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Retina
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Advancements in Retina: 2023 Highlights and 2024 Forecasts

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Mark Dlugoss:

In April 2000 the FDA approved photodynamic therapy using VISUDYNE for the treatment of neovascular age-related macular degeneration. It was the first pharmacological treatment for retina disease. Since that breakthrough approval, retina clinicians have seen a dynamic evolution in retina. With better pharmaceuticals, advanced treatments and therapies, and cutting-edge technologies, addressing all areas of the retina disease.

Hello, this is Mark Dlugoss, Senior Contributing Editor for Ophthalmology 360, and welcome to the Ophthalmic Project, powered by Ophthalmology 360. In today’s Ophthalmic Project we’ll get the latest update on the retina space. We will discuss the 2023 year in review, emerging technologies in 2024, and potential advances that may change how clinicians treat retina diseases in the future. Joining The Ophthalmic Project to provide his expertise and insight into all things related to retina is Pravin Dugel, MD. Dr. Dugel is internationally recognized as a major clinical researcher and has been a principal investigator in over 100 clinical trials. He’s also the former president of Iveric Bio. He’s been a practicing retina specialist for many years, and he is also the member of The Ophthalmology 360 Editorial Advisory Board. Dr. Dugel, welcome to The Ophthalmic Project.

Pravin Dugel, MD:

Mark, thank you. Thanks for having me here. I’m honored to be here. Thank you.

Mark Dlugoss:

Okay, well, let’s begin our discussion, because there’s a lot of things going on in retina. Let’s talk about a 30,000 feet overview of the retina space. We’ve come a long way, obviously from Photodynamic therapy and VISUDYNE. What does the retina market look like as we entered 2024?

Pravin Dugel, MD:

I think it’s actually quite profound that you started with the PDT experience, because for me personally that was the reason that I left the traditional route, which was really the academic route. Because that’s where I was, and I was really quite happy with that. Because that represented the first time significantly that industry had actually come into our field. And quite honestly before that there was really not much industry, at least on the medical side. Now, Alcon was there, Bausch + Lomb was there, Zeiss and so forth, but that was really more on the medical device and surgical side.

When that came into the laser pharmaceutical field, I think that really changed everything in our field. But it also changed me. I looked at that and I thought, “Wow, there’s really stuff that could be done that could be very significant in terms of advancing patient care.” And it was clear to me the only way to do that was really having a partnership with industry. And at that time it was a town and gown kind of thing where if you were participating with anything with industry, you’re sort of considered the devil. And I think that that experience with PDT and the general direction that retina was going in is actually a milestone in terms of not just retina, but also in my career.

Mark Dlugoss:

Where is things going in terms of the growth of retina, the evolution of technology, surgical techniques? Is this all moving forward, and how is it moving forward?

Pravin Dugel, MD:

Well, I think it’s moving forward in amazing pace, quite honestly. Especially, in all of ophthalmology, but particularly in retina. I mean, what we’ve seen in the last three decades is, I hate to use the word miraculous, but I’ll use it anyway, it’s actually practically miraculous. I mean to think that, at least in my training we would watch people go blind with neovascular macular degeneration. In fact, and people don’t remember this, but the standard of care at a certain time was actually laser the fovea in order to decrease the size of the scotoma. A patient would come in and say they would have 20/60 vision, the standard of care was the same as [inaudible 00:04:28], “Today I’m going to make you 20/100, but two years from now, thank me because the size of your blind spot will be less than it would have been had I left you alone.”

We went from that to having the Anti-VEGF, which has been nothing short of miraculous. And again, that’s having a family history of macular degeneration that has had a personal impact on my family very much in the positive. The trends that are going on with not just neovascular macular degeneration, but now with dry macular degeneration and geographic atrophy with surgical retina has been tremendous. Now, we wanted to go faster. There’s a lot more to be done. I think there are gaps in between, because things have progressed so quickly. We can talk about that. But I think the progress has been phenomenal and I think the opportunity to progress even further is tremendous.

Mark Dlugoss:

And before we continue on, move to the 2024, let’s talk about 2023 a little bit. The FDA approved several pharmaceutical therapies in the space. Can we discuss some of them like Apellis Pharmaceuticals, SYFOVRE, Genentech, Vabysmo, and of course, Iveric Bio’s IZERVAY. And of course, Regeneron got two new approvals for their EYLEA, and we talk about some of those new things that got approved this past year.

Pravin Dugel, MD:

Yeah, I think before we talk about it, we probably should talk about the FDA in general. I think we’re extraordinarily lucky and blessed to have Dr. Wiley Chambers lead the FDA on our behalf. And his retirement at the end of this year is momentous. And I have no doubt that the team that he’s put together will continue the amazingly collaborative and supportive path that he has pioneered. The first thing I think we ought to do is to step back and thank Dr. Chambers and the team that he has put together for allowing these medications to come to patients.

In general, in neovascular macular generation, look, I think the progress that has been made by the companies that you mentioned, Regeneron and Roche have been tremendous, it does highlight two things. First of all, we still are in a position now where the sustainability of treatment is a big deal. Unfortunately, there are still a tremendous number of patients that with neovascular macular generation that do not get fully treated, because the treatment is not sustainable. And we’ve always known that we’re making progress in that with the high-dose EYLEA, as well as with faricimab. And that’s certainly happening. It also highlights the fact that we have sort of been stuck for a long time with anti-VEGFs, which is phenomenal. I mean, again, as I mentioned earlier on, almost miraculous. But understand that 30 years ago when the anti-VEGFs came, I amongst others, my friends, my colleagues were saying, “Look, this is just the first. I mean, you’ve got this very complicated process of neovascular molecular degeneration. You can’t possibly just have one target.” And we just haven’t had another target that has succeeded. We’ve had many that have failed, but we haven’t had that has succeeded.

Now, faricimab comes with an anti-ANG-2. The impact that that’s having on the effects may be somewhat controversial. But I think oddly speaking, one of the handicaps that we have, which is both a handicap and a benefit, is the OCT. The OCT is so perfectly suited to measure the anti-VEGF effect that we have really a hard time figuring out, as a biomarker the other effects, not just the anti-ANG-2 effects, but there’ve been things like neuro protectors and other things. And other things that are coming in like Winton inhibitors and so forth. And other than showing an improvement in visual acuity, which is really important, is there another way to look at those as a biomarker? Because the OCT just happens to be the perfect biomarker for the anti-VEGF. We have challenges, but certainly those two companies have done a phenomenal job, Regeneron and Roche, in advancing the sustainability of treatment.

As far as geographic atrophies concerned, look, there are two companies. One is Iveric Bio, which has now been bought by Astellas, as well as Apellis that I think have advanced the treatment of geographic atrophy for the first time. Very, very importantly, we have two FDA approved products for geographic atrophy. The challenge that we have there is not just the sustainability which is the same as neovascular macular generation. But we also have a challenge in terms of showing the benefit from a functional point of view. And although approved in the United States, it is a bit of a challenge outside the United States, because to translate what you see anatomically into a functional benefit is not easy. We can intuit that it’s there, but how do you actually document that? The bottom line is, look, there are tremendous advancements that have been made, as you mentioned in neovascular macular generation as well as geographic atrophy.

Challenges do remain. However, there’s another field that I don’t want us to forget about, which is diabetic retinopathy and diabetic macular edema. That is a humongous need that we have, not just in this country but around the world. And this sustainability issue that I mentioned is particularly important there. We talk about patients with neovascular macular degeneration that start treatment and aren’t able to continue after a certain while because they simply can’t come in often enough. We have patients with diabetic retinopathy and we know these drugs work, who simply aren’t getting treated. They’re young patients and they’re in the workforce, and this is a terrible term. We call them noncompliance as though it was their fault for not coming in. But I think it’s about time we step back and say, “Look, what we’re asking them to do is simply not possible.”

I remember a long time ago, not that long ago, maybe five years, six years ago, I did a study that was published that looked at the number of doctor days these patients with diabetic retinopathy had. And these are sick patients. The number of doctor days they had in a year was 28. And just think about that. You’re taking whatever job you have as a young person with diabetic retinopathy. You’re taking twenty-eight days a month out of a year to go see doctors for other things than ophthalmology. It could be foot ulcers, it could be kidney problems, it could be a whole host of things. And then now you’re asking them to come in every month on top of that. I mean, what we’re asking them to do is almost the impossible. When we brush this aside as, “Well, these patients are non-compliant.” It just simply is not fair. And it also speaks to the opportunity there and the need that we have to treat these patients.

Mark Dlugoss:

As we begin the new year with pharmaceutical therapies you feel in the pipeline that show some promise. Now, you mentioned that we needed a lot of stuff in diabetic retinopathy and geographic apathy, or macular edema rather, I’m sorry. What do you see in the pipeline, or the potential coming as we move into 2024?

Pravin Dugel, MD:

Well, I think we’ve got tremendous things in the pipeline. The answer depends on, it’s really everything, which is really exciting. If you want, we talked about new vascular macular degeneration, I think there are a lot of other companies that are looking at that in terms of sustainability as well. And I think there’s great potential there to be able to inject, for instance, a hydrogel that may remain for six months or longer, because that’ll translate very nicely, not just in patients with neovascular macular degeneration, but as I mentioned, diabetic retinopathy and other things like vein occlusion, et cetera. Geographic atrium we’ve talked about, there are two drugs that are FDA approved. There are a lot of other companies looking at either the same pathway or pathways that may be different to slow this down. There’s certainly tremendous opportunity there. In a little bit further long run there’s been tremendous advancements that have been made in gene therapy as well.

And whether it’d be in rare diseases or in chronic diseases, there are companies that have recently shown great promise there. With gene therapy, I think there are different challenges that one has with rare diseases versus chronic diseases. We have a challenge of introducing three trillion viruses at once if we inject in the vitreous and making sure there is not insufficient … That there’s sufficient immune suppression to decrease the inflammation that would normally occur. And the alternative obviously is to do a surgical procedure. But to me that would seem to be less sustainable for chronic disease as opposed to rare disease.

We have challenges, but tremendous advancements have been made by several companies there. As far as artificial intelligence is concerned, there’s no doubt whatsoever in my mind that that will be a major player not just with us, but with all society, let alone medicine. And it can happen at various levels, right? It can happen from a clinical trials perspective, designing clinical trials, maybe even decreasing the need to have a control. A group identifying patients that would fit that clinical trial once the drug may be approved. Identifying patients that would be eligible for the drug, then following the effect of the drugs. I think there’s tremendous promise that, that holds, which is easy to recognize. Maybe what’s less easy to recognize. And one of the things that I really struggle with when I think of artificial intelligence that’s not talked about a lot is really the dangers of artificial intelligence.

And I don’t mean that in some kind of an evil way. We put in information for artificial intelligence by design. It’s a self-learning algorithm in a very simplistic way that occurs. And that algorithm is only going to be as good as information you put in. Well, the information that we have from medical point of view is honestly quite biased. It entails information from a demographic that can afford to have healthcare that can afford to see their doctors that oftentimes can afford to come to clinical trials on a regular basis. It doesn’t include the demographics that may have a different ethnic orientation, may have maybe less capable of coming to doctors, because they may not have health insurance. And so whatever information we put into the algorithm may actually negatively bias those patients, which really would be propagating a sort of data discrimination. And that’s rarely talked about. And I do worry about that a lot. Because we may actually be getting information in many ways that may be fantastic information, but maybe very biased information if we’re not aware of this. That’s what I worry about with artificial intelligence.

Mark Dlugoss:

You mentioned gene therapy, and it’s one of these new technologies that have surfaced that provide provincial therapies for retina diseases. There’s some others as well. There’s nanotechnology, neuroprotection, stem cell therapy. And the other thing I think is probably the hottest thing going on is biosimilars. Can you talk about a little bit about some of those technologies?

Pravin Dugel, MD:

Yeah, well, that’s a huge broad swath of technologies, but here’s what I’d say. Let’s start with gene therapy and go one by one with gene therapy. I think it’s very important to, when people talk about that, to distinguish gene therapy for rare diseases versus chronic diseases. Realize that the application of that, the administration of gene therapy and the results of gene therapy in many ways are completely different. In rare diseases, for instance, I think is quite acceptable to have a surgical procedure which will alleviate the need to worry about inflammation, so on and so forth that you would get from injecting intravitrally. Because presumably there are very few patients and maybe done by super experts that are in selective sites. And that’s actually quite sustainable. The result that one would expect from that is in general, and I’m talking in very broad terms. Maybe a reconfiguration of a gene anomaly via deletion, etc. Now, when you look at chronic diseases it’s very, very different. I think it’s very difficult to have a sustainable chronic disease gene therapy administration that’s surgical and that’s broadly done.

You would worry about surgical complications being at a level that may not be acceptable. And here again, the results would have to be not so much a gene correction, but actually a production of a protein, be it an anti-VEGF, etc. With a chronic disease, one would have to emphasize the administration in a way that would reduce the amount of complications being intravitrally or super cordially, etc. We talk about gene therapy and we throw everything in the same bucket. And we don’t separate these things in terms, is it a gene therapy for a rare disease? Is it a gene therapy for chronic disease? Are we talking about gene correction or modification, or are we talking about protein production? The implications of those things are vastly different. I think we’ve got to be very careful just throwing out the term gene therapy. Now, I think we switched from that. I talked a little bit about artificial intelligence. I think it’s fair to also say the same things apply to things like nanotechnology and non-viral mediated gene introduction therapies. There are others as well, the same things that I mentioned apply to them.

And I think now we switched also, which is a fairly drastic switch to biosimilars. Now, that’s a whole different topic altogether. And as you know, biosimilars are very different than generics. Biosimilars are defined very differently and they have a very different regulatory pathway. And as such, biosimilars usually are discounted by about 20% or so. And I think there’s certainly a place for biosimilars, but where they fit in and how they fit in, has an enormous economic impact. And a economic needle that must be changed. And it’s different in different countries. It’d be very different in the U.S, for instance, as opposed to say in Europe and even in Europe, in regions in Europe or Asia, etc. It’s a whole different topic. It’s a very interesting thing. But I just want everybody to realize that biosimilars and generics are quite different. The regulatory pathway for biosimilars are completely different. And the discount rate, it’s not like 100% percent discount. It’s really about 20, maybe 30%, which is very meaningful, but there is a significant cost to getting a biosimilar out there because of the regulatory requirements.

Mark Dlugoss:

With a lot of these new advancements comes challenges. What are some of the challenges both for industry and for clinicians in finding new therapeutic solutions to retina diseases?

Pravin Dugel, MD:

Yeah. Well, again, that’s a really broad question. What I would say is, look, let me just start from the early developmental point of view to the later stages. Typically, small companies, which really drive our industry at the end of the day. And I really so admire these visionaries that start small companies and found small companies. Because that’s really the lifeblood of our innovation. These are incredibly bright, passionate, driven people that want to change the world. They may have a fantastic idea, and they often do. They drive that idea. They may have some seed money. Oftentimes it starts with friends and family. I think what I see as a main challenge there is what happens after that? And these aren’t necessarily people that are interested or versed in development, certainly not in business usually. And then my biggest concern is that these fantastic ideas oftentimes don’t go further than that, because they suddenly come into problems with capital and into business development and so on and so forth.

It’s an entirely different skill set that’s required. And I think one of the challenges that we have in general is how do we incubate those incredibly bright visionaries and allow them to transition to this model of business development that actually works? I think that’s a huge challenge in our industry. The other challenge in the industry really is, what happens after you get beyond that? What happens once, say you get beyond what I just mentioned, that first hurdle? The next biggest hurdle that I see is, okay, so you’ve got a clinical trial that works. You’ve got a drug that has proven to be effective. What now? What’s the plan? Do you go ahead and just do it entirely on your own and commercialize on your own? Do you partner with somebody? Do you exit? Do you sell?

I think, again, for the same reasons as I said earlier on, that’s the second big pivot point that happens in a company when you go from development to commercialization, it’s an entirely different mindset. It’s an entirely different company that has to pivot that way. And in the vast, vast majority it’s actually not successful. In the life cycle of drug development, in my opinion those are the two, and I’m being very simplistic, of course there are many others. But those are the two major hurdles where companies and mindsets have to almost completely change. That I’ve seen happen successfully in other fields like oncology, rheumatology, etc. Because those fields are a lot more mature than we are. And as we discussed earlier on, it’s only been about three decades or so, or maybe just over three decades, that industry actually came into our field. We’re actually a very immature field in that sense. And oncology, rheumatology, immunology are actually very mature fields in that sense. We will learn how to do that.

We will learn. We have to learn how to take care of our innovators and our innovation to take them through this, how to incubate that properly, how to train companies and executives properly through this. But I think that’s from a broad perspective, that’s really the main challenge that we have in our industry.

Mark Dlugoss:

We’ve been talking a lot about pharmacological technologies. How about in the area of retina surgery? Are there any new developments in areas, say immaculate puckers or retina tears or retina detachments, or how about in surgical instruments in technology in that area? Is there anything new or looks on the horizon that looks promising?

Pravin Dugel, MD:

Yeah, what I would say is that there’s a lot of opportunity there. What we have done, and I don’t mean this in a pejorative way, but is to talk about technology, which is meaningful and important. You cut faster, you suck harder, you have forceps that grab better and so on and so forth. Those are incremental changes. But what we haven’t talked about are really profound changes. And I think those changes, the game changer changes really involve visualization. And when you think about what we’re doing, we are looking face down onto the retina, trying to peel membranes or trying to insert things into spaces that are microns deep, and oftentimes spaces that don’t exist at our potential spaces. And we have no visualization whatsoever. Now, contrast that with say, neurosurgery, right? A neurosurgery, you have amazing visualization as 3D visualization where a surgeon can actually look at a 3D tone of graph and basically rotate that and say, “Okay, here are the vessels, here’s the brain, here’s where I’m going to go, here’s where I’m going to make my incision.”

We’re not there yet, and we absolutely should be there. And we’re not there yet because unfortunately what has happened historically is that we’ve been in two different silos, and still companies function like this. Which I think is actually very unfortunate, where there’s a surgical silo and there’s a pharmaceutical silo. And there’s no crosstalk whatsoever. There’s no horizontal communication. That’s an archaic way of looking at things that doesn’t exist. We talked about gene therapy, we talked about nanotechnology, we talked about different implants. Inevitably, there has to be to make progress a crosstalk, a horizontal integration, if you will, between the surgical and the pharmaceutical field. Those silos have to be broken down. Because you may need to insert a specific drug in a very specific place to make that work. And until you get proper visualization to do that, it’d be very, very difficult to do that.

I think the short answer to your question is, look, the advancement in my mind comes from visualization. But in the long run it really comes from breaking down the pharmaceutical and surgical silo. And the ironic thing is that we really already have the technology there to think that we’ve got OCT now for several decades, but we don’t have the OCT to routinely integrate it. Now, I know we have some rudimentary OCT with certain technology and microscopes and so forth, I get that surgically. But we really don’t have technology that one would say is routinely used and is sufficient to be able to, with OCT say, to be able to actually utilize that visualization to, for instance, peel a macular whole membrane or ILM, peel the ILM, or to be able to insert something specifically in a place in the retina is, to me quite surprising. I think we should have had it by now. But I think that’s where the challenge is, and that’s where the opportunity is.

Mark Dlugoss:

Yeah. Now, all this growth of technology and the evolution changes that we’ve been discussing, how’s it going to change the way clinicians diagnose, treat, and manage retina diseases?

Pravin Dugel, MD:

Yeah, that’s a great question. And I think that’s where a lot of the things that we discussed, specifically AI will come in. I think what’s going to happen, and it is not just AI, but it’s a lot of things. For instance, if you look at neovascular macular degeneration, for instance. When I was in practice, there were some patients, fortunately very few, that literally had to come in every two weeks to keep their vision or save their vision. There are others I could treat every six months. And we still call that all neovascular macular degeneration. Clearly, we’re just scratching the surface of our knowledge. Everybody, those patients behave completely differently. They require different treatment. And I think what will happen is that we will hopefully have a data bank of patients and patients’ behaviors, and I know that’s already starting in a rudimentary way with several large data banks that are currently starting or functional.

But we’ve got to go far beyond that so that if Mrs. Jones comes in, we’re able to look at Mrs. Jones, maybe with an OCT, maybe with other things, with algorithms, specifically with artificial intelligence and say, “Mrs. Jones, based on your parameters, this is what we expect from your prognosis, and this is how we would like to treat you.” The short answer to your question is, is I think the diagnostics are going to be married, as is the case in oncology, for instance, and rheumatology and immunology. Where the diagnostics are going to be married with not just diagnosing the case, but also a specific. And the most important thing here is personalized medical care, and I think that’s where we’re going to have to go to provide better care, is to go to personalized medicine.

Mark Dlugoss:

Now, in glaucoma we have seen the emergency of what they call a multidisciplinary approach to treating the disease. Do you see a similar in multidisciplinary approach being adapted in retina, especially in finding new therapies or finding direct causes for many of these retina diseases?

Pravin Dugel, MD:

Yeah, I think there has to be, again, I talked about that earlier on in terms of personalized medicine, and we touched a little bit on artificial intelligence and the pros and cons of that as well. Look, we know that when we talk about … Let me back up a little bit. When I was starting out in training, it was taught that neovascular macular degeneration was a disease of northern Europeans in a Caucasian … Not northern Europeans, that it simply didn’t occur in patients who were colored. And there were articles written about that. I remember distinctly, there’s an article that I read from South Africa that it simply didn’t occur in blacks. Now we know that’s absolutely not true. It occurs in everybody. In some people it may not have manifested, because the lifespan simply was so short. In others of different ethnic descents, it just manifests differently. We know now that in Asians, for instance, there’s something called PCV that occurs, a polyploidal coroidal vasculopathy, which may be a variant in a very broad way of neovascular macular degeneration.

I mean, just think about the impact of that for just a second. If we had artificial intelligence 35 years ago and we’re going to put in the information that we had, what we would have are algorithms that basically said, “There is no macular generation in this ethnic variety.” It would have been completely wrong, and it wouldn’t have been beneficial for these patients at all. It would have been completely biased ethnically, and again, we have to worry about that. But having said that, I think the advancements that we’ll have are, if we are able to recognize the patterns of diseases that are personal, not just from an ethnic point of view, from an environmental exposure point of view, from a age point of view, etc. We know for sure that’s the case in glaucoma, for instance. We know that black patients behave differently and react differently to different drugs. Their progression is different. There’s no doubt that that’s true for retinal diseases as well. We just have to have the capacity to recognize that and treat that accordingly.

Mark Dlugoss:

In our discussion today we’ve covered a lot of information on the outlook of retina in 2024. Is there anything we may have missed, or you would like to add regarding the retina spaces as we begin the new year?

Pravin Dugel, MD:

I think we’ve touched on a lot of things. The only thing that I would add maybe has come out already, I hope it has, from our discussion is how incredibly exciting the field is. I don’t think that, in fact I know that at least in my career, I’ve never been in a time where there’s more innovation, where there are more amazingly smart human beings that are passionate, that are driven, that are totally dedicated to advancing this field. And I’m just fortunate and blessed to be part of it.

Mark Dlugoss:

You mentioned in our beginning of our discussion about photodynamic therapy and VISUDYNE launching everything. And that was probably an early part of my career working in the ophthalmic space that it really started taking off from there. And it was just amazing where it go and what they’re talking about now. What we talked about today, I think is pretty incredible.

Pravin Dugel, MD:

Yeah, I think the field has changed so much in this short amount of time. But it also means that there are challenges and we can’t ignore that. It also means at the end of the day, if there weren’t challenges, there wouldn’t be opportunities. That goes hand in hand. I don’t be willing the challenges. In fact, I think we should all embrace those challenges because that really represents further opportunity.

Mark Dlugoss:

Great. Well, that concludes today’s Ophthalmic Project podcast. I want to thank Dr. Pravin Dugel, for spending some time with me and providing an update on the retina space. And I want to thank you, the viewers for watching, and I hope you’ll join us for the next edition of The Ophthalmic Project. Have a great day.

 

This content is independent editorial sponsored by Astellas. Astellas had no input in the development of this content.

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