PERTH, Australia – Melbourne, Australia-based Opthea Ltd. announced positive phase IIb results demonstrating that OPT-302 combination therapy met the primary endpoint of superiority in mean visual acuity gain at 24 weeks compared to Lucentis (ranibizumab, Roche Holding AG/Novartis AG) monotherapy in treatment-naïve patients with wet age-related macular degeneration (AMD).

The company's lead molecule, OPT-302 is a soluble form of the vascular endothelial growth factor receptor 3 (VEGFR3) or "trap" molecule that blocks the activity of VEGF-C and VEGF-D.

"We are ecstatic about results. It showed a highly statistically significant benefit in vision gain in our drug compared to the standard of care," Opthea CEO Megan Baldwin told BioWorld.

"We were hoping for results like this, but that we hit it with such high statistical significance, and that we did so against a control arm that outperformed all other clinical trials we've seen, is quite extraordinary. We're over the moon that now we can move forward into pivotal, registrational phase III development, and firmly believe that OPT-302 will have a significant commercial role in the treatment landscape for wet AMD patients," she said.

The phase IIb, randomized, double-blinded, sham-controlled trial recruited 366 patients with wet AMD who were allocated to two intravitreal doses of OPT-302 (0.5 mg and 2 mg), administered monthly in combination with 0.5-mg Lucentis over 24 weeks, vs. a control group that received standard of care 0.5-mg Lucentis administered monthly.

Patients who received the higher dose of 2-mg OPT-302 combination therapy gained a mean of 14.2 letters of vision from baseline on the Early Treatment of Diabetic Retinopathy Study (ETDRS) standardized eye chart at 24 weeks, compared to 10.8 letters in the Lucentis control group, a statistically significant benefit of 3.4 letters (p=0.0107). The low-dose OPT-302 group had a similar outcome to the control group of gaining roughly 9.4 letters.

The higher-dose OPT-302 combination treatment showed improvements across multiple secondary endpoints: 45% gained 15 or more letters from baseline to week 24, compared to 40.5% of patients in the Lucentis control group. The proportion of patients gaining 10 or more letters was also greater, at 70% vs. 57.8%, respectively. Stable vision was achieved in 99.2% with the higher-dose OPT-302 combination treatment, compared to 96.7% of the Lucentis control group.

About half of the patients receiving VEGF-A therapies for wet AMD are considered nonresponders, Baldwin said, noting that OPT-302 blocks VEGF-C and VEGF-D, which cause vessels to grow and leak and are hallmarks of wet AMD disease progression. Approved therapies such as Lucentis and Eylea (aflibercept, Bayer AG/Regeneron Pharmaceuticals Inc.) inhibit VEGF-A. Opthea will position its therapy as an additive benefit to existing therapies.

Combination therapy of OPT-302 and a VEGF-A inhibitor achieves more complete blockage of members of the VEGF family, blocking mechanisms contributing to suboptimal responses to selective VEGF-A inhibitors and has the potential to improve vision outcomes by more completely inhibiting the pathways involved in disease progression.

"In testing for superiority against very intensive anti-VEGF-A therapy, the bar was set high. Despite this, OPT-302 (2-mg) combination therapy showed statistical superiority for the most accepted and sensitive primary efficacy outcome, mean visual acuity," said Tim Jackson, chief investigator of the study and an ophthalmic surgeon at King's College London. Key secondary endpoints were supportive of the primary outcome, he said.

Excess retinal thickness measured on spectral domain optical coherence tomography was decreased and normalized consistently across all treatment groups by week 24. In the 2-mg OPT-302 combination group, mean central subfield thickness (CST) was reduced by -147 µm, from 414 µm at baseline to 266 µm at week 24. The mean CST was reduced by -134 µm, from 413 µm at baseline to 278 µm at week 24 in the Lucentis control group.

"OPT-302 has the potential to be a game-changer in the treatment landscape, not just for wet AMD but also for other debilitating retinal vascular diseases where there remains a significant unmet medical need for more efficacious therapies," said Pravin Dugel, managing partner of Retinal Consultants of Arizona and clinical professor at the University of Southern California Roski Eye Institute, Keck School of Medicine, and a study investigator on the trial.

"We've really reached the ceiling of anti-VEGF-A monotherapy, regardless of the anti-VEGF-A that is used," Dugel said. He explained that patients can't be injected as regularly as they should with VEGF-A therapy, and that from an efficacy point of view, one-third of patients don't gain significant vision. Up to 40% of patients don't get visual acuity sharp enough to drive, and after two years of treatment, 50% of patients gradually start losing their vision.

Road ahead clear

"We've shown vision gain over and above what patients currently have available, and small gains in patients who lose vision makes a massive difference in patients' lives," Opthea's Baldwin said.

"We are the only drug that has demonstrated significant efficacy above standard of care. A number of other drugs have failed, including big pharma companies, but the reality is, if you can change the efficacy of a drug, you can drive the most benefit," she said.

Baldwin delivered results six months earlier than planned. She said the trial was able to recruit patients much faster than anticipated, and she was able to wind the timeline forward by a quarter.

"This means we now have additional cash runway," she said.

She said she hopes to get feedback from regulators in the European Union and the U.S. on Opthea's proposed phase III program in the next six months.

Opthea is in a strong cash position with roughly AU$20 million (US$13.4 million) in cash and an additional AU$14 million from an anticipated research and development tax rebate later this year.

Opthea is fully funded through the remaining phase IIb trial close-out activities and completion of the ongoing phase IIa study in diabetic macular edema. The company has enough capital to begin phase III registration trial activities.

Baldwin anticipates reporting top-line data from its ongoing phase IIa trial of OPT-302 in patients with persistent diabetic macular edema in early 2020.

Opthea's stock on Australia's Securities Exchange (ASX:OPT) gained 138% following the news; its shares were trading at AU$2.06 by market close Wednesday.

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