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.

Transcription

1 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 ranibizumab therapy may result in additive antiangiogenic 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 (NCT ) 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 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 ranibizumab dose cohort (n=2). Mean BCVA gain in prior treated pts administered OPT ranibizumab at week 12 was 4.1 letters (n =10 evaluable pts; mean prior treatments = 10.5, range 3-55). Central subfield thickness (CST)

2 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.

3 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 1, David Boyer 2, Andrew Antoszyk 3, Michael Varenhorst 4, Joel Pearlman 5, Patrick Higgins 6, Michael Tolentino 7, Robert Finger 8, Ian Leitch 9, Megan Baldwin 9 and Mark Gillies 10 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

4 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

5 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 Aflibercept Ranibizumab VEGF-B PIGF VEGF-A OPT-302 VEGF-C VEGF-D 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

6 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., Mechanisms of evasion to antiangiogenic therapy in glioblastoma Rose et al., 2010.

7 OPT-302 Activity in Mouse Wet AMD Model Combined inhibition of VEGF-A (Aflibercept), VEGF-C and VEGF-D (OPT-302) is more effective than inhibition of VEGF-A alone Control OPT % 78% 91% Aflibercept OPT Aflibercept * 5 Tammela et al. Nature., 2008 * Pairwise comparison: OPT-302 vs Aflibercept + OPT-302 (p<0.02) Aflibercept vs Aflibercept + OPT-302 (p<0.05)

8 pg/ml Elevated VEGF-C in Wet AMD Patients 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* (pg/ml) 66% * ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144

9 VEGF-C/D VEGF-C/D 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 Extra-Cellular Domains 1-3 hvegfr-3 higg1 Fc (ASX :OPT)

10 28 Day DLT window Follow-up to week 12 Long Primary term follow-up Analysis after at Week all 24 subjects complete 12 weeks OPT-302 Phase 1/2a Phase 1: Dose-escalation (Open-label) Phase 2a: Dose-expansion (Randomised) OPT-302 (2 mg) Monotherapy* IVT Q4W x 3 OPT-302 (2 mg) Monotherapy* IVT Q4W x 3, ~n=15 pts Cohort 4 OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 Cohort 1 OPT-302 (1 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 Cohort 2 OPT-302 (2 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3 Cohort 3 OPT-302 (2 mg) + Ranibizumab (0.5 mg) IVT Q4W x 3, ~n=15 pts *Access to rescue anti-vegf-a Tx Comprises of 4 treatment cohorts of 5 subjects each

11 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% Cohort treatment-naïve Treatment # Naïve Pts # Prior Treated Pts 1 OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) OPT-302 (1 mg) + Ranibizumab (0.5 mg) 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 intercurrent illness unrelated to study drugs.

12 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

13 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 ranibizumab therapy.

14 Mean gain in VA from Baseline (# letters) Mean CST (µm) Combination Therapy: All Patients (Naïve & Prior-Tx) 10 Mean VA gain from baseline at Week Mean decrease in CST from baseline to Week Letters µM OPT Ranibizumab (n=14*) * 1 pt not evaluable at W Baseline Week 12 OPT Ranibizumab (n=14*)

15 Mean gain in VA from Baseline (# letters) Mean CST (um) Combination Therapy: Treatment-Naïve Patients Mean Gain VA from Baseline Mean Central Subfield Thickness um (42.7%) OPT Ranibizumab (n=4) 0 Baseline Week 12 OPT Ranibizumab (n=4)

16 Mean gain in VA from Baseline (# letters) Mean CST (um) Combination Therapy: Previously Treated Patients Mean number prior treatment injections: 10.5 (range 3 55) Mean Change VA from Baseline 4 letters Mean Central Subfield Thickness 42 um (11%) Week 12 OPT Ranibizumab (n=10) 330 Baseline Week 12 OPT Ranibizumab (n=10)

17 Mean gain in VA from Baseline (# letters) Mean CST (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 Mean VA gain from baseline at Week 12 Mean Central Subfield Thickness letters µM OPT-302 (2mg) (n=5) 0 OPT-302 (2 Nonresue Rescue (2mg) pts (n=3) mg) Non (n=3) 250 Baseline Week 12 OPT-302 (2 mg) Non Rescue pts (n=3)

18 Combination OPT-302 (0.3 mg) + Ranibizumab (0.5 mg) Male aged 64 Occult lesion Prior Treatment: Aflibercept/REGN910-3 x 6 Baseline Week 4 Week 12 VA: 77 letters CST: 365 µm VA: 83 letters CST: 281 µm VA: 79 letters CST: 298 µm

19 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 VA: 74 letters CST: 270 µm VA: 74 letters CST: 258 µm VA: 84 letters CST: 255 µm

20 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 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)

21 Pravin U. Dugel, M.D Managing Partner Retinal Consultants of Arizona LTD Retinal Research Institute LL Phoenix, Arizona Clinical Professor USC Roski Eye Institute Keck School of Medicine University of Southern California Los Angeles, California Physician Executive Director Phoenix Eye Institute Banner University Medical Center Phoenix, Arizona