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Cellular Strategies: Protect the Nerve
Is neuroprotection just a marketing ploy—or a valid therapeutic option? A look at the next generation of glaucoma therapy.
Lowering IOP isn’t enough. On one hand, reduction of IOP is the only scientifically proven—and the only FDA-approved—treatment for glaucoma. But specialists now realize that lowering IOP provides only a partial solution to treating this blinding disease.
Thus, the search is on for new therapeutic avenues. The leading contender? Neuroprotection. Neurorepair also is being studied, as are a bevy of new drugs (see “Bringing Cells Back to Life” and “A Peek at the Pipeline” below).
Not a Pressure Disease
Investigations into protecting the optic nerve began more than a decade ago, when scientists recognized that glaucoma is a progressive optic neuropathy and not a pressure disease. That was a paradigm shift that triggered the search for a different approach, said Leonard Levin, MD, PhD. “You’re no longer just lowering the pressure; you’re protecting the nerve.”
Now neuroprotection “is everybody’s favorite buzzword,” said Harry Quigley, MD, who began studying retinal ganglion cell death two decades ago. By now, it is understood that retinal ganglion cells, which are responsible for visual signaling from the eye to target areas in the brain, die by apoptosis. The goal of neuroprotection research is to find treatments that interrupt the process that leads to the death of retinal ganglion cells.
The discovery of something that prevents, or even reverses, apoptosis would be radical, given that it would be the first glaucoma treatment that doesn’t involve lowering IOP, Dr. Levin said. “If it’s clinically proven, it will be the first new treatment to work through a different mechanism.”
What makes neuroprotection even more appealing is the recognition that there are limits to lowering IOP. For example, some patients do get worse, even with successful IOP reduction. In the Collaborative Normal Tension Glaucoma Study, for example, 20 percent of patients progressed at three and five years, despite pressure lowering of 30 percent or more.
That deterioration is true of all glaucomas, said Theodore Krupin, MD. “You may be able to lower the pressure, but people still get worse. So the concept of neuroprotection is now directing therapy towards the villain itself—the death of the retinal ganglion cell.”
The concept of neuroprotection isn’t new. Neurologists have conducted numerous large trials and spent hundreds of millions of dollars investigating neuroprotection as a treatment for stroke and head trauma. Until recently, however, they had little success.
The breakthrough came with the drug memantine (Namenda), which was approved last year by the FDA for Alzheimer’s disease. “It took years to show that a drug was apparently neuroprotective in clinical disease,” Dr. Levin noted.
Now, he added, “Everybody is very impatient to find out whether neuroprotection is useful for glaucoma.”
Two Contenders, Three Trials
The brimonidine rationale. Brimonidine (Alphagan), a highly selective alpha2-adrenergic agonist, was developed to treat glaucoma. Administered twice daily, it reduces IOP by 25 to 30 percent in eyes with elevated pressure.
In laboratory experiments, alpha2-agonists have been shown to increase the neurons’ ability to survive in cell culture and animal models of glaucoma. Brimonidine exerted a neuroprotective effect on the rat retina/optic nerve when injected intraperitoneally after experimental injury. Administered orally, it has protected the retinal ganglion cells of rats from ocular hypertensive injury. It also has been shown to help in experimental models of stroke and oxidative stress.
Missing so far, however, is proof that brimonidine, or any other alpha2-agonist, works in humans. “Everything has been done in the laboratory,” Dr. Levin said. “There must be more than a dozen different articles on the use of various alpha2-agonists in cell culture and animal models of glaucoma or retinal neuronal injury. But showing that it works in a randomized clinical trial—that’s the one piece that’s missing.”
Without clinical trials, many ophthalmologists remain skeptical about the drug’s neuroprotective powers, though it already is being prescribed for off-label use as a neuroprotective agent.
The skepticism, Dr. Levin said, translates into the question: Is neuroprotection just a marketing ploy or is it a valid therapeutic option?
The memantine rationale. Memantine, an uncompetitive N-methyl D-aspartate (NMDA) antagonist, is a different class of drug from brimonidine. Unlike the latter, it is administered orally and does not reduce IOP. Memantine works by blocking persistent activation by an excitatory amino acid, glutamate, which is felt to play a role in damage to the retinal ganglion cells.
While NMDA antagonists failed in numerous clinical trials involving stroke or other acute diseases, memantine’s success with Alzheimer’s is considered to bode well for glaucoma. In theory, the same principle that makes the drug effective for Alzheimer’s should apply to glaucoma, said Scott Whitcup, MD. Given that the retina is part of the brain, whatever neuroprotective principles apply to the brain for Alzheimer’s should also apply to neuroprotection in the retina, he said.
Study #1: Brimonidine vs. ALT. In a prospective, investigator-masked clinical trial conducted by Stefano A. Gandolfi, MD, and his colleagues at the University of Parma, Italy, 27 eyes were randomized to 0.2 percent brimonidine twice daily, and 25 eyes were treated with 360-degree argon laser trabeculoplasty (ALT). The patients were followed for 18 months, during which time visual field examinations, IOP readings, visual acuity and optic disc evaluation were recorded every three to four months.
Dr. Gandolfi reported that despite poorer IOP control, brimonidine was more effective than was ALT in reducing field deterioration in progressing human glaucomatous eyes.1
Because of its small sample size, the Gandolfi study is somewhat controversial, Dr. Levin said. But it could carry more weight, depending upon the results of a much larger clinical trial, which is pitting brimonidine against timolol maleate (Timoptic).
Study #2: Brimonidine vs. Timolol. In this four-year, double-masked study, headed by Dr. Krupin, 160 patients with low-pressure glaucoma have been randomized to either brimonidine 0.2 percent or timolol 0.5 percent.
“The aim is to see if visual field stability or progression is different between these two drugs,” Dr. Krupin said.
Dr. Krupin prefers the term low-pressure glaucoma instead of normal-tension glaucoma, because, he said, “There’s nothing normal about these eyes.” He noted that these patients show progressive visual field and optic nerve damage, despite IOP readings in a statistically normal range, usually +/– 21 mmHg. They are useful subjects because at least in some of them, pressure-independent mechanisms may be the primary, and perhaps the only, cause of optic neuropathy. In the Baltimore Eye Survey, for example, nearly half of open-angle glaucoma patients did not have an elevated IOP, suggesting that something other than pressure may be the cause of the optic neuropathy.
The results of the study, which will be closing soon, may reassure the skeptics who contend that animal models are not the same as human subjects. “I’m skeptical, too,” Dr. Krupin said. “The way to prove this is with a large clinical trial. That’s the aim of our study.”
Study #3: Memantine. This drug is being investigated in a second large trial. More than 2,000 glaucoma patients are enrolled in Phase 3 of the trial, which is designed to evaluate the drug’s ability to prevent vision loss.
Allergan began testing memantine before the FDA approved the sale of the drug (to a different company) for Alzheimer’s. But it helps knowing, said Dr. Whitcup, that the drug was safe and well-tolerated. “Now we have positive, Phase 3 data for diseases like Alzheimer’s.”
If the trial, which is expected to end in 2006, proves effective, Allergan claims that memantine will be the first and only oral medication that directly protects the optic nerve in the treatment of glaucoma.
When it comes to maintaining the integrity of the optic nerve, neuroprotection isn’t the only game in town. Researchers are also investigating ways to repair dead retinal ganglion cells. Here’s a brief look at some approaches:
However, it could be years before a new drug comes along that usurps the primacy of prostaglandins, predicted Carl B. Camras, MD. “The prostaglandins have been so effective and well tolerated, it’s going to be very difficult to come up with an improvement soon.”