Long-term delivery strategies for neovascular AMD

Take-Home

The chronicity of neovascular age-related macular degeneration and the burden of frequent intravitreal anti-vascular endothelial growth factor injections are driving research to develop long-term delivery therapeutic strategies.

By Cheryl Guttman Krader; Reviewed by David S. Boyer, MD

Los Angeles-The development of strategies able to provide longer-acting therapeutic delivery for neovascular age-related macular degeneration (AMD) is an area of active research with some promising technologies now in clinical trials.

However, the viability of these approaches awaits further study that establishes their efficacy and safety, especially considering the effects of chronic anti-vascular endothelial growth factor (VEGF) therapy are unknown, according to David S. Boyer, MD.

“There is not a retinal specialist who would not like to have a system for treating neovascular AMD that would eliminate the burden of frequent injection while maintaining the same vision benefit,” said Dr. Boyer, clinical professor of ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles. “However, there are significant barriers to retinal drug delivery.

“While there are agents being investigated that are based on topical or episcleral drug delivery, these approaches may have limitations,” he said.

Approaches

Intravitreal implantation of a device encapsulating VEGF receptor Fc-fusion protein-releasing cells (NT-503, Neurotech) is one approach for achieving long-term therapeutic delivery to treat neovascular AMD.

The encapsulated cell technology device is implanted in the vitreous through a tiny scleral incision and anchored by a single suture. It has a semipermeable membrane allowing for outward diffusion of the drug plus other cellular metabolites and inward diffusion of nutrients to support cell survival while protecting the contents from host cellular immunologic attack.

The VEGF receptor Fc-fusion protein is 20-fold more efficient at neutralizing VEGF than ranibizumab, and studies in rabbit eyes demonstrated constant release for up to 1 year.

The technology is being evaluated in a phase I/II clinical trial.

A microelectromechanical system offers another interesting approach to achieving chronic intravitreal drug delivery.

The device has an electrolysis chamber with electrolysis actuation to release the desired volume of drug solution, and a drug reservoir with a refill port. The reservoir is implanted in the subconjunctival space, and a flexible cannula is inserted through an incision into the posterior segment.

The Port Delivery System (ForSight Vision4) is another refillable device in development.

The delivery system is placed through the pars plana on the outside of the sclera and delivers drug into the vitreous cavity through a small tube. The procedure for device implantation requires a trip to the operating room, but no sclera sutures are required, and the device is easily refilled in the office setting.

ForSight Vision4 is collaborating with Genentech to develop this technology for intravitreal delivery of ranibizumab, which has entered clinical testing.

Genentech is also collaborating with SurModics in the development of biodegradable ranibizumab-loaded microparticles. This technology is expected to provide drug delivery for a period of 4 to 6 months, although it has not advanced into clinical development.

Other techniques in development-including microneedles and microcatheter delivery (iTrack, iScience Interventional)-target drug delivery into the suprachoroidal space. However, of all of the approaches, gene delivery is probably the most exciting, and there are a number of companies working in this space, said Dr. Boyer.

As an example, he cited data showing long-term VEGF suppression after subretinal delivery of AVA-101 (Avalanche Biotech)-a platform based on adeno-associated viral vector delivery of a gene for an anti-VEGF protein.

David S. Boyer, MD

E: vitdoc@aol.com

Dr. Boyer is a consultant/advisor to Alcon Laboratories, Alimera, Allergan, Genentech, Neurotech, Regeneron, and Ohr Pharmaceuticals, and a speaker for Alcon, Allergan, Genentech, and Regeneron.

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