New treatment may usher new era for AMD patients

Winter Haven, FL-A number of new pharmacologic options for exudative age-related macular degeneration (AMD), mostly designed to block different steps in the angiogenic cascade, are in various stages of development and testing, and some may one day be shown to improve outcomes, said Michael J. Tolentino, MD, director of clinical research, Center for Retina and Macular Disease, Winter Haven, FL.

"This is an exciting time for our patients with exudative wet AMD," Dr. Tolentino said.

The treatment objectives for patients with wet AMD are to stop vascular leakage and the growth of new blood vessels.

He added that the way to achieve this goal is likely to involve therapies targeting vascular endothelial growth factor-A (VEGF-A), since wet AMD is characterized by chronic upregulation of VEGF-A. VEGF-A represents a family of VEGF proteins that are differentiated by the length of their amino acid chains. The shorter VEGF isoforms are soluble while the longer isoforms are bound. All these isoforms bind two main VEGF receptors that trigger neovascularization and permeability.

"I look at this whole interaction between VEGF and its receptors as the trigger that kicks off the neovascular cascade," Dr. Tolentino said. "When VEGF-A binds with VEGF receptor 2, this signals the vascular leakage and angiogenesis that results in wet AMD.

"How can we stop the effects of VEGF? Stopping VEGF before it binds to a receptor would prevent it from initiating that trigger," Dr. Tolentino continued. "The other way to do it is to stop it after VEGF has already triggered the whole neovascular cascade and stop the downstream effects of VEGF."

Taking the first approach, VEGF can be stopped before it binds to a receptor by preventing its production through destroying VEGF messenger RNA (mRNA), by neutralizing it once it is made, or by blocking the receptor.

"If you don't stop VEGF before it binds its receptors, you get neovascularization," Dr. Tolentino said.

Protein antagonists stop VEGF after it is made. Agents in this category include pegaptanib sodium (Macugen, OSI/Eyetech Pharmaceuticals), bevacizumab (Avastin, Genentech), ranibizumab (Lucentis, Genentech), and VEGF Trap (Regeneron Pharmaceuticals Inc.). Bevacizumab is the full-length antibody against VEGF and is the parent molecule for ranibizumab.

Pegaptanib is a VEGF aptamer, ranibizumab is an antibody fragment to VEGF, bevacizumab is a recombinant humanized antibody to VEGF, and VEGF Trap is a composite decoy receptor fusion protein that contains portions of the extracellular domains of two VEGF receptors, VEGFR-1 and VEGFR-2, and can bind VEGF very strongly. While they are all anti-VEGF agents, the compounds work slightly differently. Pegaptanib binds only VEGF165, an isoform important in angiogenesis and permeability, while ranibizumab, bevacizumab, and VEGF Trap bind all isoforms of VEGF-A.

These four compounds are in various stages of development and testing.

"Pegaptanib sodium is approved and ranibizumab is in phase III trials. Bevacizumab is being used off-label at this time, and VEGF Trap is starting a phase II clinical trial," Dr. Tolentino said.

Describing the mechanism of action of these compounds, Dr. Tolentino explained that they are injected into the eye and VEGF is taken up and neutralized within the extracellular space.

"If you do not neutralize all the VEGF and some gets through, you will have continued vascular permeability and progression of neovascularization," he said.

The positive side of using protein antagonists to treat wet AMD is the effectiveness of this neutralization process, while the negative side is that a sustained effect can only be achieved through repeated injections.

"It's rather inefficient because there is a lot of VEGF being produced, and you need a molar excess of antagonist in order to neutralize all the VEGF produced," he added.

A mechanism called RNA interference (RNAi) can turn off VEGF before it is made, by destroying its mRNA.

"By destroying VEGF mRNA, you can silence the production of VEGF, which will prevent new vessels from leaking and growing," he said.