David Fell, MD:

All right, so welcome back to The Fellow Eye. I am David Fell. I'm a uveitis and retina specialist at Will's Eye Hospital and we have Justin Muste, our faithful fellow and co-host here. And we are very, very honored today to be joined by Dr. Allen Ho, one of my colleagues here at Will's Eye and one of the co-directors of the research department and the retina service in general. And we are very excited to talk about the gene therapy space today a little bit, which Dr. Ho has been very involved in over the last couple of years. We also have Curtis Heisel. Curtis, you want to introduce yourself?

Curtis Heisel, MD, MBA:

I'm Curtis Heisel. I'm a fellow over in San Diego at UCSD at Shiley Eye Center. Thrilled to be with such a great group of people and talk the genetic space of Retina.

David Fell, MD:

And where did you do your residency?

Curtis Heisel, MD, MBA:

I did my residency at Northwestern in Chicago. Just moved out here.

David Fell, MD:

And I think we'll just get right into it. This is going to be a little different than the other episodes we've done where it was a little more fellow focused just because we have Dr. Ho here and we wanted to talk about this kind of specific topic. So I was just curious, Dr. Ho, if you wouldn't mind just talking about your journey in retina and how you got as involved as you are now in gene therapy treatments for retinal diseases, when you first remember maybe hearing about the beginning of the gene therapy movement that we're now kind of living through.

Allen C. Ho, MD:

First of all, congratulations on this format. I think it's a great idea and I'm happy to be with Justin, who's one of our fellows, David, one of my partners and Curtis, who I'm just meeting now. And he trained at Northwestern where one of my great colleagues, sadly he left Penn when I was there and went to Northwestern, Nick Volpe, I'm a really big fan. So Curtis, I'm honored to be with you as a Volpe disciple. Really bringing up Penn, that's where gene therapy, human gene therapy really started. University of Pennsylvania, 2017 approval of voretigene neparvovec for Leber congenital amaurosis really was the very beginning of in-human gene therapy. It started in the subretinal space of all places, Jean Bennett, Albert Maguire. Nick Volpe was there. I was there at Penn. My journey in ophthalmology was Will's residency, New York City for retina fellowship, then back to Penn as faculty.

Allen C. Ho, MD:

And it was a very exciting time. And Penn was very advanced. Jim Wilson was there, Jean Bennett, and actually gene therapy stopped in the United States for a while because there was a death in 1999 of a young patient, Jesse Gelsinger, who was receiving systemic gene therapy and he developed for his metabolic disease, he developed fulminant hepatitis and liver failure and passed away at a young age. So gene therapy stopped in the United States. Actually, it was moving forward in other places around the world, but it stopped for a while in the United States. But to Jean Bennett and Albert Maguire's credit for that niche retinal degeneration, Leber congenital amaurosis, RPE65 biallelic mutation where you're basically not isomerizing rhodopsin to be a light signal, those patients lose a lot of vision at a very early age. And they continue to charge for it probably because it was not systemically administered.

Allen C. Ho, MD:

They developed this and it's subretinal delivery and they showed it preclinically and they showed it in the clinical trials for those subjects. They created endpoints that were novel like mobility courses. How do you measure vision in maybe a child or there are a lot of things that they trailblazed and to their credit. And in 2017, this was the approval of gene therapy. So now we are 9 years later, 2026. And since that time there've been over 30 gene therapies approved across all areas of medicine. So the very first started in the subretinal space. And you asked me my journey to clinical research and really in delivery. Maybe one of the things that when I started and I finished my fellowship in 1994, there was really no drugs, there were no biologics. There was surgical evolution and surgical research that we were doing in industry sponsored surgical research.

Allen C. Ho, MD:

So maybe because I had interest in that, that's how as a young attending at Scheie Institute, that's how I kind of got involved in academic work. My chairman at that time, Stuart Fine, was involved in a ... We were thinking about a laser to drusen study. So it was not biologics, but it was a procedure for dry AMD. Turns out it didn't reduce the incidence of choroidal neovascularization, actually increased it. But some of those patients where there were drusen reduction had some improvement in vision. That was kind of buried because all of a sudden we had these events of laser-induced choroidal neovascularization, but something was happening and I was the reading center director and I knew that and now we have photobiomodulation for dry AMD. There are those that are believers in the data set and the FDA had just approved that. There are those that are still doubters on the sidelines and I don't blame them.

Allen C. Ho, MD:

But these are the basis for my involvement in some of the clinical research work that I've been lucky enough to be a part of in my career. The surgical aspect goes to the gene therapy because we did submacular surgery trial where we pulled out choroidal neovascularization from under the retina. So I guess the take home is as a young person who is considering a private practice job or an academic job or some combination is to continue to stay involved. Well, how do you stay involved? You have to be hardworking, you have to bring something to the party.

Allen C. Ho, MD:

This is like a potluck dinner. You're not going to be invited again, unless you have to bring something, whether it's energy, enthusiasm, patients, a new way of thinking about something. That's really a take home from my career, I would say, that is important for those that are interested and continuing to work in the field. And the field is so ... I mean, we have the very best specialty in all of medicine. What we do is meaningful. There are surgical aspects. There are pharmaceutical aspects. There are biologics and gene and cell therapy. There are imaging aspects. There are public health issues like this diabetes epidemic where we have treatments we can prevent blindness and so many people walk in like a bomb's blown up in one eye already and they don't come in until the second eye goes. I mean, there's a lot. There's very fertile ground for a variety of different skill sets across the very talented fellowship pool in our country.

Allen C. Ho, MD:

Coming back to your question about gene therapy. So 2017 Spark started in the subretinal space. Now a lot of gene therapy now we're in retina, I think in the next couple years, we're going to be seeing potentially gene therapy back in the subretinal space or in the vitreous cavity for not just a very small number of patients with LCA RPE65 biallelic mutations, but common diseases like wet age-related macular degeneration, shots on goal for diabetic retinopathy. Wouldn't it be great if we could potentially constitutively suppress VEGF in the appropriate patients of these very advanced diabetics who have not only macular edema, but vision-threatening complications of neovascularization or even beyond that? Gene therapy for atrophic AMD, that would be fantastic. Wouldn't that be immune modulation instead of coming back? I'm still getting worse. I'm still getting worse. Well, you don't have to come back for many months. We just need to monitor you.

Allen C. Ho, MD:

We have a biofactory going on there that's maybe modulating the immune system. So common diseases, I think over the past several years, people were on the sideline thinking gene therapy, maybe it's, is it really going to work? Well, we have now clinical evidence of production of anti-VEGF molecules, for example, in a number of wet AMD gene therapy trials showing durable production over time as opposed to injecting the medicines we do for wet AMD where we get pharmacokinetic spikes, maybe we have evidence of constitutive production of molecules just like ranibizumab or just like aflibercept. So I think it's really exciting. I think coming back to the specific example of wet AMD, I don't think injections are going to go away. I don't think gene therapy is going to displace what we do as retina specialists today, but I'm hopeful that it can for the appropriate patients be a foundation therapy and then allow us to think about even more.

Allen C. Ho, MD:

We have these amazing treatments and yet there's still such an unmet need even in wet AMD; 30 to 40% do have improvement with injections, but there is long-term vision loss, progressive atrophy, burden of treatment, people coming back in all the time. It's really exciting to think about the possibilities of gene therapy in our toolbox for a number of major common diseases, bringing it back to retina.

David Fell, MD:

That was awesome. Thank you so much.

Allen C. Ho, MD:

I think I went on too long, but

David Fell, MD:

No, no, no. I have so many questions about what you just said, but Justin, why don't you start off? Do you have anything you wanted to talk about or ... Always the pragmatist.

Justin C. Muste, MD:

I'm going to go with pragmatic question, but as new fellows that are coming in, we lack the longitudinal perspective unless we're talking to you. We don't get the history and how things are building up. We suddenly enter in a space where there's 30, 40 new things going on. So that brings up a few questions, which is, is it really just as simple as you make an Excel sheet and you try and update it with what's going on to try and keep abreast of all of these trials and how are you staying on top of it? And more importantly, what do you choose to stay on top of? What do you think are the places that we should start diverting our focus or interest in as we read about all of these events and all the things coming out and FDA approvals or phase 2, phase 1, phase 3 type things.

Allen C. Ho, MD:

I think it's a really good question reflecting how rich our ecosystem is in terms of clinical research for, you name it, disease. I mean, retinoschisis, advanced retinitis pigmentosa, diabetic retinopathy, diabetic macular edema, proliferative vitreoretinopathy. How do you stay on top of it? Well, I think you don't stay on top of what's going on by looking at peer-reviewed literature. If you want to know what's happening, I think you look to trade publications. And my disclosure is I work with Retina Today. I have done it with Bob Avery for quite a while. It's been a great way to put out information. And there are other ones, Retinal Physician, Retina Times. They're all great I think at synthesizing what might be important. Now, when a patient comes to you and the office and says, "I've got cone dystrophy," and you say, "Ah, I'm not sure." Clinicaltrials.gov you to search by disease and with other filters in them actively enrolling or completed enrollment, this kind of thing.

Allen C. Ho, MD:

So that's another resource for knowing what's happening. You're supposed to register your clinical trials on clinicaltrials.gov. So I think trade publications, media from communication companies like Eyewire is another example.

Allen C. Ho, MD:

I'm close to them because that's the same company as Retina Today. I think going to meetings, I mean, you can go to a retina meeting every other week seriously, it's crazy, but you can stay on top of things by these methods either asynchronously or at live meetings on your laptop, talking to colleagues. That's how you do it.

David Fell, MD:

I would love to talk just a little bit for the fellows, just the different kinds of gene therapy treatments that are out there. I know you work with Nanoscope. Also, a lot therapeutics who do a different kind of gene therapy. And then we have these trials, like the one we're doing at Will's in retinitis pigmentosa, that's for a very specific genetic mutation in a very specific gene. Could you just talk just like for fellows, especially a ground level, what they should know in terms of the different types of therapies that are out there, optogenetics, just a little bit about that.

Allen C. Ho, MD:

You have to just think about basically the genetics, basic genetics that we know. And it's more complicated than the basic genetics we know to be sure, but you can have, let's take Spark voretigene. You've got a bad gene and the gene therapy strategy is we're going to take a viral vector with the transgene that works, have that viral vector go to the cell that's affected, RPE cells, have that virus then transfect that cell with RPE65 that works, have the body cellular machinery, transcription, translation, protein production, do its job and then see if it works. And the crazy thing is it can work and it can work in other areas of medicine, gene replacement therapy. You can have gene silencing therapy where you have a mutant gene creating a problem protein or basically protein structural or enzyme cellular metabolism and you can have gene therapy strategies silence that abnormal gene; that's gene silencing.

Allen C. Ho, MD:

We usually think about gene replacement or gene augmentation. So in augmentation is the example that we're talking about a lot now because we're taking a transgene, let's say for ranibizumab in the Regenxbio/Abbvie RGX-314 trials that are using an evolved highly efficient AAV8 viral vector, a transgene that encodes for ranibizumab, that AAV8 vector is delivered subretinally. There's also suprachoroidal program as well for diabetic retinopathy. In wet AMD and having those AAV8 viral vectors with the ranibizumab transgene transfecting retinal cells, retinal pigment epithelial cells to create a biofactory. We tap the eyes over time and we see protein production. It is working. I mean, could it work? It is working. We've seen the protein production in the Abbvie/Regenxbio program. We've seen it in intravitreal injection with the Adverum program where they produce aflibercept. These are by aqueous taps over time, 1 month, 6 months, 1 year, even beyond steady state protein production.

Allen C. Ho, MD:

We see it in the 4DMT program as well. And that's producing aflibercept and a VEGF-C inhibitor. So these are the ways we think about some of the major methods of gene therapy. Optogenetics is interesting in that it's targeting patients that have retinal degenerations and taking a viral vector in the Nanoscope or in the other major program, Ray Therapeutics, it's injected intravitreally. So you have a viral vector that then transfects certain layers of the retina, Ray Therapeutics, ganglion cells, Nanoscope is ON bipolar cells. And that transgene, for example, in Nanoscope program, MC0-010 encodes for a bioengineered option. So those patients don't have with severe RP don't have rods and cones for the most part. So you're using gene therapy to reanimate the retina by transfecting the bipolar cells to activate the ganglion cell network that goes bipolar to ganglion to basically the occipital cortex.

Allen C. Ho, MD:

That's another method of gene therapy. That's optogenetics. I think that's interesting. The data are being submitted to the FDA now for one program, the Nanoscope program and they're looking at it for severe RP, but also for geographic atrophy, no cells, but maybe bioanimating the remaining macular ganglion cells and also for Stargardt disease. Optogenetics, this is like next-generation optogenetics. There have been a few programs that have not worked, but the dataset for the Nanoscope program I think is compelling. But by the way, as disclosures go, I consult with surgical companies like Alcon, gene therapy companies like Regenxbio, Adverum, 4DMT, optogenetic company like Nanoscope, anti-VEGF injection companies like Regeneron and I'm pretty conflicted.

David Fell, MD:

Which makes you not conflicted.

Allen C. Ho, MD:

I'm very conflicted, but I also have the privilege of being involved in a lot of these programs so I can kind of get a top down look. And I think it's exciting. I think some of this is going to happen and it's not for the company's benefit, it's for our patients and that's what's really exciting for me.

Curtis Heisel, MD, MBA:

Yeah. I mean, that's such a fantastic summary and it really is exciting to think about all these different ways and how we're going to affect our patients and ways that we currently don't have options or ways to augment our current options. One of the things that I always wonder about, especially given that timeline you mentioned of 2027, 2028, right around when Justin and I are going to be starting out, I always wonder, I'm sure Dr. Ho, throughout your career, you've seen a million different new technologies, new surgical approaches get taken up and advanced. And I kind of wonder, in fellowship, we get a lot of exposure to surgery, but there's going to be new things that we haven't seen or haven't tried (subretinal injections, suprachoroidal injections). How do you feel like one would go about getting comfortable with these new technologies and specifically, I guess from the surgical approach, like trying those first new techniques on your own once you're an attending and taking care of those patients?

Allen C. Ho, MD:

For the surgically delivered treatments, potential treatments, there's going to be training programs. Let me go back to photodynamic therapy, which we rarely do now. There are massive training programs out there. Okay, you got to inject a dye into someone's vein over a period of time. You got to sit there at a slit lamp with a cold laser. And I mean, I was one of the trainers, but I mean, I was just at a fellowship. Well, no one knew how to do it. I mean, my point is that that's a really good point, but as a field, as with regulatory oversight, for example, you approve something like subretinal injection, you got to show to the regulatory agencies that you've trained surgeons to do, not even surgeons, retina specialists to do suprachoroidal injections or parse plana vitrectomy, transvitreal subretinal surgery delivery, which by the way is not that hard.

Allen C. Ho, MD:

I mean, if you could do retinal surgery, you can do that. The Regenxbio program is training. I mean, there's 2,000 subjects in that phase 3 study. They've trained over 500 surgeons around the world. They've delivered this in hundreds of patients and not once have they not been able to deliver to the subretinal space. So that's one aspect, but there are more nuanced kind of deliveries. Young patients, subretinal gene therapy, more challenging. Vitreous is attached. There's cortical gels still there that block the tiny subretinal cannula that you're trying to inject in the subretinal space of a patient with LCA10 and you can't raise the bleb and you're sweating. So there are some challenges and it's really good to think about it, but the real responsibility, yes, is upon us as someone who might want to do this, but you're not going to do this unless you demonstrate proficiency without having to feel like you're just trying it on a patient because the regulatory agency will demand that appropriately.

Allen C. Ho, MD:

Suprachoroidal injection, you want it approved? You got to show that you can train people. Subretinal injections, you got to ... We did in a cell therapy program, a transscleral suprachoroidal to subretinal delivery for the Janssen cell therapy program that didn't work, but the delivery duct device survives where you take a catheter and go through the sclera in the operating room, pass the catheter in the suprachoroidal space all the way to the back behind the macula, and then a needle comes up into the subretinal space and then you can deliver in the subretinal space without creating a hole in the retina. That was one of the more interesting journeys and a great process to be involved with actually in surgical device development. Rajeev Muni, who you guys know has a ... I mean, that guy's a great thinker and not just a great thinker, but he executes.

Allen C. Ho, MD:

He's developing a suprachoroidal delivery device to help fix retinal detachments with agents that will create volume to close the retinal tear. But those devices can also not just deliver viscoelastics to create a choroidal detachment to repair retinal detachment, but can deliver to the suprachoroidal or even the subretinal space in the office. He's working on it.

Allen C. Ho, MD:

But disclosure, I know a little bit about it because we're working together on that.

David Fell, MD:

That's awesome. Yeah. What Dr. Ho was just talking about just made me think about how when you are, especially when you're a first-year fellow, there's this thing in the back of your head, especially if you're in a program where you're not operating a lot as a first-year fellow, there's this thing in the back of your head that's like, okay, I have to learn how to do everything before I get out of here. And there's this idea that you're actually going to do everything that you'll ever have to do in your career before you finish fellowship and you'll be comfortable with it. And I think usually around halfway through your second year, you start realizing that's not even remotely possible, but all these skills are kind of related and build upon each other. And so I have not done any of these gene therapy surgeries yet, but I've done a bunch of subretinal blebs for macular holes and things like that.

David Fell, MD:

And I always think back to, I worked with Jeff Heier who's very involved in pretty much every study that he was just talking about as well when I was a fellow and I remember asking him, because he would just get these blebs in a second for all these gene therapy surgeries. And I remember asking him, "How did you get so proficient at this? " And first of all, he'd been doing these surgeries for a year or two at that point, but he said, "I've been doing these blebs in other contexts for a decade." It's just repurposing skills. And once you build those foundations as a fellow, you can start getting creative and more comfortable being innovative with different surgical approaches.

Allen C. Ho, MD:

I totally agree with that comment. As a fellow, yes, you might be anxious about all these different things that you're hearing about, but just the foundation of the basics, the foundation of knowing that if something doesn't go right in a surgical case, you have to study your failures to be a better surgeon. You got to understand what maybe you could have done better and just knowing that you're not going to learn everything in fellowship. That's a really good point too. That takes the pressure off. You really learn a lot actually in the first five years after fellowship, put away all the- Here's

David Fell, MD:

Five months.

Allen C. Ho, MD:

All the new unfamiliar procedures, but you have to be a lifelong learner. To be a good learner, you have to study your mistakes and take the pressure off yourself about new things because you should focus on the fundamentals. And if your fundamentals are good and you're a good surgical learner, then you'll be fine. You'll be fine.

David Fell, MD:

100% agree. Awesome.

Curtis Heisel, MD, MBA:

That's a great point.

David Fell, MD:

Both for me and for the fellows, do you have any advice just based on your experience about how to best get involved in these big collaborations with pharmaceutical companies where you get to play a bigger role in innovating? Is it really always just having the idea? Are you just in the right place at the right time knowing the right people?

Allen C. Ho, MD:

I think there's always a little bit of that, but let's say you don't know the right people. Let's say you don't have the right timing, you really lean on your mentors, lean on your mentors. That's number one. Number two, like we said earlier, if you want to be a welcome guest at the party, you got to bring something to the party. So think about what you're interested in and then think about how you can bring something to the party that's valuable, that's delicious, that's going to make them want to bring you back. So for example, you're not a lab scientist. I wasn't. I didn't have a National Eye Institute research grant, but I was willing to learn and roll up my sleeves and chose an academic job and did have good timing because my chair said, "We're thinking about this program." Before he even said, "Are you interested in ... " I said, “I'm in.”

Allen C. Ho, MD:

Enthusiasm, energy, patients are very valuable to clinical trials. If you have patients and you have a clinical research infrastructure and it's important to realize that you need an infrastructure and there are articles in Retina Today, for example, or Retina Times, Retinal Physician about setting up a clinical trial process. It's very specific. There are certain things you have to do. It's all patient focused whether or not IRB. Well, you can get an IRB.

Allen C. Ho, MD:

If you're not at an institution, there are other IRBs that advocate for informed consent documents. You need someone that's very detail oriented. You need specific hardware or cameras that you may have already because they're required for the OCTs or the fundus photos or the autofluorescent photos or the wide angle photos, for example. You need a specific vision requirement. You need a certified vision tester. There's a checklist. It's doable. It's doable, but you want to get involved, bring patients, develop this infrastructure. It's among the most valuable. Some of the best recruiters are private practitioners in retina that just kill it. They just crush recruitment. They're so good. I'm really kind of envious of how well they recruit and they do it because they're interested, they're motivated, they're systematic. You can bring something to the party if you're very systematic.

David Fell, MD:

And their enthusiasm probably is very contagious to their patients also when you're so passionate about it.

Allen C. Ho, MD:

Yeah. They get good at it. They get really good at it.

Justin C. Muste, MD:

Actually, I don't know if it gels with a question, but when you're counseling patients for something new, let's say you're down the line or even now you're handling a gene therapy signup or someone that you're about to enroll. I think experience has shown, at least in science in general, there's always side effects we can't predict and there can be catastrophic side effects. I don't know. I'm just spit-balling. But how do you counsel patients on that possibility or is that something that you touch on or how is that approached?

Allen C. Ho, MD:

Even standard of care has risks. So that's one, I guess, counterbalance right away that might favor enrollment in a clinical trial. But you have to see things through the eyes of the patient to be a good clinical researcher. You have to understand, listen, I think this would be good for you for these three reasons, one, two, three. Yes, here's things that we hope will be in your favor and positive effects that might be better than what we're doing now. Here are things that can happen even with standard of care, but they could happen with this new treatment and maybe because it's new, there are things that we can't foresee. We've seen that in some not just biologic trials, but we've seen it in drug trials too. Anti-VEGFs that have gone away because of unexplained severe inflammation. We've seen vitreolysis really not continue commercialization because of small rates of side effects.

Allen C. Ho, MD:

So how do you manage this? From a patient standpoint, it's a trust issue with your doctor and if you have the equipoise to say to a particular patient that if you were my family member, here is why I would consider this. That's kind of the bottom line in a lot of what we do. They don't know enough. They are trusting you to make a synthesis on their behalf from their best interests and you always present options. You don't have to do this, for example, I don't have a treatment for geographic atrophy. You can have injections. It's not going to make you better. It's going to slow down the growth of your age spot. You can get risks of infection that you wouldn't have if you did nothing.

Allen C. Ho, MD:

So you put yourselves in their shoes, think about how to explain in plain English what risks and benefits are and then they have to jump. Vision's important. They have to jump off a curb. It's not cardiac surgery where they have to jump off a rooftop of a building, but they're looking for someone who they trust who understands their particular situation. Why is this something that you would consider for me? And if you can do that and explain it, engender trust and really have good equipoise and say, honestly, if you're my mother, I would say you could do this or you can stay with what we have. That's the bottom line.

David Fell, MD:

I had a question about something you'd said earlier. It's a little off-topic now, but I am kind of interested in your thoughts about it. Just getting back ... Well, two questions actually. Getting back to the trials, the gene therapy treatments that we have now that are maybe surgical for things that we're now treating in the clinic like wet AMD and diabetes, do you have a vision for ... Because obviously as unmanageable as the treatment burden is with monthly anti-VEGF, thinking about putting all patients with DME or wet AMD, signing them up for surgery sounds extremely untenable. So do you have a framework that you think about for patients in the future that might be more of candidates right off the bat for things like surgery that might decrease their treatment burden and patients who will still remain in that kind of treatment paradigm that we have now in the clinic?

Allen C. Ho, MD:

A variety of gene therapies are not surgical-based. Intravitreal, for example, of course, an advantage for a patient.

David Fell, MD:

Do you see the surgical ones as just proving the concept until we can do the same process with ...

Allen C. Ho, MD:

No, I think surgical therapy ... So what are we looking at? We're looking at ... Right currently we have, for example, port delivery, that's a surgical therapy. I don't do a lot of that because I've focused a little more on gene therapy as a durable treatment. We have Encelto, for example, for Mactel. We don't have any other treatments. That's kind of a-

David Fell, MD:

That's an easy.

Allen C. Ho, MD:

That's a little bit more easy to think because no other options. But for anti-VEGF injection, for wet AMD, for example, I see if it's approved subretinal surgery, I think it would be a small piece of the pie for a specific patient that has high frequency injection need. As I said earlier, I don't see injections going away, but it could be a foundation therapy and a basis for maybe better vision over the long term. In wet AMD, we see this initial increase in vision over the first year and then it kind of plateaus and then you see it go down over time and then you're about year 3 or 4, you're back to baseline and then 4, 5, 6, 7, you're below baseline where you started in vision from a variety of reasons, whether it's progression of wet AMD despite treatment or progression of atrophy.

Allen C. Ho, MD:

And maybe continuous constitutive biofactory or port delivery lower dose pharmacokinetics of anti-VEGF will be better for that vision curve where we won't get the big decline. So that remains to be shown. There is some signal of that in port delivery. There is some signal of that in some of the gene therapy trials, but I'd say it's too early to say. For me, it's about vision. If you're going to have to come in every 6 weeks, all right, you're going to have to come every ... I'll be there. I want better vision. I want better vision over time for my patients. So that's where that small piece of the pie for subretinal delivery might increase when we can say, "You know what? I think you fit the profile of someone who would do better with this baseline therapy and maybe get topped off with injections over time."

Curtis Heisel, MD, MBA:

Loving the discussion. One question I have is, and maybe this is not more of a policy type of question, but obviously these treatments are going to be very exciting and there's going to be a lot of new things coming down the pipeline. It always kind of comes to my mind on some level how we're going to manage the whole cost element of it all and how we're going to be able to get these two patients in a way that's widespread and equitable. And I'm curious if you have any thoughts on how or any prognostications on how that kind of topic is going to play out over time.

Allen C. Ho, MD:

If there's a gene therapy approved for wet AMD, it's not going to be the same price as Spark for voretigene. It just not sustainable in ecosystem. So there are independent groups. ICER is one; ICER that kind of takes a disease, takes a cost of existing treatments and then considers what the cost savings would be. Let's say if you had 80% less injections and they put it through their models and they come out with a number. So how is this sustainable? It's not really sustainable for everyone to get a gene or cell therapy or very expensive therapy. But I have concerns about that, but that's not my focus. My focus is trying to figure out something better. Our responsibility, yes, we have a responsibility to overall health care, but really our responsibility from my lens is that we continue to try and do better and not think too much about cost right now.

Allen C. Ho, MD:

And cost, there are ways that we mitigate costs now. We have step therapies, we have a very strict criteria for expensive therapies. So, unless we lead on this in terms of the science and the clinical research science, it's not going to happen, for example, in Europe where they suppress pricing, etc. So we should focus on the science, doing better. I'm aware of the costs though, every day in my clinic.

David Fell, MD:

It's already pretty unsustainable just with the anti-VEGF medication.

Allen C. Ho, MD:

Yeah. What we have going for us is people really, really, really value vision. You pick the right specialty. We pick the right specialty. Our listeners pick the right specialty.

David Fell, MD:

Awesome. I think that's a great place to end it. Thank you so much, Allen Ho, for joining us today and thank you, Curtis and Justin as always.

Justin C. Muste, MD:

So thank you everybody for tuning in.

David Fell, MD:

We hope this is helpful and for any fellows watching or listening, please reach out with any suggestions for future topics or if you want to be a part of an episode.

Justin C. Muste, MD:

And remember to watch out for new episodes of The Fellow Eye on New Retina Radio.