“Beyond anti-VEGF-A for - Opthea · “Beyond anti-VEGF-A for Retinal Diseases” New York City,...
Transcript of “Beyond anti-VEGF-A for - Opthea · “Beyond anti-VEGF-A for Retinal Diseases” New York City,...
“Beyond anti-VEGF-A for
Retinal Diseases”
New York City, KOL Forum, November 6 2018
Megan Baldwin PhD, CEO & Managing Director
NEOVASCULAR AMDCURRENT TREATMENT PARADIGMS AND UNMET NEEDS
ARSHAD M. KHANANI MD,MAM 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 PS I E R R A E Y E A S S O C I A T E SC 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 - R E N O
OBJECTIVES
▪ PR ACT ICE SE T T ING
▪ STANDAR D OF CAR E DOSING ST R AT EGIES
▪ CL INICA L T R IA L S DATA HIG HL IG HTING UNME T NE E DS
▪ NEW T R EAT MENT S ON T HE HOR IZ ON
PRACTICE SETTING
▪ PR IVAT E O FFICE B A SE D PR ACT ICE
▪ MULTISPECIALT Y WIT H 2 R ET INAL PHYSICIANS
▪ 55 E MPLOYE ES TOTA L
▪ 7 T E CHNICIA NS, 3 R E SE A R CH CO O R DINATO RS
▪ 1 5 - 20 ACT IVE CL INICA L T R IA L S
▪ 70 PAT IE NT S A DAY O N AVE R AG E
▪ A PPR OXIMATELY 50 0 INJ E CTIO NS A MO NT H
ANGIOGENESIS IN AGE-RELATED MACULAR DEGENERATION COMPLEX CASCADE OF EVENTS
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.
Basementmembranedegradation
Tubeformation +remodeling
VEGF
Vascular Endothelial
Growth Factor
Endothelial cell activation
Endothelial cell proliferation,migration
CURRENT PARADIGM – BLOCK VEGF-A
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.
Basementmembranedegradation
Tubeformation +remodeling
VEGF
Vascular Endothelial
Growth Factor
Endothelial cell activation
Endothelial cell proliferation,migration
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- SAILOR
- CATT
- HARBOR
TREAT AND
EXTEND- LUCAS
- TREX
- ALTAIR
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 FIXED MONTHLY DOSING: VISUAL ACUITY FROM
BASELINE THROUGH MONTH 24
MONTHS MONTHSMARINA1 ANCHOR2
VIEW 1 and 23
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
▪ E X PE NSE : DIR E CT A ND INDIR ECT CO ST S
▪ INCONVENIENCE: FR EQUENT VISIT S
▪ INCR E A SE D R ISK (CUMULATIVE )
▪ INFECTION
▪ SUSTAINED IOP ELEVATION/GLAUCOMA
WHY?AVOID OVERTREATMENT
SAFER
MORE
COST-EFFECTIVE
HOW?
PRN (AS NEEDED)
TREAT-AND-EXTEND
GOALS
SUPPRESS CNV GROWTH, EXUDATION
FREQUENT OCT IMAGING WITH “ZERO
TOLERANCE”
INDIVIDUALIZED ANTI-VEGF TREATMENT
PRN DOSING IN HARBOR
Ho AC, Busbee BG, Regillo CD, et al. Ophthalmology. 2014;121(11):2181-2192.
DISTRIBUTION OF THE NUMBER OF RANIBIZUMAB INJECTIONS OVER 2 YEARS
UNDERTREATMENT COMPROMISES VISUAL ACUITYPOSITIVE CORRELATION OF VA GAINS AND NUMBER OF
ANTI-VEGF-A INJECTIONS OVER 12 MONTHS
Hussain RM et al. Ophthalmic Surg Lasers Imaging Retina. 2017;48:780-784.
MANY PATIENTS RECEIVE FEWER INJECTIONSIN 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
PRO RE NATA (PRN) DOSING
PATIENTS RECEIVE:
▪ A SER IES OF MONT HLY LOADING INJ ECT IONS OF ANT I - VEGF T HER APY
▪ R E G ULA R O FFICE VISIT S FO R A SSE SSMENT O F VISUA L ACUIT Y
▪ A NATO MIC ME A SURE S B A SE D O N O CT, FA O R OT HE R IMAG ING MO DA L ITIES
▪ A L LO WS FO R R E CUR R E NCE O F NE OVA SCULA R L E A K AG E A ND G R O WT H
▪ MULTIPLE R E CUR R ENCES L E A DS TO PR O G R ESSIO N O F DISE A SE
▪ PO O R E R LO NG -TER M VISUA L O UTCO MES IN SO ME PAT IE NTS
Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1.
POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN
▪ SER IES OF LOADING ANT I - VEGF INJ ECTIONS, (T YPICALLY 4 - WK INT ER VAL S), WIT H VA A ND A NATO MIC A SSE SSMENT
▪ WHE N CR IT E R IA INDICAT ING NO DISE A SE ACT IVIT Y A R E ME T, PAT IE NTS R E CE IVE A N INJ E CTIO N; T R E AT MENT INT E R VA L IS E X T E NDE D, USUA L LY B Y 2 WEEKS AT A T IME, UNT IL MAX IMUM INT ER VAL OF 1 2 – 1 6 WEEKS IS R EACHE D
▪ IF CNV L E SIO NS A R E R E ACT IVAT ED, T R E AT MENT INT E R VA L IS R E DUCED
Spaide R. Am J Ophthalmol. 2007;144:679-680
TREAT-AND-EXTEND DOSING: WHAT IS IT?
▪ 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
BENEFITS OF TREAT-AND-EXTEND DOSING
CURRENT UNMET NEEDS IN nAMD
+25
-20
-15
-10
-5
0
5
10
15
0 6 12 18 24
Me
an
Ch
an
ge
i in
ET
DR
S B
CV
A
Months ANCHOR, MARINA, HARBOR, CATT, VIEW1/2
NEOVASCULAR AMD ANTI-VEGF A BLOCKADE
20/100
20/63
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
-25
-15
-5
5
15
25
35
0 6 12 18 24
Me
an
Ch
an
ge
i in
ET
DR
S B
CV
A
MONTHS
20/100
20/20
#1 EFFICACY
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
>70% VA REMAINS TO BE GAINED
20/200
20/200
20/40
X 8 #2 Durability
0
5
10
15
0 3 6 9 12
Me
an C
han
ge in
ETD
RS
BC
VA
Months
MARINA 0.5 mg
ANCHOR (0.5 mg)
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)
VIEW1 (2q8)
VIEW1 (2q4)
VIEW2 (0.5q4)
VIEW2 (2q8)
VIEW2 (2q4)
11.3
5.9
ANCHOR, MARINA, HARBOR, CATT, VIEW1/2
ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE FIXED OR PRN DOSING
Mean = 8.4
InjectionsMean = 10.2
Range = 6.6-12.3
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
0
5
10
15
0 3 6 9 12
Me
an C
han
gei i
n E
TDR
S B
CV
A
Months
LUCAS Ranibizumab
LUCAS Bevacizumab
TREND
TREX AMD
10.5
6.6
LUCAS, TREND, TREX-AMD
ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE TREAT & EXTEND DOSING
InjectionsMean = 8.9
Range = 8.0-10.1
Mean = 8.6
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
Holz FG, et al. Presented at: EURetina 2017; September 7-10, 2017; Barcelona, Spain.
7.48.5
19.6
12.213.5
11.7
9.5
5.95.1
2.92.1
1.0 0.5 0.1 0.00
5
10
15
20
1 (n=250)
2(n=287)
3(n=661)
4(n=412)
5(n=455)
6(n=396)
7(n=322)
8(n=199)
9(n=173)
10(n=97)
11(n=72)
12(n=35)
13(n=17)
14(n=2)
15(n=1)
Pro
po
rtio
n o
f p
atie
nts
(%
)
Number of ranibizumab injections up to Month 12
≈73% ≤ 5 injections LUMINOUS
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.
DUAL-TARGETING
▪ GENE THERAPY ▪ STEM CELLS▪ DROPS ▪ PILLS
DRUG DELIVERYAPPROACHES
ADDITIONAL ANTI-VEGF AGENTS BROLUCIZUMAB & ABICIPAR
VE
GF
-C/D
VE
GF
-C/D
hIgG1 Fc
Extra-Cellular Domains 1-3hVEGFR-3
FARICIMAB(RG7716)
VEGF-C/D BLOCKADE: OPT-302
INTO THE FUTURE
MOONSHOTS
COMPARISON OF CURRENT VS EMERGING ANTI-VEGF-A AGENTS
Bevacizumaba Ranibizumab Aflibercept Brolucizumabb Abicipar pegolb
FormatFull 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
aOff-label; not FDA-approved for any ocular indicationsbUnder 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
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02462928. 2. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT02462486.
Abicipar pegol 2 mg
Ranibizumab 0.5 mg
Sham treatme
No treatment
n = 900 (1:1:1)
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
PRIMARY ENDPOINT
Week
CEDAR PRIMARY ENDPOINT: STABLE VISION AT WK 52 ABICIPAR Q8WK AND Q12WK NONINFERIOR TO RBZ Q4WK
RBZ, ranibizumabAllergan. 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
15.7% 15.3%
0.6%
CEDAR STUDY
15.1% 15.4%
0.0%0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Abicipar Q8 Abicipar Q12 Ranibizumab Q4
Intraocular Inflammation Events
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
Regula JT et al. EMBO Mol Med. 2016;8:1265-1288.
• 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
AVENUE:PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL
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.
TOTAL N = 273 PATIENTS*
• AGE ≥50 YEARS
• TREATMENT-NAÏVE NAMD
• SUBFOVEAL CNV LESION
• BCVA 20/40–20/320 (73–24 ETDRS LETTERS)
0 4 8 12 16 20 24
TIME, WEEKS
R
28 32 36
STUDY TREATMENT FINAL VISIT
6.0 MG FARICIMAB
1.5 MG FARICIMAB
0.5 MG RANIBIZUMAB
PRIMARY ENDPOINT
SHAM
AVENUE: MEAN CHANGE IN BCVA FROM BASELINE TO WEEK 36
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.
LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE BCVA CHANGE FROM BASELINE, ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT02484690).
0
5
10
15
0 4 8 12 16 20 24 28 32 36
Time, Weeks
Ad
just
ed
Me
an B
CV
A C
han
ge F
rom
B
ase
line
, ETD
RS
Lett
ers
+ 9.1 letters
+ 7.6 letters
+ 7.2 letters
+ 6.0 letters
+ 5.9 letters
6.0 mg faricimabQ4W
6.0 mg faricimabQ4W/Q8W
1.5 mg faricimabQ4W
0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W
0.5 mg ranibizumabQ4W
AVENUE: MEAN CHANGE IN CST FROM BASELINE TO WEEK 36
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. .
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.
-300
-200
-100
0
0 4 8 12 16 20 24 28 32 36
Time, Weeks
Ad
just
ed
Me
an C
ST C
han
ge
Fro
m B
ase
line
, µm – 147 μm
– 156 μm
– 172 μm
– 175 μm
– 185 μm
6.0 mg faricimabQ4W
6.0 mg faricimabQ4W/Q8W
1.5 mg faricimabQ4W
0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W
0.5 mg ranibizumabQ4W
STAIRWAY: PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL
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.
Study Treatment
0 4 8 12 16 20 24
Time, Weeks
28 32 36 40 44 48 52
Final Visit
Q12W dosing
Q16W dosing
Active disease at Week 24†
Q4W dosing
R
Total N = 76 patients*
• Age ≥50 years
• Treatment-naïve nAMD
• Subfoveal CNV lesions
• BCVA 20/40–20/320 (73–24 ETDRS letters)
6.0 mg faricimab
0.5 mg ranibizumab
Primary endpoint
Sham
Prespecified disease assessment at Week 24
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.
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)
“Beyond anti-VEGF-A for
Retinal Diseases”
New York City, KOL Forum, November 6 2018
Megan Baldwin PhD, CEO & Managing Director
Cole Eye Institute
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
1994 1998 2003 2008 2015
4.5%‒5.9%
7.5%‒8.9%
<4.5%
6.0%‒7.4%
≥9.0%
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
Rowley et al. Popul Health Manag. 2017;20:6.
Percent of Total Population With Diabetes (Diagnosed and Undiagnosed)
2020
9%-11%
15%-17%
7%-8%
12%-14%
18%-20%
20202020 2025 2030
Cole Eye Institute
≈13.6% have diabetic macular edema (DME)2
Diabetes Is Associated With Serious Comorbidities
Diabetic retinopathy1
28.5% in patients aged ≥40
Diabetic nephropathy3
29.9% in diabetic patients
Stroke4
11.5 per 1000 persons with diabetes
Diabetic neuropathy1
60%-70% in diabetic patients
Ischemic Heart Disease4
18.3 per 1000 persons with diabetes
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
Boyer DS, et al. Ther Adv Endocrinol Metab. 2013;4(6):151-169.
Inflammation
↑ AGEs
↑ ROS
↑ ICAM
PKC activation
↑ Nitric oxide
↑ Polyols
↑ Eicosanoids
Microvascular damage Leukostasis
Pericyte loss
Endothelial damage
VEGF overexpression
DME
AGEs = advanced glycation end-products
ICAM = intercellular adhesion molecule
PKC = protein kinase C; ROS = reactive oxygen
species
Cole Eye Institute
● Approved Treatments
● Anti-VEGF
● Lucentis –
Genentech/Roche
● Eylea – Regeneron
● Steroid
● Ozurdex – Allergan
● Iluvein – Alimera
Current Approved and Off-label Therapies for Diabetic Macular Edema
● Unapproved Treatments
● Anti-VEGF
● Avastin –
Genentech/Roche
● Steroid
● Triamcinolone
● Triescence - Alcon
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
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.
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.
CLINICAL TRIAL TREATMENT DOSAGE(S) UNDER STUDYNUMBER OF
PATIENTS
≥15-LETTER BCVA INCREASE AT 1 YEAR
(%)
RISE ranibizumab0.3 mg 125 45%
0.5 mg 125 39%
RIDE ranibizumab0.3 mg 125 34%
0.5 mg 127 46%
DRCRPROTOCOL I
ranibizumab + prompt laser
0.5 mg ranibizumab+ focal / grid laser 3-10 days after first IVT
187 30%
ranibizumab + deferred laser
0.5 mg ranibizumab+ focal / grid laser ≥24 weeks after first IVT
188 28%
BOLT bevacizumab 1.25 mg 42 12%
VISTA* aflibercept2 mg every 4 weeks 154 42%
2 mg every 8 weeks* 151 31%
VIVID* aflibercept2 mg every 4 weeks 136 32%
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.
Even when treatment regimens are optimized under
clinical trial conditions, meaningful visual acuity
increases are only achieved by 30% to 45% of DME
patients
Cole Eye Institute
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
* OCT thickness decreased ≥20% from baseline.Bressler SB, et al. Arch Ophthalmol. 2012.
Early and
Consistent
Early but
Inconsistent
Slow and
Variable
No
Response
Type of
Response
Improvement*
at 16 Weeks
Improvement*
at 32 Weeks
and/or 1 Year
% of Patients 49.6%n=143/288
14.9%n=43/288
12.5%n=36/288
22.9%n=66/288
✓✗
✗
✓✓✗✓ ✗✓
✗
= 50.4%
Non responders
Cole Eye Institute
We Know Very Quickly Whether or Not Patients Will Respond to Anti-VEGF-A
-0.3
2.8 3.0
6.9 8.2 8.2
15.2
16.5
13.8
-5
0
5
10
15
20
BL 12 16 20 24 28 32 36 40 44 48 52 . .. … 68 . .. … 84 . .. … …. 104 . ..
…
120 . ..
…
136 . . . .. . … . …. 156
BC
VA
Ch
an
ge f
rom
Baselin
e
p<0.001
Weeks
≥10 letters
at 12w (N=126)
5-9 letters
at 12w (N=79)
<5 letters
at 12w (N=135)
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
PlGF 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 sub-optimal 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 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
PGF is elevated in aqueous humour in patients with DME and PDR
Control DME PDR
Not detected
***
**
PG
F (
pg
/mL
)
100
0
20
40
60
80
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
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
STUDY
VISITS
56-day observation period, with
LUCENTIS® treatment allowed as
needed
PLACEBO subcutaneous BID
3 doses intravitreal LUCENTIS (0.3
mg) q4
15 mg AKB-9778 subcutaneous BID
3 SHAM injections q4
15 mg AKB-9778 subcutaneous BID
3 doses intravitreal LUCENTIS (0.3
mg) q4
N=144
R 1:1:1
Intravitreal LUCENTIS
injectionSham injection65
Cole Eye Institute
-10 -8
60
-91
-102
-110-106
-146-164
-170
-150
-130
-110
-90
-70
-50
-30
-10
10
Baseline Month 1 Month2 Month 3
Change in CST from Baseline to Month 3
AKB-9778 (N=46)
Lucentis (N=47)
AKB-9778 + Lucentis (N=48)
AKB-9778 + Lucentis significantly reduced retinal thickness compared to Lucentis alone,
66
p = 0.008
CS
T R
eduction (
µm
)
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)
Phase 2b – Stage 2: Avastin pretreatment vs combination therapy with 5-month follow-up (n=80)
Drug Safety
Dose Ranging
Durability
Efficacy vs anti-VEGF-A
Goal
Increase efficacy by
clearing out pre-
existing VEGF-A load
Goal
Cole Eye Institute
Phase 2b DEL MAR Stage 1: Primary and Secondary Endpoints Were Met (n=136)
Secondary Endpoint
Mean OCT CMT non-inferiority at study week 20 (≤30µ)
NO LUMINATE DOSING NO LUMINATE DOSING
Primary Endpoint
Mean BCVA non-inferiority at study week 20 (≤3 letters)
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
“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
VEGFR-1 VEGFR-2 VEGFR-3
Ig-like domainPathway blocked by OPT-302
Kinase domainLigand
Aflibercept
Angiogenesis
Vascular Permeability
VEGF-B
PlGFVEGF-A
Ranibizumab
Bevacizumab
Angiogenesis
Lymphangiogenesis
VEGF-C
VEGF-DOPT-302
ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144
VEGF-A Inhibition Upregulates VEGF-C/D
66%
5.37
6.91
8.91
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
Baseline 1m 2m
Aq
ueo
us
Hu
mo
rV
EG
F-C
(pg/
ml)
BevacizumabBevacizumab
Neovascular AMD Patients2
OPT-302 (anti-VEGF-C/-D):
• Inhibits angiogenesis &
vascular leakage
• Overcomes escape mechanism
to VEGF-A suppression
Control OPT-302
Aflibercept OPT-302 + Aflibercept
70%78%
91%
*
* 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
VE
GF
-C/D
VE
GF
-C/D
hIgG1 Fc
Extra-Cellular Domains 1-3hVEGFR-3
• 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 a Novel ‘Trap’ Inhibitor of VEGF-C/D
OPT-302 Inhibition of CNV in Rodent Model of AMD
OPT-302 (0.3 mg) +
Ranibizumab (0.5 mg)
IVT Q4W x 3
OPT-302 (1 mg) +
Ranibizumab (0.5 mg)
IVT Q4W x 3
OPT-302 (2 mg) +
Ranibizumab (0.5 mg)
IVT Q4W x 3
28
Day D
LT w
ind
ow
OPT-302 (2 mg)
Monotherapy*
IVT Q4W x 3
Cohort 4
Cohort 3
Cohort 2
Cohort 1
• Comprises of 4 treatment cohorts of 5 subjects each
Part 1: Dose-escalation
(Open-label)
Pri
ma
ry A
na
lysi
s a
fte
r a
ll
su
bje
cts
co
mp
lete
12
we
eks
Lo
ng
te
rm fo
llow
-up
at
We
ek 2
4
*Access to rescue anti-VEGF-A Tx
Fo
llow
-up
to
we
ek 1
2
OPT-302 (2 mg)
+ Ranibizumab (0.5 mg)
IVT Q4W x 3, n=23 pts
OPT-302 (2 mg)
Monotherapy*
IVT Q4W x 3, n=8 pts
Part 2: Dose-expansion
(Randomised 3:1)
OPT-302 Phase 1b/2a First-in-Human Study in nAMD Patients (n=51)
ClinTrials Identifier NCT 02543229
Treatment Groups
OPT-302 + ranibizumab
Combination TherapyN=38
Prior-Treated
with anti-VEGF-A
N=20
OPT-302
Monotherapy
N=13
Wet AMD Patients
N=51
Treatment
Naïve
N=18
Prior-Treated
with anti-VEGF-A
N=6
Treatment
Naïve
N=7
• 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 (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 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)
Intravitreal OPT-302 (2 mg)(± 0.5 mg ranibizumab)
Cmax
(ng/mL)Tmax
(hours)AUC0–last
(ngh/mL)T1/2
(days)
Mean ± SD(n)
21.1 ± 17.3(n = 41)
31 ± 24(n = 41)
2760 ± 1110(n = 30)
8 ± 2(n = 10)
• Non-compartmental OPT-302 PK analysis indicated:
• low systemic exposure
• a half-life of 8 ± 2 days
• 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.
1.0
10.0
100.0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336
OPT-302 Monotherapy (2 mg)
Combination OPT-302 (2 mg) +
Ranibizumab (0.5 mg)
Mean OPT-302 serum concentrations
Time (hours)
Me
an
(+
SD
) O
PT
-30
2 S
eru
m C
on
cen
tratio
ns
(ng
/mL
)
Intravitreal OPT-302 (2 mg) monotherapy
Change in mean Best Corrected Visual Acuity
from Baseline to week 12
+5.6 letters
+4.4 letters
+ 2.8 letters
OPT-302 Monotherapy Patients:n = 13 (wk 4, 8), 12 (wk 12); Mean Baseline VA = 55.7 Letters
• OPT-302 monotherapy at 2 mg to assess biological
activity in absence of standard of care
• 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 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness
Change in mean BCVA Change in mean Central Subfield Thickness
+10.8 letters
-54 µM
+ 4.9 letters
-119 µM
Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg)Mean Baseline VA = 56.5 Letters
Prior-Treated Patients:n = 20 (wk 4, 8), 19 (wk 12); OPT-302 (0.3-2.0 mg) + ranbizumab (0.5 mg)Mean Baseline VA = 64.5 Letters
0
5
10
15
0 4 8 12
Time (weeks)
Ch
ange
fro
m b
asel
ine
in V
isu
al A
cuit
y (E
TDR
S Le
tter
s) Naïve pts (n=18)Prior treated pts (n=20)
-160
-140
-120
-100
-80
-60
-40
-20
0
0 2 4 6 8 10 12
Ch
ange
fro
m b
asel
ine
in C
ST (
µM
)
Time (weeks)
Naïve pts (n=18)Prior treated pts (n=20)
OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness
Reduction in CNV size on FA % Patients with absent CNV on FA
0
1
2
3
4
5
6
7
8
9
Baseline Week 4 Week 12
CN
V S
ize
(mm
2 )
7.71
3.74
2.03
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
OPT-302 + Ranibizumab
0
10
20
30
40
50
60
Baseline Week 4 Week 12
% P
atie
nts
wit
h A
bse
nt C
NV
on
FA
5.6 %*
27.8 %
50 %
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 µMSRF: 192 µMSHRMw: 1053 µMSHRMh: 94 µM
CST: 217 µMSRF: 0 µMSHRMw: 0 µMSHRMh: 0 µM
CST: 233 µMSRF: 0 µMSHRMw: 0 µMSHRMh: 0 µM
OPT-302 (2 mg) + ranbizumab (0.5 mg)
Case Study Prior Treated Patient (Occult): OPT-302 + Ranibizumab
Baseline Week 4 Week 12
VA: 72 letters VA: 78 lettersVA: 65 letters
CNV: 5.28 mm2CNV: 11 mm2 CNV: 8.04 mm2
CST: 303 µMSRF: 140 µMSHRMw: 1042 µMSHRMh: 133 µM
CST: 249 µMSRF: 41 µMSHRMw: 0 µMSHRMh: 0 µM
CST: 248 µMSRF: 0 µMSHRMw: 0 µMSHRMh: 0 µM
Patient was heavily pre-treated with Ranibizumab (0.5 mg) x 28 IVT injections
OPT-302 (2 mg) + ranbizumab (0.5 mg)
• 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.
Conclusion
“Beyond anti-VEGF-A for Retinal Diseases”
New York City, KOL Forum, November 6 2018
Megan Baldwin PhD, CEO & Managing Director
Investment in Opthea Limited (‘Opthea’) is subject to investment risk, including possible loss of income andcapital invested. Neither Opthea nor any other member company of the Opthea Group guarantees anyparticular 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 aninvestment is appropriate to their particular investment needs, objectives and financial circumstances andconsult an investment advisor if necessary.
This presentation may contain forward-looking statements regarding the potential of the Company’s projects andinterests and the development and therapeutic potential of the company’s research and development. Anystatement describing a goal, expectation, intention or belief of the company is a forward-looking statement andshould 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 andeffective for use as human therapeutics and the financing of such activities. There is no guarantee that theCompany’s research and development projects and interests (where applicable) will receive regulatory approvalsor prove to be commercially successful in the future. Actual results of further research could differ from thoseprojected or detailed in this presentation. As a result, you are cautioned not to rely on forward-lookingstatements. Consideration should be given to these and other risks concerning research and developmentprograms referred to in this presentation.
Disclaimer
88
OPT-302
Target: VEGF-C/D
OPT-302
Target: VEGF-C/D
OPT-302
Target: VEGF-C/D
Diabetic Macular Edema
Neovascular AMD
Phase 1
Combination
Agent Preclinical Phase 2a Phase 2b Phase 3 Status1o Data
Analysis
RanibizumabTarget: VEGF-A
RanibizumabTarget: VEGF-A
AfliberceptTarget: VEGF-A,
PlGF, VEGF-B
Complete
Ph 1/2a (n=51) April 2017
Ongoing
Ph 2b (n=351) Early 2020
Ongoing
Ph 1b/2a (n=117) 2019
OPT-302 Clinical Program
• Two ongoing randomised controlled clinical trials in nAMD & DME
89
OPT-302 +/- Ranibizumab Phase 2b Trial in Treatment-Naïve nAMD (n=351)
Randomized 1:1:1 to treatment arms
IVT dosing at every 4 weeks (x 6)
Treatment-Naive
Neovascular AMD
OPT-302 (2 mg) + Ranibizumab (0.5 mg)
OPT-302 (0.5 mg) + Ranibizumab (0.5 mg)
Sham + Ranibizumab (0.5 mg)
We
ek 2
4 F
ollo
w-u
p
n=117
n=117
n=117
• Currently enrolling
• Primary data analysis early 2020ClinTrials Identifier NCT 0334508290
Phase 1b Dose Escalation study of OPT-302 + Aflibercept in DME
N=
14
Day
DLT
win
dow
Cohort 3
Cohort 2
Cohort 1
Phase 1b Dose-Escalation
Pri
ma
ry A
na
lys
is a
fte
r a
ll
su
bje
cts
co
mp
lete
12
we
ek
s
PR
N a
nti-V
EG
F-A
We
ek 1
2 to
24
Fo
llow
-up
to
we
ek 1
2
Phase 2a Dose-Expansion
(Randomised 2:1 ratio)
OPT-302 (0.3 mg)+ Aflibercept (2.0 mg)
IVT Q4W x 3, n=3ClinTrials Identifier
NCT 03397264
• 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
Key Exclusion Criteria
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
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
N=9 patients
Key Inclusion Criteria
• Age ≥ 18 years; centre-involving DME• CST ≥ 335 µm*• BCVA 73 – 24 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. 91
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: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)
Intraocular inflammation 0 0 0 0Endophthalmitis 0 0 0 0Retinal detachment 0 0 0 0Vitreous hemorrhage 0 0 0 0
Hypertension 1* 0 0 1*
APTC events#
Nonfatal myocardial infarction 0 0 0 0Nonfatal stroke 0 0 0 0Vascular or cardiac death or death of unknown cause 0 0 0 0Combined 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*Determined by treating investigator as unrelated to study drug(s)93
OPT-302 + Aflibercept: Gains in BCVA at Week 12Dose Response Relationship
Dose of OPT-302
+ 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%) 7.3
2 mg 3/3 (100%) 6.7
0.3 to 2 mg 6/9 (67%) 6.3
0
5
1 0
1 5
2 0
Mean
Ch
an
ge f
rom
baselin
e i
n B
CV
A (
Lett
ers
)
0.3 mg
OPT-302
1 mg
OPT-302
2 mg
OPT-302
0.3 - 2 mg
OPT-302
+ 2 mg Aflibercept
(N=9)(N=3)(N=3) (N=3)
+7.7
+14.3
+3.0+5.7
Error Bars: SEM94
OPT-302 (0.3-2 mg) + Aflibercept (2 mg):Mean changes in CST from Baseline to Week 12
Mean
Ch
an
ge f
rom
Baselin
e i
n
CS
T o
n S
D-O
CT
(µ
m)
Week
- 71 µM
-100
-80
-60
-40
-20
0
20
0 2 4 8 12
Error Bars: SEM; Mean Baseline CST = 434 µm95
DME Patients with Bilateral Disease* Study Eye vs Fellow Eye (N=5)
Mean Change in BCVA Baseline to Week 12
Mean
Ch
an
ge B
CV
A (
Lett
ers
)
OPT-302 +
AfliberceptAnti-VEGF-A
Monotherapy
+10.0
+2.6
Mean Change in CST (uM) Baseline to Week 12
Mean
Ch
an
ge C
ST
(µ
M)
Anti-VEGF-A
Monotherapy
OPT-302 +
Aflibercept
-80 µM
-6.0 µM
Study Eye:
0.3 – 2mg OPT-302 + 2 mg Aflibercept
Fellow Eye:
Anti-VEGF-A Monotherapy*
*Patients with bilateral disease and persistent DME in the fellow eye receiving anti-VEGF-A (ranibizumab or aflibercept) monotherapyPrior 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)# Excess foveal thickness was determined by using 300 µm Spectralis scan values and 285 µm Cirrus scan values96
Perc
en
tag
e P
ati
en
ts
% Pts with ≥ 50% Reduction in Excess Foveal Thickness
OPT-302 +
AfliberceptAnti-VEGF-A
Monotherapy
20%
60%
OPT-302
Target: VEGF-C/D
OPT-302
Target: VEGF-C/D
OPT-302
Target: VEGF-C/D
Diabetic Macular Edema
Neovascular AMD
Phase 1
Combination
Agent Preclinical Phase 2a Phase 2b Phase 3 Status1o Data
Analysis
RanibizumabTarget: VEGF-A
RanibizumabTarget: VEGF-A
AfliberceptTarget: VEGF-A,
PlGF, VEGF-B
Complete
Ph 1/2a (n=51) April 2017
Ongoing
Ph 2b (n=351) Early 2020
Ongoing
Ph 1b/2a (n=117) 2019
OPT-302 Clinical Program
• Two ongoing randomised controlled clinical trials in nAMD & DME
97
Megan Baldwin, PhDCEO & Managing DirectorT +61 (3) 9826 0399M +61 447 788 674E [email protected]
Suite 0403, Level 4,650 Chapel Street,South Yarra 3141 Victoria Australia