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Numerous potential treatments are in the pipeline for wet age-related macular degeneration.
New York-Numerous potential treatments are in the pipeline for wet age-related macular degeneration (AMD), including innovative approaches that look beyond the current therapies that inhibit existing vascular endothelial growth factor (VEGF) and address other points in the VEGF cascade. Jason S. Slakter, MD, reviewed these phase I emerging therapies.
"There are some very effective drugs that are approved and off-label use of other drugs that are directed to attack VEGF when it is freely diffusing before binding to the receptor," he continued. "However, there are other ways of controlling this process."
Investigators are looking upstream of where VEGF is produced. One of the key steps in the cascade leading to production of VEGF is the molecule mTOR (mammalian target of rapamycin).
"This is a key strategic protein kinase that regulates a number of downstream molecules including VEGF," Dr. Slakter said. "A molecule called sirolimus (rapamycin, Macusight/Santen) attacks mTOR. In preclinical studies, rapamycin is anti-inflammatory, anti-angiogenic, anti-proliferative, and anti-fibrotic. Sirolimus has been very exciting in preclinical AMD studies."
Phase I testing of sirolimus has shown some positive effects. The drug seems to have extended-release properties and can be injected subconjunctivally and intravitreally. When delivered by both routes in a phase I study of 23 patients with advanced AMD, short-term visual improvement along with a short-term decrease in retinal thickening was seen on optical coherence tomography. Phase II clinical trials of the drug are underway; 20 previously untreated patients with AMD are enrolled. The study will compare the effects of subconjunctival versus intravitreal delivery.
Another molecule being used for targeting the upstream processes is PF-4523655 (formerly RTP801i-14) (Quark/Pfizer), a small interfering RNA. This molecule may be able to target the REDD1 molecule and suppress the production of VEGF and mTOR. A phase I/II clinical trial showed short-term decreased retinal thickness and improved visual acuity.
"The results suggest that there is biologic activity by targeting the upstream pathway," Dr. Slakter said. The drug is in phase II trials.
Another potential area of treatment is the VEGF receptors on vascular endothelial cells, and some early preclinical studies are looking at ways to block them.
In addition, integrins, a family of heterodimeric proteins, are being investigated. These proteins have a role in signaling and modulation of downstream kinase signaling pathways and they are a great target to explore, Dr. Slakter said.
"An interesting property of integrins is that when they are blocked, regression of vessels that are already present may occur," he said.
Volociximab (Ophthotech), a chimeric IgG4 monoclonal antibody against α5β1 integrin, has been shown in preclinical studies to suppress choroidal neovascularization growth and leakage. Phase I clinical trials are underway.
Downstream in the cascade, after VEGF attaches to its receptors, tyrosine kinase inhibitors are being investigated. Pazopanib (GlaxoSmithKline) is one of the drugs being explored, as are oral and extraocularly delivered drugs.