 letters VA: 64 letters VA: 73 letters

CNV: 3.11 mm2 CNV: 2.91 mm2 CNV: 0 mm2

CST: 279 µM CST: 217 µM CST: 233 µM SRF: 192 µM SRF: 0 µM SRF: 0 µM SHRMw: 1053 µM SHRMw: 0 µM SHRMw: 0 µM SHRMh: 94 µM SHRMh: 0 µM SHRMh: 0 µM

OPT-302 (2 mg) + ranbizumab (0.5 mg) Case Study Prior Treated Patient (Occult): OPT-302 + Ranibizumab

Patient was heavily pre-treated with Ranibizumab (0.5 mg) x 28 IVT injections Baseline Week 4 Week 12

VA: 65 letters VA: 72 letters VA: 78 letters

CNV: 11 mm2 CNV: 5.28 mm2 CNV: 8.04 mm2

CST: 303 µM CST: 249 µM CST: 248 µM SRF: 140 µM SRF: 41 µM SRF: 0 µM SHRMw: 1042 µM SHRMw: 0 µM SHRMw: 0 µM SHRMh: 133 µM SHRMh: 0 µM SHRMh: 0 µM OPT-302 (2 mg) + ranbizumab (0.5 mg) Conclusion

• Current treatments target primarily VEGF-A

• OPT-302 is a novel biologic that binds and neutralizes VEGF-C/-D

• Dual targeted inhibition of VEGF-C/-D (with OPT-302) and VEGF-A signaling pathways may offer benefits that exceed the inhibition of either target alone

• Multiple dosing with OPT-302 ± ranibizumab was well tolerated with a favourable safety profile in 51 patients with nAMD

• Improvements in BCVA and key OCT / FA parameters were observed in eyes that were either treatment-naïve or suboptimal responders despite being heavily pre-treated with multiple anti- VEGF-A treatments,

• These results warrant further evaluation of OPT-302 in larger patient populations with retinal diseases. “Beyond anti-VEGF-A for Retinal Diseases”

New York City, KOL Forum, November 6 2018 Megan Baldwin PhD, CEO & Managing Director Disclaimer

Investment in Opthea Limited (‘Opthea’) is subject to investment risk, including possible loss of income and capital invested. Neither Opthea nor any other member company of the Opthea Group guarantees any particular rate of return or performance, nor do they guarantee the repayment of capital.

This presentation is not an offer or invitation for subscription or purchase of or a recommendation of securities. It does not take into account the investment objectives, financial situation and particular needs of the investor. Before making any investment in Opthea, the investor or prospective investor should consider whether such an investment is appropriate to their particular investment needs, objectives and financial circumstances and consult an investment advisor if necessary.

This presentation may contain forward-looking statements regarding the potential of the Company’s projects and interests and the development and therapeutic potential of the company’s research and development. Any statement describing a goal, expectation, intention or belief of the company is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercialising drugs that are safe and effective for use as human therapeutics and the financing of such activities. There is no guarantee that the Company’s research and development projects and interests (where applicable) will receive regulatory approvals or prove to be commercially successful in the future. Actual results of further research could differ from those projected or detailed in this presentation. As a result, you are cautioned not to rely on forward-looking statements. Consideration should be given to these and other risks concerning research and development programs referred to in this presentation.

88 OPT-302 Clinical Program

• Two ongoing randomised controlled clinical trials in nAMD & DME

Combination 1o Data Agent Preclinical Phase 1 Phase 2a Phase 2b Phase 3 Status Analysis Neovascular AMD

OPT-302 Ranibizumab Complete Target: VEGF-C/D Target: VEGF-A Ph 1/2a (n=51) April 2017

OPT-302 Ranibizumab Ongoing Target: VEGF-C/D Target: VEGF-A Ph 2b (n=351) Early 2020

Diabetic Macular Edema

OPT-302 Aflibercept Ongoing Target: VEGF-C/D Target: VEGF-A, Ph 1b/2a (n=117) 2019 PlGF, VEGF-B

89 OPT-302 +/- Ranibizumab Phase 2b Trial in Treatment-Naïve nAMD (n=351)

OPT-302 (2 mg) + Ranibizumab (0.5 mg) n=117

up -

Treatment-Naive OPT-302 (0.5 mg) + Ranibizumab (0.5 mg) n=117

Neovascular AMD Week24Follow Sham + Ranibizumab (0.5 mg) n=117

Randomized 1:1:1 to treatment arms IVT dosing at every 4 weeks (x 6)

• Currently enrolling • Primary data analysis early 2020 90 ClinTrials Identifier NCT 03345082 Phase 1b Dose Escalation study of OPT-302 + Aflibercept in DME Phase 1b Dose-Escalation N=9 patients Phase 2a Dose-Expansion (Randomised 2:1 ratio)

OPT-302 (2.0 mg) OPT-302 (2.0 mg) + Aflibercept (2.0 mg) + Aflibercept (2.0 mg)

IVT Q4W x 3, n=3 IVT Q4W x 3, n=~72 pts A A

Cohort 3 -

OPT-302N= (1.0 mg) Aflibercept (2.0 mg)

+ Aflibercept (2.0 mg) VEGF

IVT Q4W x 3, n=~36 pts -

IVT Q4W x 3, n=3 up to week 12 week to up

Cohort 2 - 14 Day DLT window DLT Day 14 OPT-302 (0.3 mg) 24 to 12 Week

+ Aflibercept (2.0 mg) antiPRN

Primary Analysis all after Analysis Primary Follow IVT Q4W x 3, n=3 weeks12 completesubjects ClinTrials Identifier Cohort 1 NCT 03397264

Key Inclusion Criteria Key Exclusion Criteria • Age ≥ 18 years; centre-involving DME • HbA1c ≥ 12% • CST ≥ 335 µm* • Uncontrolled hypertension ≥ 180 mmHg systolic or • BCVA 73 – 24 ETDRS letters (20/40 – 20/320 Snellen ≥ 110 mmHg diastolic • Prior exposure to anti-VEGF-A therapy with sub-optimal • Eyes needing PRP within 3 months of screening therapeutic response • Concurrent / prior use of intravitreal injections of • ≥ 3 intravitreal injections steroids within 4 months of study start • Last injection ≤ 6 wks prior to study day 1 • Prior bevacizumab only allowed if switched to IVT aflibercept or • Concurrent / prior use of dexamethasone or ranibizumab prior to study fluocinolone implant in study eye 91 *CST as measured by Spectralis (Heidelberg) at screening, ≥ 320 µm for Cirrus. OPT-302 + Aflibercept Safety Results • OPT-302 (0.3, 1 or 2 mg) + aflibercept (2 mg) administered by IVT injection (Baseline, Week 4, Week 8) • OPT-302 intravitreal doses up to 2 mg in combination with aflibercept (2 mg) • No dose limiting toxicities (Maximum Tolerated Dose not reached) • No study drug related adverse events • Ocular AEs in the study eye primarily related to IVT injection procedure (Mild/moderate, resolved)

• No clinically significant changes in IOP, ECG’s, or vitals.

• OPT-302 was generally safe and well tolerated + aflibercept

OPT-302 has a favorable safety profile when administered with aflibercept (DME) expanding upon similar results when given as monotherapy or in combination with ranibizumab (wet AMD) 92 OPT-302 + Aflibercept – Safety Summary of selected AEs

Selected Adverse Events: OPT-302 (0.3 mg) + OPT-302 (1 mg) + OPT-302 (2 mg) + Total Number of Ocular or Systemic Aflibercept (2.0 mg) Aflibercept (2.0 mg) Aflibercept (2.0 mg) Subjects (n=3) (n=3) (n=3) (N=9)

Intraocular inflammation 0 0 0 0 Endophthalmitis 0 0 0 0 Retinal detachment 0 0 0 0 Vitreous hemorrhage 0 0 0 0 Hypertension 1* 0 0 1*

APTC events# Nonfatal myocardial infarction 0 0 0 0 Nonfatal stroke 0 0 0 0 Vascular or cardiac death or death of unknown cause 0 0 0 0 Combined APTC events 0 0 0 0

Any other death 0 0 0 0

IOP, mmHg: Baseline, week 12; (change from baseline) 13.0; 15.7 (2.7) 17.3; 15.3 (-2.0) 16.7; 17.0 (0.3) 15.7; 16.0 (0.3) • No safety signals or unexpected findings #APTC = Antiplatelet Trialists' Collaboration 93 *Determined by treating investigator as unrelated to study drug(s) OPT-302 + Aflibercept: Gains in BCVA at Week 12 Dose Response Relationship

+14.3 2 0

Dose of OPT-302 % of pts with Mean # prior + Aflibercept BCVA gain anti-VEGF-A 1 5 (2 mg) ≥ 5 letters injections 0.3 mg 1/3 (33%) 5 1 mg 2/3 (67%) 7.3 1 0 +7.7 2 mg 3/3 (100%) 6.7 +5.7 +3.0 0.3 to 2 mg 6/9 (67%) 6.3 5

(N=3) (N=3) (N=3) (N=9) 0

Mean Change from baseline in BCVA (Letters) Mean Change from baseline in BCVA 0.3 mg 1 mg 2 mg 0.3 - 2 mg OPT-302 OPT-302 OPT-302 OPT-302

94 Error Bars: SEM + 2 mg Aflibercept OPT-302 (0.3-2 mg) + Aflibercept (2 mg): Mean changes in CST from Baseline to Week 12

-20

OCT OCT (µm) -40 -

-60

- 71 µM CST on on CST SD

-80 Mean Change from Baseline in

-100 0 2 4 8 12 Week

95 Error Bars: SEM; Mean Baseline CST = 434 µm DME Patients with Bilateral Disease* Study Eye vs Fellow Eye (N=5)

Mean Change in BCVA Baseline Mean Change in CST (uM) Baseline % Pts with ≥ 50% Reduction in to Week 12 to Week 12 Excess Foveal Thickness

OPT-302 + Anti-VEGF-A OPT-302 + Anti-VEGF-A OPT-302 + Anti-VEGF-A Aflibercept Monotherapy Aflibercept Monotherapy Aflibercept Monotherapy +10.0 60% -6.0 µM

+2.6

Percentage Percentage Patients 20% Mean Change CST (µM)

Mean Change BCVA (Letters) Mean Change BCVA -80 µM

Study Eye: *Patients with bilateral disease and persistent DME in the fellow eye receiving anti-VEGF-A (ranibizumab or aflibercept) monotherapy 0.3 – 2mg OPT-302 + 2 mg Aflibercept Prior anti-VEGF-A therapy in Fellow Eyes BL to Wk 12: 3x Aflibercept, 3x Ranibizumab, 1x Ranibizumab, 4x Ranibizumab, 3x Aflibercept Fellow Eye: Anti-VEGF-A Monotherapy* Mean baseline BCVA, CST: Study Eyes (63 letters, 445 µM); Fellow Eye (73 letters, 389 µM) 96# Excess foveal thickness was determined by using 300 µm Spectralis scan values and 285 µm Cirrus scan values OPT-302 Clinical Program