EURetina Late-Breaking Abstract - Opthea … · EURetina Late-Breaking Abstract ... Michael Tolentino, Robert Finger, ... 2 Retina Vitreous Associates Medical Group

EURetina Late-Breaking Abstract

A first-in-human Phase 1/2a study of the novel VEGF-C/D inhibitor OPT-302 alone and in combination with ranibizumab in patients with wet AMD Pravin Dugel, David Boyer, Andrew Antoszyk, Michael Varenhorst, Joel Pearlman, Patrick Higgins, Michael Tolentino, Robert Finger, Ian Leitch, Megan Baldwin and Mark Gillies. Purpose: Improved outcomes for patients with wet AMD may be achieved by more complete inhibition of the VEGF/VEGFR pathway. VEGF-C and VEGF-D are additional members of the VEGF family that are associated with resistance to anti-VEGF-A therapy. OPT-302 is a biologic inhibitor of VEGF-C/D. Combination OPT-302 + ranibizumab therapy may result in additive anti-angiogenic and anti-vascular leakage effects by targeting multiple VEGF signalling pathways involved in wet AMD progression. Here we report safety outcomes and preliminary measures of activity from a 20 patient (pt) Phase 1 dose escalation study of OPT-302 administered alone or in combination with ranibizumab in wet AMD patients. Setting: The Phase 1/2a study is being run under an Investigational New Drug (IND) program with the FDA at 14 sites across the US. Methods: A two part Phase 1/2a trial (NCT02543229) comprising an open-label, sequential dose escalation (Part 1, n=20 pts) and a randomised dose expansion study (Part 2, up to ~30 pts) was initiated in pts with active CNV secondary to AMD. Pts were either treatment naïve or received prior intravitreal (IVT) anti-VEGF-A therapy. In Part 1, pts were treated once every 4 weeks x 3 with OPT-302 (0.3, 1or 2 mg) in combination with ranibizumab (0.5 mg) given by sequential IVT injection or OPT-302 monotherapy (2 mg) in cohorts of 5 pts. For pts receiving OPT-302 monotherapy, ranibizumab rescue therapy was provided at PI discretion or if pts had a ≥5 letter decrease in vision and no reduction in central subfield thickness (CST) of at least 10% with presence of fluid. Part 2 is a dose expansion study and will enrol ~30 pts, randomised to two groups of OPT-302 given once every 4 weeks x 3 as a monotherapy or in combination with ranibizumab. Part 1 pt safety data through the 28 day dose limiting toxicity period was reviewed for each cohort before escalating to the next dose level and also prior to starting the Part 2 dose expansion. Assessments included ocular and systemic safety/tolerability, intraocular pressure, maximum tolerated dose (MTD), systemic pharmacokinetics, anti-OPT-302 antibody formation as well as preliminary clinical activity measured by EDTRS BCVA and SD-OCT. Results: 20 pts (6 naïve and 14 prior treated with anti-VEGF-A therapy; 19 evaluable at week 12) have been treated; 5 pts with OPT-302 (2 mg), and 15 pts with OPT-302 (0.3 – 2 mg) + ranibizumab (0.5 mg). There were no dose limiting toxicities and a MTD was not reached. There were no treatment related serious adverse events. One pt with metastatic ovarian cancer died at study day 68 (prior to the week 12 visit) due to intercurrent illness unrelated to study drugs. Adverse events were primarily related to the IVT injection procedure and were mild and manageable. There were no signs of endophthalmitis and no clinically significant changes in intraocular pressure, electrocardiograms, blood pressure or other vital signs. Overall, a majority of pts (16/19 evaluable pts; 84%) maintained or gained vision by week 12 compared to baseline. None of the 3/19 patients lost more than 3 letters (range -2 to -3 letters) and all received combination OPT-302 + ranibizumab therapy. At week 12, the mean gain in BCVA from baseline for naïve pts who received OPT-302 (0.3 or 2.0 mg) + ranibizumab (0.5 mg) was 16.5 letters overall (n=4) and 9.5 letters in the 2.0 mg OPT-302 + ranibizumab dose cohort (n=2). Mean BCVA gain in prior treated pts administered OPT-302 + ranibizumab at week 12 was 4.1 letters (n =10 evaluable pts; mean prior treatments = 10.5, range 3-55). Central subfield thickness (CST)

decreased in all combination cohorts, with a mean reduction of 214 M in naïve pts (n=4) and 42.4

M in prior treated pts (n=10 evaluable pts) at week 12. In the OPT-302 monotherapy cohort, 3/5 patients (1 naïve and 2 prior treated) did not require any rescue. At week 12, in pts that did not undergo rescue, there was a mean VA gain of 3.3 letters from baseline (range 2-6 letters) and a

mean increase in CRT of 18 M. Conclusion: OPT-302 is a novel biologic inhibitor of VEGF-C and VEGF-D that may block compensatory mechanisms that contribute to sub-responsiveness to VEGF-A inhibition. In an ongoing Phase 1/2a clinical study, OPT-302 administered IVT as a monotherapy or at three escalating doses in combination with ranibizumab was safe and well tolerated with preliminary evidence of clinical activity. A majority of patients who were either treatment naïve or previously treated either maintained stable vision or showed improvements from baseline through week 12, with evidence of anatomic activity on SD-OCT. Further clinical evaluation of OPT-302 in combination with anti-VEGF-A therapy is warranted and is ongoing in the Phase 2a dose expansion cohorts.

Retinal Consultants of Arizona I Retinal Research Institute

A first-in-human Phase 1/2a study of the novel VEGF-C/D inhibitor OPT-302 alone and in combination with

ranibizumab in patients with wet AMD

Pravin Dugel1, David Boyer2, Andrew Antoszyk3, Michael Varenhorst4, Joel Pearlman5, Patrick Higgins6, Michael Tolentino7, Robert Finger8, Ian

Leitch9, Megan Baldwin9 and Mark Gillies10

1 Retinal Consultants of Arizona; 2 Retina Vitreous Associates Medical Group (Beverly Hills); 3 Charlotte Eye Ear Nose & Throat Associates; 4 Vitreo Retina Consultants & Surgeons (Wichita); 5 Retinal

Consultants Medical Group (Sacramento); 6 Retina Centre of New Jersey; 7 Centre for Retina and Macular Disease (Florida); 8 University of Bonn (Germany); 9 Opthea Limited (Melbourne, Aust); 10 Save

Sight Institute, University of Sydney (Australia)

EURetina, Copenhagen, September 10 2016


Financial Disclosures

Pravin U. Dugel, MD

Consultant for: Abbott/AMO, Aerpio, Alcon, Alimera Sciences, Allergan, Annidis, Acucela, ArcticAx, Avalanche Biotechnologies, Clearside Biomedical, Digisight, DOSE Medical, Genentech, Graybug Vision, Lutronic, Lux BioScience, Neurotech, Novartis, OD-OS, Omeros, Ophthotech, Opthea, Optovue, ORA, Regeneron, Roche, Pentavision, Shire Human Genetic Therapies, Stealth BioTherapeutics, Thrombogenics, TopCon

Minor Shareholder: Alimera, Aerpio, Annidis, Digisight, Ophthotech, TrueVision


Resistance to Anti-VEGF-A Therapy

Long-term single-agent therapy with VEGF-A inhibitors is associated with sub-optimal response

Sub-optimal improvements in visual acuity (<15-letter gain)

Persistent retinal fluid

Resistance to VEGF-A inhibitors may be related to other VEGF family members

• OPT-302 combination therapy achieves more complete suppression of the VEGF/VEGFR pathway

• Targets incomplete response to VEGF-A inhibition

Aflibercept Ranibizumab OPT-302

VEGF-BPIGF VEGF-A

VEGF-C VEGF-D


VEGF-A Inhibition Upregulates VEGF-C/-D in Cancer

“The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer” - Lieu et al., 2013.

“Mechanisms of evasion to antiangiogenictherapy in glioblastoma”Rose et al., 2010.


OPT-302 Activity in Mouse Wet AMD Model

5 Tammela et al. Nature., 2008

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), VEGF-C and VEGF-D (OPT-302) is more effective than inhibition of VEGF-A alone


Elevated VEGF-C in Wet AMD Patients

* ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144

66%

pg

/ml

(pg/ml)

• VEGF-C levels in the retina increase with disease severity

• Aqueous levels of VEGF-C are significantly increased at 1 and 2 months following IVT injection of bevacizumab to wet AMD pts*


OPT-302

• OPT-302: a soluble form of VEGFR-3

• Comprises the extracellular domains 1-3 of VEGFR-3 and the Fc Fragment of human IgG1

• Potent inhibitor of VEGF-C (~5pM) and VEGF-D (~0.5 nM)

• A ‘trap’ that binds and neutralises the activity of VEGF-C and VEGF-D, blocking binding to the receptors VEGFR-2 and VEGFR-3

VE

GF

-C/D

VE

GF

-C/D

hIgG1 Fc

Extra-Cellular Domains 1-3hVEGFR-3

(ASX :OPT)


OPT-302 Phase 1/2a

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

DLT

win

do

w

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

Phase 1: Dose-escalation(Open-label)

Pri

mar

y A

nal

ysis

aft

er

all

sub

ject

s co

mp

lete

12

we

eks

Lon

g te

rm f

ollo

w-u

p a

t W

ee

k 2

4

*Access to rescue anti-VEGF-A Tx

Follo

w-u

p t

o w

ee

k 1

2

OPT-302 (2 mg)+ Ranibizumab (0.5 mg)IVT Q4W x 3, ~n=15 pts

OPT-302 (2 mg)Monotherapy*

IVT Q4W x 3, ~n=15 pts

Phase 2a: Dose-expansion(Randomised)


OPT-302 Phase 1: Patient Demographics• Run under FDA IND at 14 clinical sites in the US

• 20 pts (mean age 74.8)

• 14/20 females, 6/20 males

• 17/20 occult, 2/20 min classic, 1/20 predominantly classic

• Each patient received 3 intravitreal injections of OPT-302 either alone or in combination with ranibizumab every 4 weeks, with a week 12 follow-up one month after the third dose.

• 70% difficult to treat patients sub-responsive to anti-VEGF-A therapy

• Mean number prior anti-VEGF-A treatments: 10.5 (range: 3 – 55)

• 30% treatment-naïveCohort Treatment # Naïve Pts # Prior

Treated Pts

1 OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) 2 3

2 OPT-302 (1 mg) + Ranibizumab (0.5 mg) 0 5

3 OPT-302 (2 mg) + Ranibizumab (0.5 mg) 2 3*

4 OPT-302 (2 mg) 2 3

*One pt with metastatic ovarian cancer died prior to the week 12 (day 78) visit due to intercurrentillness unrelated to study drugs.


OPT-302 Safe & Well-Tolerated in Phase 1 Study

• OPT-302 successfully met primary safety objective in Phase 1 dose escalation study

• No dose limiting toxicities (and MTD not reached) through week 12 in:

• OPT-302 monotherapy (2 mg), and

• Cohorts of OPT-302 (0.3, 1, 2 mg) in combination with Lucentis® (0.5 mg)

• No signs of infection (endophthalmitis)

• No clinically significant changes in:

• Intraocular pressure

• ECGs

• Blood pressure

• Blood chemistry or other vital signs

• No evidence of drug-related immunogenicity


OPT-302 Phase 1 Secondary Endpoints

• Overall, 16/19 evaluable pts maintained or gained vision from baseline to week 12

• No patient lost more than 3 letters. All of the patients that lost VA from baseline received combination OPT-302 + ranibizumabtherapy.


Combination Therapy: All Patients (Naïve & Prior-Tx)

0

1

2

3

4

5

6

7

8

9

10

OPT-302 + Ranibizumab(n=14*)

Mean VA gain from baseline at Week 12

Me

an g

ain

in

VA

fro

m B

ase

line

(#

lett

ers

) 8 Letters

Me

an C

ST (

µM

)

250

275

300

325

350

375

400

425

450

Baseline Week 12

Mean decrease in CST from baseline to Week 12

OPT-302 + Ranibizumab(n=14*)

-91µM

* 1 pt not evaluable at W12


Combination Therapy: Treatment-Naïve Patients

16.5

9.5

0

2

4

6

8

10

12

14

16

18

Mean Gain VA from Baseline

OPT-302 + Ranibizumab(n=4)

Me

an g

ain

in

VA

fro

m

Bas

elin

e (

# le

tte

rs)


Week 120

100

200

300

400

500

600

Baseline

214 uM (42.7%)

Mean Central Subfield Thickness

Me

an C

ST (

uM

)


Combination Therapy: Previously Treated Patients• Mean number prior treatment injections: 10.5 (range 3 – 55)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Mean Change VA from Baseline

Week 12OPT-302 + Ranibizumab

(n=10)

4 letters

Me

an g

ain

in

VA

fro

m

Bas

elin

e (#

lett

ers

)

330

340

350

360

370

380

390

400



Week 12Baseline

42 uM (11%)

Me

an C

ST (

uM

)


OPT-302 Monotherapy• 3/5 patients did not require ‘rescue’ therapy

• 2 patients were rescued (at d25 and d29). At week 12, despite rescue with ranibizumab, both had lost vision compared to baseline.

• At week 12, in patients that did not require rescue therapy, mean VA gain of 3.3 letters from baseline (range 2 to 6 letters) and mean increase in CST of 18 uM

Baseline Week 12OPT-302 (2 mg)

Non Rescue pts (n=3)

250

275

300

325

350

375

400

Me

an C

ST (

uM

)


+18µM

0

1

2

3

4

5

6

7

8

9

10

OPT-302 (2mg)(n=5)

OPT-302 Non-resue (2mg) (n=3)

Mean VA gain from baseline at Week 12

0

1

2

3

4

5

6

7

8

9

10

OPT-302 (2 mg)Non Rescue pts (n=3)

Me

an g

ain

in

VA

fro

m B

ase

line

(#

lett

ers

)

3.3 letters


Combination OPT-302 (0.3 mg) + Ranibizumab (0.5 mg)

• Male aged 64• Occult lesion• Prior Treatment: Aflibercept/REGN910-3 x 6

VA: 77 lettersCST: 365 µM



Baseline Week 4 Week 12


Combination OPT-302 (1.0 mg) + Ranibizumab (0.5 mg)

• Female aged 71• Occult lesion• Prior Treatment: Bevacizumab x 10




Baseline Week 4 Week 12


OPT-302 Program Highlights

• Large unmet medical need for neovascular AMD

• Current treatments target VEGF-A

• OPT-302 targets VEGF-C and VEGF-D that may be associated with incomplete response to VEGF-A inhibition

• OPT-302 met primary objective of Phase 1 study:

OPT-302 safe & well tolerated

• Totality of data warrants advancing OPT-302 + ranibizumab to a Phase 2b randomised, controlled trial

• Actively accruing into Phase 2a, planning for Phase 2b in 2017, sponsored by Opthea Limited (ASX:OPT)


Pravin U. Dugel, M.D ([email protected])

Managing PartnerRetinal Consultants of Arizona LTDRetinal Research Institute LLPhoenix, Arizona

Clinical ProfessorUSC Roski Eye InstituteKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, California

Physician Executive DirectorPhoenix Eye InstituteBanner University Medical CenterPhoenix, Arizona

Documents

EURetina Late-Breaking Abstract - Opthea … · EURetina Late-Breaking Abstract ... Michael Tolentino, Robert Finger, ... 2 Retina Vitreous Associates Medical Group