PRESENTATION FROM THE RETINAL PHYSICIAN SYMPOSIUM

Treatments on the Horizon for AMD Highlighted at RPS

Research is going beyond anti-VEGF to novel approaches to wet and dry AMD.

William F. Mieler, MD, chair of the Department of Ophthalmology at the Pritzker School of Medicine of the University of Chicago, spoke at the Retinal Physician Symposium in Fort Myers, FL, about several treatments under development for the treatment of age-related macular degeneration (AMD). Coverage of small interfering RNA, vascular endothelial growth factor (VEGF) inhibitors, and combination therapy having been covered by his colleagues, Dr. Mieler proceeded to discuss tubulin-binding agents, squalamine gene therapy, radiation therapy, and antisense molecules (all for exudative AMD), as well as experimental treatments for dry AMD.

ORGANIC AGENTS

Dr. Mieler began by discussing tubulin-binding agents. The agent was originally derived from the African bark willow and was used by Zulu warriors many years ago," Dr. Mieler said, noting tubulin's efficacy in poisoning arrows. As an ophthalmic therapy, tubulin is administered intravenously and is converted into an active drug in the endothelial cells. Describing how tubulin-binding agents inhibit angiogenesis, Dr. Mieler said the agent "disrupts the cytoskeleton of new blood vessels, which are new and not mature, so it causes endothelial cells to round up and collapses the lumen."

Dr. Mieler then spoke briefly about squalamine, noting its derivation from shark cartilage. "It inhibits endothelial cell migration, VEGF signaling, endocrine expression, and skeletal expression," Dr. Mieler said, describing its mechanism of action. Pointing out that the number of 3-line gainers in phase 2 trials with squalamine were in the range of 4% to 5% while ranibizumab (Lucentis, Genentech) is producing 3-line gainers in the 40% range, Dr. Mieler said, "Squalamine studies that were done in the past probably will not be forthcoming."

Dr. Mieler turned next to GenVec, Inc., a Gaithersburg, MD-based company that develops gene therapies, and he described how one of GenVec's products in development, GV-003.001, a gene coding for pigment epithelial-derived growth factor (PEDF) that inhibits neovascularization and may have potential as a neuroprotective for photoreceptors as well as the retinal pigment epithelium (RPE). "This certainly is quite exciting," Dr. Mieler said.

GENETIC APPROACHES

Retinostat gene therapy, a gene delivery system that introduces angiostatic genes, endostatin, and angiostatin into RPE cells, was Dr. Mieler's next topic, which he quickly explained using an existing murine model and indicated human trials may be forthcoming. He then turned to radiation therapy, focusing on devices by NeoVista (Fremont, CA) and Theragenics (Buford, GA), which are using isotopes of strontium and palladium, respectively, to deliver two-level radiation to the retina. The NeoVista device, Dr. Mieler reported, has improved vision by 3 lines in 37% of patients in clinical trials in 1 month and in 42% of patients in 2 months.

Discussing antisense therapy, Dr. Mieler called attention to work by iCo Therapeutics (Vancouver, British Columbia) and TargeGen (San Diego). Speaking of TargeGen's TG 100801, Dr. Mieler said, "It's been described as having a dose-related response through a single drop. Applied topically, it's once against touted to reduce leakage more than bevacizumab (Avastin, Genentech) and pegaptanib sodium (Macugen, OSI/Pfizer). Dr. Mieler touched briefly on the role of inflammation in wet AMD and pointed to small α-5-β-1 antagonist under development that has shown proof of being effective in vivo. "So," Dr. Mieler said, "we're looking at a number of agents that can be delivered not only intravitreally but certainly topically or, potentially, transsclerally."

The last wet AMD treatment Dr. Mieler discussed was ATG003, under development by CoMentis, Inc. (South San Francisco, CA; formerly Athenagen, Inc.). Of this topical formulation, Dr. Mieler said, "This once again certainly is highly concentrated in the retina, has negligible systemic exposure, and certainly has potential once again in terms of blocking angiogenesis."

Turing to dry AMD therapies, Dr. Mieler said, "We are certainly looking at a number of things that potentially can either prevent the progression of dry into wet disease or potentially even involve the type of dry disease." He gave credit to Emily Y. Chew, MD, and her presentation on the AREDS/AREDS 2 studies, and then discussed anecortave acetate, summarizing the drug's results in treating AMD as "somewhat equivocal."

Dr. Mieler then reported on the Anecortave Acetate Risk-reduction Trial (AART), which enrolled 2600 patients for juxtascleral injections of anecortave and will be followed until 2009. "So we have to wait a few more years to see if this truly reduces the risk of neovascularization," Dr. Mieler said.

OTHER DRY AMD THERAPIES

Dr. Mieler discussed encapsulated cell technology, being developed by NeuroTech USA (Lincoln, RI) with their NT-501 implant, which contains human RPE cells secreting ciliary neutrophic factor. Dr. Mieler said, "This may lead to further studies in the realm of AMD patients looking at patients who have dry, atrophic disease as to whether we can actually improve function with these engineered RPE cell implants.

Dr. Mieler also discussed OT-51 and OT-674, both being studied by Othera Pharmaceuticals, Inc. (Exton, PA). OT-551, developed for treatment of cataracts, is currently in dry AMD trials. "The rationale for use of OT-551," Dr. Mieler said, "is to impede progression of dry AMD. Oxidative and inflammatory damage to the RPE cells and photoreceptors occurs in dry AMD and is thought to contribute to vision loss. As has been shown in studies with light-induced damage to rats, the damage was preserved in rats exposed to OT-551. And in similar fashion, OT-674 has shown some similar results in preservation of the anatomic function of the retina."

A BRIGHTER FUTURE

Finally, Dr. Mieler discussed rheotherapy, "I think we're all aware of studies done previously that had somewhat equivocal results because of incomplete data," Dr. Mieler said. "More recent studies have shown more promising results in OccuLogix, Inc. [Boston]."

"So we've come a long way," Dr. Mieler said in conclusion. "Twenty-five years ago we have only the MPS laser therapy, which, as we know, was quite destructive. In April 2000, PDT came on board, lived a relatively short life, but yet is still ongoing as a form of combination therapy. December 2004, pegaptanib came on board, and July 2006 ranibizumab came onboard. In 2007 and after, we have lots of things to look forward to." RP