Opthea Limited · ASX:OPT
Opthea — Investor Day (November 2018)
97 slides from Opthea's investor day presentation, Nov 6, 2018
Slide 1: 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
Slide 2: Neovascular AMD: Current Treatment Paradigms and Unmet Needs
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 AT E S C L I N I C A L A S S O C I AT E P R O F E S S O R U N
Slide 3: Objectives
OBJECTIVES ▪ PR ACT ICE S E T T I NG ▪ STA ND A R D OF CAR E DOSING ST R AT EGIES ▪ CL INICA L T R I A L S D ATA HI G HL I G HTING U NME T NE E D S ▪ NE W T R E AT MENT S ON T HE HOR IZ ON
Slide 4: Practice Setting
PRACTICE SETTING ▪ PR IVAT E O F F I CE B A S E D P R ACT I CE ▪ MU LTI SPE CIALT Y WIT H 2 R ET INAL PHYSICIANS ▪ 55 E MPLOYE ES TOTA L ▪ 7 T E CHNICIA NS , 3 R E S E A R CH CO O R D I NATO RS ▪ 1 5 - 20 ACT I VE CL I NI CA L T R I A L S ▪ 70 PAT IE NT S A D AY O N AVE R AG E ▪ A PPR OXIMATELY 50 0
Slide 5: Angiogenesis in Age-Related Macular Degeneration
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; Da
Slide 6: Current Paradigm – Block VEGF-A
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):
Slide 7: Current Anti-VEGF-A Therapies for nAMD
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)
Slide 8: Anti-VEGF-A Dosing Strategies Used in Clinical Trials
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
Slide 9: Continuous Fixed Monthly Dosing: Visual Acuity
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.
Slide 10: Continuous Monthly Dosing
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 S
Slide 11: Consequences of Overtreatment
CONSEQUENCES OF OVERTREATMENT ▪ E X PE NSE : D I R E CT A ND I ND I R ECT CO S T S ▪ I NCO NVENIENCE: FR EQUENT VISIT S ▪ INCR E A SE D R I S K (CU MULATI VE ) ▪ INFECTION ▪ SUSTAINED IOP ELEVATION/GLAUCOMA
Slide 12: Individualized Anti-VEGF Treatment
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
Slide 13: PRN Dosing in HARBOR
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.
Slide 14: Undertreatment Compromises Visual Acuity
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 &
Slide 15: Pro Re Nata (PRN) Dosing
PRO RE NATA (PRN) DOSING PATIENTS RECEIVE: ▪ A SE R I E S OF MONT HLY LOADING INJ ECT IONS OF ANT I - VEGF T HER APY ▪ R E G ULA R O F F I CE VI S I T S F O R A S S E S S MENT O F VI S U A L ACU I T Y ▪ A NATO MIC ME A S U RE S B A S E D O N O CT, FA O R OT HE R I MAG I NG MO D A L ITI ES
Slide 16: Potential Limitations of Discontinuous PRN
POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN ▪ A L LO WS FO R R E CU R R E NCE O F NE OVA S CULA R L E A K AG E A ND G R O WT H ▪ MULTIPLE R E CU R R ENCES L E A D S TO P R O G R ES SIO N O F D I S E A S E ▪ P O O R E R LO NG -TER M VI S U A L O U TCO MES I N S O ME PAT I E NTS Wai KM et al. Am J Opht
Slide 17: Treat-and-Extend Dosing: What Is It?
TREAT-AND-EXTEND DOSING: WHAT IS IT? ▪ SE R I E S O F LOADING ANT I - VEGF INJ ECTIONS, (T YPICALLY 4 - WK INT ER VAL S), WIT H VA A ND A NATO MI C A S S E S S MENT ▪ WHE N CR IT E R IA I ND I CAT ING NO D I S E A S E ACT I VI T Y A R E ME T, PAT I E NTS R E CE IVE A N I NJ E CTIO N; T R E AT MENT I
Slide 18: Benefits of Treat-and-Extend Dosing
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
Slide 19: Current Unmet Needs in nAMD
CURRENT UNMET NEEDS IN nAMD
Slide 20: Neovascular AMD Anti-VEGF-A Blockade
NEOVASCULAR AMD ANTI-VEGF A BLOCKADE 15 10 20/63 Mean Changei in ETDRS BCVA 5 20/100 0 0 6 12 18 24 +25 -5 -10 -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. Ophthalmo
Slide 21: Shortcomings of VEGF-A Blockade: Efficacy
NEOVASCULAR AMD – SHORTCOMINGS OF VEGF-A BLOCKADE 20/20 35 25 >70% VA REMAINS TO BE GAINED Mean Changei in ETDRS BCVA 15 5 20/100 0 6 12 18 24 -5 -15 #1 EFFICACY -25 MONTHS 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.
Slide 22: 20/200
20/200
Slide 23: #2 Durability
20/200 #2 Durability X8 20/40
Slide 24: Anti-VEGF-A Treatment of nAMD – Fixed or PRN Dosing
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 Mean Change in ETDRS BCVA 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 CATT Bevacizuma
Slide 25: Anti-VEGF-A Treatment of nAMD – Treat & Extend Dosing
ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE TREAT & EXTEND DOSING LUCAS, TREND, TREX-AMD 15 Injections Mean = 8.9 Range = 8.0-10.1 Mean Changei in ETDRS BCVA 10 10.5 Mean = 8.6 6.6 5 LUCAS Ranibizumab 0 LUCAS Bevacizumab 0 3 6 9 12 TREND Months TREX AMD Berg K, et al. Ophthalmology. 2015 Jan;122(1):
Slide 26: Real-World Data: Majority of nAMD Patients Likely Undertreated
REAL-WORLD DATA: MAJORITY OF nAMD PATIENTS LIKELY UNDERTREATED 1ST YEAR OF MANAGEMENT ≈73% ≤ 5 injections LUMINOUS 19.6 Proportion of patients (%) 20 15 13.5 12.2 11.7 9.5 10 8.5 7.4 5.9 5.1 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=39
Slide 27: Key Points & Issues with Current Anti-VEGF-A Therapy
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
Slide 28: Into the Future
ADDITIONAL ANTI-VEGF AGENTS DUAL-TARGETING BROLUCIZUMAB & ABICIPAR FARICIMAB (RG7716) INTO THE FUTURE VEGF-C/D BLOCKADE: OPT-302 MOONSHOTS VEGF-C/D VEGF-C/D Extra-Cellular Domains 1-3 DRUG DELIVERY ▪ GENE THERAPY hVEGFR-3 APPROACHES ▪ STEM CELLS ▪ DROPS ▪ PILLS hIgG1 Fc
Slide 29: Comparison of Current vs Emerging Anti-VEGF-A Agents
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 Molec
Slide 30: Brolucizumab: Phase 3 Study Design
BROLUCIZUMAB: PHASE 3 STUDY DESIGN Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018.
Slide 31: Brolucizumab Was Non-Inferior to Aflibercept
BROLUCIZUMAB WAS NON-INFERIOR TO AFLIBERCEPT Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018
Slide 32: Brolucizumab Superior Reductions in Central Subfield Thickness
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
Slide 33: Abicipar Pegol: Phase 3 CEDAR and SEQUOIA Study Design
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
Slide 34: CEDAR Primary Endpoint: Stable Vision at Week 52
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.
Slide 35: Incidence of Intraocular Inflammation Events
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/e
Slide 36: Port Delivery System with Ranibizumab: How Does It Work?
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
Slide 37: Faricimab Overview: First Bispecific Antibody for Intraocular Use
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.
Slide 38: AVENUE: Phase 2 Clinical Trial
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
Slide 39: AVENUE: Mean Change in BCVA
AVENUE: MEAN CHANGE IN BCVA FROM BASELINE TO WEEK 36 15 Adjusted Mean BCVA Change From Baseline, ETDRS Letters + 9.1 letters 10 + 7.6 letters + 7.2 letters + 6.0 letters 5 + 5.9 letters 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
Slide 40: AVENUE: Mean Change in CST
AVENUE: MEAN CHANGE IN CST FROM BASELINE TO WEEK 36 0 Adjusted Mean CST Change -100 – 147 μm From Baseline, µm – 156 μm – 172 μm – 175 μm -200 – 185 μm -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/Q8
Slide 41: STAIRWAY: Phase 2 Clinical Trial
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 1
Slide 42: BCVA Outcomes with Q16W and Q12W Faricimab
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,
Slide 43: Conclusions
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 DURA
Slide 44: 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
Slide 45: Beyond Anti-VEGF-A for Diabetic Macular Edema
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
Slide 46: Financial Disclosures
Financial Disclosures ● Consultant For Regeneron, Genentech, Shire, Zeiss, Optos, Allergan ● Sponsored Researched – Apellis, Genentech/Roche, Regeneron, Alcon/Novartis Cole Eye Institute
Slide 47: How Common Is Diabetes?
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.
Slide 48: Future Prevalence Projections Of Diabetes
Future Prevalence Projections Of Diabetes Percent of Total Population With Diabetes (Diagnosed and Undiagnosed) 7%-8% 9%-11% 12%-14% 15%-17% 18%-20% 2020 2020 2025 2030 Rowley et al. Popul Health Manag. 2017;20:6. Cole Eye Institute
Slide 49: Diabetes Is Associated With Serious Comorbidities
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 Diabet
Slide 50: Chronic Hyperglycemia Pathways Leading to DME
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
Slide 51: Current Approved and Off-label Therapies for DME
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 ● Iluve
Slide 52: Why we need additional treatments
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
Slide 53: Anti-VEGF-A has limited efficacy
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
Slide 54: Patients With DME Categorized by Response to Anti-VEGF-A
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 ✓ ✓✗ ✓✗ ✗ Improv
Slide 55: We Know Very Quickly Whether Patients Will Respond
We Know Very Quickly Whether or Not Patients Will Respond to Anti-VEGF-A 20 BCVA Change from Baseline 16.5 15.2 13.8 15 10 6.9 8.2 8.2 p<0.001 5 2.8 3.0 0 -0.3 -5 BL 12 16 20 24 28 32 36 40 44 48 52 . .. … 68 . .. … 84 . .. … …. 104 . .. 120 . .. 136 . . . .. . … . …. 156 … … Weeks <5 letters 5-9 le
Slide 56: Targets for future DME treatment
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
Slide 57: Anti-PLGF: THR-317 (Thrombogenics)
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 100 Vitreous PlGF and VEGF-A are elevated 3x and 1.8x respectively in pati
Slide 58: Ang-2 Being Investigated In Two Studies
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 ve
Slide 59: Faricimab (RG7716) Molecular Structure
Faricimab (RG7716) Molecular Structure Cole Eye Institute
Slide 60: BOULEVARD Trial
BOULEVARD Trial Cole Eye Institute
Slide 61: Secondary endpoints from the BOULEVARD Study
Secondary endpoints from the BOULEVARD Study Cole Eye Institute
Slide 62: Secondary endpoints from the BOULEVARD Study
Secondary endpoints from the BOULEVARD Study Cole Eye Institute
Slide 63: Activating the Tie-2 Receptor Pathway - Aerpio
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
Slide 64: TIME-2 tested AKB-9778 alone and with Lucentis
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
Slide 65: AKB-9778 + Lucentis Reduced Retinal Thickness
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 CST Reduction (µm) AKB-9778 (N=46) -70 Lucentis (N=47) -91 -90 AKB-9778 + Lucentis (N=48) -102 -110 -110 -106 -130 p = 0.008 -150 -146 -164 -170 Ba
Slide 66: Integrin Inhibition for DME: Allegro - Risuteganib
Integrin Inhibition for DME: Allegro - Risuteganib Cole Eye Institute
Slide 67: Del Mar Phase 2b With Risuteganib (Luminate)
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
Slide 68: Phase 2b DEL MAR Stage 1: Endpoints Met
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
Slide 69: Conclusions
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
Slide 70: 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
Slide 71: Targeting a More Complete Blockade of VEGF: OPT-302 Phase 1b/2a Results
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
Slide 72: Financial Disclosures
Financial Disclosures Consultant for: • Alimera Sciences, Genentech, Regeneron, Regenerative Patch Technologies Speaker for: • Genentech, Notal Vision, Regeneron Research Funding: • Genentech, Zeiss
Slide 73: VEGF-A Inhibition Upregulates VEGF-C/D
VEGF-A Inhibition Upregulates VEGF-C/D Ranibizumab Aflibercept Bevacizumab Neovascular AMD Patients2 VEGF-B VEGF-C VEGF-A OPT-302 PlGF VEGF-D 10.00 OPT-302 (anti-VEGF-C/-D): 8.91 9.00 • Inhibits angiogenesis & Aqueous Humor VEGF-C (pg/ml) vascular leakage 8.00 6.91 • Overcomes escape mechanism 66% V
Slide 74: OPT-302 a Novel 'Trap' Inhibitor of VEGF-C/D
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- 2 and VEGFR-3 70% 78% • Potent inhibitor of VEGF-C (~5pM) and
Slide 75: OPT-302 Phase 1b/2a First-in-Human Study in nAMD Patients
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 24 Cohort 4 Follow-up to week 12 at Week 28 Day DLT window subjects c
Slide 76: Treatment Groups
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% trea
Slide 77: OPT-302 ± Ranibizumab Safety Results in nAMD
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 tox
Slide 78: Summary of Adverse Events Reported in ≥5% of Subjects
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
Slide 79: OPT-302 Serum Pharmacokinetic Profile
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 Mean (+SD) OPT-302 Serum Concentrations (ng/mL) Combination OPT-302 (2 mg) + Ranibizumab (0.5 mg) • a ha
Slide 80: Intravitreal OPT-302 (2 mg) Monotherapy
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 let
Slide 81: OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness
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) Change from baseline in Visual Acuity (ETDRS Letters) Prior treated pts (n=20) 0 2 4 6 8 10 12 0 Change from baseline in CST (µM) -20 +10.8
Slide 82: OPT-302 + Ranibizumab: Reduced CNV Size
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 % Patients with Absent CNV on FA 50 % 7 50 CNV Size (mm2) 6 40 5 3.74 30 27.8 % 4 3 20 2.03 2 1 10 5.6 %* 0 0 Baseline Week 4 Week 12 Baseline Week 4 Week 12 OPT-
Slide 83: Case Study Naïve Patient (Occult): OPT-302 + Ranibizumab
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 SHR
Slide 84: Case Study Prior Treated Patient (Occult): OPT-302 + Ranibizumab
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
Slide 85: Conclusion
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
Slide 86: 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
Slide 87: Disclaimer
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 ca
Slide 88: OPT-302 Clinical Program
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 Ranibizuma
Slide 89: OPT-302 Phase 2b Trial in Treatment-Naïve nAMD
OPT-302 +/- Ranibizumab Phase 2b Trial in Treatment-Naïve nAMD (n=351) OPT-302 (2 mg) + Ranibizumab (0.5 mg) n=117 Week 24 Follow-up Treatment-Naive OPT-302 (0.5 mg) + Ranibizumab (0.5 mg) n=117 Neovascular AMD Sham + Ranibizumab (0.5 mg) n=117 Randomized 1:1:1 to treatment arms IVT dosing at every
Slide 90: Phase 1b Dose Escalation of OPT-302 + Aflibercept in DME
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) 14 Day DLT window IVT Q4W x 3, n=3 IVT Q4W x 3, n=~72 pts Follow-up to w
Slide 91: OPT-302 + Aflibercept Safety Results
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 d
Slide 92: OPT-302 + Aflibercept Safety Summary of Selected AEs
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 End
Slide 93: OPT-302 + Aflibercept: Gains in BCVA at Week 12
OPT-302 + Aflibercept: Gains in BCVA at Week 12 Dose Response Relationship Mean Change from baseline in BCVA (Letters) +14.3 20 Dose of OPT-302 % of pts with Mean # prior + Aflibercept BCVA gain anti-VEGF-A 15 (2 mg) ≥ 5 letters injections 0.3 mg 1/3 (33%) 5 1 mg 2/3 (67%) 7.3 10 +7.7 2 mg 3/3 (100%
Slide 94: Mean Changes in CST from Baseline to Week 12
OPT-302 (0.3-2 mg) + Aflibercept (2 mg): Mean changes in CST from Baseline to Week 12 20 0 Mean Change from Baseline in CST on SD-OCT (µm) -20 -40 -60 - 71 µM -80 -100 0 2 4 8 12 Week 95 Error Bars: SEM; Mean Baseline CST = 434 µm
Slide 95: DME Patients with Bilateral Disease
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 Aflib
Slide 96: OPT-302 Clinical Program
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 Ranibizuma
Slide 97: Megan Baldwin, PhD CEO & Managing Director
Megan Baldwin, PhD CEO & Managing Director T +61 (3) 9826 0399 M +61 447 788 674 E [email protected] www.opthea.com Suite 0403, Level 4, 650 Chapel Street, South Yarra 3141 Victoria Australia