A New Chapter in Retinal Disease Therapy

Combination Therapy for AMD

Roger F. Steinert, MD: Hello. I am Dr. Roger Steinert, Director of the Gavin Herbert Eye Institute and Professor and Chair of Ophthalmology at the University of California at Irvine. Welcome to Medscape Ophthalmology Insights, coming from the American Academy of Ophthalmology (AAO) meeting in Chicago.

Joining me today is Dr. Barry Kuppermann. Dr. Kuppermann is Chief of the Retina Service and the Department of Ophthalmology at the Gavin Herbert Eye Institute, University of California at Irvine. We are going discuss highlights in the retina and retinal disease area from this year's meeting.

Barry, tell me about this new combination therapy, E10030 (Fovista; Ophthotech; Princeton, New Jersey), for age-related macular degeneration (AMD) and what it is doing for us.

Baruch Kuppermann, MD, PhD: An interesting study was presented by Pravin Dugel^[1] on Saturday at Retina Subspecialty Day. Fovista is an anti-platelet-derived-growth-factor (PDGF) agent, and it was used in combination with anti-vascular endothelial growth factor (VEGF) therapy [for AMD]. We have had 3 choices of anti-VEGF therapy: aflibercept, ranibizumab, and bevacizumab. But we hit a wall. We helped so many patients, and we are grateful for all of those compounds, but we have discovered that giving more of the same drug doesn't achieve a better result. So, we are looking for combination therapeutic strategies. Fovista, which is a PDGF inhibitor, was given on a monthly basis together with ranibizumab, and in a fairly large phase 2 (450-plus patient) study, they showed a significantly increased likelihood of achieving good vision, a 62% increase. It was quite significant and it really excited us. It's still a phase 2, though. We have to do more work. Phase 3 is still coming, but this is our first sense that combination therapeutic approaches can be of benefit to our patients. So, it's an exciting new chapter that's beginning to open.

Dr. Steinert: Moving anti-VEGF on will be great.

Dr. Kuppermann: Anti-VEGF agents will be a cornerstone of this approach but in combination with another agent.

New Option for Central Serous Retinopathy

Dr. Steinert: Is there a potential new therapy for central serous retinopathy?

Dr. Kuppermann: Yes. Some very clever work was reported by Francine Behar-Cohen.^[2]She is a very creative scientist and retina specialist in France. She has a large laboratory that has focused on steroids, primarily glucocorticoids. She is now looking at mineralocorticoids and has discovered that they may be involved in the pathway that leads to central serous retinopathy, which is a breakdown with leakage in the subretinal space. We don't have a treatment for it. Ironically, it is frequently precipitated by stress, but one of the systemic agents that can cause it is corticosteroids -- the classic steroids. By understanding the mineralocorticoid pathway better, Dr. Behar-Cohen has come up with a therapeutic approach using systemic spironolactone, a drug that has been around a long time. She was able to show in a significant number of patients that she can resolve the leak and improve vision. So, she is going directly from science to a therapeutic approach, all in the same laboratory. It's really clever.

Stem Cells: Ready for Prime Time?

Dr. Steinert: We have been hearing for a couple of years about stem cells and the potential for reversing some retinal damage, macular degeneration, and things like retinitis pigmentosa. What is the latest on stem cells?

Dr. Kuppermann: There is a study going on, and Allen Ho presented data^[3] on Retina Subspecialty Day. It's a Johnson & Johnson (New Brunswick, New Jersey) and Janssen Biotech (Horsham, Pennsylvania) product -- stem cells that are derived from umbilical cords. They are injected subretinally with a clever device that tracks underneath the retina to deliver the stem cells to the macular area. Of importance, he is describing a generation of stem cells that are not designed to integrate into the retina. They may do so in a partial fashion, but they are not really regrowing the retina. They are young, healthy cells that can deliver trophic factors to a disease state environment. They already have more than a dozen patients. They are seeing some nice signs of visional improvement in eyes that were thought to be incapable of improving. It's just the beginning of the stem cell era, and this seems to be primarily associated with using stem cells as trophic drug delivery agents. Still, it's exciting new work, and they are making good progress and opening up more sites and enrolling more patients. We should learn a lot more in the near future.

Dr. Steinert: This is emerging as an unexpected benefit of stem cells. Dr. Henry Klassen, from our department, has been finding similar things with his work on stem cells, and then there is an Alzheimer's research group that is using stem cells, not to create new brain cells but to rescue the cells that we have.

Dr. Kuppermann: The challenge of stem cells is still quite daunting, but we didn't expect that we would get this break -- that instead of having to rebuild the whole thing we can just make the environment a little healthier with the young, healthy cells.

First Look at Long-term Retinal Drug Delivery

Dr. Steinert: What about drug delivery in the retina?

Dr. Kuppermann: There was an interesting presentation at Retina Subspecialty Day by Anat Loewenstein^[4]of Israel. It was a device developed by Gene de Juan in San Francisco. Gene is a retinal specialist based out of University of California in San Francisco in Palo Alto and has developed a lot of products, but this is a stent that goes in with the reservoir. We are in the era of pharmacotherapy for retinal diseases, and many patients have to come in every month to get an injection. It's a very effective therapeutic strategy, but we would like to minimize the burden of treatment, if possible, while still having good results. This is one approach, the first to get this far. They have more than a year's worth of good human data with this reservoir and chronic indwelling catheter, and they were able to refill the reservoir. It is sutured to the eye wall. The data show good control of the choroidal neovascularization associated with macular degeneration. This is the first of the long-term therapeutic strategies.

The era of injections will eventually come to an end. Many of these drug-delivery strategies are going to be considered new drugs, so they will have to go through rigorous long-term testing. At the end of the day, we are not going to be doing so many intravitreal injections and we will have more long-term delivery strategies.

Dr. Steinert: How do they control the delivery, though, with this reservoir?

Dr. Kuppermann: There are ways to control it. There is a little bolus of drug that goes in at the beginning. It wasn't clear to me exactly how that is being done. Mark Humayun, who was Gene de Juan's partner, has a separate drug-delivery company using a stent that has microprocessor controls and can control the release rate. His company is called Replenish (Pasadena, California). That is a similar technology. There will be other things. All of the big drug companies that have products and anti-VEGFs are looking at how to advance their franchises by having long-term drug-delivery strategies. We will be hearing more about this. This is the first time we have seen any data from any of these approaches.

Dr. Steinert: Insulin pumps for the eye.

Dr. Kuppermann: That is exactly the analogy.

Prophylactic Antibiotic Drops Before Injections: Yes or No?

Dr. Steinert: There is an issue about endophthalmitis prophylaxis and antibiotics with injections. Was anything presented about this at AAO?

Dr. Kuppermann: It was very interesting. At a session today, some researchers in Toronto^[5] looked at an interesting question, which is still a source of controversy: Is there any benefit to using antibiotic drops for 3 days after every monthly injection of anti-VEGF? It is clear that povidone-iodine is key to antisepsis. Every eye is treated with that before an injection. The question is whether anything else is necessary. The retina community is divided, although the pendulum is swinging against the use of antibiotic drops, although many people still use them. They looked at the flora in the fornix and cultured the conjunctiva before any povidone-iodine was applied, every month. Patients were randomly assigned to antibiotic drops (moxifloxacin) or no antibiotic drops. They looked for progressive resistance to moxifloxacin, and in fact after 4 months they found that. By prescribing the topical antibiotic prophylaxis, we could be breeding resistant organisms that may be more problematic. Their recommendation was that antibiotic prophylaxis should not be used. It was a very interesting way to go about it, because endophthalmitis rates are low (about 1 in 3000) so it's very hard to show that you're reducing infections. This was a way to show scientifically that you could be increasing rather than reducing risk by using antibiotics on a prophylactic basis.

Ranibizumab: RISE and RIDE

Dr. Steinert: What about RISE and RIDE?

Dr. Kuppermann: This is ranibizumab, first studied for wet AMD and then retinal vein occlusion, both branch and central. The results were great. Then along cameRISE and RIDE, and we now have 3-year data and approval from the US Food and Drug Administration (FDA) [for diabetic macular edema]. The data show a few interesting things.^[6]With the other studies looking at anti-VEGF agents, it seems that after 3 injections, the visual acuity tends to plateau. First there is a dramatic rise in vision and then a plateauing. RISE and RIDE were monthly injections for 2 years after the first 3 injections, which led to the notion of a loading dose of 3 injections, and this results in 50%-60% up the vision chart. If you keep injecting, the vision keeps improving. The plateau doesn't occur entirely for about 2 years. In the third year, there is a plateau.

We have been relatively sanguine about the systemic safety concerns associated with the use of anti-VEGF: hypertension, stroke, cerebral vascular accidents, and arterial thrombotic events. A whole host of things can happen. We thought that with the low dose, we weren't seeing any real signal of safety concerns, but the studies were underpowered to show any signal.

However, in RISE and RIDE, the clinical efficacy results were similar between the 2 doses studied (0.3 mg and 0.5 mg), and there was a bit of a safety signal about a slightly increased risk for stroke in the 0.5-mg group compared with the 0.3-mg group. That small difference in drug level was borderline statistically significant in this relatively small study. So, for the first time, we are paying attention to what could be a safety signal. Along with the company, the FDA chose to approve the lower dose, 0.3 mg. For other indications, the dose is 0.5 mg. Now we have a 0.3-mg dose. It might be different for patients with diabetes. Many patients with diabetes have bilateral disease, so they may need to get injections in both eyes. This is a way to make the drug a little safer, because for the first time we may be seeing a slight safety signal from what we thought were fairly safe drugs.

Dr. Steinert: A lot of exciting new developments in retina that I think are of great interest to every ophthalmologist regardless of the subspecialty. Thank you very much for that great synopsis and for taking time out of your busy Academy. I'm Dr. Roger Steinert with Dr. Barry Kuppermann, for Medscape Ophthalmology.