, “Advancement in Management of Age-Related Macular Degeneration.” I am Caroline Baumal, I’m a professor of ophthalmology at Tufts University School of Medicine in Boston, and today I’m joined by 3 of my colleagues and good friends. I am really happy to see them on Zoom, and hopefully to see them in person soon. First, we have Dr. Thomas Albini, professor of ophthalmology at Bascom Palmer Eye Institute in Miami, Florida. Hi, Tom.

: We also have Dr Aleksandra Rachitskaya, who is an assistant professor at Cole Eye Center in Cleveland.

: Nice to see you, too. We also have Dr Michael Singer, who is a professor of ophthalmology at University of Texas at San Antonio, and he is also in private practice. Hi, Dr Singer.

Hi, Caroline. Thanks for having me. I am excited to be here.


: Oh, so am I. Today we are going to talk about several topics pertaining to wet macular degeneration. We will be talking about diagnosis, clinical manifestations, and focusing on treatment, the mechanisms of treatment, and new treatments that are in the pipeline. We’re going to wrap it up talking about how we care for patients in this era of COVID-19 [coronavirus disease 2019] and how’ve changed our practice.

First, we are going to talk a little bit about wet macular degeneration and its definition. We all can agree that one of the hallmark signs of wet macular degeneration is choroidal neovascularization. The pathophysiology of macular degeneration is multifactorial as far as we know, and it is a complex mechanism involving metabolic, functional, genetic, and environmental factors. There’s so much that we need to know. Tom, what about the incidence of macular degeneration? I know that you are in Florida where you probably feel that almost every patient has macular degeneration.

: It is very prevalent, and the real thing to know about it is how it’s exploding. The prevalence of macular degeneration is increasing to the point that it may double over the next 2 decades. But by current estimates, there are somewhere between 10 million and 11 million Americans affected by macular degeneration in all forms. Wet macular degeneration, which is the focus of our discussion tonight, comprises about 10% of that.

But by 2040 to 2050, they are anticipating that we’re going to be up to 20 million-plus patients living with macular degeneration. Globally, almost a quarter of a billion people are anticipated to have macular degeneration by 2040. It is a huge medical area in terms of cost in the United States and around the world. In the United States and Canada, the WHO [World Health Organization] estimates that it’s almost $100 billion that’s being spent on patients diagnosed with macular degeneration, the majority of that being direct health care costs. It is a big deal, and it is getting much more common.

: Those numbers are incredible to think about. I remember when I started my practice, sometimes I would see patients come in just for general checkups, but now almost every patient I see really has a problem, usually macular degeneration or diabetes, and needs treatment.

Introduction and definition of macular degeneration

: Aleksandra, what is the typical patient that you see with macular degeneration in your practice, an example of a patient who has not yet been treated for macular degeneration?

We [at Cole Eye Center] are seeing so many more patients. The big point is that our patients are getting older and older. As we see older patients, we see more advanced stages of the disease, be it neovascular AMD [age-related macular degeneration] or even geographic atrophy. I am seeing more geographic atrophy than ever before.

When we talk about macular degeneration, our standard patient is a female Caucasian, typically in her 70s. The studies show that, as time passes, gender becomes less of a risk factor as we go into later stages of AMD. We also know that patients who have a history of smoking, or are actively smoking, are at a higher risk, and we usually see patients who also have a history of hypertension and cardiovascular disease. The other subset of patients might not be as strong, but BMI [body mass index] has been considered and if the patient has been diagnosed with other vascular diseases.

The standard patient is usually coming in, in my clinic, with vision somewhere between 20/40, 20/60, and I’m actually glad when they come in with that state of vision because a lot of times the treatments we have are very effective. Unfortunately, we still see patients, some of whom are older and have problems with their nondominant eye, when they come in with very advanced wet AMD, we often cannot bring the vision back as much as we could have if we had seen them earlier.

: That’s interesting because it seems that the word is out there that we do have treatments for wet macular degeneration. People, on the average, compared to a decade ago, do tend to come in earlier. However, due to COVID-19 [coronavirus disease 2019], I feel like I have been seeing patients later again. Maybe it is the patients with later stage AMD that really stick in your mind.

Dr Singer, I know you are in a busy practice [at the University of Texas at San Antonio]. On the average, how many injections do your patients get a year for neovascular AMD? Do you have any insight into that?

 It is about 8 or 9 [injections] a year. I typically start with 3 loading doses. Depending on whether they are dry, I will extend them out every 2 weeks with typical treatment extensions. If I start seeing increasing fluid or decreasing vision, I may contract by 2 weeks, and obviously, if I happen to see a huge hemorrhage, then I am going back to monthly injections until we get this stabilized.

: Do you treat differently if it is intraretinal fluid versus subretinal fluid?

 I do. Essentially, my initial goal is to get rid of all the fluid. From lots of studies that have been conducted, such as the work we [at the University of Texas at San Antonio] have done with the VIEW trial, and what Nancy Holekamp, [MD,] in Boston has done with HARBOR, we can see that there are patients who have chronic subretinal fluid who actually have no effect on vision. The reality is subretinal fluid is something I am going to end up with. If I have given you 3 shots and I see the same subretinal fluid at a month and it has not changed, if your vision is the same, I’ll try extending it out. I also use the patient as the guide because they look at the OCT [optical coherence tomography] at every visit. By that time, they’re starting to get shot fatigue because it’s about the fifth or sixth injection. They are then pushing me to go out a little bit and I am pushing to go out, but if anything changes, then I contract back.

: That is great. You teach your patients how to read the OCT. That is a good skill.

One thing you mentioned is shot fatigue. It is very hard for patients to keep up the treatment regimens that are in a lot of clinical studies. We do not stop following patients at 1 or 2 years; we follow patients for decades.

Identifying a typical patient with Wet AMD

: Dr Rachitskaya, what are your treatment strategies, and how do you take some of the real-world studies that we know of and use that data to inform how you treat your patients?

That’s a great question. Showing patients the images is useful because I think they also get invested. They get excited when they are doing well. They come to your clinic, they’ve already looked at their OCT [optical coherence tomography], and they say, “I’m doing so great,” or “I need a shot today.” Knowing that we do not have to have that discussion is great.

When we look at the studies, the patients have one set of outcomes. When we look at real-world studies or when we look at the extension studies, the outcomes are just not as good.

It is multifactorial; we must consider injection fatigue and compliance. A lot of these patients are elderly. We are also operating now in the world of COVID-19 [coronavirus disease 2019], and elderly patients have to rely on their caregivers and their families to bring them. Sometimes it feels like a burden to them. All those factors play into following the schedule that we set up.

There are 3 approaches that I think on average people use. It could be monthly injections, and a lot of studies utilize a monthly injection arm. You also have patients you see PRN [pro re nata, or as needed]. With the traditional PRN, the patient is seen on a monthly basis, but treated only if there is a presence of fluid in the eye or vision loss.

There is also treat and extend. In the cases of the classic treat and extend, you see the patient until they are dry, and then you start extending by 2 weeks, and you treat regardless. If they are still dry, you inject and then extend by a couple of weeks more. You can then cut back by a couple of weeks as well.

Some of the trials, especially the pivotal trials such as CATT, for instance, showed that on average, if you compare the monthly [injections] versus PRN, PRN overall does well. In the CATT trial, with PRN visits patients had about 2.4 letters worse than those seen monthly, but the outcomes are comparable.

On average, about 10% to 20% of patients require 3 injections or less a year, according to the CATT trial. If you commit a patient and treat them via monthly injection, you’re not going to catch those patients who might not need as many injections. We have all seen patients who, when we just do a couple of injections, improve and then they do not need as many injections.

In my practice, I use treatment extend because, with PRN, if you don’t treat them during their visit, if they have fluid in the 8 weeks between visits, they may experience discomfort or regress. We do not want them to have fluid, whenever possible. I try to keep them as dry as possible with a treat and extend regimen.

: What about you, Dr Albini? What is your treatment strategy?

I agree with Dr Rachitskaya and have similar experiences. This decision is very patient-specific and personalized to the individual, considering their family situation, and their ability to drive in. I agree that PRN is the optimal treatment paradigm, but that means that patients are coming in every 4 weeks, and patients often do not want or cannot do that. Some of them opt to do that and can do it without a problem, but most tend to do treatment extend. A little bit less than treatment extend is the reality of what they are doing. There can be more of an extension than there should be if they miss an appointment.

Now with COVID-19, it has been even more challenging. Seeing patients regularly has been difficult for the last 6 months, so it is really patient-specific what you do.

: I usually use a combination of treat and extend, but I look at the patient factors. There are some patients who have a very small classic CNV [choroidal neovascularization] or type 2 CNV, and they really do not need many treatments. They are reliable patients who can do home monitoring or an Amsler grid. Eventually, we may have something like home OCT, so we can do PRN and not see patients monthly, but use OCT or other parameters.

Clinical trials vs real-world data on wet AMD

: We have some FDA approved anti-VEGF agents and some off-label agents. Dr Albini, do you want to go through the anti-VEGFs that we have and tell us how you decide what you are going to use?

 You are going to make me choose sides here?

: No…we are very fortunate that we all have access to everything. We are in places where we treat a lot of patients, and that is not always the case for everyone. In brief, tell us how the mechanisms differ between the agents.

 There are a lot of similarities between the options that we have, both FDA approved, and non-FDA approved. They are all basically products based on antibody technology that target vascular endothelial growth factor [VEGF]. It is apparent and incredible how targeting this one molecular pathway really helps patients with wet age-related macular degeneration [wet AMD] as well as other forms of pathophysiology, like diabetic macular edema and other forms of macular edema.

In any event, the first FDA-approved agent was pegaptanib, which was a lot better than the standard of care at the time, but it is not used anymore because the subsequent agents do a much better job of restoring vision in patients. Then the most used agent is bevacizumab, which is used off-label and aliquoted from larger doses that are used for metastatic cancer. That allows this agent to wind up being less in cost than the other FDA-approved agents, which is an important factor for patients with high deductibles or co-pays. Around the world, it is by far the most commonly used agent because of the cost issue.

Ranibizumab is very similar; it is a slightly smaller molecule and was shown to have very similar visual acuity outcomes in a prospective randomized NEI-[National Eye Institute]-sponsored trial, the CATT trial. It showed that, whether this drug is given on a monthly basis or given on an PRN [pro re nata, or as needed] basis, the visual acuity outcomes are within 3 letters or so, regardless of the strategy or the drug that is used.

Aflibercept was then shown to be noninferior to ranibizumab in the pivotal VIEW trials. This drug has a much higher binding affinity and can be used at a lower or less frequent dosing interval. I think this is now the most commonly FDA-approved drug used in the United States for wet macular degeneration. People feel that it has a better drying potential, and again, that doctors can extend patients further out on this drug and have fewer injections relative to other drugs.

Then we have the recent addition of brolucizumab, which we have all been very excited about. This is an antibody fragment that is the smallest molecule of all these drugs, which allows them to pack in more molar equivalent, a higher number of molecules into each injection. This extends the half-life of the drug and should reduce the dosing frequency even further. In fact, half of patients in the pivotal HAWK and HARRIER trials were able to be extended out to 3 months with this drug.

However, there has been a rate of intraocular inflammation 4 times higher than that seen with aflibercept, including a small subpopulation of patients who have had severe vision loss associated with intraocular inflammation, particularly occlusive retinal vasculitis. Between that high rate and COVID-19 [coronavirus disease 2019], the widespread adoption of this drug has stalled for a year now that it has been out on the market. We will all see how that progresses. Later, we will be talking about future options, but hopefully we will have more to the armamentarium.

: Dr Rachitskaya, we have a host of anti-VEGF agents available for use. What sort of strategy do you use when deciding which agent to use?

We have several agents to choose from, and all these agents work very well. There are specific patient characteristics that guide me. Routinely, I start with Avastin. It is very easy to get, there are no issues with insurance. We [at Cole Eye Center] have it aliquoted at our pharmacy, so it is reliable. Then I see the response. Whatever you start the patient with, in AMD, we usually see a response rapidly. If the response is suboptimal and they could do better, I consider switching them to another agent. Some patients can be extended a little bit longer on different agents, so I utilize that.

When we look at large trials, all these drugs are similar; the differences are minimal. When we look at trials, it’s EDTRS [Early Treatment Diabetic Retinopathy Study] vision [acuity assessment] versus the clinic vision. All these drugs do well. With brolucizumab, there is some more potent drying. As we develop newer drugs, we have drugs that last longer. In the current armamentarium, they are overall similar, and patients do well on all of them.

Anti-VEGF agents for treatment of wet AMD

I am sure we all have a wish list of things that we would like to achieve when we treat neovascular AMD [age-related macular degeneration]. We have been given this gift of therapies that use anti-VEGF agents, but now we want to do better. We want our patients to have better vision, and we want our treatments to be safer and more durable. We want to do the best for our patients in a way that is easy for both the patient and for us. Michael, what is your experience with the current intravitreal anti-VEGFs? They all have slightly different dosing intervals. How do you approach that?

Dosing depends on the patient. There are obviously a lot of factors that are beyond my control when I decide which drug to prescribe. Insurance coverage is obviously an issue, and a lot of companies are now giving us step therapy that we have to go through, such as bevacizumab, and at certain points you may be able to progress to the branded drugs.

Given my preferences, I like prescribing the branded drugs. Although we talked about the studies of CATT, when we look at all the studies where they compare bevacizumab versus branded drugs, essentially branded drugs always dry better. They do not provide better vision, but they dry better. What is interesting to observe is that, if you give the same dosing, that’s how we typically monitor patients in our office [at the University of Texas at San Antonio], is how dry you are on the OCT [optical coherence tomography] because that is an objective measure. That is when I typically extend a patient out. I have seen patients who do very well on ranibizumab, aflibercept, and brolucizumab, and I’ve seen certain people do well on one when I had thought they would do well on the other. Everybody is a little different.

Aleksandra, what’s your experience with intravitreal anti-VEGF agents?

 I echo what everybody has been saying. We have been really lucky. When patients complain about injections, I tell them about this example. I have a patient who had neovascular AMD in both eyes, and the patient hated injections. She absolutely hated them. She decided that she was going to pick an eye to keep functional. It was so hard for me to do that, but we met with the whole family. It was a whole ordeal, and this patient and I have a natural history. Now, one treated eye is staying 20/30, and we also have to consider the other eye for which she refused treatment. It’s been so dramatic to see how fast she lost vision in that eye.

We have been extremely lucky with the treatments that we have. The newer technologies that you have alluded to hopefully will address the biggest unmet need, which is the injection burden, right? The problem we must address is the number of injections and how frequently patients require them. If we can address that through new injectables, such as combination therapies and something that decreases the frequency of injections, like core delivery systems or gene therapy, we could see real improvement in our quality of care. There are so many exciting things that are happening. Whenever patients mention the injection fatigue, I say, (a) you’re doing great, and without the injections we wouldn’t be talking, so I’m so glad you’re seeing well, and (b) there’s always hope. I try to stress that to my patients as well.

That is great. That is the way to do it. Tom, let me ask you a quick question. You have a patient, they are on treat and extend, and you have got them at 3 months. You have treated them every 12 weeks or 3 months, and they’ve been stable. Do you ever stop injecting these patients? What is your scientific reason to continue this forever? How do you feel about that?

I do not have great data to guide me on when to stop treatment. My experience with that dilemma is that I remember a time when, back in 2005 or 2006, when we started with Avastin, and ranibizumab was FDA approved, people were saying never extend out past 3 months. I had a patient like this, who was not injected for 6 months or 8 months, and then that patient came back to us with a massive submacular hemorrhage. Now, that experience got me into that habit of not extending patients beyond a certain point, and that number has increased over time. It was 3 months, then it was 6 months.

But I still tend to feel uncomfortable about extending people out to fewer injections than 1 per year. I’ll still try to sneak 1 in and convince the patient to receive 1 injection, even if they’re perfectly flat. That is something that is tailored to the patient, however, because I do not yet have great science to guide me about when to stop. My suspicion is that it is OK to stop and that some small number of patients are going to have submacular hemorrhages, but I do not know if that 1 injection every 6 months or every year really makes a difference. I may just be treating my own nerves when doing that. I’d be interested in what other people do, but that’s honestly the way I look at it.

When I start to see a little bit of atrophy, or if the patient has been dry for a long time and I see nothing on the OCTA [optical coherence tomography angiography], I will stop treating. It is a big discussion. We have to discuss these complex issues with patients who we might see only for brief periods, especially now it may be even more brief because our patients do not want to be in the office very long. We do need some guidance from studies on when to stop treatment.

Personal experience with anti-VEGF agents for wet AMD

Mike, you gave us a little bit of insight into how many injections you perform a year. Do you think there is any evidence to support PRN [pro re nata, or as needed] treatment, and do you ever move patients from one treatment regimen to another?

: I do. It is interesting to examine PRN studies because we say the word PRN, but it is not really PRN. With the PRN studies, the patients in the study were still seen every month. They were just not given shots every month. But to speak to Tom’s point, you have got patients who you do not see every month, and they come back, and you extend and bleed. There was a series out of Wills [WillsEye Hospital] that looked at patients who bled within the same month as patients who had anti-VEGF injections. We do not really understand what it is, and atrophy is an issue as well. It has become a discussion with the patient. It is not me telling them what to do, and injection fatigue plays into this. I do believe when we have home monitoring, it is going to be a lot easier to have patients go for longer periods without injections. We have realized, as a result of COVID-19 [coronavirus disease 2019], that we can go without injections a little longer and do a little less, and patients still do OK for the most part.

I will put it out to the panel: What are the things that motivate you to switch to a different agent? How do you judge the treatment effect? Is it usually persistent subretinal fluid or intraretinal fluid that causes you to switch? Do you feel like there is some vision to save? Mike, do you have any thoughts on that?

: I use 3 factors to make a decision as to whether I will switch. The first, most obvious factor to consider is if there is persistent fluid on OCT [optical coherence tomography] after giving 3 injections that are 4 weeks apart. If nothing changes, that is going to motivate me to switch. Another thing that may motivate me to switch agents is the quality of the patients’ objective vision. If patients are seeing and their vision is starting to drop or change, I will consider a change. Of course, I also consider subjective vision. What does the patient say? If they start feeling that they are losing vision on certain medications, even if the OCT looks great and the vision looks great, I may talk about changing the agent with them. If they’ve been getting shots monthly, I may talk about changing that as well. The other issue is extension. When patients say, “Look, I want to go longer without injections, I’m getting too many shots,” I will consider the potential of changing to a different agent, one with better or longer drying ability.

 When it comes to patients who are not responding to treatment, I take a step back and consider masquerade syndromes. Patients sometimes are just treated with anti-VEGF agents, and they do not respond the way you think they are supposed to. Looking for conditions like CSR [central serous retinopathy], or IPCV [idiopathic polypoidal choroidal vasculopathy] is important. A lot of times you might have a patient who you believe is receiving the best treatment, and they still don’t respond. It is helpful to bring patients back a few weeks after the injection. I’ve had a couple of instances where I bring patients back and they present with the OCT that I’ve been waiting to see. For some patients it just doesn’t last as long.

 I would also consider third party payers. The insurance companies have something to do with what is available and to what treatment we may switch. That is part of the consideration. Atrophy has become another thing that I consider. If a patient has good vision, but has atrophy, I will attempt to reduce the anti-VEGF exposure and stick with an agent, if the patient is receiving an agent and can tolerate some fluid, if their vision is doing well.

The FLUID study from the group from Australia showed us that patients could tolerate some fluid. Although when we looked at the group that tolerated fluid versus the group that had not been tolerating fluid, there was not much of a difference in the number of anti-VEGF injections between those 2 groups at the end of their study period. There are so many important factors to consider. Polypoidal choroidal vasculopathy is a big imitator of AMD [age-related macular degeneration], and it’s important to recognize those patients because adding photodynamic therapy to the anti-VEGF regimen, as shown in the EVEREST study, may provide the patient with a more durable treatment effect

Reasons for switching between agents for wet AMD

Tom, you talked a little bit about safety. What sort of conversation do you have with your patients about safety, especially if it is a treatment-naïve patient and it is the first injection, and have you had any issues with safety in your own practice over the last decade? Have you seen changes in the anti-VEGF safety?

The most important conversation to have, one that is routine for me but not for the patient, concerns the risk of endophthalmitis. Those numbers have been steady, with about 1 in 3000 or so patients being at risk with intravitreal injections. That is important to talk about. The other issues that I used to worry about back in 2005, such as retinal detachments or vitreous hemorrhages, are now uncommon. I may mention that, but retinal detachments never quite materialized, so endophthalmitis is the biggest concern I have.

The one concern that is becoming increasingly discussed is intraocular inflammation. That is a low-risk condition, so I do not always talk to patients about that. Even when we would see occasional outbreaks of intraocular inflammation with aflibercept, those cases were self-limited. You could treat them with topicals; the inflammation would go away, and the patients would visually do well. Now that we have seen some more severe cases with occlusive vasculitis with brolucizumab, I have had that discussion with the patients I have on brolucizumab, so that they are aware of what risk exists in reference to vision loss with that agent. There is such a differential between the other agents. Endophthalmitis risk is the same regardless of what agent you use as far as we can tell, but the inflammation and the severity of vision loss associated with that inflammation differs. That is going to be a key feature of agents going forward.

We have been lucky with how well these agents work. We have been really lucky, considering how safe they were, especially now that, in retrospect, we can see what pharmaceutical companies are having difficulties with, with the new agents coming up. Also, we have had an amazing revolution in imaging. We have been very lucky with OCT [optical coherence tomography]. It helps us guide all of these therapies. We do not have to approach this with standard injection protocols for every patient, since treatment is really guided by the anatomy that you see on the scan on a monthly basis.

Since we are talking about safety, Aleksandra, how do you feel about bilateral injections? Do you make any modifications? Do you try to get different lot numbers? Do you use a different setup per eye?

 I do bilateral injections, and usually it is patient-driven, as are many of the topics we have talked about today. Many patients just want to get it done and do not want to come back. I try to do separate lot numbers. I am not sure if there is any evidence to support that, and sometimes I believe that is for my own peace of mind more than anything else. But there is not a hard and fast rule for that. I have the patient numbed in both eyes at the same time, but I do finish one eye and let them wash the eye before I do the other injection. There is definitely a role for that for a patient who wants to proceed with that, who has a ride and does not want to come back.

Anyone else do anything different? I do bilateral injections for the occasional patient, but it took me some time to get comfortable with it.

 I also try to go for different lot numbers because, although inflammation is very rare in the standard drugs, I was part of the aflibercept group. I had a case of inflammation, and obviously I feel better. In response to Tom’s point and Aleksandra’s, however, I’m probably treating myself more than I am treating the patient. They are so well packaged that it probably does not make a difference, but it makes me feel better.

 One other important safety concern is about bevacizumab. We must be careful about our source of bevacizumab, because there have been clustered outbreaks. We had a case in Florida where we had 20 strep endophthalmitis cases, with the majority of them going on to NLP [no light perception] vision. There was a subsourcing from one pharmacy to another, and the medicine was processed at a place that did not have experience with aliquoting the medicine, and that is what caused the outbreak. You have to be careful; there can be things happening behind the scenes of which you are unaware. Those of us who work in hospital settings are lucky because we know that it is controlled. There is less control in the external world.

Safety concerns with anti-VEGF agents for wet AMD

I read a great article by Dr Rachitskaya. I was hoping that since we are still talking about anti-VEGF agents, could you quickly tell us the difference between biosimilars and generics? This is going to be a field that we are likely going to be dealing with soon. I read this article, and then I finally understood what the difference was.

I have to give all the credits to my colleague [from the Cleveland Clinic], Sruthi Arepalli, [MD]. She is the lead author of that article, but thank you for the kind words.

Biosimilars are going to play a bigger role. They are already playing a bigger role in countries such as India. In fact, I was on a webinar on biosimilars, and the majority of people in attendance were not from the United States because it is so prevalent outside of the United States. I think the big difference to understand is that all the drugs that we use are biologics. They are derived from living organisms. Biosimilars are not supposed to be a carbon copy of your aflibercept or ranibizumab. They are supposed to be similar, and they are supposed to provide the same therapeutic end point, whereas the generic drug is just a carbon copy of the original drug. When a company develops biosimilars, they are not given a recipe by the original drug creators. They have to develop their own, and that process involves looking back at the original and analyzing how to create this biosimilar. Ultimately, although biosimilars are definitely cheaper than the original medications, they are still quite expensive to develop, and development is not fast nor inexpensive. The FDA requires trials to show that the biosimilars are noninferior to the original drug. Once again, it is not the same as bringing a totally new drug to the market, but there are development costs and other costs associated with the trials.

The patents are expiring on the drugs that we are using, and what we are grappling with now is how biosimilars will enter the market. The biggest question is going to be what is going to be the price point of these medications? Where are they going to fall in the armamentarium of what we use right now?

The other difference between the United States and some other countries is the use of Avastin. Avastin, as we have discussed, is affordable, readily available, and we use it often. For instance, in countries like India, they do not use Avastin as much, so their biosimilar price point is likely less than what we would see in the United States. It is going to be interesting to see this develop, but the big point to understand is that biosimilars are not generics. When compared to the generics, the process to create and approve biosimilars is different. It is not something that can happen overnight.

That was a great paper. It really informed me about the importance of the topic. I’m interested because it seems like there will be many different agents as a result of this phenomenon, but our fridges are only so big. When we consider how many different agents to stock and the approval processes of each agent, it is sure to be interesting in the future.

Role of biosimilars in management of wet AMD

Mike, tell us about some of the new compounds that we might have to get a different storage place for. What’s new, what’s in development, and what are your thoughts on efficacy, trials, and promising pathways?

 There are a number of medications that are in development in phase 2 and phase 3 trials, and some of them are different. Some are actually using a real combination therapy. There is obviously faricimab, which is an ANG-2 blocker that is in combination with an anti-VEGF. It is all in 1 molecule. The STAIRWAY study showed some really good results in terms of being able to control disease activity in the majority of people and being able to extend patients out 12 to 16 weeks. The TENAYA and LUCERNE studies have finished enrolling, and they are going to have data release relatively soon. In that regard, this may be something that comes to market very soon, and it works in a different way. The ANG-2 pathway basically has to do with vessel stabilization. If you are able to close the vessels and stabilize them at the same time, you may end up having a longer duration of activity and potentially even more potency, leading to better vision.

The other thing that has come, which Aleksandra [Rachitskaya] talked about, is the port delivery system. The port delivery system is a pump in the eye. I always tell my patients that it is like an insulin pump. It gives a steady release of medicine over time. It is a surgical procedure, so in that regard, patients have to be willing to go to the operating room for a procedure. What is really interesting is that the Archway study showed that 98% of people did not need a refill before 6 months. This medication does a good job of giving sustained release over time, and there may be some data that show that it may show less macular atrophy, or not more at least, than monthly injections. I am excited about that, and those things are going to come to market sooner.

Further down the pike are going to be other medicines still in development like KSI-301, with an antibody-binding conjugate, which is this big platform that the medicine stays on. Their phase 1 study showed that essentially 44% of people were able to go out for 6 months. It really has some great potential going down the pike. The future is very bright.

Great. Tom, is there anything you are particularly excited for about neovascular AMD [age-related macular degeneration]?

 I am excited about everything that Michael mentioned. In addition, what also is really promising and even more revolutionary, in terms of drug delivery, is gene therapy options. A number of therapeutic strategies employ vectors of various kinds to manipulate your own cells, whether those are retinal pigment epithelial cells, photoreceptors, or other cells in the eye, to make the drug that we’re injecting. Instead of having an injection or a reservoir that is releasing the drug, you would have a drug that is continually made. It is not clear how well those vector systems may work, but the goal is to find something that could perform even a onetime delivery, whether that is a vitrectomy with subretinal injection, a suprachoroidal injection, or even an intravitreal injection. All those strategies are being tried by different companies, and we will see what pans out with that. That is very exciting and would be probably the most commonly used gene therapy in medicine if 1 of those strategies works out.

I am excited about home monitoring, specifically home OCT [optical coherence tomography]. I hope my patients can come in and tell me when they need a treatment. That would really revolutionize how we treat patients. Of course, I like the idea of having an anti-VEGF agent combined with something else. It is like something that you already know, having an anti-VEGF agent’s effects and something else.

Compounds and home monitoring device in development for wet AMD

Aleksandra, why don’t you tell us how things are going at the Cole Clinic with COVID-19 [coronavirus disease 2019] and how that’s affected you and your patient flow?

 It has affected all of us. There is no question about it. We actually looked at our data, and 1 of the studies that we have done is to look at patients who kept their appointments, especially when we talk about MD [macular degeneration] patients. With patients who are on injections, we do want to continue seeing them. We also looked at patients who had canceled appointments and no-show appointments. When you look by subspecialties, retina actually kept most of the patients, and then those patients who canceled were rescheduled to be seen.

We even analyzed a little more by looking at the patients who got the injections, patients with AMD [age-related macular degeneration] and diabetes, as well as our patients with RVO [retinal vein occlusion], and it was interesting. We found that when we looked at the overall population—not individual patients, since we all can think of an individual AMD patient who came back and lost vision because of a delay in care—on average, the AMD patients did pretty well even with that delay. This is the care delay in March, when we had the mandated lockdown. On average, there was a 5½-week delay. In fact, patients with diabetic retinopathy who require injections and RVO patients tend to lose more vision in our experience.

We did this study, but we are still dealing with COVID-19. We are still having patients who have delayed care. It is not something that is over. Based on all the things that we talked about being excited about, hopefully we can learn from our COVID-19 experience what the patients’ needs really are when our patients can come in as frequently as we would want.

That is a great point. Tom, how are things in Florida?

 Similarly, we [at Bascom Palmer Eye Institute] came to a grinding halt in March. Our clinics were cut by about 80%, and that was true in the retina service too. We were really seeing only emergent cases and urgent follow-ups that absolutely needed to be seen, and we were doing injections. We looked at patients who had been receiving injections at a fairly regular interval, and we just had those patients come in for the procedures themselves and not get an OCT [optical coherence tomography] and get a full visit. It was surprising to me that there was a substantial group of patients who really wanted to see their OCTs, even if it meant staying in the hospital, with all the excitement about COVID-19 and whatnot. The hospital was empty at that point.

We started bringing them back in, and now the vast majority of patients are getting OCTs and full evaluations again. As Mike was saying earlier, my patients, like everybody’s patients, like to look at the OCTs, and they get good at reading them over time. They want to see what is going on, even if they get an injection every single time. That has been our practice.

The other thing we have done is for patients who weren’t getting injections at very regular intervals, but needed to be monitored—maybe they have a disciform scar in 1 eye but dry AMD in the other eye, or they were at high risk for having problems but did not have wet AMD—we were bringing those patients in for imaging-only visits. They would come in and get an OCT. Then the OCT would be reviewed, and we’d call them or do a telemedicine visit. That was very popular for a while. We have shifted from telemedicine to bringing patients back into the clinic so we can actually do a real exam.

In ophthalmology, telemedicine is very useful. This kind of hybrid, where you have them get an imaging study and then talk to the patient, is an interesting option that works for a lot of patients. You cannot really beat a real examination, especially for uveitis patients, and with uveitis, that hybrid is impossible. For a lot of patients with medical retina, you could do it, but you still might miss something in the peripheral retina or something else that is going on, like new onset corneal edema that is causing the patient’s problem. We are doing less of that through telemedicine, but it is still something we are trying to do as much as we can to help patients stay out of the clinic unless they absolutely need to be there.

The other thing that has changed is we do not have patients coming in with visitors as often, and in the AMD population, that’s very common. Somebody brings the patient in and then sits with them for 3 hours. We cut our waiting room volume in half by allowing visitors only when it is absolutely necessary for patients to have somebody with them.

The impact of COVID-19 on the management of wet AMD 

Mike, tell me, have you done telemedicine at all or used phone calls? Have you cut imaging?

 Considering the things we [at The University of Texas at San Antonio] have done is funny because we haven’t embraced telemedicine as much as everybody else. But because I have been slightly frustrated, I did use the call model. They did a great job trying to get OCT [optical coherence tomography]–only visits. When we were shut down, for starters, you did not wait in the waiting room. You would walk in, we would send you a text message when it was time for you to come in, and then we’d streamline you through the process in general. What I did is basically decreased the examination of the patient’s eyes. I used to do it every 3 to 4 months, and now I do it every 6 months. That has actually kept going because I realized I do not really need to see, and I have tried to decrease the number of OCTs going forward.

It is interesting. I’ve spent a lot of time thinking about this. I was very frustrated by the whole process when we started telemedicine because I tried to do a video chat and I held up the phone, and obviously you have to be HIPAA [Health Insurance Portability and Accountability Act] compliant. I actually worked with a couple of companies to resurrect some apps. Verona used to have this great app, My Vision Tracker, and I helped persuade them to bring that back to life. It is interesting that there is value there. I do believe, as Tom said, that for the complex cases, you cannot just use telemedicine. I also live in a state that locked down for a very short period of time. I am in Texas, so it really was a much smaller time frame. We were cut down in March, but in mid-April, they started letting people go.

It is so hard to find the right balance. We want to be safe. We want our staff to be safe and our patients to be safe, so we have to find the balance when working and taking care of our patients. We have to make sure they get the care that they need because we treat so many blinding eye diseases. I found that I have really cut down on my imaging, although we have moved that up, but I have changed my whole flow with patients. I will actually have my patients come in, get the OCT first, and then I will see them right away. I will put the anesthetic eyes in and have the trays ready to go, which really cuts down on the time.

One thing I did that really cut down on time is to make the patient’s appointment right when they are in the chair with me. I do not have them go out to a desk or receptionist anymore. It has bothered people to change the flow a little because, for those of you who are academics, you know that the checkout can be the longest wait of the day because people are checking in and checking out. I have really cut down on the visit by just saying, “Here is your appointment in 4 weeks.” Sometimes I just make multiple appointments for 4 weeks, 6 weeks down the road. I say, “Here are the appointments. Come in then.” It has really cut down on patient time.

The use of telemedicine for wet AMD treatment

 Let’s have a wrap-up comment from everyone about neovascular AMD [age-related macular degeneration]. Tell me what you think is exciting, or just say anything you want to say. Let’s start with Aleksandra.

We covered a lot of ground and a lot of topics. The future is promising for neovascular AMD. There is a lot of work being done, both on the imaging side and on the therapeutics side. I have to say that COVID-19 [coronavirus disease 2019] obviously has been challenging for us and for our patients, but at the same time, I am so glad that it allows us to do this. In reality, it probably would have been so hard to get all 4 of us in the same room to do this program. There is that silver lining, and I appreciate being here with all you guys.

To me, the thing that stands out the most is the historical perspective. I finished my fellowship training in 2006. Pegaptanib was FDA approved in December 2004, and the bevacizumab articles first came out in 2005. I was right on the cusp of that era. I remember patients losing vision from wet AMD without really any recourse. Aleksandra had the patient who let 1 eye go. They just did really badly, and we do not even see that now. People who have been training since then do not appreciate what the natural history of this disease is. We have an amazing group of drugs to choose from. The armamentarium, by all accounts, seems to be getting better as we are going forward, and it is just important to refer these patients and to work them up appropriately so we can make the diagnosis. It is an amazing era and has been a huge change for ophthalmology.

 I echo what my other colleagues have said. I have the historical perspective to see what life was like when PDT [photodynamic therapy] was your option. We talked about the words 

—and now we’re talking about restoration. It is amazing. It is funny because I’ve had frustration over the years, watching other fields of medicine like oncology have multiple mechanisms of action using combination and chemotherapy, and what is really nice is we are going there.

I look at the development in the same way I look at development of the portable telephone. You make a revolutionary thing like an iPhone, and then it is followed by another revolution, like a video phone. We are about to hit that revolution again with the fact that we have got new ways of taking care of patients, new mechanisms of action, and new mechanisms of delivery. It is a great time to be in retina, and our patients are the ones who are going to benefit. What is really nice, to speak to Tom’s point, is that you are not going to see as many people be legally blind. I remember when we heard what the No. 1 cause of blindness is, and it’s no longer AMD. That is because of the anti-VEGF drugs. It is great that our field is really changing the way we look at things, and the hope is that it is going to get better.

 You guys have all given me hope. It was so nice to talk to you all. I agree: We are lucky. We are in 1 of the best fields of medicine because we can do so much to help our patients, and we have come so far. We have such amazing colleagues, and we all work together. The No. 1 thing is we want to do the best for our patients and give them the best care. I am really excited to try to figure out a little more about the science of AMD and why some people get anti-VEGF responsive diseases and other people do not. They get geographic atrophy, and that has become, as patients get older, more of a problem. What is the switch that makes you experience 1 form of advanced AMD that is dry, and what causes the other patients to go to wet? We have so much more to learn.

I want to thank all of you for being here today. I want to thank our audience. We hope you found the viewpoints to be rich and informative. I hope we get to meet one another soon in person or, if not, by Zoom again. We will take what we can get. Thank you, everybody.

Advancement in the management of wet AMD