Exploring new therapies for neovascular AMD

Listen to Lawrence J. Singerman, MD, present The Ronald G. Michels Memorial Lecture during the Current Concepts in Ophthalmology meeting at the Wilmer Eye Institute/Johns Hopkins University. Dr. Singerman's presentation is entitled "Perspectives in the Management of Macular Degeneration."

Take-home

Combination treatment for neovascular age-related macular degeneration is more likely to provide more favorable results by eliminating vascular endothelial growth factor and possibly causing true regression of choroidal neovascularization, reducing the risk of visual loss.

Dr. Singerman

By Liz Meszaros; Reviewed by Lawrence J. Singerman, MD, FACS

Cleveland-Though anti-vascular endothelial growth factor (VEGF) therapy-currently the primary treatment modality for neovascular age-related macular degeneration (AMD)-has changed the game, ophthalmologists and researchers press on for other possible and even better options.

“We still have a way to go with this, and this is why we are looking at other drugs to enhance what we can achieve with anti-VEGF therapy,” said Lawrence J. Singerman, MD, FACS, clinical professor of ophthalmology, Case Western Reserve University School of Medicine, Cleveland.

“We have already made dramatic progress in understanding and treating AMD, allowing us now to maintain and improve vision in many cases that were untreatable just several years ago,” Dr. Singerman said. “This has made managing AMD much more gratifying for ophthalmology professionals and their patients.”

The treatment of neovascular AMD, he noted, has evolved through three eras: the thermal laser era, the photodynamic laser era (which was shorter), and now the pharmacologic era.

“But don’t throw away your thermal laser,” added Dr. Singerman, also professor of clinical ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami.

“I have many patients [whom] I treated with one thermal laser treatment very close to the fovea even decades ago, and they still have decent vision and don’t need monthly anti-VEGF injections,” he said. “Many patients will go many years without the need for further treatment after well-applied thermal laser for extrafoveal choroidal neovascularization.”

Why combination therapy?

A combination of therapies can also work well in some patients, Dr. Singerman continued.

“You can combine thermal laser with anti-VEGF therapy if you have a broad area of choroidal neovascularization (CNV),” he said. “If you are treating someone with anti-VEGF therapy, you could treat the extrafoveal area with thermal laser and cut down on the number of injections you will have to give the patient over the next year or two.

“You will need fluorescein angiography to follow these cases, so don’t throw that away either,” he added. “It’s not all optical coherence tomography.”

Combination treatment is more likely to provide more favorable results by eliminating VEGF and possibly causing true regression of CNV, reducing the risk of visual loss, according to Dr. Singerman.

The approach may also reduce the number of injections needed, thereby reducing the rate of complications-the most significant of which, including endophthalmitis, retinal detachment, and cataract, relate directly to the frequency of injections.

“Finally, combined treatment may reduce the overall cost of treatment due to a reduction in the number of injections necessary for successful outcomes,” Dr. Singerman said.

Anti-VEGF and other agents

Currently, monotherapy anti-VEGF therapy is the mainstay in the treatment of neovascular macular degeneration and has changed the game for ophthalmologists, Dr. Singerman said.

This therapy has its limitations, however, he noted. The majority of patients do not achieve significant visual gain or final visual acuity of 20/40 or better. Up to 25% to 30% of patients actually lose vision.

Along with anti-VEGF agents, numerous other agents are being studied, including:

E10030 (Fovista, Ophthotech) is an anti-PDGF drug, which-according to a recent phase IIb study, when given with ranibizumab (Lucentis, Genentech)-confers a 62% comparative benefit over Lucentis alone. A phase III study is currently under way.

Squalamine (Ohr Pharmaceutical) is an eye drop that inhibits VEGF, platelet-derived growth factor, and basic fibroblast growth factor using a novel anti-angiogenic mechanism and may reduce the number of intravitreal anti-VEGF injections needed. Squalamine was awarded FDA fast-track designation for wet AMD in May 2012. A phase II study is now under way, comparing placebo with squalamine drops.

ACU-4429 (Acucela) is a visual cycle modulator taken orally and is being evaluated for treatment of geographic atrophy. This agent is designed to be selective for rod photoreceptors and has demonstrated efficacy in multiple preclinical models. A phase IIa study has demonstrated its safety and tolerability and confirmed its biological activity, and a phase IIb/III study is under way.

LFG316 (Novartis) is a complement inhibitor against C5, administered intravitreally. A phase II study is currently under way for the treatment of geographic atrophy.

Anti-factor D (Genentech) is a promising treatment for geographic atrophy and is the first study to show a beneficial treatment effect with a complement inhibitor. The phase II study showed that the drug reduced the rate of disease progression, with a greater reduction in progression rate in subjects with a specific biomarker.

ALG-1001 (Allegro Ophthalmics) is a synthetic anti-integrin oligopeptide that is currently being investigated as a treatment for AMD, diabetic macular edema, and vitreomacular traction. For AMD, a phase Ib/IIa 6-month clinical study evaluating the dose-ranging safety in human subjects showed no significant toxicities across all study metrics.¹

“Further research will maximize our options in treating AMD to minimize the devastating visual consequences of subfoveal CNV and advanced geographic atrophy,” Dr. Singerman said. “Participating in these studies is a privilege, and I encourage those of you who have not to consider doing so.”

Reference

1. Kaiser PK, Boyer DS, Campochiaro PA, et al. Integrin peptide therapy: the first wet AMD experience. Association for Research in Vision and Ophthalmology, 2013. Program Number 3290, Poster Board Number A0141.

Lawrence J. Singerman, MD

P: 216/831-5700

E: [email protected]

Dr. Singerman delivered the Ronald G. Michels Memorial Lecture at the annual Current Concepts in Ophthalmology conference at the Wilmer Eye Institute in association with Ophthalmology Times. He discloses research support and/or serves on the advisory boards with Acucela, Alcon Laboratories, ArcticDx, Genentech, National Eye Institute, Ophthotech, Novartis, Ohr Pharmaceutical, and Valeant Pharmaceuticals.

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