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November/December 2004

Cellular Strategies: Protect the Nerve

By Miriam Karmel


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.”

Critical Breakthrough
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.

Looking Ahead
If brimonidine or memantine—or even another drug—proves to be neuroprotective, what’s next?

If this happens, “It will be a huge benefit in providing an additional mode of treatment,” said Dr. Levin. “Right now in glaucoma the only therapy we have is lowering IOP. This will add a whole other way of treating the optic neuropathy.”

Combined therapy. Others agree that a neuroprotective drug is likely to be just one more tool in the glaucoma specialist’s armamentarium.

“I don’t think we will ever get to the point of saying, ‘Forget the IOP,’” said Dr. Krupin, who predicts that neuroprotection will become an adjunct to lowering pressure.

Dr. Whitcup concurred. “The nice thing about neuroprotection is that it’s additive to the other medications. It’s not necessarily one or the other. It’s very complementary, too. It gives patients the potential for better treatment.”

Other applications. Glaucoma neuroprotection research could lead to better treatments for other diseases as well, including macular degeneration or retinal degenerations. “Once you have one neuroprotectant that works in clinical trials, you start thinking, ‘Wait a minute, we should investigate other drugs and other diseases,’” Dr. Levin said. “We’re really at the cusp of a paradigm shift in how we treat otherwise untreatable diseases.”

1 Poster #2298, presented at the Association for Research in Vision and Ophthalmology, Tuesday, April 27, 2004.

Bringing Cells Back to Life

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:

The goal of neuroregeneration/neurorepair is the production of new axons that will reconnect retinal ganglion cells to the central nervous system and restore a normal retinotopic distribution. In other words, the retinal ganglion cells are there, but they’ve lost their connection.

One challenge is that cells die very quickly after they lose their connection, Dr. Levin said.

Gene Therapy
There are two kinds of gene therapy. One involves fixing a mutation; the other entails inserting a retrovirus into a cell to make neuroprotective proteins.

The first reported gene therapy success in glaucoma falls into the second category, as it involved inserting the gene for a neurotrophin into rat cells.1 The findings support the potential feasibility of neurotrophic therapy as a complement to lowering IOP in the treatment of glaucoma.

Stem Cell Research
The burning question is how to bring back retinal ganglion cells that have already died, said Dr. Levin. That’s where stem cell research comes into play.

The hope is to take stem cells from the retina or even the ciliary body of patients—or, alternatively, embryonic human stem cells—and induce them to differentiate into retinal ganglion cells within an eye with a damaged optic nerve.

A difficulty will be in achieving extension of the retinal ganglion cell axons into the optic nerve and then connecting with targets in the brain, assuming that the target neurons are still there.

“We’re much closer to the use of neuroprotective agents in the clinic than we are to neuroregeneration,” Dr. Levin cautioned. “Even in the laboratory, it’s difficult to achieve significant regeneration of the optic nerve.” He predicts that it could be 10 to 20 years before researchers find a way to bring back lost cells in patients.

1 Martin, K. R. et al. Invest Ophthalmol Vis Sci 2003; 44(10):4357–4365.

A Peek at the Pipeline

On one hand, there’s good news: A number of new pressure-lowering agents—as many as 50 to 100—are under investigation. However, finding a hands-down winner among them may be harder than ever.
Drugs under study run the gamut in action:

  • Those that increase outflow. Drugs in this category include cytoskeletal agents, matrix metalloproteinase inducers, adenosine agonists, natriuretic peptides and agents that affect the cyclic GMP (guanosine monophosphate pathway).
  • Those that reduce aqueous flow. Dopaminergic agonists fall into this category.
  • Those with mixed or unclear action. Some agents—such as marijuana, anadamide and tetrahydrocannabinol—might increase outflow and/or reduce aqueous flow.

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.”

He added, “Within the next five years or so, there might very well be another class of agents. But I’m not sure the new [drug] will be an improvement over the prostaglandins.”

Dr. Camras recalled a similar situation after beta-blockers were introduced in the 1970s. “It took another 20 years to find something more effective.”

Meet the Experts

Carl B. Camras, MD  Professor and chairman of ophthalmology at the University of Nebraska, Omaha. Financial interests: None.

Theodore Krupin, MD Clinical professor of ophthalmology at Northwestern University, Chicago. Financial interests: Dr. Krupin’s study is conducted by the Low-pressure Glaucoma Study Group, which is supported by an unrestricted grant from Allergan, which also supplies the medications. He receives research support from Allergan, Merck and Pfizer.

Stefano A. Gandolfi, MD University of Parma, Italy. Financial interests: None.

Leonard Levin, MD, PhD  Associate professor of ophthalmology and visual sciences, neurology and neurological surgery at the University of Wisconsin, Madison. Financial interests: Is a consultant to Allergan and has been a consultant for Alcon, Mitokor, Novartis, Pharmacia, Teva and Santen.

Harry Quigley, MD  Professor of ophthalmology at Johns Hopkins’ Wilmer Eye Institute. Financial interests: None.

Scott Whitcup, MD  Executive vice president and head of research and development at Allergan. Financial interests: Allergan markets brimonidine-purite and will market memantine, if it is approved for a glaucoma indication by the FDA.