With AMD on the rise, new retina drugs abound

Pharmacological treatments for AMD and other retinal diseases are about to dramatically reshape the way retina specialists look at the back of the eye, one expert predicts.

The list of new treatment options for retinal disease is growing faster than we retinal specialists can keep up. The landscape is dramatically changing, and we need to be aware of what is available now or is soon to be. This is a welcome fact because the number of patients with age-related macular degeneration will explode as the baby boomers age.

Here are some statistics that help put the baby-boomer phenomenon into perspective. One of three Americans over the age of 75 years will develop AMD. Currently, a new case is diagnosed every 3 minutes. There will be a 20% increase in Medicare beneficiaries by 2010 and a doubling by 2040. While we are worried about attaining perfect vision for our cataract patients, the reality is that many of them will suffer vision loss related to other reasons as they age.

AREDS

Peter K. Kaiser

The first Age-Related Eye Diseases Study (AREDS) demonstrated that taking certain vitamins might help slow the progression of AMD. We have also learned that smokers should not be taking the high-dose beta-carotene, so several companies have been creating “smoker’s versions” of the vitamin supplements.

However, it is important to remember that the AREDS formula is recommended only for category 3 or 4 AMD. Most of us, even we retina specialists, do not understand these categories. Patients with few, small drusen should not be automatically placed on the AREDS formula. We do not really know what the high-dose vitamins might do to patients over the course of 30 or more years, so not everyone should be taking them. They theoretically could lead to problems including liver abnormalities, Alzheimer’s disease or other issues associated with high-dose vitamins.

The easiest way to understand who should receive the AREDS formulation is via a point scheme. The latest information to come out of AREDS is that you can assign points based on the presence of drusen and pigmentary changes to figure out which category a patient belongs in.

First, look for large drusen – bigger than the width of a vein at the disc – and count that as one point in either eye. Then look for either hyper- or hypopigmentation, or non-central geographic atrophy. If you see any of these characteristics, you assign another point to each eye where it is present. If you find neovascular AMD in one eye, that is an automatic two points.

Anyone with two or more points should be on the AREDS formulation.

Macular carotenoids

Your patients will ask about lutein and zeaxanthin, which are macular carotenoids. These seem to work, but they were not included in the first AREDS because at the time they were not available in pill form. Now they are, and they will be included in the AREDS 2 that is being planned. Until then we do not have level 1 proof of efficacy, but I tell my patients to take lutein supplements; for example, if they take Centrum Silver supplements they will get about 6 mg of lutein.

Rheotherapy

The concept of rheotherapy is still unclear to many of us. We don’t really understand how it works or whether it works at all.

With rheotherapy, the patient’s blood plasma is filtered to remove toxic proteins and other substances, theoretically allowing increased blood flow to the macula. It is similar in concept to dialysis.

This has been studied in a randomized clinical trial, the Multicenter Investigation of Rheotherapy for AMD, which enrolled 185 patients with categories 3 and 4 AMD. Early results suggested that this treatment might improve visual acuity. What remains to be seen is if the treatment prevents wet AMD.

As it stands now, rheotherapy is an experimental treatment for dry AMD. Most people in the retina community are still skeptical, pending further study results. As I scientist myself, I certainly want to see more data, and I look forward to the results of the on-going trials.

Macugen for AMD

Pharmacology is the area that is generating most of the excitement in retina these days. It seems that every company, even those that have never had a retina product, are jumping into this. The drug development that is going on in retina right now is amazing, especially when you consider that, for 25 years, all we had was laser for treatment.

There are several new options available for AMD treatment. Macugen (pegaptanib sodium injection, Eyetech/Pfizer), which was approved in December 2004, is an aptamer that acts by blocking a particular isoform of vascular endothelial growth factor.

Macugen blocks only VEGF 165. Much like a Lego piece, Macugen fits that piece precisely. While this is partly why aptamer technology is so perfect, it also means that Macugen does not block other isoforms of VEGF that can cause problems.

According to the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial – the largest to date on AMD – patients lose vision even with Macugen treatment. At the 12-month time point in the VISION study, 70% of the 0.3 mg Macugen-treated patients vs. 55% of the placebo-treated patients lost less than 15 letters of best corrected visual acuity from baseline (P < .001)="" only="" 6%="" of="" patients="" had="" a="" significant="" improvement="" in="" vision="" at="" month="" 12.="" the="" point="" is="" that="" we="" are="" not="" able="" to="" improve="" vision="" with="" either="" photodynamic="" therapy="" or="" macugen="">

An advantage of Macugen is that is has been approved for all lesion types: predominantly classic, minimally classic and occult. A disadvantage is the price tag; Macugen costs $995 per injection, and in the United States we get reimbursed around $250 to $300 per injection. The injections must be done every 6 weeks for at least 2 years and probably longer. In light of this expense, Eyetech is investigating sustained-release molecules that would dispense Macugen for longer periods of time.

Combination therapy

The buzz today is surrounding adjunctive therapies. In the not-too-distant past, we might have told a patient who had 20/400 visual acuity after three photodynamic therapy treatments that the outlook was not hopeful, but now the idea of using Macugen or intravitreal steroids in combination with Visudyne (verteporfin for injection, Novartis/QLT) PDT is emerging. Case series have shown promising results with improved visual outcomes and dramatically lower re-treatment rates. There are several clinical trials exploring combination therapies.

Lucentis

In the wake of Macugen’s approval, there are a few other anti-VEGF drugs in the pipeline, and they are each a little different. These differences will affect how each one works.

Lucentis (ranibizumab, Genentech) binds VEGF at the receptor-binding site, consequently binding to all isoforms of VEGF. Contrast this to Macugen, which blocks only the one isoform, albeit the most pathologic one.

Two phase 3 trials on Lucentis are under way, and the company hopes the drug will reach the marketplace some time in 2007. So far, one phase 3 study, called MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab in the treatment of neovascular AMD), has shown that almost all patients maintained or gained lines of vision after 1 year. More impressive was the fact that 25% to 34% of patients receiving Lucentis had a three-or-more-line improvement in vision. This is an exciting finding because no other AMD treatment has had such positive clinical results.

Another, the ANCHOR study (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization AMD), is comparing two doses of Lucentis to PDT in 423 patients with predominantly classic CNV. Results are expected later this year.

A third trial, called FOCUS (RhuFab V2 Ocular treatment Combining the Use of Visudyne to evaluate Safety), is looking at combination treatment of PDT and Lucentis vs. PDT alone in predominantly classic CNV. The 12-month results reported that more than 90% of patients maintained or improved vision when treated with the combination of Lucentis and Visudyne, compared with approximately 68% of those treated in the Visudyne-only control arm (P = .0003).

Genentech is also conducting an additional phase 3b study to look at alternate dosing regimens. This study, called PIER (a Phase 3, multicenter, randomized, double-masked, sham Injection-controlled study of the Efficacy and safety of Ranibizumab in subjects with subfoveal choroidal neovascularization with or without classic CNV secondary to AMD), with 184 wet AMD patients enrolled in the United States, seeks to establish whether changing the dosing of Lucentis from every month is effective. In this trial, Lucentis is administered once a month for the first three doses followed by injections once every 3 months for 2 years.

The prospect of not having to treat every 4 to 6 weeks – of being able to figure out a dosing regimen on an as-needed basis – is exciting.

Systemic drugs

A systemic VEGF inhibitor currently in trials is the VEGF Trap, from Regeneron Pharmaceuticals. This drug works by combining two VEGF receptors domains with a human Fc fragment to create an antibody-like molecule that binds VEGF with high affinity. It works like a receptor decoy, so VEGF gets into the extracellular space and binds to VEGF Trap instead of its receptor.

The advantage of VEGF Trap is that it binds tighter than either Lucentis or Macugen, and it blocks other growth factors besides just VEGF.

One major disadvantage is that, as a systemic drug, it is administered intravenously. For patients with cardiac or renal problems this is a major drawback. On the other hand, you avoid common problems with injections, such as endophthalmitis, and you can treat both eyes simultaneously.

A phase 1 study of an intravitreal formulation of VEGF Trap is under way to see if the systemic side effects can be ameliorated, but it is unclear if a molecule of this size can be administered directly into the eye.

Another systemic anti-VEGF drug, Avastin (bevacizumab, Genentech), is undergoing trials. Six-month data were reported at the American Society of Retina Surgeons annual meeting in Montreal, showing that patients might not need additional treatments after an initial course of Avastin administered intravenously. Avastin is currently approved for use in colorectal cancer. There have been reports from Bascom Palmer Eye Institute of promising results with intravitreal Avastin.

A third systemic drug for wet AMD, Evizon (squalamine, Genaera), recently entered phase 3 trials. Squalamine – a naturally occurring aminosterol from the dogfish shark – is selectively absorbed by endothelial cells, where it inhibits and reverses the angiogenic process. Basically, squalamine causes apoptosis of the endothelial cells and vessel regression. As with the other systemic drugs, Evizon has produced systemic side effects, so we’ll have to see if these will continue to be an issue in the future.

RNA interference

Another promising area of development involves RNA interference, or RNAi technology, which seeks to “turn off” growth factors at the source, rather than trying to inhibit growth once it has started. An analogy I like to use is a faucet leaking water all over the ground. Using Macugen or Lucentis is like taking a mop and trying to mop up the water. RNAi technology is like turning off the faucet, so there is nothing there to mop up.

Sirna Therapeutics, using the abbreviation for short interfering RNA as its name, has begun a phase 1 trial for its RNAi compound, which it calls Sirna-027. Injected directly into the eye, this compound targets VEGF receptor-1 (VEGFR-1) to shut down activation of angiogenesis.

Another company, Acuity Pharmaceuticals, is working on an RNAi compound called Cand5, which also seeks to shut down VEGF at the source by targeting the VEGF protein. Cand5 safety studies have been promising, and Acuity is initiating a phase 2 trial.

One potential problem with this technology is that VEGF may be needed at low levels for ocular functioning. At this point, we don’t know if this is the case or not, but it is something to consider.

All things considered, if RNAi technology is found to be safe for the eye, it could be a good option.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors, or TKIs, may be more potent than VEGF inhibitors. They are small proteins that work at the VEGF-receptor level to block activation of endothelial cells and retinal pigment epithelial cells.

Many companies have TKIs in the works. The first to enter clinical testing is a TKI from Novartis, which is looking at an oral formulation in combination with PDT.

Anecortave acetate

Alcon has a steroid analogue in trials called Retaane (anecortave acetate). Steroids were one of the first anti-angiogenic molecules described, back when Judah Folkman, MD, invented the field of angiogenesis research.

While steroids have drawbacks, with Retaane Alcon has permanently altered the steroid backbone so that it is devoid of the glucocorticoid activity. It is actually a more potent anti-angiogenic than a steroid. They took the bad part of the steroid out and improved the good part with this drug. Anecortave acetate is an angiostatic cortisene, and the first of its type.

Retaane works further downstream from VEGF inhibitors, VEGF Trap or the RNAi technologies by preventing extracellular matrix breakdown, migration and proliferation of endothelial cells.

Perhaps the most exciting aspect of anecortave acetate is that is can possibly be combined with these other drugs, much like with chemotherapy.

Another good feature is that it is administered not by intravitreal injection, but rather as a posterior juxtascleral depot using a blunt-tipped cannula. You place the depot right over the macula, where it releases for up to 6 months. This is preferable to a monthly injection.

In trials, an important factor determining the effectiveness of anecortave acetate was whether or not there was reflux. A drug is not going to work if it is dripping down your cheek and landing on your shoes – it has to get where it needs to be. And if it is there, the treatment works very well.

Also, the drug starts to lose its effect in about 4 months, so patients need to be re-dosed properly – no later than 6 months. Alcon is now looking at a new dosing regimen, every 3 months instead of every 6 months, and is also looking at a higher dose of anecortave acetate.

The most exciting study involving anecortave acetate is the AART Study (Anecortave Acetate Risk Reduction Trial). This trial has enrolled 2,500 patients with wet AMD in one eye and dry AMD in the other. The patients are being injected every 6 months for 4 years to see if the drug can prevent them from developing wet AMD in the fellow eye. This is the Holy Grail of AMD, and if it works it will be a huge step for our patients.

Other diseases, other approaches

Diabetic retinopathy is another disease that is on the rise. The number of patients developing diabetes in this country is steadily increasing, with the poor diets, high cholesterol levels and sedentary lifestyles that are common.

Most people with diabetes are going to develop visual problems, mostly diabetic macular edema (DME), and here too pharmacology holds great promise.

We know steroids work for DME, but investigators are looking at ways to deliver them for a longer period of time to cut down on complications.

Bausch & Lomb recently had their Retisert, a sustained-release steroid implant that lasts 3 years, approved for inflammatory uveitis. It is based on the Vitrasert platform, a device that delivers ganciclovir intraocularly in patients with AIDS-related cytomegalovirus retinitis.

One major problem with the Retisert implants is that almost everyone implanted with one develops cataracts, and roughly 30% develop glaucoma. The glaucoma may not be controllable with drops, so these complications will obviously need to be addressed.

Control Delivery Systems is working with Alimera Sciences Inc. to develop a device for DME that is essentially an injectable version of the Retisert implant. The implant is small enough to be injected with a 23-gauge needle and also delivers steroids for about 3 years. Since this requires no surgery, it is exciting because it is an in-office procedure. Clinical trials are expected to start this year.

Oculex and Allergan have developed the Posurdex implant, made with a biodegradable polymer called PLGA. It breaks down to water over roughly a 4-to-6-month time period. Allergan is conducting two phase 3 trials worldwide with Posurdex in DME and macular edema from vascular occlusions. In these studies, a beveled, 23-gauge incision is made into the mid-vitreous cavity, and this little implant is injected into the vitreous base.

Because the implant last only 4 to 6 months, the challenge will be to find a way to make it last longer. In order to do this, they would need to make the actual device longer, because its duration is based on the length of the implant. This presents a problem: How long can you make it before you start to run into problems with the vitreous? This is a trade-off that will have to be evaluated in terms of duration vs. complications.

Macugen has also been studied for DME, and so far results have shown that 70% of patients had stability of vision and a significant number experienced improved vision. Furthermore, Macugen has shown that it decreases retinal thickness. A phase 3 trial is ongoing.

Another pharmacological treatment possibility for DME is protein kinase C (PKC) inhibition. PKC-beta in particular is what we worry about in diabetic patients. It can cause damage throughout the body, not just in the eye. In the retina it causes endothelial dysfunction, ischemia, macular edema and proliferative disease.

Eli Lilly and Co. have has developed an oral inhibitor of PKC-beta. The drug, ruboxistaurin mesylate, was shown to reduce the occurrence of vision loss in a phase 3 trial, but only in a subset of patients who have reasonable control of their diabetes. Additional phase 3 trials are under way to verify these results.

Finally, there is Vitrase (hyaluronidase for injection, Ista Pharmaceuticals), which was approved this year. It is taken from the testes of New Zealand sheep. The idea is that Vitrase can be injected into a vitreous hemorrhage to help clear the hemorrhage more quickly, leading to faster visual recovery and earlier treatment of the underlying problem.

Interestingly, the FDA did not approve Vitrase for vitreous hemorrhage, as the company had hoped. Instead, it was approved as a spreading agent for anesthesia, even though the company did not ask for that indication.

For Your Information

• Peter K. Kaiser, MD, can be reached at the Cole Eye Institute of the Cleveland Clinic Foundation, Medical and Surgical Retina Unit, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702; fax: 216-445-2226; e-mail: pkkaiser@aol.com. Dr. Kaiser receives research grant support from Alcon, Allergan, Bausch & Lomb, Novartis, Eyetech, Genentech and Sirna.

• Eyetech Pharmaceuticals Inc., developer of Macugen, can be reached at 666 Fifth Ave., 35th Floor, New York, NY 10103; 212-582-8376; fax: 212-582-2645; Web site: eyetech.com.
• Novartis, comarketer of Visudyne, can be reached at 11695 Johns Creek Parkway, Duluth, GA 30097; 770-905-1000; fax: 770-905-1883; Web site: www.novartisophthalmics.com.
• Genentech, developer of Lucentis and Avastin, can be reached at 1 DNA Way, South San Francisco, CA 94080-4990; 650-225-1000; fax: 650-225-6000; Web site: www.gene.com.
• Regeneron Pharmaceuticals, developer of VEGF Trap, can be reached at 777 Old Saw Mill River Road, Tarrytown, NY 10591; 914-345-7400; fax: 914-347-2847; Web site: www.regeneron.com.
• Genaera Corporation, developer of Evizon, can be reached at 5110 Campus Drive, Plymouth Meeting, PA 19462; 610-941-4020; fax: 610-941-5399; Web site: www.genaera.com.
• Sirna Therapeutics, developer of Sirna-027, can be reached at 185 Berry St., Suite 6504, San Francisco, CA 94107; 415-512-7624; fax: 415-512-7022; Web site: www.sirna.com.
• Acuity Pharmaceuticals, developer of Cand5, can be reached at 3701 Market St., Philadelphia, PA 19104; 215-966-6191; Web site: www.acuitypharma.com.
• Alcon Pharmaceuticals, developer of Retaane, can be reached at 6201 South Freeway, Fort Worth, TX 76134; 817-293-0450; fax: 817-568-6142; Web site: www.alconlabs.com.
• Bausch & Lomb, developer of the Envision implant, can be reached at 1400 N. Goodman St., Rochester, NY 14609; 585-338-6000; fax: 585-338-6896; Web site: www.bausch.com.
• Control Delivery Systems can be reached at 313 Pleasant St., Watertown, MA 02472; 617-926-5000; fax: 617-926-5050.
• Oculex Pharmaceuticals Inc., maker of Posurdex, can be reached at 601 W. California Ave., Sunnyvale, CA 94086; 408-481-0424; fax: 408-481-0662; Web site: www.oculex.com.
• Eli Lilly and Co., developer of ruboxistaurin mesylate, can be reached at Lilly Corporate Center, Indianapolis, IN 46285; 317-276-2000; fax: 317-433-4340; Web site: www.lilly.com.
• Ista Pharmaceuticals, developer of Vitrase, can be reached at 15279 Alton Parkway, Suite 100, Irvine, CA 92618; 949-788-6000; fax: 949-788-6010; Web site: www.istavision.com.