Given the expense and risks involved in monthly intraocular injections, companies continue to generate new alternatives for drug delivery. Here are two new approaches currently under development.


An On-Demand Implant

A new device being developed by On Demand Therapeutix (ODTx) purports to overcome many of the limitations of current drug implants by allowing multiple doses of one or more drugs to be placed inside the eye and then released as determined by the ophthalmologist.

John Santini, PhD, president and CEO of On Demand Therapeutics explains how the new device works. "The implant is a small rod made of biocompatible polymers with multiple chambers along its length," he says. "Each chamber is designed to hold a drug, preferably in a solid form such as a powder or pellet.

"The doctor takes a needle or cannula and inserts the device into the vitreous, out of the line of sight," he continues. "No fixation is necessary. After insertion, the physician uses a standard mirrored lens to locate the device. He can see the individual reservoirs, and at later visits can easily tell which ones have released their contents. Using a standard retinal photocoagulation laser, he targets the reservoir he wants to open. One short laser pulse perforates the reservoir wall, allowing the drug to begin diffusing into the vitreous."

Dr. Santini says the company plans to start out with implants carrying a single drug, with uniform doses in the chambers. "You control dosing by how often you activate the reservoirs," he explains. "We think for some typical anti-VEGF molecules, and certainly for steroid molecules, we can create an implant that will provide therapy for a year or more. In the future, if you need to use concomitant therapies involving multiple drugs, you could either use two devices or place the drugs in separate compartments of a single implant." Dr. Santini says that when the device is empty it can remain in the eye.

Robert S. Langer, ScD, David H. Koch Institute Professor at the Massachusetts Institute of Technology, who discussed this technology in his Keynote Lecture at the 2010 meeting of the Association for Research in Vision and Ophthalmology, notes that it has multiple benefits compared to current options. "Current steroid implants continue to release drug at a steady rate for years, even if the patient's symptoms resolve," he says.
"Such constant steroid exposure can lead to serious side effects such as cataracts and glaucoma that may require surgery to resolve. This new approach reduces the need for frequent incursions into the eye and allows the physician better control over drug therapy. That includes the possibility of reducing drug side effects by giving the patient a 'drug holiday.' The multi-reservoir nature of the device also makes it uniquely suited for the delivery of concomitant drug therapies."

"ODTx allows drugs to be administered to the patient as needed, painlessly and safely," adds Gil Kliman, MD, a founder of ODTx and inventor of their intraocular approach. "This is the only existing technology capable of doing this in a non-invasive, physician-controlled manner."

Dr. Santini says that a steroid product could be on the market within a couple of years. "A protein-based macromolecule product that's targeting retinal disease like wet AMD or diabetic retinopathy or uveitis will require more development," he notes. "That could take three to five years."


Using Nanoparticles to Deliver Avastin

Nanoparticles are proving to be a potentially powerful ally in medicine. Nanoparticles composed of gold are especially promising because they're biocompatible and nontoxic (within certain range limits), yet are also highly reactive, which allows them to be coated with therapeutic molecules. They're capable of carrying a much greater quantity of drug per volume of material injected than standard current injections.

In the past several years a team of researchers headed by Kattesh V. Katti, PhD, professor of radiology, physics and medical research, and director of the University of Missouri Cancer Nanotechnology Platform, in Columbia, Mo., has been developing a gold nanoparticle delivery system that can carry bevacizumab (Avastin) to the retina to treat age-related macular degeneration. They refer to the resulting vehicle as "Super Avastin." Results of their work have been presented at several recent ARVO meetings.

In their presentations, Dr. Katti has noted the affinity these nanoparticles have for leaky vasculature in both cancer and AMD. According to published data, in their early clinical trials using an animal model, more than 90 percent of the Super Avastin injected migrated to the retina.

Perhaps most notably, Avastin delivered via nanoparticle appears to remain available inside the eye longer than Avastin delivered by injection. According to their reports, hundreds of Avastin molecules can be attached to a single gold nanoparticle, resulting in the gradual release of the drug. Furthermore, the greater potency of a nanoparticle injection may allow treatment via intraperitoneal injection instead of intraocular injection.
The group's early research found that treatment with this therapy resulted in 80 to 95 percent shrinkage of problematic blood vessels.

To evaluate the relative longevity of Super Avastin in the eye, the group compared the half life of Avastin molecules in Brown Norway rat eyes after injection. In the rats receiving standard Avastin, the drug was found to be present in the rat vitreous at one hour, but not at one week. Rats receiving Super Avastin demonstrated focal areas of fluorescent staining both at one hour and at one week, confirming the long-term, slow release of Avastin.

The group is currently standardizing large-quantity synthesis protocols for the Super Avastin nanoparticle delivery system and conducting experiments to determine how long the Super Avastin can continue to release the drug at the retina.