Beyond anti-vegf-a for Retinal Diseases. New York City, KOL Forum, November Megan Baldwin PhD, CEO & Managing Director

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1 Beyond anti-vegf-a for Retinal Diseases New York City, KOL Forum, November Megan Baldwin PhD, CEO & Managing Director

2 NEOVASCULAR AMD CURRENT TREATMENT PARADIGMS AND UNMET NEEDS ARSHAD M. KHANANI MD,MA M A N A G I N G PA R T N E R, D I R E C T O R O F C L I N I C A L R E S E A R C H, D I R E C T O R O F F E L L O W S H I P S I E R R A E Y E A S S O C I A T E S C L I N I C A L A S S O C I A T E P R O F E S S O R U N I V E R S I T Y O F N E V A D A - RENO

3 OBJECTIVES PRACTICE S E T T I NG STA NDARD OF CARE DOSING STRAT EGIES CLINICAL T R I A L S D ATA HIGHLIGHTING U NMET NEEDS NEW T R E AT MENT S ON T HE HORIZON

4 PRACTICE SETTING PRIVAT E O F F I CE B A S E D P R ACTICE MULTISPECIALT Y WITH 2 RETINAL PHYSICIANS 55 EMPLOYEES TOTA L 7 T E CHNICIANS, 3 RESEARCH COORDINATO RS ACTIVE CLINICAL T R IALS 70 PAT IENT S A DAY O N AVERAG E A PPROXIMATELY 50 0 I NJECTIONS A MONTH

5 ANGIOGENESIS IN AGE-RELATED MACULAR DEGENERATION COMPLEX CASCADE OF EVENTS VEGF Vascular Endothelial Growth Factor Endothelial cell activation Tube formation + remodeling 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):

6 CURRENT PARADIGM BLOCK VEGF-A VEGF Vascular Endothelial Growth Factor Endothelial cell activation Tube formation + remodeling 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):

7 CURRENT ANTI-VEGF-A THERAPIES FOR namd ANTI-VEGF-A THERAPY HAS REVOLUTIONIZED THE MANAGEMENT OF namd IN THE PAST YEARS THREE MOLECULES CURRENTLY USED: RANIBIZUMAB (LUCENTIS) BEVACIZUMAB (AVASTIN) AFLIBERCEPT (EYLEA)

8 ANTI-VEGF-A DOSING STRATEGIES USED IN CLINICAL TRIALS TO OPTIMIZE OUTCOMES AND MANAGE namd DISEASE MONTHLY - ANCHOR - MARINA - CATT - HARBOR PRN - SAILOR - CATT - HARBOR TREAT AND EXTEND - LUCAS - TREX - ALTAIR

9 CONTINUOUS FIXED MONTHLY DOSING: VISUAL ACUITY FROM BASELINE THROUGH MONTH 24 MARINA 1 MONTHS MONTHS ANCHOR 2 VIEW 1 and Rosenfeld PJ et al. N Engl J Med. 2006;355: Brown DM et al. N Engl J Med. 2006;355: Heier JS et al. Ophthalmology. 2012;119:

10 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

11 CONSEQUENCES OF OVERTREATMENT E X PENSE: D I R E CT A ND I NDIRECT COSTS I NCONVENIENCE: FREQUENT VISITS INCREASED R I S K (CUMULATIVE) INFECTION SUSTAINED IOP ELEVATION/GLAUCOMA

12 INDIVIDUALIZED ANTI-VEGF TREATMENT WHY? HOW? GOALS AVOID OVERTREATMENT SAFER MORE COST-EFFECTIVE PRN (AS NEEDED) TREAT-AND-EXTEND SUPPRESS CNV GROWTH, EXUDATION FREQUENT OCT IMAGING WITH ZERO TOLERANCE

13 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):

14 UNDERTREATMENT COMPROMISES VISUAL ACUITY POSITIVE CORRELATION OF VA GAINS AND NUMBER OF ANTI-VEGF-A INJECTIONS OVER 12 MONTHS MANY PATIENTS RECEIVE FEWER INJECTIONS 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:

15 PATIENTS RECEIVE: PRO RE NATA (PRN) DOSING A SERIES OF MONTHLY LOADING INJECT IONS OF ANTI - VEGF T HERAPY R E G ULAR O F F I CE VISITS F O R A S SESSMENT O F VISUAL ACUITY A NATO MIC MEASURES B A SED O N O CT, FA O R OT HER I MAG I NG MODALITIES

16 POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN A L LO WS FOR R E CURRENCE O F NEOVA S CULAR L E A K AG E A ND G R O WTH MULTIPLE R E CURRENCES L E A D S TO PROGRESSION O F DISEASE P O O R E R LO NG -TERM VISUAL O U TCOMES I N SOME PAT I E NTS Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1.

17 TREAT-AND-EXTEND DOSING: WHAT IS IT? SERIES OF LOADING ANTI - VEGF INJECTIONS, (TYPICALLY 4 - WK INTERVALS), WITH VA A ND A NATO MIC A S SESSMENT WHEN CRITERIA I NDICAT ING NO DISEASE ACTIVITY A R E MET, PAT I E NTS R E CEIVE A N INJECTION; T R E AT MENT I NTERVA L I S E X T E NDED, U S U A L LY B Y 2 WEEKS AT A T IME, UNTIL MAXIMUM INTERVAL OF WEEKS IS REACHE D IF CNV L E S IONS A R E R E ACTIVAT ED, T R E AT MENT I NTERVA L I S R E D U CED Spaide R. Am J Ophthalmol. 2007;144:

18 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:

19 CURRENT UNMET NEEDS IN namd

20 Mean Changei in ETDRS BCVA NEOVASCULAR AMD ANTI-VEGF A BLOCKADE /63 20/ Months ANCHOR, MARINA, HARBOR, CATT, VIEW1/2 Brown DM, et al. Ophthalmology Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355: ; Ho AC, et al. Ophthalmology Nov;121(11): ; Martin DF, et al. Ophthalmology. 2012; 119(7): ; Heier JS, et al. Ophthalmology Dec;119(12):

21 Mean Changei in ETDRS BCVA NEOVASCULAR AMD SHORTCOMINGS OF VEGF-A BLOCKADE 20/ >70% VA REMAINS TO BE GAINED 15 20/ #1 EFFICACY MONTHS Brown DM, et al. Ophthalmology Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355: ; Ho AC, et al. Ophthalmology Nov;121(11): ; Martin DF, et al. Ophthalmology. 2012; 119(7): ; Heier JS, et al. Ophthalmology Dec;119(12):

22 20/200

23 20/200 #2 Durability X 8 20/40

24 Mean Change in ETDRS BCVA ANTI-VEGF-A TREATMENT OF namd - PROSPECTIVE FIXED OR PRN DOSING 15 ANCHOR, MARINA, HARBOR, CATT, VIEW1/2 Injections Mean = 10.2 Range = MARINA 0.5 mg ANCHOR (0.5 mg) Mean = 8.4 HARBOR 0.5 mg Monthly CATT Ranibizumab Monthly HARBOR 0.5 mg PRN CATT Bevacizumab Monthly CATT Ranibizumab PRN CATT Bevacizumab PRN VIEW1 (0.5q4) Months VIEW1 (2q8) VIEW1 (2q4) VIEW2 (0.5q4) VIEW2 (2q8) Brown DM, et al. Ophthalmology Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355: ; Ho AC, et al. Ophthalmology Nov;121(11): ; Martin DF, et al. Ophthalmology. 2012; 119(7): ; Heier JS, et al. Ophthalmology Dec;119(12): VIEW2 (2q4)

25 Mean Changei in ETDRS BCVA ANTI-VEGF-A TREATMENT OF namd - PROSPECTIVE TREAT & EXTEND DOSING 15 LUCAS, TREND, TREX-AMD Injections Mean = 8.9 Range = Mean = Months LUCAS Ranibizumab LUCAS Bevacizumab TREND TREX AMD Berg K, et al. Ophthalmology Jan;122(1):146-52; Silva R, et al. Ophthalmology Jan;125(1):57-65; Wykoff CC, et al. Ophthalmology Dec;122(12):

26 Proportion of patients (%) REAL-WORLD DATA: MAJORITY OF namd PATIENTS LIKELY UNDERTREATED 1 ST YEAR OF MANAGEMENT 73% 5 injections LUMINOUS (n=250) (n=287) 3 (n=661) 4 (n=412) 5 (n=455) 6 (n=396) (n=322) (n=199) (n=173) (n=97) (n=72) (n=35) (n=17) 14 (n=2) 15 (n=1) Number of ranibizumab injections up to Month 12 Holz FG, et al. Presented at: EURetina 2017; September 7-10, 2017; Barcelona, Spain.

27 KEY POINTS & ISSUES WITH CURRENT ANTI-VEGF-A THERAPY U P P E R L I M I T F O R VA ~ 9 L E T T E R S F O R n A M D I M P R O V E M E N T S I N VA A P P E A R D E P E N D E N T U P O N NUMBER OF INTRAVITREAL INJECTIONS CLOSE MANAGEMENT OF ANATOMICAL CHANGES AV O I D U N D E R T R E AT M E N T 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 P O S S I B I L I T Y TO I N D I V I D U A L I Z E T R E AT M E N T W I T H P R N O R TA E >12 WEEK TREATMENT INTERVAL POSSIBLE IN ~25-50% OF PATIENTS N E W T R E AT M E N T M O D A L I T I E S I N C L U D I N G C O M B I N AT I O N T H E R A P Y A R E N E E D E D TO I M P R O V E V I S I O N A N D / O R D U R A B I L I T Y O F R E S P O N S E VEGF-A JUST ONE MOLECULAR PATHWAY IN THE PATHOGENESIS OF namd Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1.

28 VEGF-C/D VEGF-C/D INTO THE ADDITIONAL ANTI-VEGF AGENTS BROLUCIZUMAB & ABICIPAR DUAL-TARGETING FARICIMAB (RG7716) FUTURE VEGF-C/D BLOCKADE: OPT-302 MOONSHOTS GENE THERAPY STEM CELLS DROPS PILLS Extra-Cellular Domains 1-3 hvegfr-3 DRUG DELIVERY APPROACHES higg1 Fc

29 COMPARISON OF CURRENT VS EMERGING ANTI-VEGF-A AGENTS Format Bevacizumab a Ranibizumab Aflibercept Brolucizumab b Abicipar pegol b Full antibody (IgG1) Monoclonal humanized antibody fragment VEGFR-1/2-Fc fusion protein Single-chain antibody fragment (scfv) Designed ankyrin repeat protein (DARPin) 1 Molecular structure Molecular weight 149 kda 48 kda 115 kda 26 kda 34 kda Clinical dose for namd 1.25 mg (unlicensed use) 0.5 mg 2.0 mg 6.0 mg 2.0 mg a Off-label; not FDA-approved for any ocular indications b Under investigation for treatment of namd 1. Molecular Partners. Accessed 7/17/18.

30 BROLUCIZUMAB: PHASE 3 STUDY DESIGN Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018.

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

32 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

33 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 2Q8 2Q12 RQ4 Week BL Abicipar pegol 2 mg Ranibizumab 0.5 mg Sham treatme No treatment PRIMARY ENDPOINT n = 900 (1:1:1) 1. ClinicalTrials.gov ClinicalTrials.gov.

34 CEDAR PRIMARY ENDPOINT: STABLE VISION AT WK 52 ABICIPAR Q8WK AND Q12WK NONINFERIOR TO RBZ Q4WK RBZ, ranibizumab Allergan. 7/19/18. Accessed 7/22/18.

35 INCIDENCE OF INTRAOCULAR INFLAMMATION EVENTS SEQUOIA STUDY 15.7% 15.3% 0.6% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CEDAR STUDY Intraocular Inflammation Events 15.1% 15.4% 0.0% Abicipar Q8 Abicipar Q12 Ranibizumab Q4 Intraocular Inflammation Events Allergan. 7/19/18. Accessed 7/22/18.

36 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. Accessed 6/7/ Helzner J. Retinal Physician. 1/18/17. Accessed 6/15/18.

37 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:

38 AVENUE:PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL STUDY TREATMENT FINAL VISIT TOTAL N = 273 PATIENTS* AGE 50 YEARS TREATMENT-NAÏVE NAMD SUBFOVEAL CNV LESION BCVA 20/40 20/320 (73 24 ETDRS LETTERS) R 6.0 MG FARICIMAB 1.5 MG FARICIMAB 0.5 MG RANIBIZUMAB PRIMARY ENDPOINT SHAM 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.

39 Adjusted Mean BCVA Change From Baseline, ETDRS Letters AVENUE: MEAN CHANGE IN BCVA FROM BASELINE TO WEEK letters letters letters letters letters Time, Weeks 6.0 mg faricimab Q4W 6.0 mg faricimab Q4W/Q8W 1.5 mg faricimab Q4W 0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W 0.5 mg ranibizumab Q4W LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE BCVA CHANGE FROM BASELINE, ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT ). 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.

40 Adjusted Mean CST Change From Baseline, µm AVENUE: MEAN CHANGE IN CST FROM BASELINE TO WEEK μm 156 μm 172 μm 175 μm 185 μm Time, Weeks 6.0 mg faricimab Q4W 6.0 mg faricimab Q4W/Q8W 1.5 mg faricimab Q4W 0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W 0.5 mg ranibizumab Q4W LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE CST CHANGE FROM BASELINE. ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT ). 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.

41 STAIRWAY: PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL Study Treatment Final Visit Total N = 76 patients* Q16W dosing Age 50 years Treatment-naïve namd Subfoveal CNV lesions R Active disease at Week 24 Q12W dosing BCVA 20/40 20/320 (73 24 ETDRS letters) Q4W dosing Time, Weeks Prespecified disease assessment at Week mg faricimab 0.5 mg ranibizumab Primary endpoint 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.

42 BCVA OUTCOMES WITH Q16W AND Q12W FARICIMAB WERE COMPARABLE TO Q4W RANIBIZUMAB 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.

43 CONCLUSIONS 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)

44 Beyond anti-vegf-a for Retinal Diseases New York City, KOL Forum, November Megan Baldwin PhD, CEO & Managing Director

45 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

46 Financial Disclosures Consultant For Regeneron, Genentech, Shire, Zeiss, Optos, Allergan Sponsored Researched Apellis, Genentech/Roche, Regeneron, Alcon/Novartis Cole Eye Institute

47 How Common Is Diabetes? Age-adjusted Prevalence of Diagnosed Diabetes in US Adults 1,2 <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% Centers for Disease Control and Prevention. Accessed March 5, Centers for Disease Control and Prevention. Accessed March 5, Cole Eye Institute

48 Future Prevalence Projections Of Diabetes Percent of Total Population With Diabetes (Diagnosed and Undiagnosed) 7%-8% 9%-11% 12%-14% 15%-17% 18%-20% Rowley et al. Popul Health Manag. 2017;20:6. Cole Eye Institute

49 Diabetes Is Associated With Serious Comorbidities Diabetic retinopathy % in patients aged % have diabetic macular edema (DME) 2 Stroke per 1000 persons with diabetes Diabetic nephropathy % in diabetic patients Ischemic Heart Disease per 1000 persons with diabetes Diabetic neuropathy 1 60%-70% in diabetic patients 1. Centers for Disease Control and Prevention Accessed June 11, Varma, et al Joint Meeting of the American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology; November 10-13, 2012; Chicago, IL. Poster PO United States Renal Data System atlas of CKD and ESRD. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Accessed February 7, Centers for Disease Control and Prevention National Diabetes Statistics Report. Accessed July 10, Cole Eye Institute

50 Chronic Hyperglycemia Initiates a Number of Inter-related Pathways that Lead to DME Microvascular damage Leukostasis Pericyte loss Endothelial damage DME Inflammation AGEs ROS ICAM PKC activation Nitric oxide Polyols Eicosanoids VEGF overexpression Boyer DS, et al. Ther Adv Endocrinol Metab. 2013;4(6): AGEs = advanced glycation end-products ICAM = intercellular adhesion molecule PKC = protein kinase C; ROS = reactive oxygen species Cole Eye Institute

51 Current Approved and Off-label Therapies for Diabetic Macular Edema Approved Treatments Anti-VEGF Lucentis Genentech/Roche Eylea Regeneron Steroid Ozurdex Allergan Unapproved Treatments Anti-VEGF Avastin Genentech/Roche Steroid Triamcinolone Triescence - Alcon Iluvein Alimera Cole Eye Institute

52 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

53 Anti-VEGF-A has limited efficacy CLINICAL TRIAL TREATMENT DOSAGE(S) UNDER STUDY RISE RIDE DRCR PROTOCOL I ranibizumab ranibizumab ranibizumab + prompt laser ranibizumab + deferred laser NUMBER OF PATIENTS 15-LETTER BCVA INCREASE AT 1 YEAR (%) 0.3 mg % 0.5 mg % 0.3 mg % 0.5 mg % 0.5 mg ranibizumab clinical trial conditions, % + focal / grid laser meaningful 3-10 days after visual first IVT acuity 0.5 mg ranibizumab increases are only achieved % + focal / grid laser 24 weeks after first IVT BOLT bevacizumab 1.25 mg 42 12% VISTA* VIVID* aflibercept aflibercept Even when treatment regimens are optimized under by 30% to 45% of DME patients 2 mg every 4 weeks % 2 mg every 8 weeks* % 2 mg every 4 weeks % 2 mg every 8 weeks* % *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): ; Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Ophthalmology. 2014;121(11): Michaelides M, Kaines A, Hamilton RD, et al. Ophthalmology. 2010;117(6): ; Nguyen QD, Brown DM, Marcus DM, et al. Ophthalmology. 2012;119(4): Cole Eye Institute

54 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 Response Improvement* at 16 Weeks Early and Consistent Early but Inconsistent Slow and Variable No Response Improvement* at 32 Weeks and/or 1 Year % of Patients 49.6% n=143/ % n=43/ % n=36/ % n=66/288 = 50.4% Non responders * OCT thickness decreased 20% from baseline. Bressler SB, et al. Arch Ophthalmol Cole Eye Institute

55 We Know Very Quickly Whether or Not Patients Will Respond to Anti-VEGF-A BCVA Change from Baseline p< BL Weeks <5 letters at 12w (N=135) 5-9 letters at 12w (N=79) 10 letters at 12w (N=126) Am J Ophthalmol Dec;172: 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

56 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

57 Anti-PLGF: THR-317 (Thrombogenics) PGF (pg/ml) PlGF expression is elevated in hypoxic human RPE cells in vitro PlGF is elevated in aqueous humour in patients with DME and PDR PGF is elevated in aqueous humour in patients with DME and PDR Vitreous PlGF and VEGF-A are elevated 3x and 1.8x respectively in patients with active PDR compared to quiescent PDR ** Phase 1/2: 49 patients, including anti- VEGF-A naïve patients as well as suboptimal anti-vegf-a responders 30% of the anti-vegf-a treatment naïve study subjects treated with THR-317 in the 8mg group showed a > or equal to 15 letter gain from baseline at Day 90 versus 5.3 % in the 4mg group Phase 2 clinical study by Q Not detected *** Control DME PDR 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): ; Martinsson-Niskanen et al; 2011 Clinical Therapeutics 33: Cole Eye Institute

58 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

59 Faricimab (RG7716) Molecular Structure Cole Eye Institute

60 BOULEVARD Trial Cole Eye Institute

61 Secondary endpoints from the BOULEVARD Study Cole Eye Institute

62 Secondary endpoints from the BOULEVARD Study Cole Eye Institute

63 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

64 TIME-2 tested AKB-9778 alone and in combination with Lucentis 15 mg AKB-9778 subcutaneous BID 3 SHAM injections q4 56-day observation period, with LUCENTIS treatment allowed as needed N=144 R 1:1:1 15 mg AKB-9778 subcutaneous BID 3 doses intravitreal LUCENTIS (0.3 mg) q4 PLACEBO subcutaneous BID 3 doses intravitreal LUCENTIS (0.3 mg) q4 STUDY VISITS 65 Intravitreal LUCENTIS injection Sham injection Cole Eye Institute

65 CST Reduction (µm) AKB Lucentis significantly reduced retinal thickness compared to Lucentis alone, Change in CST from Baseline to Month AKB-9778 (N=46) Lucentis (N=47) AKB Lucentis (N=48) Baseline Month 1 Month2 Month 3 p = Cole Eye Institute

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

67 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 preexisting VEGF-A load Cole Eye Institute

68 Phase 2b DEL MAR Stage 1: Primary and Secondary Endpoints Were Met (n=136) Primary Endpoint Mean BCVA non-inferiority at study week 20 ( 3 letters) Secondary Endpoint Mean OCT CMT non-inferiority at study week 20 ( 30µ) NO LUMINATE DOSING NO LUMINATE DOSING Cole Eye Institute

69 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

70 Beyond anti-vegf-a for Retinal Diseases New York City, KOL Forum, November Megan Baldwin PhD, CEO & Managing Director

71 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

72 Financial Disclosures Consultant for: Alimera Sciences, Genentech, Regeneron, Regenerative Patch Technologies Speaker for: Genentech, Notal Vision, Regeneron Research Funding: Genentech, Zeiss

73 VEGF-A Inhibition Upregulates VEGF-C/D Aqueous Humor VEGF-C (pg/ml) Aflibercept Ranibizumab Bevacizumab VEGF-B PlGF VEGF-A VEGF-C VEGF-D VEGFR-1 VEGFR-2 VEGFR-3 OPT-302 OPT-302 (anti-vegf-c/-d): Inhibits angiogenesis & vascular leakage Overcomes escape mechanism to VEGF-A suppression Neovascular AMD Patients % Baseline 1m 2m Angiogenesis Vascular Permeability Angiogenesis Lymphangiogenesis Bevacizumab Bevacizumab Ligand Ig-like domain Kinase domain Pathway blocked by OPT-302 ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144

74 VEGF-C/D VEGF-C/D OPT-302 a Novel Trap Inhibitor of VEGF-C/D OPT-302 A trap molecule that binds & neutralises the activity of VEGF-C/-D, blocking their activation of receptors VEGFR- 2 and VEGFR-3 Potent inhibitor of VEGF-C (~5pM) and VEGF-D (~0.5 nm) OPT-302 Inhibition of CNV in Rodent Model of AMD Control OPT % 78% 91% Extra-Cellular Domains 1-3 hvegfr-3 Aflibercept OPT Aflibercept * higg1 Fc * Pairwise comparison: OPT-302 vs Aflibercept + OPT-302 (p<0.02) 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

75 OPT-302 Phase 1b/2a First-in-Human Study in namd Patients (n=51) 28 Day DLT window Follow-up to week 12 Long Primary term follow-up Analysis after at Week all 24 subjects complete 12 weeks Part 1: Dose-escalation (Open-label) Part 2: Dose-expansion (Randomised 3:1) OPT-302 (2 mg) Monotherapy* IVT Q4W x 3 OPT-302 (2 mg) Monotherapy* IVT Q4W x 3, n=8 pts Cohort 4 OPT-302 (2 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 OPT-302 (2 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3, n=23 pts OPT-302 (1 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 Cohort 3 OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 Cohort 2 Cohort 1 Comprises of 4 treatment cohorts of 5 subjects each *Access to rescue anti-vegf-a Tx ClinTrials Identifier NCT

76 Treatment Groups Wet AMD Patients N=51 OPT ranibizumab Combination Therapy N=38 OPT-302 Monotherapy N=13 Treatment Naïve N=18 Prior-Treated with anti-vegf-a N=20 Treatment Naïve N=7 Prior-Treated with anti-vegf-a 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

77 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

78 Summary of Adverse Events Reported in 5% of all Subjects OPT-302 (0.3 mg) + RBZ (0.5 mg) (n=5) OPT-302 (1 mg) + RBZ (0.5 mg) (n=5) OPT-302 (2 mg) + RBZ (0.5 mg) (n=28) OPT-302 (2 mg) Monotherapy (n=13) Total Number of Subjects (N=51) Total pts with at least one AE (79%) Total pts with at least 1 Ocular AE (69%) Ocular AEs Conjunctival Haemorrhage (39%) Punctate Keratitis (22%) Eye pain (22%) Retinal haemorrhage (8%) Eye irritation (6%) Ocular discomfort (6%) Vitreous floaters (6%) Total pts with at least 1 Non-Ocular AE (45%) Non-Ocular AEs Nasopharyngitis (6%)

79 Mean (+SD) OPT-302 Serum Concentrations (ng/ml) OPT-302 Serum Pharmacokinetic Profile (± Ranibizumab) Mean OPT-302 serum concentrations OPT-302 Monotherapy (2 mg) Combination OPT-302 (2 mg) + Ranibizumab (0.5 mg) Non-compartmental OPT-302 PK analysis indicated: low systemic exposure a half-life of 8 ± 2 days mean C max 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 Intravitreal OPT-302 (2 mg) (± 0.5 mg ranibizumab) C max (ng/ml) T max (hours) AUC 0 last (ng h/ml) T 1/2 (days) Mean ± SD (n) 21.1 ± 17.3 (n = 41) 31 ± 24 (n = 41) 2760 ± 1110 (n = 30) 8 ± 2 (n = 10) Time (hours)

80 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 +4.4 letters letters Anti-VEGF-A (ranibizumab) rescue therapy criteria: <10% decrease in CST and 5 letter loss of BCVA 7/13 (56%) patients (4 treatment-naïve, 3 prior treated) did not require rescue therapy through week 12 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

81 OPT Ranibizumab: Gains in BCVA & Reduced Retinal Thickness Change from baseline in Visual Acuity (ETDRS Letters) Change from baseline in CST (µm) Change in mean BCVA Change in mean Central Subfield Thickness 15 Naïve pts (n=18) Prior treated pts (n=20) 0 Time (weeks) letters µm letters µm Time (weeks) Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg) Mean Baseline VA = 56.5 Letters Naïve pts (n=18) Prior treated pts (n=20) Prior-Treated Patients: n = 20 (wk 4, 8), 19 (wk 12); OPT-302 ( mg) + ranbizumab (0.5 mg) Mean Baseline VA = 64.5 Letters

82 OPT Ranibizumab: Gains in BCVA & Reduced Retinal Thickness CNV Size (mm 2 ) % Patients with Absent CNV on FA Reduction in CNV size on FA % Patients with absent CNV on FA % % %* 0 Baseline Week 4 Week 12 OPT Ranibizumab 0 Baseline Week 4 Week 12 OPT Ranibizumab Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg); * Absent on FA, present on OCT

83 Case Study Naïve Patient (Occult): OPT Ranibizumab Baseline Week 4 Week 12 VA: 53 letters VA: 64 letters VA: 73 letters CNV: 3.11 mm 2 CNV: 2.91 mm 2 CNV: 0 mm 2 CST: 279 µm SRF: 192 µm SHRMw: 1053 µm SHRMh: 94 µm CST: 217 µm SRF: 0 µm SHRMw: 0 µm SHRMh: 0 µm CST: 233 µm SRF: 0 µm SHRMw: 0 µm SHRMh: 0 µm OPT-302 (2 mg) + ranbizumab (0.5 mg)

84 Case Study Prior Treated Patient (Occult): OPT 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 mm 2 CNV: 5.28 mm 2 CNV: 8.04 mm 2 CST: 303 µm SRF: 140 µm SHRMw: 1042 µm SHRMh: 133 µm CST: 249 µm SRF: 41 µm SHRMw: 0 µm SHRMh: 0 µm CST: 248 µm SRF: 0 µm SHRMw: 0 µm SHRMh: 0 µm OPT-302 (2 mg) + ranbizumab (0.5 mg)

85 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.

86 Beyond anti-vegf-a for Retinal Diseases New York City, KOL Forum, November Megan Baldwin PhD, CEO & Managing Director

87 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

88 OPT-302 Clinical Program Two ongoing randomised controlled clinical trials in namd & DME Neovascular AMD Combination Agent Preclinical Phase 1 Phase 2a Phase 2b Phase 3 Status 1 o Data Analysis OPT-302 Target: VEGF-C/D OPT-302 Target: VEGF-C/D Ranibizumab Target: VEGF-A Ranibizumab Target: VEGF-A Complete Ph 1/2a (n=51) April 2017 Ongoing Ph 2b (n=351) Early 2020 Diabetic Macular Edema OPT-302 Target: VEGF-C/D Aflibercept Target: VEGF-A, PlGF, VEGF-B Ongoing Ph 1b/2a (n=117)

89 Week 24 Follow-up OPT-302 +/- Ranibizumab Phase 2b Trial in Treatment-Naïve namd (n=351) OPT-302 (2 mg) + Ranibizumab (0.5 mg) n=117 Treatment-Naive Neovascular AMD OPT-302 (0.5 mg) + Ranibizumab (0.5 mg) n=117 Sham + Ranibizumab (0.5 mg) n=117 Randomized 1:1:1 to treatment arms IVT dosing at every 4 weeks (x 6) 90 Currently enrolling Primary data analysis early 2020 ClinTrials Identifier NCT

90 14 Day DLT window Follow-up to week 12 PRN anti-vegf-a Week 12 to 24 Primary Analysis after all subjects complete 12 weeks Phase 1b Dose Escalation study of OPT Aflibercept in DME Phase 1b Dose-Escalation N=9 patients Phase 2a Dose-Expansion (Randomised 2:1 ratio) N= OPT-302 (1.0 mg) + Aflibercept (2.0 mg) IVT Q4W x 3, n=3 OPT-302 (2.0 mg) + Aflibercept (2.0 mg) IVT Q4W x 3, n=3 Cohort 3 OPT-302 (2.0 mg) + Aflibercept (2.0 mg) IVT Q4W x 3, n=~72 pts Aflibercept (2.0 mg) IVT Q4W x 3, n=~36 pts Cohort 2 OPT-302 (0.3 mg) + Aflibercept (2.0 mg) IVT Q4W x 3, n=3 Cohort 1 ClinTrials Identifier NCT Key Inclusion Criteria Age 18 years; centre-involving DME CST 335 µm* BCVA ETDRS letters (20/40 20/320 Snellen Prior exposure to anti-vegf-a therapy with sub-optimal therapeutic response 3 intravitreal injections Last injection 6 wks prior to study day 1 Prior bevacizumab only allowed if switched to IVT aflibercept or ranibizumab prior to study * CST as measured by Spectralis (Heidelberg) at screening, 320 µm for Cirrus. Key Exclusion Criteria HbA1c 12% Uncontrolled hypertension 180 mmhg systolic or 110 mmhg diastolic Eyes needing PRP within 3 months of screening Concurrent / prior use of intravitreal injections of steroids within 4 months of study start Concurrent / prior use of dexamethasone or fluocinolone implant in study eye

91 OPT 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 92 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 Aflibercept Safety Summary of selected AEs Selected Adverse Events: Ocular or Systemic OPT-302 (0.3 mg) + Aflibercept (2.0 mg) (n=3) OPT-302 (1 mg) + Aflibercept (2.0 mg) (n=3) OPT-302 (2 mg) + Aflibercept (2.0 mg) (n=3) Total Number of Subjects (N=9) 93 Intraocular inflammation Endophthalmitis Retinal detachment Vitreous hemorrhage Hypertension 1* 0 0 1* APTC events # Nonfatal myocardial infarction Nonfatal stroke Vascular or cardiac death or death of unknown cause Combined APTC events Any other death 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) # APTC = Antiplatelet Trialists' Collaboration *Determined by treating investigator as unrelated to study drug(s) No safety signals or unexpected findings

93 Mean Change from baseline in BCVA (Letters) 2 0 OPT Aflibercept: Gains in BCVA at Week 12 Dose Response Relationship Dose of OPT Aflibercept (2 mg) % of pts with BCVA gain 5 letters Mean # prior anti-vegf-a injections 0.3 mg 1/3 (33%) 5 1 mg 2/3 (67%) mg 3/3 (100%) to 2 mg 6/9 (67%) (N=3) 0.3 mg OPT-302 (N=3) 1 mg OPT-302 (N=3) 2 mg OPT-302 (N=9) mg OPT Error Bars: SEM + 2 mg Aflibercept

94 Mean Change from Baseline in CST on SD-OCT (µm) OPT-302 (0.3-2 mg) + Aflibercept (2 mg): Mean changes in CST from Baseline to Week µm Week 95 Error Bars: SEM; Mean Baseline CST = 434 µm

95 Mean Change BCVA (Letters) Mean Change CST (µm) Percentage Patients DME Patients with Bilateral Disease* Study Eye vs Fellow Eye (N=5) Mean Change in BCVA Baseline to Week 12 Mean Change in CST (um) Baseline to Week 12 % Pts with 50% Reduction in Excess Foveal Thickness OPT Aflibercept Anti-VEGF-A Monotherapy OPT Aflibercept Anti-VEGF-A Monotherapy OPT Aflibercept Anti-VEGF-A Monotherapy % -6.0 µm % -80 µm *Patients with bilateral disease and persistent DME in the fellow eye receiving anti-vegf-a (ranibizumab or aflibercept) monotherapy Prior anti-vegf-a therapy in Fellow Eyes BL to Wk 12: 3x Aflibercept, 3x Ranibizumab, 1x Ranibizumab, 4x Ranibizumab, 3x Aflibercept 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 Study Eye: 0.3 2mg OPT mg Aflibercept Fellow Eye: Anti-VEGF-A Monotherapy*

96 OPT-302 Clinical Program Two ongoing randomised controlled clinical trials in namd & DME Neovascular AMD Combination Agent Preclinical Phase 1 Phase 2a Phase 2b Phase 3 Status 1 o Data Analysis OPT-302 Target: VEGF-C/D OPT-302 Target: VEGF-C/D Ranibizumab Target: VEGF-A Ranibizumab Target: VEGF-A Complete Ph 1/2a (n=51) April 2017 Ongoing Ph 2b (n=351) Early 2020 Diabetic Macular Edema OPT-302 Target: VEGF-C/D Aflibercept Target: VEGF-A, PlGF, VEGF-B Ongoing Ph 1b/2a (n=117)

97 Megan Baldwin, PhD CEO & Managing Director T +61 (3) M E megan.baldwin@opthea.com Suite 0403, Level 4, 650 Chapel Street, South Yarra 3141 Victoria Australia