State of the Art: Managing retinal disease in the era of injectable drugs

John A. Hovanesian, MD, FACS, interviews Steven D. Schwartz, MD, and David M. Brown, MD, FACS, on injectable retinal drugs.

Issue: June 10, 2008

John A. Hovanesian

John A. Hovanesian, MD, FACS: We are joined by two experts in injectable retinal drugs, Steven D. Schwartz, MD, and David M. Brown, MD, FACS. Dr. Schwartz, tell us about how injectable retinal drugs may have changed your way of thinking about macular degeneration and diabetes.

Steven D. Schwartz, MD: The injectable retinal drugs that have changed what we do started with injectable steroids. While these were fashionable for a time, they have largely fallen out of fashion. Now, we have a choice of anti-VEGF agents. There are two that are quite important to know about. One is Avastin (bevacizumab, Genentech), and the other is Lucentis (ranibizumab, Genentech). I think for the sake of the discussion today, we should just refer to the trade names, Avastin and Lucentis.

Steven D. Schwartz

Lucentis was proven to be beneficial for the treatment of exudative wet age-related macular degeneration, reducing three lines of vision loss to about 5% of the cohort. In other words, patients in this study, with whatever type of angiographic subtype of lesion they had, lost three lines only 5% of the time, or 95% of patients were protected. On top of that, an additional 30% to 40%, depending on the study, gained three lines of vision.

What is different today is that now we use Avastin, a cancer drug, off label quite frequently. It has the same mechanism of action as Lucentis, but it is a much more economical alternative. It seems to have similar, if not parallel, efficacy. So that has changed what we do in AMD dramatically because we used to slice and dice every diagnosis. Every patient who came in had to be categorized angiographically and according to where the new vascularization was, whether it was present or not, whether it was classic or occult or predominantly classic, how much recent visual loss they had, whether it was a retinal angiomatous proliferation lesion or a polypoidal lesion. None of that seems to matter anymore. Now, basically, if it is wet, we treat it. And we tend to treat with anti-VEGF drugs.

Dr. Hovanesian: Dr. Brown, do we treat nonexudative lesions with these drugs as well?

David M. Brown

David M. Brown, MD, FACS: No. Basically, anti-VEGF agents work in two ways: They stop blood vessel growth, and they eliminate macular edema. The main reason why people’s vision gets better is that elimination of edema. I tell patients it works like a mop. If there is no fluid, there is nothing to mop up. Anti-VEGF agents do not have a role that we know of in dry macular degeneration. However, because of the success in wet macular degeneration trials, now both the National Institutes of Health and multiple pharmaceutical companies are looking at different agents to help that pathway, but they are nowhere near prime time yet.

Dr. Hovanesian: In other words, they are still in trials with the U.S. Food and Drug Administration?

Dr. Brown: Absolutely, they are still in early phase 1 or phase 2 trials. Companies and researchers are trying to find agents that will attack the degenerative changes of dry AMD that affect every patient with AMD. They are essentially looking for the fountain of youth because the underlying problem in macular degeneration is that the retinal pigment epithelium, the layer behind the retina, wears out too soon. So you are trying to find a way to protect the RPE so it gets less oxidative damage or so that it ages less and survives longer. It is hoped that by doing that, you can eliminate neovascular macular degeneration, or wet macular degeneration, and that you can also eliminate the 10% of patients who get severe vision loss from geographic atrophy.

Dr. Hovanesian: These are nonexudative, and the anti-VEGF agents provide no benefits to these patients at all.

Dr. Brown: Not that we know of. Theoretically, if you could provide constant anti-VEGF therapy, then it is likely that neovascular AMD would never develop. However, at this point, no one is willing to put up with the risks of a monthly or even quarterly intravitreal injection for a preventative therapy. We also do not know the potential risks of continuous anti-VEGF blockade.

Dr. Hovanesian: Which of the products in the anti-VEGF category is exciting to retina specialists, based on the early evidence?

Dr. Brown: Both Lucentis and Avastin, as well as the upcoming VEGF Trap (Regeneron Pharmaceuticals), which is in phase 3 clinical trials, are very exciting. The interesting thing about the Lucentis trials was that they showed a huge improvement over the standard of care. Avastin is relatively unique in that we have only clinical data. With a bunch of anecdotal trials, it seems like it works. You do not know if it works as well, but you know it works. Like they say, the first guy who saw a cart with round wheels did not need a randomized trial to prove it was better than square wheels. However, there is no way to know the head-to-head differences at this point, but the economic difference for both the practice and the patient is significant.

Dr. Schwartz: It is about 200 times difference in price, so the economic difference is pretty remarkable.

Dave led the phase 3 trials for Lucentis and published results in the New England Journal of Medicine with some other authors, and I was in the group that first injected Lucentis, back when it was known as RhuFab. So we both have a unique perspective on how much of an impact these drugs have for patients. It is remarkable for us, as retina specialists, to now be able to take a patient and tell them, “If you do what we tell you and you’re compliant, you have a 90% to 95% chance of not having a substantial visual loss. And you have a 30% or 40% chance of getting your vision back.” The other place where we are improvising is the frequency of dosing. So that is the real difference for us now.

Evolution of thought

Dr. Hovanesian: Can you speak to the difference between Avastin and Lucentis, or the evolution of thought about both drugs?

Dr. Schwartz: It is an evolution from the clinical trial to clinical reality. What we see is a change from the clinical trial setting, with a rigorous treatment schedule, to reality, where we are looking for an effect and maybe one or two bonus injections. Then we increase the intervals between injections or discontinue the injections altogether. Again, many anecdotal studies now are starting to answer questions around that issue of interval of injections.

Everybody has their own treatment pattern. But the important thing is that we are not giving patients 24 injections over 2 years like a cookbook. We are trying to individualize it for each patient. One thing I would mention is that we have started the Comparison of Age-Related Macular Degeneration Treatment Trials, or CATT, which will compare Avastin to Lucentis. This is sponsored by the National Eye Institute. There has been an enormous effort by the Executive Committee to get it through the legal and regulatory hurdles, but everyone is behind it because it could have such an enormous economic impact, not just domestically, but internationally.

Dr. Hovanesian: What about the implications of this trial using Avastin off label?

Dr. Brown: The problem with off- label Avastin is that the same company makes both drugs. If you are a company that has an expensive drug and a cheap drug, you are obviously going to try keep people from using the cheap drug. It is possible that they may be able to limit access to Avastin by changing the way it is priced. Some oncology drugs are priced by the patient by the year, and if they went to that model, they could greatly diminish our access to Avastin. It would really alienate the retina community from Genentech. And they would probably then have to license the drug to another company to avoid that backlash.

What I love about the CATT trial is twofold. As Steve said, I think it is very important that we see the relative efficacy of these drugs. But in my mind, the most important part of the CATT trial is that, in the original clinical trials, we gave people one injection every month for 24 months. We do not do that anymore, both for the patients’ convenience and our own convenience. The question is, do we lose much by having recurrent edema? It is possible that we may not have as robust results without monthly injections. But we might, and there will be a PRN arm in the CATT trial that is similar to the way we treat patients in clinical practice. That alone is worth its weight in gold, as well as finding out the relative efficacy of those two agents.

Dr. Hovanesian: And that PRN arm will also be a comparison of the two drugs, correct?

Dr. Brown: It is going to be a comparison of the two arms with the same PRN intervals. And that brings me to another area of interest for the general ophthalmologist and anybody who does retinal work. Before Lucentis and before high-resolution imaging, imaging was done around every 3 months at the most. Now, the OCT directs our care and, basically, it is almost considered malpractice to manage patients without OCT.

Dr. Schwartz: I would agree with David. You need an OCT if you are going to stop treatment. You need to see that it is flat and without subpigment epithelial fluid, if you are going to stop treating. If you are going to continue treating, you do not need to image. I think the other important point for the general ophthalmologist is the idea that early treatment is incredibly important. So what you want to do as a general ophthalmologist is, if you have a patient who has wet AMD and has not been treated, or one who is recurring but has been treated, you want to get that patient in as quickly as possible for initiation or re-initiation of anti-VEGF therapy. This is critically important, I think. The sooner you treat these patients, the less treatment they are going to need, and that is good for everybody because each injection carries a risk.

The other thing that is important and often overlooked by the general ophthalmologist is that surface disease has become a huge issue for retinologists. You cannot give intravitreal injections in eyes with blepharitis. You must have a clean surface. So whatever your regimen is, stop ignoring surface disease in your AMD patients. I have a boatload of patients who have bad cases of blepharitis that are hard to manage. Thank goodness I have good anterior segment colleagues who are on top of the latest and greatest treatments for that condition.

Early detection

Dr. Hovanesian: What is the mildest lesion you will treat, and how do you most sensitively detect? What can the general ophthalmologist do to try to early detect the presence of exudative AMD?

Dr. Brown: The OCT machine that is in many people’s offices has several different ways of looking at the macula. The two main programs are called the fast macular thickness map and the macular thickness map. The fast map sounds like a great thing, but it is only one-fifth of the best resolution the machine is capable of in each scan. The fast maps quantitative retinal thickness measurement is also extremely dependent on the patients’ fixation. Old patients with macular degeneration and tremors cannot fixate, especially when they are 20/200. The “regular” macular thickness map gives you higher-resolution images, which may or may not be centered. You look at the pictures. If there are bubbles in the retina or fluid underneath the retina, they need to be evaluated by a retinologist to make sure they do not need more treatment or new treatment. And if there is a change, that is a fairly urgent need. If you catch it smaller before there is damage to the overlying retina, you have a great chance of preserving the retinal function.

Dr. Schwartz: I think the other issue there is visual change. Any change on the Amsler grid or other screening device, or even a visual acuity change, is probably worth a referral. We do see a lot of false positives for new, exudative change, but that is probably OK for the time being. Unfortunately, with all of these repeat injections, our offices have become fuller, with less mindful decision-making going on.

But we need to see the patients early. And for the time being, the best we have is good clinical judgment. It is not like the old days with photodynamic therapy, where we were so excited because the era before that was macular photocoagulation, when it was a true emergency anytime there was any leakage at all. The retinologists can remember standing there with a hair dryer drying their negative to see whether or not it was a laserable lesion. In the old days with the Macular Photocoagulation Study, we were urgently trying to treat these patients quickly. And then PDT came along, and all of a sudden we breathed a sigh of relief and thought we could relax and see the patient anytime in the next 2 or 3 weeks and get them treated with PDT. Now the sense of urgency is back up again because we actually can do something.

Drug delivery devices

Dr. Hovanesian: What drug delivery devices are you excited about that you can discuss?

Dr. Brown: That is the biggest problem with our current drugs that work is that they are made of proteins that degenerate at body temperature. You cannot have a sustained drug delivery device for a protein because it is like a ham sandwich. If you have a ham sandwich on your kitchen counter, in 2 days it is bad. If you have 10 ham sandwiches, they are still bad in 2 days. They do not last 10 times as long. One exciting thing out there is a product by Neurotech Pharmaceuticals, a biotechnology company, that has an implant of cells that makes a growth factor called ciliary neurotrophic factor. This particular protein may or may not work for retinitis pigmentosa and geographic atrophy, but the exciting thing is that this technology has the capability of creating any protein, such as Lucentis of Avastin, continuously like your local doughnut shop — “made fresh daily.”

Dr. Schwartz: The idea there is cell-based therapy. And I think, without saying too much positive or negative about anything that has not been approved, cell-based therapy is probably what is going to happen. We are going to be looking for a bio-factory creating a drug in some tissue around the eye that can be turned on and off in an easy and safe way and produce steady-state pharmacokinetic levels of whatever the therapeutic protein is. I think that is a huge push. The other push is, there are about to be a number of other molecules that have anti-VEGF activity that are not proteins, or ham sandwiches. As a result, we may be much more amenable to depot-device delivery.

Dr. Hovanesian: What advice would you give the general ophthalmologist who is taking care of aging patients, with regard to these new therapies?

Dr. Brown: The main thing to know is that we have a treatment that works. If you refer patients with wet macular degeneration, they have a great chance of maintaining their independence and keeping their driver’s license and functioning in today’s society. It is sometimes a hassle for the patients, especially in smaller communities, to get access to these drugs, but it is worth encouraging them to be diligent. And, if you have any suspicion, try to seek help because it is available.

Dr. Schwartz: I would echo that sentiment. We can do a lot for patients with macular degeneration. The other thing, I think, to tell their patients is to relax a little bit because, while we need to be vigilant and diligent about watching for new exudative neovascular events and while we need to be quick to refer, there is a lot of direct-to-consumer marketing out there right now. So patients are scared to death. They are maybe told they have macular degeneration because somebody saw the macula. Or it may be that there are actually drusen. Or occasionally somebody picks up a real lesion. So we do a lot of retinal psychiatry right now to try to calm people down. I think the general ophthalmologist can play a big role in telling them, “Look, you are going to be fine whether it is or it isn’t actually AMD.”

For more information:

David M. Brown, MD, FACS, can be reached at Vitreoretinal Consultants, 6560 Fannin St., Suite 750, Houston, TX 77030; 800-833-5921; e-mail: dmbmd@houstonretina.com. Dr. Brown is a paid consultant for Genentech, Novartis and Regeneron. His research center gets research support from Genentech, Regeneron, Novartis, Neurotech Pharmaceuticals and the NIH for the CATT, AREDS and other trials.

John A. Hovanesian, MD, FACS, can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Suite 300, Laguna Hills, CA 92653; 949-951-2020; fax: 949-380-7856; e-mail: drhovanesian@harvardeye.com.

Steven D. Schwartz, MD, can be reached at Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095; 310-206-7474; fax: 310-825-3350; e-mail: schwartz@jsei.ucla.edu. Ocular Surgery News was unable to determine whether Dr. Jones has a direct financial interest in the products discussed in this article or if he is a paid consultant for any companies mentioned.