• A dose-response relationship of increased gains in visual acuity (VA) was shown with ascending dose levels of OPT-302
• OPT-302 is also being studied in wet AMD patients

Opthea Limited (ASX:OPT), a clinical-stage biopharmaceutical company developing innovative biologic therapies to treat retinal diseases, today announced positive data from the Phase 1b dose escalation study of OPT-302 for patients with diabetic macular edema (DME).  The study evaluated three escalating dose levels of OPT-302 (0.3, 1.0 or 2.0 mg), a novel VEGF-C/D ‘Trap’ therapy, in combination with aflibercept (Eylea®, 2.0 mg) administered once every 4 weeks for a total of 3 intravitreal injections in 9 patients with persistent central-involved DME despite sub-optimal responses to standard of care anti-VEGF-A therapy.

Eyes with persistent DME sub-responsive to multiple prior anti-VEGF-A injections demonstrated visual and anatomic improvement at 12 weeks following conversion to OPT-302 combination treatment.  A dose-response relationship of increased gains in visual acuity (VA) was shown with ascending dose levels of OPT-302 combination treatment which also produced reductions in retinal swelling.

“Alternative approaches such as combination therapies are needed for treating patients with DME who have persistent macula swelling and vision loss despite treatment with standard of care,” says David Boyer, MD, Clinical Professor of Ophthalmology at USC/Keck School of Medicine and principal investigator on the trial. “I am highly encouraged by the evidence of efficacy and continued favourable safety profile for OPT-302 combination therapy which has potential to benefit the many diabetic patients who have limited responses to anti-VEGF-A treatment.”

Patients enrolled in the study had a history of diabetes with a mean duration of 14.1 years and persistent DME despite receiving a mean of 6.3 prior anti-VEGF-A injections.  The mean change at week 12 from baseline in best corrected VA (BCVA) across all OPT-302 combination therapy dose groups was a gain of +7.7 letters (baseline of 65 letters) with a corresponding mean reduction in central subfield thickness (CST) of -71 µM (baseline of 434 µm).  A dose-response relationship of improved visual acuity at all time-points from baseline to week 12 was demonstrated with ascending dose levels of combination treatment with BCVA gains of +3.0, +5.7 and +14.3 letters seen at 0.3 mg, 1.0 mg and 2.0 mg of OPT-302 respectively. A similar dose-response was observed in the proportion of patients gaining ≥ 5 letters in BCVA, with 33% (1/3), 67% (2/3) and 100% (3/3) of patients gaining 5 or more letters in each of the respective 0.3, 1.0 and 2.0 mg dose levels of OPT-302 in combination with aflibercept (2.0 mg).
 
The demonstration of a dose response relationship for OPT-302 combination treatment to improve visual acuity in patients with persistent DME in the Phase 1b study together with biological responses on anatomic measures in both DME and wet AMD lesions indicates that pan-VEGF (A, C and D) inhibition may offer benefits that exceed the inhibition of VEGF-A alone.  OPT-302 combination therapy achieves more complete suppression of the VEGF/VEGFR pathway by blocking all members of the VEGF family of growth factors, including VEGF-A, VEGF-C and VEGF-D.

Dr Megan Baldwin, CEO and Managing Director of Opthea, commented “We are very encouraged by the results of this Phase 1b dose escalation study in patients with persistent DME.  Together with previously reported results from our Phase 1/2a trial in wet AMD patients, we have now demonstrated a well-tolerated safety profile of OPT-302 in combination with aflibercept and ranibizumab (Lucentis®) and promising signs of clinical activity in both wet AMD and DME patients.  Our data suggests that VEGF-C/D blockade may provide additional clinical benefit over standard of care anti-VEGF-A therapy.  To that end, we look forward to reporting outcomes from our two international, multicentre Phase 2 trials that are currently ongoing and actively recruiting patients with newly diagnosed wet AMD and persistent DME despite prior anti-VEGF-A therapy.”

OPT-302 is a soluble form of vascular endothelial growth factor receptor 3 (VEGFR-3) or ‘Trap’ molecule that blocks the activity of two proteins (VEGF-C and VEGF-D) that cause blood vessels to grow and leak, processes which contribute to the pathophysiology of retinal diseases.  Opthea is developing OPT-302 for use in combination with inhibitors of VEGF-A (eg. Lucentis®/Eylea®).  Combination therapy of OPT-302 and a VEGF-A inhibitor achieves more complete blockade of members of the VEGF family, blocks mechanisms contributing to sub-optimal response to selective VEGF-A inhibitors and has the potential to improve vision outcomes by more completely inhibiting the pathways involved in disease progression.

Opthea has completed a Phase 1/2a clinical trial in the US investigating OPT-302 wet AMD patients as a monotherapy and in combination with Lucentis®.  The trial was conducted under an FDA approved IND at 14 US clinical sites.  The purpose of the trial was to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics of OPT-302 administered as monthly intravitreal injections for 3 months with and without Lucentis® in patients with wet age related macular degeneration (AMD).  Of the 51 patients enrolled, 25 were treatment naïve and 26 had received prior intravitreal anti-VEGF-A therapy.