Management of Wet Age-Related Macular Degeneration - Episode 14

Emerging Treatment Options for the Management of Wet AMD

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Dante J. Pieramici, MD; Roger A. Goldberg, MD, MBA; and Lloyd Clark, MD, review novel compounds in development for the treatment of wet AMD.

John W. Kitchens, MD: I’d like to move into our final topic here for the last few minutes, which is emerging treatment options. This is something that gets us all excited. Dante, I’d like to start with you on emerging treatment options and talk about one that you’ve been involved with, the port delivery system. Can you talk to us about what a port delivery system is?

Dante J. Pieramici, MD: As I had mentioned before, if you ask retina specialists what do they want, do they want anti-VEGF agents that are more efficacious, or do they want ones that last longer? We’re pretty happy with the efficacy we can get out of these agents, if we can get the patient to have them on a frequent basis. What we really want are agents that last longer, so that we don’t have to do the injections as frequently and the patient isn’t burdened so much. One of the developments is essentially a reservoir, it’s about the size of a piece of rice. It’s a drug reservoir like one you might use systemically, but it’s just this tiny thing we put in, in the operating room, it’s an outpatient procedure with local anesthesia. We place this thing, similar to a cataract surgery, and we fill it up with a drug, ranibizumab, that’s the port delivery system. The drug is then delivered by simple passive diffusion over time. You can measure the drug being delivered from these devices out to a year and a half in some patients.

This provides potentially a long-term delivery device for the drug, and you can refill the device in the office. You don’t have to do an injection in the eye, you access through a septum in the device. It sits under the conjunctiva, so it’s covered, it’s behind the eye, under the eyelid. Patients don’t see it, but it can be accessed multiple times to refill the drug in these patients. This is going to provide not necessarily a more efficacious treatment, but a treatment where patients won’t need to come in as frequently. Eventually, we may be able to monitor some of these patients at home with a home OCT [optical coherence tomography]-type device. It’s going to really answer this durability, burden of therapy question. It’s a pretty exciting thing. It just got FDA approved about a month ago. Hospitals are ramping up to start providing it to patients. The data looked good. There was a big reduction in the burden of therapy, the number of treatments that were necessary. There may be a slightly increased risk—a small absolute risk, but about 3 times the risk—of infection in the eye, but the overall risk is relatively low. It’s exciting.

John W. Kitchens, MD: It’s definitely exciting. There’s another drug, faricimab, that looks like it’s going to be approved in early 2022. This is the first bispecific antibody. Roger, talk to us a bit about what faricimab is.

Roger A. Goldberg, MD, MBA: Yes. It is a full-length antibody, and for those of you who remember your immunology, that’s a little Y-shaped molecule. One arm of the Y is basically ranibizumab, an anti-VEGF agent. The other arm of the Y is an Ang2 inhibitor; angiopoietin-2 plays on this Tie2 pathway. It’s one that frankly the retina specialists are starting to learn about as we’ve seen good data emerge in inhibiting this, but it’s a good cop, bad cop. There’s a molecule that’s constitutively expressed on blood vessels, including in the retina, called Ang1, angiopoietin-1. That stimulates this receptor, the Tie2 receptor, and it leads to a whole cascade of positive effects that maintain the normal nonpathologic permeability, normal homeostasis, and desensitizes the blood vessel to the effects of free-floating vascular endothelial growth factor, or VEGF.

What happens though in situations where there’s oxidative stress or free radical formation or inflammation, you get an upregulation of the expression of Ang2. Ang2 is the bad cop, it kicks Ang1 off of that Tie2 receptor. It stimulates that whole cascade of pro-inflammatory effects, pro-permeability, pro-leakage. As Lloyd and Dante both talked about, leakage is our enemy here in treating both diabetic retinopathy and diabetic macular edema [DME], as well as wet AMD [age-related macular degeneration]. Then it also sensitizes those same blood vessels to the effect of VEGF, which we know is circulating at excess levels in wet AMD. Faricimab is a novel approach. It has this neat science where you can inhibit and target 2 pathways with 1 antibody. And unlike the port delivery, this has a conventional drug delivery system, it’s an intravitreal injection. There’s no learning curve to doing an intravitreal injection for those of us who are already performing thousands of these. We’re cautiously optimistic, the data looked good that have been shared so far both in wet AMD and in DME. We’re cautiously optimistic that we’ll get approval of that drug in the first quarter of 2022.

John W. Kitchens, MD: Roger, Dante had mentioned the benefits of the port delivery system being extended durability. Is there better efficacy with this bispecific treatment, greater durability? What can we expect from it?

Roger A. Goldberg, MD, MBA: The clinical trials were designed as what are called noninferiority trials vs aflibercept in this case. Our expectation isn’t necessarily better visual acuity outcomes, but hopefully a better drying agent, and therefore that is has better durability, can last longer, reducing that treatment burden, that injection burden.

John W. Kitchens, MD: Lloyd, I’m going to ask you a 2-part question. Both Dante and Roger have talked about increased durability, decreased treatment burden. Have we capped out at what we can expect from a visual acuity standpoint from treating these patients with wet AMD?

Lloyd Clark, MD: We talked about this earlier, the biggest predictor of final vision is presenting vision, so early diagnosis, early detection it appears is key. We can have unbelievable outcomes in patients if we catch them early. If you catch a new small choroidal neovascular membrane and you treat it aggressively with an effective anti-VEGF agent, we have patients who are 20/20, 20/25, and stay that way for years on end. At this point, we don’t think it’s particularly feasible or realistic that there’s a new agent on the horizon that’s going to offer better efficacy for the individual patient than what we have now. We do believe, however, that durability is definitely achievable; it’s a modest incremental goal. Down the road, I would like to believe that we can have better, more effective clinical outcomes.

The realistic goal today in terms of what we have in the pipeline, be it these drugs, these devices, and other compounds as well, is that we have a realistic shot of treating patients somewhere between 2 and 4 times a year and maintaining the same outcomes as monthly therapy. That is an improvement over what we’re doing now. Many clinicians and many patients just can’t keep up, most people can’t keep up with 12 injections a year. These interventions that both Dante and Roger have described, these are compared against aggressive therapy with on-label treatment, monthly therapy. That’s the gold standard treatment. If we can deliver that type of clinical outcome with treatments 2 or 3 times a year, that’s important to patients, and that’s the next step in delivering better care.

John W. Kitchens, MD: You mentioned early on the ability to treat these patients earlier in the course of their disease. Is there anything that is coming that may help us diagnose these patients earlier?

Lloyd Clark, MD: Dante mentioned home OCT, which the idea is to do non-office–based surveillance of patients. There are different ways potentially that this could be done. We could do this with Amsler grid testing at home; that’s been tried and is not particularly effective. But the OCT is this clinical tool that we use in practice that actually looks at the retinal anatomy in high magnification. It can measure the retinal thickness and find subtle changes in terms of fluid. There’s now technology that can be deployed at home so that patients can acquire these images and send them to us in clinical practice. We’re still trying to figure out how that fits into clinical medicine today. We also have a number of logistical issues to work through in terms of payers and access. But that would be a dramatic opportunity to put these devices in patients’ hands, and have highly durable agents. That would free them up for a much higher quality of life. They’d spend less time with us, and they would enjoy that tremendously.

John W. Kitchens, MD: When you think about the advent of these amazing therapies, we’ve also had the advent of the imaging you refer to, the OCT test that we’ve talked about on multiple occasions. We’ve gone in the last 20 years from having prototypes and $100,000 scans that were very rudimentary, to now possibly being able to put that instrumentation in patients’ homes at an affordable level and allowing us to diagnose and monitor these patients on a daily basis. It’s absolutely amazing where we’ve come from and where we’ve come to.

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Transcript Edited for Clarity