Glaucoma
Treatment strategies for glaucoma

At a glance

• Prostaglandins are first-line, gold standard therapy for glaucoma • Compliance continues to be a primary concern • Despite promising drug delivery options (drug eluting lenses, subconjunctival injections), safety is primary concern • Surgery remains tertiary management strategy • Among novel therapeutics in development: cannabinoids, seratonergics, Rho kinase inhibitors

The prostaglandin class remains the gold standard for treatment, and will be for the immediate future

There is little argument that when it comes to glaucoma medical therapy, the prostaglandin class of drugs is the gold standard, much like trabeculectomy is the gold standard for surgical procedures. When it comes to patient management, “The large majority of patients want to try medications before they will opt for surgery,” said Thomas K. Mundorf, M.D., Charlotte, N.C. “And in that case, we’re looking at prostaglandins as the first-line therapy.” In the recent past, a couple of combination prostaglandin-beta blocker drugs have been approved that offer slightly more IOP lowering than either drug used concurrently.
“When we look at the past few years, there’s been a continuation of the products we’ve had available and an incremental improvement phase, where each class of drugs has had slight improvements,” said Robert J. Noecker, M.D., M.B.A., vice chair, University of Pittsburgh Medical Center Eye Center, Pittsburgh. “Prostaglandins have become the newest gold standard in glaucoma pharmacotherapy,” said Louis B. Cantor, M.D., Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education and vice chairman, Education, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis. “But we still need better drugs for glaucoma. We’re nowhere near having the perfect drug.”
Some time during 2011, several of the prostaglandins will have generic competition, which may not be the ‘savior’ they have been in other classes for Medicare, however.
“We’ll then have generic competition in every class of glaucoma drugs currently available,” said Kuldev Singh, M.D., professor of ophthalmology and director, Glaucoma Services, Stanford University School of Medicine, Palo Alto, Calif.
Dr. Singh does not expect the introduction of any “amazing breakthrough” medications for glaucoma in the near future, and that “medical therapy is not going to change much” as a result of the generic competition. “While we may not have the perfect drug, the risk-benefit profile with the prostaglandin analogs make them hard to beat,” he said.
Dr. Singh pointed out that it would be important to make certain that the generics work as well as branded medications in the prostaglandin class and is hopeful that there will be comparative studies to assess equivalence once the generics are available. “Prostaglandins are the gold standard, and I would be surprised if that changes within the next five years,” he said. “I would also be surprised if laser trabeculoplasty replaces prostaglandin use as the preferred first line therapy for most patients in that same time frame. Additionally, there is little data on how well prostaglandins can control IOP if laser is used first and is not effective, he said. Dr. Mundorf added the combination drugs are also gaining acceptance (see sidebar), for several reasons. Among them: Although the IOP decrease is minimal when using adjunctive therapy, it may be enough for a particular patient. Second, Dr. Mundorf added, the co-pay from insurance may be similar, “so it’s like they’re getting a beta-blocker for free.”
The introduction of generics to the glaucoma prostaglandin class will likely lower the price for the branded products, but the amount of such reduction may not as be great as one would expect, Dr. Singh said.
“I have been surprised by the high cost of some present day generics and the extent to which consumers will benefit from the availability of generic prostaglandins remains to be determined,” he said.

Silent disease

Epidemiologically, the overwhelming majority of those being treated with intraocular pressure lowering medications in the United States don’t go blind from the disease, Dr. Singh said.
“The big picture is that most prevalence based surveys suggest that only half those affected even know they have glaucoma and of those who know, many are probably not receiving therapy or are taking their medications intermittently,” he said. Given the low proportion of patients who have been identified and are getting appropriate care, the rates of glaucoma blindness are surprisingly low. This is the reason why Dr. Singh believes that glaucoma will remain a disease predominantly treated medically rather than surgically. “Even if we come up with a blebless glaucoma surgical procedure that works, it would have to be very very safe to change the current paradigm of surgery being reserved for those who fail medical therapy despite all of the limitations of present day medical therapy,” he said. “You may, however, see an increasing use of safer glaucoma procedures adjunctively with cataract surgery in patients who are on medical therapy for glaucoma at the time they present for cataract removal.”
He believes that a “novel drug delivery system could have an impact but it would have to be effective and minimally invasive.” “I just can’t picture a scenario where patients with ocular hypertension or mild glaucoma, the two groups that epidemiologically make up the majority of those undertreated, would be willing to have regular invasive procedures to deliver drug,” he said. Topical medical therapy for glaucoma may be cumbersome but, for the most part, “is safer than surgery and any novel drug delivery system will have to match the safety profile of eyedrops,” Dr. Singh said. “Safety will always come first for the majority of those receiving glaucoma care who have a low likelihood of functional vision loss for the disease over their lifetimes,” he said. “This is why millions of patients receive eye drops for glaucoma and the annual number of surgical procedures performed for glaucoma can be counted in the tens of thousands.”

Drug delivery

Novel drug delivery systems to treat glaucoma, such as drug-eluting contact lenses or subconjunctival injections, “are of great interest,” Dr. Mundorf said. “We’re looking at them to see if they can help compliance.”
The introduction and rapid acceptance of intravitreal injections for age-related macular degeneration has “made it easier for us to accept that as a means to give glaucoma medications,” he said. Subconjunctival injections are not without their own set of questionable outcomes, though: “We need to know how the drug is being released, how efficacious it is to deliver it directly into the aqueous humor, how often we’ll need to re-inject,” Dr. Mundorf said. Novel drug delivery systems “are certainly a major issue,” Dr. Cantor said. “We all recognize all too well the challenges the current delivery system presents to the patient. The drops are hard to instill properly, and compliance remains a large issue. It’s difficult, and multiple studies have show how poorly patients are with compliance. It’s even worse once you’ve added an adjunctive medication to the mix.” He added drug-eluting contact lenses, or any product that can offer sustained release of the drug “can remove some of that burden for the patient.”
Before endorsing newer delivery systems, Dr. Singh said, “We should have confidence that the safety and efficacy of such systems are comparable to eye drops. If you can remove the need to give eye drops and match the safety and efficacy of contemporary medical therapy, this will definitely change what we do but this is more difficult to achieve than one might think.” It’s doubtful there will be “a new drug delivery system on the horizon that will change the current paradigm within the next five years,” Dr. Singh said.
Any delivery system—punctal plugs, subconjunctival injections, drug-eluting lenses—will continue to show promise, Dr. Cantor said. “Which of those approaches will end up being the most useful? We just don’t know. It will have to be something that is not invasive, is reversible and titratable, can offer a lot of promise in lowering IOP,” he said. “For the foreseeable short-term future, medical therapy is the primary approach to glaucoma management for the majority of patients.” Dr. Noecker believes how drugs are delivered will change glaucoma treatment strategies in the long-term. “We need to conquer the compliance problem,” he said. QLT Therapeutics (Vancouver, British Columbia) has been studying latanoprost in a punctal plug delivery with “OK” data, Dr. Noecker said. Dr. Mundorf added reports on punctal plugs “have shown the effects are not as good as the drops alone.” Prostaglandins offer efficacy in the majority of patients, with about a 25% reduction in IOP from baseline, Dr. Noecker said. “With all drug delivery systems you have to worry about failure in therapy. If the dosing is right, they can work well, but with prostaglandins there’s a narrow window for treatment, but if the drug is hyperdosed, these drugs won’t longer IOP as well,” he said. Even punctal plug delivery is not that simplistic as they can dislodge and present a new set of problems.
“It’s a pretty benign strategy to take an eye drop every day,” Dr. Noecker said. “Drug delivery will definitely be a player in the future, but eye drops are not going away. Sustained delivery will be helpful for those who can’t use eye drops. Injections take the compliance issue off the table completely.”
He said surgery will remain the third (and final) management strategy; only when less risky procedures are developed will they become more readily accepted earlier in the treatment process for the majority of patients.
“There is a lot of interest and creative thinking around surgical devices for glaucoma,” Dr. Cantor said. “If we could reliably lower IOP surgically with a low morbidity long-term, would that be a viable challenge to medical therapy? Absolutely. The main reason surgery isn’t done earlier is the risks associated with it, like filtering blebs, etc.”
If researchers can agree on the most efficacious place for an injection, they may become a truly viable option, Dr. Mundorf said. “You have to at least match the efficacy of topical administration. That will vary, depending on where the drug is delivered—sub-Tenon or anterior chamber or posterior chamber,” he said. “These are questions that need to be asked. Putting glaucoma drugs directly into the eye may be a procedure that can save patients money as well, as it would be covered by insurance and not Part D.”

Novel therapeutics

Although it is unlikely any of the therapeutics being researched currently will be as successful in managing IOP as the prostaglandins have been, development of the Rho kinase inhibitors is showing promise. Rho-kinase (ROCK) is an outflow drug that affects the trabecular meshwork, Dr. Cantor said. “As we’ve evolved, medications have focused on aqueous suppression and uveoscleral outflow. We’ve gotten away from the trabecular outflow, and for good reason—most of those drugs, such as pilocarpine, needed four times daily dosing,” he said. “Most therapy should focus on improving trabecular outflow. [Studies] have suggested that pressure-sensitive outflow is where we’re going to get the greatest effect and most stable pressure reduction.”
The most common cause of glaucoma is an underlying resistance to aqueous outflow in the trabecular meshwork, and the ROCK inhibitors may be successful at decreasing the resistance, he added. “Rho-kinase is very interesting to me,” Dr. Mundorf said, who noted most companies working on the ROCK inhibitors are doing so outside the country (with the notable exception of Inspire Pharmaceuticals [Durham, N.C.], which just completed a Phase 1 study of its Rho-kinase compound). Others working on the drug class include Novartis (Basel, Switzerland), Senju (Osaka, Japan), Santen (Napa, Calif.), and Kowa (Torrance, Calif.). “There’s been some good results reported,” he said. “But there have also been side effects, some issues with tolerability, probably one or more of those in development is going to need reformulation. We’re a few years away, but the Rho-kinase drugs do appear to work in the meshwork,” Dr. Mundorf said. If the average IOP drop is around four points, “they may prove useful in conjunction with another drug,” Dr. Mundorf said. “They don’t have to beat the prostaglandins in terms of efficacy to be useful. They set the bar extremely high. It doesn’t mean the next group of drugs being developed has to get over that bar. If they can add to what we have with a better safety profile, or if they can help in the compliance arena, that will be advantageous.”
Dr. Singh believes that the ROCK class has potential, but more likely as an adjunctive therapy to prostaglandins rather than a competitive class for first line use. He acknowledged that there just isn’t enough data available to make accurate predictions on the impact of this class on current medical therapy.
Two other novel classes of drugs, cannabinoids and seratonergics, are also being studied as treatments for glaucoma. “The cannabinoids have been looked at for a long, long time,” Dr. Cantor said. “The prostaglandins are actually cousins to the cannabinoid class. They’re all derived physiologically through fatty acids. The problem with the cannabimimetics is that in general, they’re not an effective class; there’s rapid tachyphylaxis, for one. Then there are the formulations; smoking something is a horrible drug delivery system. To date, it just hasn’t lived up to some of its expectations.”
“Cannibimemetics increase aqueous outflow but can also have effects on blood flow,” Dr. Noecker said. “If it can be shown these drugs bring something else to the table, then they’ll be beneficial. If they can be used in conjunction with prostaglandins, then they’ll be accepted more. But to date, no one knows if the preset forms we have available work in managing IOP.”
Dr. Singh goes one step further, adding that he doubts any glaucoma medication that does not work by lowering IOP will be approved within the next five years. The regulatory barriers to proving neuroprotection or vasoprotection with topical or systemically delivered medications are very high. We need better biomarkers that predict clinical outcomes before we can conduct studies of new compounds that directly preserve the optic nerve, in reasonable time frames.” Singh added. Other classes of drugs, such as the serotonergics, have been studied for numerous years, “but certainly more so in the last decade,” Dr. Cantor said. “How effective they are has yet to be seen. The serotonin class, along with the melatonin-related drugs, may be able to reduce the aqueous suppression and may be an effective treatment if that’s shown to be the case. “The problem with a log of the newer drug classes being investigated is that the bar was set so high with the prostaglandins, the newer drugs can’t attain those reductions. So they’re going to have to offer something like fewer side effects—no red eye, for example—to be broadly accepted,” Dr. Cantor said. Five years from now the story might be different, Dr. Noecker said. “I think something will pop through as better than the prostaglandins, but I don’t think any of us knows what that will be,” he said.

Editors’ note: Dr. Mundorf has financial interests with Allergan (Irvine, Calif.) and has received research support in the past from most major glaucoma medication developers. Dr. Noecker has financial interests with Alcon (Fort Worth, Texas) and Allergan. Dr. Cantor has financial interests with Alcon, Allergan, Merck (Whitehouse Station, N.J.), Pfizer (New York), and QLT Therapeutics (Vancouver, British Columbia). Dr. Singh has financial interests with Alcon, Allergan, and Santen (Napa, Calif.).

Contact information

Cantor: 317-274-8485, lcantor@iupui.edu
Mundorf: 704-334-3222, tommundorf@aol.com
Noecker: 412-526-1757, noecrj@upmc.edu
Singh: 650-575-8849, kuldev@yahoo.com