New Anti-VEGF Drug Promising for Wet Macular Degeneration

BOSTON — A new antivascular endothelial growth-factor (VEGF) drug, OPT-302 (Opthea), appears to be safe and shows signs of effectiveness in the treatment of neovascular age-related macular degeneration, new research shows.

When the experimental drug is used in combination with currently approved VEGF inhibitors, the potency and durability of the VEGF inhibitors could improve because OPT-302 suppresses different forms of VEGF, said Pravin Dugel, MD, clinical professor at the Keck School of Medicine in Los Angeles and managing partner at Retinal Consultants of Arizona.

"It's creating a lot of buzz," he told Medscape Medical News.

Neovascular macular degeneration is the result of abnormal blood vessels, which grow under the retina, bleeding and leaking fluid. VEGF binds to VEGF receptors in endothelial cells, stimulating angiogenesis. Ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) bind to VEGF-A, which prevents the protein from binding to its receptors, inhibiting angiogenesis.

In clinical trials, these two VEGF inhibitors have improved the vision of many patients with neovascular macular degeneration, but not all patients benefit. This could be because other forms of VEGF also stimulate angiogenesis. In fact, suppressing VEGF-A stimulates the production of VEGF-C and VEGF-D, said Dr Dugel.

Aflibercept (Eylea, Regeneron), which binds to both VEGF-A and VEGF-B, has also been shown to improve vision in some patients with macular degeneration but, again, not all patients benefit.

Currently, no approved drugs bind to VEGF-C or VEGF-D, but OPT-302 inhibits both these forms of the protein.

In a mouse model of macular degeneration, OPT-302 was more effective than a control antibody, and became even more effective when combined with aflibercept.

Trial of OPT-302

Dr Dugel presented results from a phase 1/2a trial of OPT-302 here at the American Society of Retina Specialists 2017 Annual Meeting.

The 51 study participants received OPT-302 at doses of 0.3 mg, 1 mg, or 2 mg. Thirty-eight patients received it in combination with ranibizumab, and 13 received it as monotherapy.

In the combination group, 18 patients had been previously treated with a mean of 17 anti-VEGF-A injections but achieved suboptimal responses, and 20 patients were treatment-naïve. In this group, 73% of the patients had occult lesions.

At 12 weeks, mean improvement in the combination group was 10.8 letters of visual acuity in treatment-experienced patients and 4.9 letters in treatment-naïve patients. In the monotherapy group, mean improvement was 5.6 letters.

In addition, subretinal fluid decreased in the combination group by 51% in treatment-experienced patients and by 83% in treatment-naïve patients.

In treatment-naïve patients in the combination group, choroidal neovascularization decreased from 7.71 mm² at baseline to 2.03 mm² at 12 weeks. In fact, half of these patients had no detectable choroidal neovascularization at 12 weeks. In addition, there was a progressive decrease in both the height and the width of subretinal hyper-reflective material in this group of patients.

Two patients in the combination group developed mild inflammation indicative of anterior uveitis and deemed to be related to OPT-302: one who received the 0.3 mg dose and one who received the 1 mg dose. Ocular emergent adverse events primarily related to intravitreal injections were experienced by 31 patients, but most were moderate and manageable. Two patients died from causes deemed to be unrelated to the study drugs.

There were no dose-limiting toxicities or drug-related serious adverse events.

"This study met its goals," said Dr Dugel, who pointed out that OPT-302 is not being developed to be used as monotherapy, but rather as combination therapy. "Now we're in the process of planning a larger phase 2b study."

There is so much to do on age-related macular degeneration, it's a waste of our time, energy, and money to work on other anti-VEGF agents.

Because there are already three VEGF inhibitors approved for the treatment of macular degeneration, drug companies might want to focus on other pathways involved in the disease, suggested session moderator Joan Miller, MD, from Massachusetts Eye and Ear in Boston.

"There is so much to do on age-related macular degeneration, it's a waste of our time, energy, and money to work on other anti-VEGF agents," she said.

In response, Dr Dugel pointed out that current VEGF inhibitors fall short in both the early and late stages of the disease, and that their effects are not durable.

These results are good news, "but we have to be cautious not to interpret them too broadly without a control group," said Peter Kaiser, MD, from the Cleveland Clinic.

He asked why the study wasn't conducted with aflibercept, which blocks both VEGF-B and VEGF-A.

"You may not want to block VEGF-B, because there is evidence that VEGF-B is neuroprotective," Dr Dugel explained.

But there is some evidence that all forms of VEGF are neuroprotective, Dr Kaiser told Medscape Medical News. And so far, blocking them doesn't seem to cause adverse events.

Dr Dugel reports relationships with 44 medical companies, including Opthea, and has stock ownership in Clearside Bomedical, Digisight, Aerpio, Alimera, Annidis, Macusight, Ophthotech, PanOptica, and TrueVision. Dr Kaiser reports that he has consulted with "just about all these companies" discussed in the session.

American Society of Retina Specialists (ASRS) 2017 Annual Meeting. Presented August 14, 2017.

Follow Medscape Ophthalmology on Twitter @MedscapeEye and Laird Harrison @LairdH

Trial of OPT-302

Dr Dugel presented results from a phase 1/2a trial of OPT-302 here at the American Society of Retina Specialists 2017 Annual Meeting.

The 51 study participants received OPT-302 at doses of 0.3 mg, 1 mg, or 2 mg. Thirty-eight patients received it in combination with ranibizumab, and 13 received it as monotherapy.

In addition, subretinal fluid decreased in the combination group by 51% in treatment-experienced patients and by 83% in treatment-naïve patients.

There were no dose-limiting toxicities or drug-related serious adverse events.

"This study met its goals," said Dr Dugel, who pointed out that OPT-302 is not being developed to be used as monotherapy. "Now we're in the process of planning a larger phase 2b study."