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Discussions on the Retina and AMD from the American Academy of Opthalmology 2013: Hear from the Experts
A discussion of the latest developments for retinal diseases presented at the 2013 AAO Annual Meeting with Dr. Carl Regillo, Chief of the Retina Service at Wills Eye Hospital in Philadelphia, Dr. Allen Ho, Director of the Retina Service at Wills Eye Hospital, and Dr. Sunir Garg, Associate Professor on the Retina Service at Wills Eye Hospital.
Developments in Wet AMD
Carl D. Regillo, MD: Hello. I’m Dr. Carl Regillo, Chief of the Retina Service at Wills Eye Hospital in Philadelphia. Welcome to Medscape Ophthalmology Insights, coming from the Academy of Ophthalmology (AAO) meeting in New Orleans. This is part of a series of commentaries produced in cooperation between Medscape and Wills Eye Hospital.
Joining me today are Dr. Allen Ho and Dr. Sunir Garg of Wills Eye Hospital. Dr. Ho is the Director of the Retina Service at Wills Eye, and Dr. Garg is Associate Professor on the Retina Service at Wills Eye.
We will be discussing the latest developments in retina presented at this year’s meeting, and there is a lot to talk about. It’s been an exciting meeting with a lot of new developments. Let’s start with wet age-related macular degeneration (AMD). What do you think are the biggest developments in wet AMD at this meeting?
Allen C. Ho, MD: The biggest developments in wet AMD were the results of some of the clinical trials, both positive and negative results. For example, in the LUCAS study,[1] we learned that a treat-and-extend approach comparing bevacizumab with ranibizumab yielded equivalent results with no new safety concerns. That was important because we previously didn’t have a treat-and-extend study including that many patients.
Dr. Regillo: Sunir, what did you think was top news in wet AMD?
Sunir J. Garg, MD: One thing that we were hoping was going to pan out was an eye drop used to treat wet AMD. Unfortunately, those data didn’t look very good, and I am not sure that this current molecule has much of a future.
Dr. Ho: I would agree, with the emphasis on the current molecule, because other eye drop molecules are in development right now that may be different, and therefore we can’t cross off that category or that delivery system yet for our patients. We need something better for the treatment burden of wet AMD.
Dr. Regillo: You are speaking specifically about pazopanib,[2] the kinase inhibitor eye drop that was tested at phase 2 and didn’t show a signal for efficacy. Is that how you took it?
Dr. Garg: Exactly. We were hoping for more.
Some Areas Still Need Work
Dr. Regillo: What about radiation therapy? Is that going to be part of what we are going to see in the future on the basis of what was presented at this meeting?
Dr. Garg: There has been a lot of interest in it over the past few years. The current studies suggest that there might be some benefit; however, I don’t know whether it is going to change how we treat patients on a day-to-day basis.
Dr. Regillo: What are the benefits? Better vision? Fewer treatments?
Dr. Garg: Fewer treatments. Patients often have to come in monthly or every other month for treatment, which becomes a big burden on the patient and their families. If you can keep them out of the office, that would be great. That was the hope with radiation, but it wasn’t as impressive as I was hoping it would be.
Dr. Regillo: How is designed ankyrin repeat protein (DARPin) looking? We have been hearing a lot about DARPin. It’s now in phase 2 testing. Will that be an antivascular endothelial growth factor (VEGF) agent that will give us an extended durability of effect?
Dr. Ho: What is attractive about the Allergan DARPin program is that the molecule is a different kind of molecule to inhibit VEGF. They believe that binding affinity is increased, with potentially longer duration of action.
We know from the presentation by David Callanan[3] that we still need to do a little work on formulation. So the answers are still out there. We don’t know the answers quite yet. But there is some promise there. We shall see.
Dr. Regillo: What is the issue with formulation?
Dr. Ho: The issue with formulation was inflammation that some of the patients experienced.
Dr. Regillo: Have we seen that decreasing as the formulation is evolving? Is it looking any better now in phase 2 than in phase 1?
Dr. Ho: There is a little bit of improvement, but they need to improve it more.
Dr. Regillo: The LUCAS study was much anticipated for quite some time because all we have had are smaller treat-and-extend-style therapies, and this was the first large prospective study that actually showed that treat-and-extend, whether with bevacizumab or ranibizumab, can have very good results. The mean number of treatments in year 1 was 8, and they achieved visual acuity results that looked good, on par with what you would expect with frequent fixed therapy — for example, ranibizumab in MARINA and ANCHOR.
Developments in Dry AMD
Dr. Regillo: Let’s move on to dry AMD, because now we are also seeing some developments in dry AMD. Sunir, what do you think is the top news in dry AMD?
Dr. Garg: There is a lot of interest in dry AMD. One of the most interesting things to come out is an in-home monitoring system that patients can use. We found that when patients present earlier, we can treat them earlier and they generally do better.[4] There is a product called ForeseeHome™ (Notal Vision; St. Louis, Missouri) that shows great promise in detecting these lesions earlier than we have otherwise been able to catch them.
Dr. Regillo: This is a home monitoring device that people use instead of the usual way they follow their vision at home — for example, with an Amsler grid?
Dr. Garg: Exactly. So when patients go home, we tell them to cover one eye at a time, look at a piece of paper with some lines on it, and tell us whether they saw any changes; whereas this system will alert the patient that there has been a change even before they notice a change at home when they are reading.
Dr. Ho: It’s a very refined detection system. It transforms the paper to technology. They stopped the study early because patients who were in the monitored technology arm actually had improved visual outcomes.
Dr. Regillo: It’s a big deal to stop a study early, especially for something positive. Patients were being detected with choroidal neovascularization (CNV) when their vision was only minimally affected, compared to the standard, in which patients had more vision loss. That was presented at this meeting. It is a big development.
What about treating dry AMD, in terms of slowing the progression of atrophy? What came out of the meeting here?
Dr. Ho: We learned 2 things about dry AMD. One was the AREDS2[5] information that has been discussed before. There has been a formulation change. The big controversy at this meeting (and I don’t know that it will be resolved in the future, because we are probably not going to do another large-scale prospective trial) is whether you can individualize therapy based on a patient’s genetics. Carl Awh[6] gave a compelling presentation, as did Emily Chew.[7] I don’t know how we are going to resolve this, but certainly time will tell. I do believe, however, that the force of personalized medicine is present in other specialties. At some point down the line, we will need to address this.
Dr. Regillo: So there is some controversy about whether genetic testing at this time plays a role in fine-tuning the way we manage dry AMD?
Dr. Garg: That’s exactly right. The question is, is personalized medicine right for dry AMD with our current therapy? Over time, we will find that there are certain indications for it. But right now, for the dry AMD patients, I don’t see it happening.
Dr. Regillo: Are we going to have resolution to this controversy anytime soon?
Dr. Garg: Not in the near future, and not for dry AMD as we understand it today.
Dr. Ho: Retina specialists will determine how they practice. Currently, I’m still not doing genetic testing routinely in my patients with dry AMD.
MAHALO: Slowing the Progression of Dry AMD
Dr. Regillo: Let’s discuss anti-factor D, the MAHALO study.[8] It received quite a bit of attention at the American Society of Retina Specialists (ASRS) meeting a couple months ago. Here at this meeting, we saw an additional genetic analysis. What does it mean to you?
Dr. Ho: This study is making an impact, because whenever you have a list of different strategies to approach a disease — for example, atrophic AMD — you don’t want to have just one good treatment. This is the first treatment to show some slowing of progression of the growth of geographic atrophy. The vitamin studies didn’t — AREDS 1 and 2 did not show this. So, it’s the first study. You can consider it a little surprising because other complement studies have failed to show this to date.
The study that you presented, Carl, was very important because we finally have some hope — although the differences weren’t great. A 20% reduction in growth of the area of geographic atrophy at 18 months is not great. The genetic subtype at 44% difference is potentially significant and could have traction for our patients with atrophy and for the practicing retina doctor.
Dr. Regillo: I’m very excited too. This is the first time that a drug has slowed the progression of dry AMD and shown a benefit in clinical testing. This is a small phase 2 study. Take it with those caveats. The genetic analysis seems to make sense. It seems to amplify the effect of the drug. The genetic polymorphism that was identified in this study is complement factor I. Those patients seem to be driving the results. The medicine is called lampalizumab; it’s a humanized antibody fragment injected in the eye that targets factor D. So we will see.
Dr. Ho: As important as that genetic specific complement factor I was, the fact that it was found in more than half the patients in the study means that it could be meaningful in terms of numbers for our patients. So I’m excited about the possibilities.
On the other hand, I will balance that statement by saying that if you are a patient with geographic atrophy and you are losing vision, when your doctor presents you with this medication down the line, you will be saying, “I’m still losing vision.” We will be in the situation of having to say, “Let’s do this treatment because you will be losing less.” Recall our early treatment days in wet AMD.
Dr. Regillo: It’s still a promising development.
Steroid Implant for Diabetic Macular Edema
Dr. Regillo: What about diabetic macular edema (DME)? Sunir, what do you think?
Dr. Garg: There is a lot of excitement in DME. New data[9] came out looking at Ozurdex®, which is a slow-release steroid implant for the treatment of DME, which is the leading cause of vision loss in patients with diabetes.
They found that for many patients, 4 injections are all that are required over 2 years to get meaningful visual improvement. That improvement was sustained for that period of time. For working-age adults who otherwise would have to come in monthly for treatment, I can see them once every quarter or so, give them an injection, keep them functioning and seeing well, and more important, avoid them having to take time off from work.
Dr. Regillo: We have had steroids for a while. How is the safety profile? How did it look in this phase 3 study?
Dr. Garg: It was very impressive. Unlike with some of the other steroids that we use, the pressure rise or the glaucoma issue here is not such a big concern anymore. The probability of people needing to have surgery after this was very low. Most of the time, if the pressure increased, it was easily treated with some drops.
Cataracts are a bit more of an issue. Many of the patients who receive this will develop a cataract and need to have surgery within 2 years. But for a lot of the patients who are older, who already have some cataract anyway, having cataract surgery a few months or a year sooner than you otherwise would might not be such a big deal.
Dr. Regillo: What do you think is the likelihood of Ozurdex being US Food and Drug Administration (FDA)-approved and available for us to use for DME in the near future?
Dr. Garg: It’s pretty good. The data are under review by the FDA. Hopefully it will be up for a vote in April, and hopefully we will have it available to our patients by the summer of next year.
Dr. Regillo: The other potentially new FDA-approved treatment is aflibercept. Allen, what about the studies there?
Dr. Ho: The studies there are surprisingly consistent to what we saw in RISE and RIDE with ranibizumab. Ranibizumab works, [aflibercept] works. Diana Do[10] gave an excellent presentation to show that we will have something else in our toolbox for patients with DME down the line. We really need the steroids there as well. That is an important statement, and the results from the MEAD trial were important. I hope that goes through.
Dr. Regillo: I certainly welcome additional options to treat our patients with DME. Another anti-VEGF agent — a good steroid that seems to have a good safety profile — is very exciting.
Unmet Needs in Retinal Disease
Dr. Regillo: We have covered all the big diseases, but we still have lots of unmet needs for other diseases that are severe and vision-threatening. What about retinal degenerations?
Dr. Ho: It’s very exciting for patients with retinal degeneration. The Argus® II study[11] showed that the Argus II vision system — the epiretinal chip implant — has been reasonably well tolerated and shows probable benefit for patients with severe vision loss.
For example, patients with little to no light perception in retinitis pigmentosa now have an FDA-approved, commercially available device that may allow them to see a door and connect to the visual world a little bit more. Our patient was able to take her laundry, look at a piece of clothing, and sort out whether it was a white piece of clothing or a colored item.
Dr. Regillo: It is exciting. It’s FDA-approved. It’s technically commercially available now. What are the obstacles? Can we use it right now?
Dr. Ho: We can use it now. In fact, the first commercial implant will probably occur before the end of 2013. Insurance coverage is evolving. That’s one of the barriers, along with surgeon training.
Dr. Regillo: It’s not your average vitreoretinal procedure.
Dr. Ho: There are about 10 centers across the country that will be doing this.
Dr. Regillo: We are doing some exciting work at Wills with other types of retinal prostheses. This is just the beginning of a whole area that is going to open up within the next decade.
Dr. Garg: One of the most exciting things about this implant is that many different centers worldwide are working on these implants. To have one FDA-approved will encourage the other centers to work even harder to get their implants to market. That competition will help this technology blossom.
When Will We Have Gene Therapy?
Dr. Regillo: Gene therapy is a real niche field. We heard a number of talks about gene therapy, either to replace a missing gene or to promote the development of a therapeutic in the eye for wet AMD, for severe retinal degenerations like RPE65. What is happening there?
Dr. Ho: Gene therapy will be a part of our treatment toolbox for patients with a variety of conditions. Al Maguire’s[12] work on Leber congenital amaurosis is fascinating. Jeff Heier’s[13] work introducing a gene that will produce an anti-VEGF that might reduce the need for injections is very clever as well. We need more information, but it’s showing that there will be some traction with gene therapy.
Dr. Regillo: This is not on the horizon, though, is it? We are making progress, but are we talking 5 or 10 years? What sort of timeline do you anticipate?
Dr. Ho: Within the next 2-3 years, we could have a gene therapy available.
Safety Profile of Ocriplasmin
Dr. Regillo: That is a big development. We have had a new therapeutic for about a year now, and we are starting to get some real-world experience with ocriplasmin[14] for treating vitreoretinal interface disorders. We have heard about the phase 3 studies. But now, at this meeting, we are starting to hear about postmarketing, commercially available use of the drug. More than 4300 injections were done in the United States this past year.
We heard a little bit about the experience — the positive, the side effects, and so forth. What are we hearing at this meeting, Sunir?
Dr. Garg: These data are really helpful. They basically confirmed what we found in the phase 3 trial, which is that the drug works and it’s quite safe. A few patients might experience some transient vision loss, but most of them recover vision very quickly. In an occasional patient, it seems as though the vision loss lasts a little bit longer, and we need longer follow-up on those patients. These data encourage retina specialists to continue to use this modality as a new treatment option for their patients.
Dr. Regillo: This surveillance is important because the phase 3 study only had 6 months of follow-up. For patients who were still having some ongoing issues –reduced vision or visual symptoms to some degree, even with successful treatment with the drug — longer-term follow-up is important. It’s like vitrectomy surgery for a macular hole. We see continued vision improvement well beyond 6 months. That sort of phenomenon could exist here too.
That is all we have time for today. We have had a lot to talk about, and we will have many more meetings sorting out these interesting points and new developments.
I would like to thank Dr. Sunir Garg and Dr. Allen Ho from Wills Eye. I’m Dr. Carl Regillo for Medscape Ophthalmology and Wills Eye Hospital. Thank you for joining us.
References
1. Berg K. Lucentis compared to Avastin study. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 05.
2. Csaky KG. A phase 2b dose-ranging study of pazopanib eye drops vs. ranibizumab intravitreal injections for the treatment of neovascular AMD. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 05.
3. Callanan DG. Designed ankyrin repeat proteins (DARPins): proof of concept study. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 12.
4. Bressler SB. Results of a randomized trial of early detection of neovascular age-related macular degeneration with the Foresee Home Monitoring Device: the HOme. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 16.
5. Clemons TE. Age-Related Eye Disease Study 2 (AREDS2) update. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 20.
6. Awh CC. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 16.
7. Chew EY. Interaction of genetic risks and AREDS supplements in progression to advanced AMD in the Age-Related Eye Disease Study. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 16.
8. Regillo CD. Lampalizumab (anti-factor D) in patients with geographic atrophy: the MAHALO phase II results. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 16.
9. Boyer DS. Ozurdex diabetic macular edema study. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 05.
10. Do DV. Intravitreal aflibercept injection (IAI) for diabetic macular edema (DME): 12-month results of VISTA-DME and VIVID-DME. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 09.
11. Ho AC, Humayun MS, daCruz L, Dagnelie G. Safety and performance results of the Argus II Retinal Prosthesis System 3 years following implant. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. PA060.
12. Maguire AA. Gene therapy: where are we now? Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 07.
13. Heier JS. Gene therapy for wet AMD. Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 18.
14. Hahn P. Safety profile of ocriplasmin in symptomatic VMA: a comprehensive review by the ASRS Therapeutic Surveillance Committee (TSC). Program and abstracts of the American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013; New Orleans, Louisiana. RET 09.