Lloyd Clark, MD

In closing, I’d like to get a thought from each of you to our primary care colleagues mainly. Dante, what would be your last parting thoughts to primary care doctors on age-related macular degeneration [AMD]?

: When I started my career 25 years ago, for the patient with AMD, the going thought was there wasn’t much you could do for them, and the patient was going to lose vision. They were not going to go totally blind but they were going to lose the center vision and probably not be able to drive or read. That’s completely different today. There’s a lot we can do for these patients. We can maintain their vision; we can improve their vision in certain circumstances. We’re doing a whole lot of work with the dry disease itself, too. I would be optimistic to those patients. I hate when I hear the patients come in and say, “Oh, I hear I’m going to go blind,” because many of them aren’t anymore. We’re going to be able to improve their vision and keep them seeing, reading, and driving. I have patients now who have been driving 15 or 20 years. They wouldn’t have been driving before the advent of these agents., So optimism would be my closing point when it comes to AMD.

: Roger, what would be your closing thoughts?

: Yes. My word was hope, not optimism, but we’ve come so far. I know everybody on this Zoom here tonight is very involved in clinical research. Generation 1.0 of the anti-VEGF agents, our ability to treat wet AMD, diabetic retinopathy and some other diseases, is incredible. The next 30 years are going to be another period of incredible innovation and growth of what we’ll be able to do for our patients. I think we’ll look back on these last 15 years and say, “Oh my gosh, you were injecting patients every month with a single class of medicine.” We’ll look back and say, “That’s barbaric,” because we’re going to have a much broader armamentarium of medicines, and diagnostics, and ways to monitor, and the introduction of artificial intelligence, and stem cells and gene therapy. As someone who’s involved in clinical research in this space, it’s an exciting time. We’ve come far in 15 years, but the next 15 and 30 years are going to be even more impressive.

: Lloyd, close us off with your parting thoughts.

: Yes. I would go back to basics a bit. The number of senior patients continues to grow dramatically. The baby boomers are coming of age, and there’s a tremendously large group of patients for whom life expectancy is much longer. As you get into your 80s and 90s, the incidence of age-related macular degeneration goes up dramatically. The incidence of diabetes is exploding, and then we have the more common senior causes of vision loss, including cataracts and glaucoma. These patients over the age of 70 need a dilated eye examination by a competent eye care provider every year. There’s a number of things that can trip them up, and their health is so good with better nutrition, better exercise, and better systemic management from you. We don’t want their vision to be their limiting factor, so make sure they get an eye exam, a dilated eye exam, every year because many of these problems if we catch them early will not impact their quality of life.

: That’s absolutely a tremendous point. I want to thank Roger, Dante, Lloyd. You guys have been fantastic, covering exudative age-related macular degeneration in such a thoughtful and in-depth way.

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A panel of eye care specialists share clinical advice and future directions for the treatment of wet AMD.

Clinical Pearls for the Management of Wet AMD

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?

: 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.

: 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.

: 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.

: 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?

: 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.

: 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?

: 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.

: 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?

: 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.

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

Emerging Treatment Options for the Management of Wet AMD

: Dante, you had mentioned safety issues surrounding this class of anti-VEGF agents. When we talk about the intravitreal injections, what safety issues are we worried about?

: First, for the class of drugs, with the intravitreal delivery of these drugs, I don’t worry too much about the agents themselves. They are well tolerated by the body and the eye, I’m talking about the anti-VEGF itself. the real risk that I talk to the patients about is the injection, because when you stick a needle in the eye you can introduce bacteria, you can get something called endophthalmitis. If it’s a bad bug, it can lead to loss of vision and potentially loss of the eye in some of these bad cases. To me, that’s the biggest risk of the procedure. The agents themselves, we’ve done this in millions of patients over the last 15 years, and they have tolerated it very well. I don’t worry about a patient who has hypertension or had a heart attack. These agents are very safe when delivered in the eye in the dosages that we’re using. My discussion with them is that there’s a risk of an infection from the injection itself. That’s why we’re going to prepare your eye. We’re going to put Betadine, iodine essentially, in your eye. It’s going to make it a bit uncomfortable that day, but it’s going to significantly reduce the chance of having an infection. And luckily, it turns out that we get infections maybe 1 out of a thousand times, and we’ve all seen these because we’ve all done hundreds of thousands of these injections. It is discouraging when it happens in those rare cases. Most of them we can manage and get vision back, but there are those cases with the bad bugs and we do get some permanent loss of vision, but otherwise, the injections, patients tolerate them fine.

: Like any drug, you read the package insert, and you’re going to be terrified, but really what it boils down to is, you can get a red eye, you can get an irritated eye. Those things all get better. You’re right. The infection risk, which is roughly 1 in 3000 to 1 in 5000 injections, is low, fortunately. And most of the infections are pretty novel bugs that are easy to treat; 

 is probably the biggest one. But a bad bug can cause a problem. You may read about retinal detachment and cataract formation, that is exceedingly rare. I can’t remember a time when I’ve given an injection that I thought caused a retinal detachment, which is frankly shocking, that we can put a needle in someone’s eye over and over through the pars plana and not induce more tears in the retina. Lloyd, what conversations do you have with patients around risks, either ocular or systemic?

: I don’t have many systemic conversations anymore. We’ve got enough clinical trial data that help us understand that these drugs don’t cause systemic complications. The dose here is around 1 500th the mole equivalent of bevacizumab used for solid tumors. This is just a sprinkle of anti-VEGF, when you think about it, in the systemic environment. I don’t talk much about systemic complications. We do talk about retinal detachments and endophthalmitis; the one that we worry most about is endophthalmitis because this can sometimes be a devastating complication. Commonly, it’s one that can be managed with intravitreal injections of antibiotics plus or minus steroids. But if you get a bad bug, the eye just doesn’t tolerate this type of fulminant inflammation. We talk to patients, maybe not so much about the complications prior to the treatment, but as they leave the clinic, we talk about the symptoms of those complications, and focus on the symptoms of a retinal detachment and endophthalmitis. In the case of a retinal detachment, it’s flashing lights, floaters, and peripheral loss of vision. In the case of endophthalmitis, it’s a red eye, progressive blurring, and progressive pain that doesn’t go away with anti-inflammatories such as Tylenol, ibuprofen, and it gets worse over time. We really emphasize the symptoms of the most common complications associated with the procedure itself.

: I’d say that as a primary care doctor or a primary eye care provider, if you get a call from a patient and they say they had a recent injection inside their eye, and their eye is painful and their vision is dropping significantly, that’s a patient who needs to get in that day to see their retina specialist to have it managed. It’s not something that you can schedule for a week or days later because we do want to treat those patients. If you get a call and the patient says, “The doctor gave me an injection in the eye the day before, or a few days ago, and I called his office, I can’t get through. Now I can’t see. What should I do?” We need to get them back to that doctor.

: It’s important that those patients don’t end up getting referred to the emergency department because that can create a further delay, unless it’s at a university medical center where they have ophthalmologists on call, and possibly in house. That’s an excellent point, both Lloyd and Dante, the discussion around what these complications look like because they are rare, but when they happen, early recognition and early treatment, especially for endophthalmitis, is absolutely critical to saving the patient’s vision. Many of these patients can do very well.

Dante J. Pieramici, MD, leads the discussion on potential safety issues of anti-VEGF agents and addressing these concerns with patients who have wet AMD.

Addressing Safety Issues for Anti-VEGF Agents in Wet AMD

: Roger, these patients, we’re talking every other month, or every month and a half, coming in. What are some of the challenges that you face, not just from a medical standpoint, but from a societal standpoint, from a familial standpoint, with treating these patients so frequently?

: We talked a bit about this idea of a treatment burden, and there is a burden for the patient to have to come in, but it’s also an office visit burden. It’s a burden for their caregiver to have to drive them, particularly with the macular degeneration population, which tends to be an older population. Many of them don’t feel comfortable driving after they’ve gotten an injection. I would say, particularly in my AMD [age-related macular degeneration] population, most of them are coming to the clinic with a driver. They need to have somebody else come with them. The medicines, particularly the on-label medicines, are expensive. There’s a societal burden in terms of the cost of care to manage and control this disease. When you look at the cost, and they do cost-benefit analyses vs the millions of people who would have gone blind, had we not had these agents available to us. Both in AMD and diabetic retinopathy, in both of those indications, the societal cost of blindness is much greater than the cost of these medications. But the burden is still there just in terms of the ongoing effort required to come in and maintain that fairly regular and regimented treatment algorithm that’s necessary to maintain the vision over time.

It’s easy for patients in that first 1 to 3 injections because they’ve seen some vision gain. They look at the OCT [optical coherence tomography] that Dante talked about at the top of this program, and they see that the fluid is gone. What they’re experiencing with their vision and what they see in terms of the anatomic response, they’re excited and on board with treatment. Every 6 months though, after that when you’re talking about stability, which is to say, “Hey, we’re keeping your retina dry. We’re keeping your vision unchanged now.” Every once in a while, I have to pull up the original scan from when they first came in and say, “Remember, this is what we’re trying to prevent you going back to.” It can be tiring to come in when you’re not experiencing the benefit like you did during those first few injections.

: It’s fascinating that you’ll have patients who have amazing responses, and after about a year, they’ll say, “Do I have to keep getting these shots, or I’d really like to take a break.” And sometimes I’ll say, and it’s always the patient’s choice, “OK, we’ll give you a little break.” And inevitably they’ll have a recurrence, where hopefully they don’t have hemorrhage. They’ll just have leakage and their vision will drop and they’ll realize, wait a second, it’s this aha moment. “These treatments are keeping me seeing. They made me better, and now they’re preserving my vision.” And you usually don’t have to have them go through that more than once before they go, “I get it. I’m going to stay on the shots.”

: Certainly I think from a lot of the retrospective data from COVID-19, when some of these patients did miss their visits, and now it wasn't every patient who missed a visit or who lost vision, but a significant proportion of patients lost vision. And then yes, like knock on wood, and I'm knocking on wood here. But patients sometimes were able to get that vision back when we re-instituted treatment. Sometimes though patients weren’t able to get the vision back that they lost, and those are bad outcomes. So we kind of did this little bit of a mass trial in some patients who were either too afraid to come in, or whatever their COVID-19 situation was; sometimes the nursing home wouldn’t even let them out of the nursing home to come in and get their treatment. So it wasn’t always by choice or their choice, that they didn’t come in.

A panel of eye care specialists review challenges faced with the management of wet AMD when patients are put on an extended treatment regimen.

Lloyd Clark, MD

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