EyePoint, Inc. (EYPT) Earnings Call Transcript & Summary

Good morning, and welcome to the EyePoint Pharmaceuticals' Key Opinion Leader Virtual Roundtable on the Future of Drug Delivery for Wet AMD. [Operator Instructions] Please note, this event is being recorded. I would now like to turn the conference over to Nancy Lurker, President and Chief Executive Officer of EyePoint Pharmaceuticals. Please go ahead.

Thank you very much, and welcome, everyone. Thank you for joining us today to this important webcast. I think you'll find it very insightful and informative about a very serious eye disease, wet age-related macular degeneration and the treatments that are available and in the pipeline. Next slide. We are a publicly traded company, and so we will be making forward-looking statements. I urge you to go to our website, where you can review all of our SEC statements. Next slide. Thank you. Joining us today is a group of very prestigious retinal surgeons. I'm very pleased to welcome them: Dr. Bob Avery; Dr. Elias Reichel; and Dr. Charles Wykoff. Our moderator today will be Dr. Jay Duker, who will give further introductions on each of our panelists. However, I would like to introduce Jay to you. Dr. Duker is Professor and Chairman of Ophthalmology at the Tufts Medical Center and Tufts University School of Medicine in Boston. He also directs the New England Eye Center and has published over 300 scientific publications. In addition, Dr. Duker is EyePoint Pharmaceuticals' Chief Strategic Scientific Officer. Thank you to each of you for taking the time out of your busy schedules to join us today. Next slide. I'm going to give just a very brief overview of EyePoint Pharmaceuticals. One of the reasons we're so excited about where we're going as a company is we have a very solid and proven technology, primarily with Durasert, but also with our Verisome technology. We have 2 products approved today using these technologies, specifically YUTIQ, which uses the Durasert technology. YUTIQ is indicated for the prevention of inflammation with posterior segment uveitis. And DEXYCU also uses the Verisome technology, and that is being directed towards the treatment of post-ocular inflammation and is currently being marketed for cataract surgeons. Both those commercial launches are continuing, and we're adjusting well to the COVID environment. Specifically today, you'll hear us talk about Durasert. And again, it's one of the reasons we're so excited about our -- the opportunities that we have at EyePoint Pharmaceuticals. Durasert's an FDA-validated delivery platform. One of the compelling things about Durasert is that it offers zero-order kinetics, which provide very sustained, consistent and stable release of therapeutics to ocular targets. That contrasts with other types of delivery mechanisms, which can give a peak and valley effect. The other issue with Durasert is that it has been delivered safely to thousands of patients' eyes across 4 FDA-approved products. One of those is YUTIQ, which is our product on the market today, and we've had others that have been approved as well. So over the past 7 years, thousands of patients have had Durasert implanted into their eyes, and it has a remarkable safety profile. I'm now going to quickly review our pipeline. Next slide. So if you look at our pipeline, we currently have YUTIQ 50, which is a shorter version of our YUTIQ on the market today. YUTIQ on the market today lasts for 3 years. We are in the process of developing one that lasts for 6 months. The good news is we only have one small Phase III study that we need to do to validate that technology and then file for a sNDA with the FDA. What we'll be speaking about today is EYP-1901, which is a twice a year anti-VEGF treatment for wet AMD. And again, that utilizes our Durasert technology, coupled with the active pharmaceutical ingredient, vorolanib, a tyrosine kinase inhibitor. We also have a number of collaborations that we are in the process of developing. And that is with partners. Most are in ophthalmology. We have a few that are in nonophthalmology. And I think of note is that we continue to have people approach us about using their API, their active pharmaceutical ingredient, in our Durasert technology. And again, it's because we believe we have a best-in-class ocular drug delivery technology that's been proven and established. I'll now turn the call, next slide, over to Dr. Jay Duker, and Jay will take us from here. So Jay, the call is yours.

Thank you very much, Nancy. And again, welcome, everybody. Thanks for listening. I hope you find this not only informative but entertaining for the next hour or so. So I'm going to give a little background in EYP-1901, which we are developing as a twice a year anti-VEGF treatment initially for wet AMD. If it's successful, we fully expect to roll it out for diabetic retinopathy and retinal vein obstruction as well. Next. I'm sure most of you on the call are aware of this, but the anti-VEGFs have been transformative in the delivery of retinal care to our patients. And it's reflected in the fact that the wet AMD opportunity is almost $8 billion worldwide and still growing. So basics about these anti-VEGF medications, first of all, they're extremely effective and extraordinarily safe. The real downside, however, is they all have a relatively short duration of effect anywhere from 1 to 2 months. And when a patient gets wet macular degeneration, they essentially have it for life, which means there's a lifelong need for the therapy. And this puts a tremendous burden on patients, on their families, on physicians and the health care system as a whole. There's also now growing evidence that treatment less than on-label, that is monthly or bimonthly, will result in long-term erosion of the initial visual acuity gains that we see in the first 3 to 6 months. And there are 2 studies that have recently come out to look at real-world use of anti-VEGFs in the United States, and it suggests that on average, patients are only getting about 6 injections a year. Next. So real world experience, this graph is from a paper that was published about 5 years ago by Frank Holz from Germany, and he looked at the European experience. And what you're looking at with this graph is that rise in visual acuity that we see initially over the first several months of treatment in wet AMD patients and the gradual erosion of that. So over 2 years, the visual acuity on average for these patients, this is well over 2,000 patients, was almost back to their baseline. Next. The story in the United States, unfortunately, doesn't look that much different. This is a paper published about 3 years ago looking at both on-label drugs, ranibizumab and aflibercept, and the similar finding that we get an initial good rise in vision, newly diagnosed patients on average, it's about 2 lines of vision in the first 3 to 6 months. But over the next months, there does seem to be an erosion of that vision in the real world. Next. So where do we think EYP-1901 will fit in? Well, we really believe that there's a strong demand for a durable and reliable sustained-release delivery system for anti-VEGF medications. And when you sit in a room of retina specialists and ask them, yes, what would you like in the anti-VEGF? I think the consensus is 6 months to 12 months of consistent anti-VEGF activity is really what we're looking for. And how would that benefit us, patient, society? Well, it does appear that if we can get sustained anti-VEGF effects, we're going to have improved visual acuity outcomes in the long term because we're going to lessen recurrences of the disease, which are manifested by repeated accumulations of fluid in the macula as well as bleeding in the macula. This will, of course, increase patient compliance. You can imagine, for elderly population, who have to come in every 4 to 6 weeks for the rest of their lives for injections, some of them are going to miss doses. They're going to get sick. Things will happen. Their families may not be able to bring them in. And by lengthening the ability of these drugs to work, we believe patient compliance will be significantly improved. And finally, this will reduce the burden of patient visits on physicians. Next. So we're not the only ones with this idea, as I'm sure you know. And in fact, companies have been working on sustained-release anti-VEGF for literally 15 years ever since they were first introduced in the market. And obviously, since there's no true sustained-release anti-VEGF currently FDA approved, this is a bit of a tough nut to crack. But what I'd like to do is just briefly talk about some of the other candidates that are out there, and probably the one that's farthest along that I believe is true sustained release is Genentech's PDS, or port delivery system, that has ranibizumab in it. This is an interesting device. It's a refillable port that's actually placed surgically under the conjunctiva across the sclera. It's loaded with ranibizumab. The ranibizumab goes out over time, and it can be easily refilled in the doctor's office. They've completed a Phase III trial where they did automatic refill of the devices every 6 months. And from an efficacy perspective, things look really good. 98% of the patients in that Phase III trial showed a durability of 6 months for their anti-VEGF effect. I think the problem here is probably going to be safety. On both the Phase II and the Phase III trial, there was over 1% incidence of endophthalmitis, which is a serious bacterial infection of the eye. And so that may limit retina surgeons' acceptance and patients' acceptance of the PDS system. Allergan, for many years, has been working on a small molecule called Abicipar. And the problems they've had with it is that it seems to be pro-inflammatory and they've gone through at least 4 different iterations of manufacture. And even in their Phase III, they could only get the rate of inflammation down to about 8%. So they did submit to the FDA, and they got CRL from the FDA back in June of this year. And since Allergan is now part of AbbVie, it's unclear to me, and maybe some of our panelists know what the plan is for this molecule. But as of now, it's not FDA-approved and not available. Kodiak has a very interesting molecule. They're taking an anti-VEGF antibody, and they're putting it in a biopolymer and they're making it last apparently for months. Their targeted duration of treatment is 4 to 6 months. They've done extensive Phase I trial on multiple indications. They're in a Phase II/b trial now. And when you look at their wet AMD patients, about 82% could go 4 months or longer before they needed a retreatment. And about half of them went 6 months without retreatment. Opthea is a company from Australia, who has an anti-VEGF trap molecule. Their targeted duration of action is 1 to 2 months. They just went public to raise money to do their Phase III. Their top line data from the Phase II looks pretty good. I think what you need to understand about their molecule is, it doesn't seem to work well as monotherapy. It has to be combined with another anti-VEGF. And when you do combination therapy in a Phase III, then you need to show superiority over your control group. And that may be a high bar for the company. Next. Ocular Therapeutix is also developing a sustained-release TKI. They're using a TKI called axitinib. Axitinib is off-patent, and so it's available. They're trying to target 4 to 6 months' duration of action. They're in a Phase I that's being done in Australia, and they've released some early data. They have a dose escalation going on and their second dose cohort 2 did show durability of about 70% at 3 months, which means durability refers to lack of need of a rescue injection. At 6 months, it was about half the patients. In 7.5 months, it was about 40% of the patients were not rescued. Graybug's another company, you may be aware of, they're also looking at TKI in a proprietary sustained-release system. Their TKI is sunitinib, which is FDA-approved for kidney cancer. Their target duration of action is 6 months. They're in Phase II. If you look at their Phase I data, they had, what looks like, pretty good efficacy. 88% of the evaluable patients did not need a rescue injection at 3 months and 68% at 6 months. These were evaluable patients. And what that meant during the study is about 20% of the patients had migration of the drug into the anterior chamber. And some of them, it caused a decrease in their visual acuity. Some of them required surgery to have the migration of the compound removed. So when you take those patients out, the statistics look pretty good for this drug. There are 2 gene therapy companies out there as well using gene therapy for essentially sustained-release drug delivery. Adverum is using an intravitreal AAV, and they're showing very good durability. They've got a cohort that's gone out almost a year with no retreatments. Their problem is there's low-grade inflammation in many of their eyes, which is -- forces the patients to be on topical corticosteroids in the long term, and that remains to be seen once they get to Phase III, whether that will be problematic. And REGENXBIO has done a Phase I using a gene therapy product that's injected under the retina during vitrectomy. They've also shown some pretty good durability in their highest doses in Phase I, and they are now in a Phase II. They're also looking at suprachoroidal delivery of their gene therapy product. Next. So suffice it to say, this is an area of very active research with plenty of excellent companies looking at this whole concept of sustained-release anti-VEGF. Our product, EYP-1901, which you've heard a little bit about already, the summary of which is we're trying for 6 months' duration. We're using Durasert technology which, you heard from Nancy already, has the advantage of having zero order kinetic release and it's FDA-approved. The FDA has seen it before. In fact, if you look at all the other competitors, we're actually the only company that's using a drug delivery system that is FDA-approved. We're also using a tyrosine kinase inhibitor called vorolanib. Vorolanib is interesting, and it was actually developed by the same protein chemists that developed sunitinib. And the idea behind vorolanib when it was developed was it was originally going to be used for the same indications as SUTENT, kidney cancer, but they felt, at least in their animal studies that the systemic toxicity was much less than SUTENT. And so the company that had the rights to Tyrogenex fell on wet AMD as a possible indication. So Tyrogenex actually did 2 studies, a Phase I and a Phase II using vorolanib orally. They called it X-82 at the time. And while there was a good efficacy signal in both those studies, and I will show you some of that data, ultimately, the drug never finished the Phase II due to systemic toxicity. So even though the animals didn't have toxicity, humans did. But of notice, there was no significant ocular adverse events. And just to put a little more color on that, when you look at all the TKIs, so far, the number of patients who have received TKI sustained-release intravitreally is low, but I'm unaware of any ocular toxicity that's been reported from the drug itself. We've now completed our GLP tox study for pre-IND, and we've got no unexpected safety issues. We did prior studies using EYP-1901 on the laser model. You may be aware there's no really good animal model for wet AMD. The industry standard is a laser model where you make a burn in the animal's retina and very soon afterwards choroidal neovascular membrane appears, and you can test your product against the amount of leakage and the size of that choroidal neovascular membrane. We did that in mini pigs. And we used to dose actually, which was only a fraction, about 15% of what we expect to use in humans, yet we were able to show a dose-related efficacy against CNV in this model, and we had no clinically observed toxicity. So we're on track to file our IND very soon. We still believe it will be filed later on this month. Next. Vorolanib, again, works at the receptor level, like all the TKIs. It doesn't block the ligand like the molecules that we have now that are FDA-approved. It will block all of the 4 VEGF receptors. We all believe that VEGF receptor 2 is the most important, and vorolanib has very good activity against VEGF receptor 2. Next. This is a data from Tyrogenex. When they were developing vorolanib, they wanted to compare it to sunitinib to see what the biochemical selectivity is. And so the IC50 is quite low for both of these drugs. And in fact, it was the same in the studies that they did, showing that it is a potent inhibitor of VEGF receptor 2. The low inhibition constant for SUTENT is -- I'm sorry, the KI, the inhibition constant for SUTENT is very low as well. And though we don't know what it is for vorolanib, we haven't studied that, we believe it will be very similar. Next. So I mentioned this already, Tyrogenex did study of vorolanib, which they called X-82 as an oral drug. Their Phase I clinical trial was an open-label trial, about 6 months, dose escalation. There was no control group. 80% of the eyes were previously treated with wet AMD for the eyes or treatment naive. Now this study is published. You can read about it. I've got the reference down there at the bottom of the slide. It was published 3 years ago. So if you've got a group of patients who have wet AMD and they're previously treated and you look at their visual acuities in an ongoing study, what you really would expect is, the visual acuity should probably be about the same. And the reason is these patients have already gotten their injections. So that initial bump in visual acuity, which you're likely to see in the first few months, has already occurred. What you don't want to see is a drop in the vision, which might indicate that either there's a toxicity to the drug or that the drug just isn't working. I would say the same thing about central retinal thickness, which is on the right of this slide. Central retinal thickness is easily measured in patients who use optical coherence tomography, or OCT, to measure it. You'll also see the term CFT or central foveal thickness. And what we're trying to do essentially is dry out the retina. It turns out these anti-VEGF agents are really antipermeability agents. And OCT is very sensitive at revealing when VEGF levels are going up in an eye because the fluid reaccumulates. So like the visual acuity, most of the improvement in OCT retinal thickness, the reduction in abnormal thickness is going to occur in the first few months of therapy. So when you look at a Phase I trial like this and you say, what to expect for OCT data in a previously treated cohort? The answer is flat. It shouldn't really get worse, probably won't get much better. And just so to put it in perspective, if you go look at the Phase III trials for ranibizumab or the other on-label drugs and say, "Well, how much OCT reduction do you see in newly diagnosed cohorts." You'll see about 120 to 140 microns on average reduction in the first year in their OCT thickness. But you have to know what the thickness was to begin with to really know if you're trying to compare apples-to-oranges because now that everybody has OCTs, the type of patient that we're enrolling in clinical trials tends to have better visual acuity and less fluid. Anyway, back to the results. This Is a Phase I trial, oral delivery. Visual acuity was essentially stable. There was a slight improvement in the group of about 4 letters, which is slightly under 1 line. Central retinal thick is essentially stable. It was slightly reduced, about 50 microns. But if you look at the 4 patients who were previously untreated, there was about an 80-micron reduction in fluid in those patients. Now all these Phase I trials, ours and all our competitors, because we don't really know how well it's going to work, we have to have a mandated rescue, which means if the eye is not doing well, we treat with an on-label medication like Lucentis or Eylea. For most of the trials that you -- the products that you've heard about, most of the Phase I trials, the rescue criteria was an increase in 75 microns of new fluid over enrollment. For this trial, it was 50 microns of new fluid. And so this was stricter rescue criteria. Nevertheless, 60% of these patients over 6 months never got rescued. All they needed was the oral vorolanib, no significant increase in fluid. And if you look at the mean time to rescue, it was about 130 days. So even the ones that got rescued, look like they had a pretty good effect here. Next. So this is the number of rescue injections from this Phase I trial. So you see there's all different doses that were tried. And what I'll say first about the 300-milligram dose, notice it's on there, but it's blank. It's blank because none of the 300-milligram patients finished the study. It was too toxic. The other thing is if you look at the 50 milligrams every other day, that's like placebo. If you look at what you'd expect in a study with rescue criteria like this, you'd expect 2 to 3 injections over 6 months, and that's what you had. But if you look at all the other doses, 100 milligrams every other, 50 milligrams daily, 100 milligrams daily, 200 milligram daily, there was a reduction in rescue over what looks like placebo there. And in fact, if you look at the high dose, the 200 milligrams daily, on average, there was less than a half of rescue injection given in that group. Next. So this is the data from Phase I on OCT. So remember, most of the improvement has occurred already, but you see, as a group, the OCTs did still get a little thinner, a little less fluid. And the blue areas, the blue squares, those are the previously untreated eyes. And you can see they had a pretty good response to oral vorolanib alone. Now if you think about it and you say, "Okay, well, if we gave these patients an injection before we enrolled them and we put them on oral vorolanib, when would that injection start to wear off, if oral vorolanib had no effect." You should start to see in month 2 or month 3 or even sooner, the OCTs getting wetter, but you're not really seeing that. So it's pretty clear to me that vorolanib has an anti-VEGF effect. Next. So Tyrogenex was really encouraged by that Phase I results. So they did a Phase II study, and the results are available. The Phase II study was published in British Journal of Ophthalmology this past summer. Remember this, again, it's orally delivered. This was a 1-year study. They wanted to enroll 157 patients. They had 3 doses with a placebo, and all of these eyes were previously treated. Now these -- remember, a couple of things about this study is, it was a placebo mass trial, so the investigators didn't know what the patients were getting. The other thing you need to know is the rescue criteria was really strict. The rescue criteria for this study was any new fluid. It wasn't 50 microns. It wasn't 75 microns. It was any new fluid from the baseline. And OCT has a reliable resolution less than 10 microns. So you imagine the investigators who got a patient sitting in front of them and they were instructed to rescue with any new fluid and they didn't know if their patient was getting placebo, there was going to be a lot of rescues. And if you look at the numbers, there was a lot of rescues. In the placebo group, the median number of anti-VEGF injections for this previously treated group over a year was 9. I already told you, in the real world, it's about 6. So this was a tightly watched group who got a lot of rescues. But if you look at all the other doses of vorolanib, there's a reduction in dose response and the number of rescue injections. And in fact, if you look at the highest dose of 200 milligrams, 20%, one out of 5 of those patients, went the entire year with no rescue. Again, this shows, in my mind, a pretty good anti-VEGF effect. Next. So back to where EyePoint is with respect to our Phase I. We have done rabbit GLP tox study out 6 months. We're collating the results. And at this point, we've seen no serious adverse finding from either the Durasert insert or the medication itself. There's been no systemic adverse findings. No IOP issues. There have been some injection-related findings, which if you're aware of the rabbit eye, the rabbit lens, relatively speaking, is about 4x larger the human lens. And so it could be hard to inject without hitting the lens. And in fact, there was some focal lens opacities that occurred at the beginning of the study and did not progress, suggesting that they were injection related. We did see at the beginning in some of the eyes, mild, self-resolving postinjection inflammation, which again not atypical for rabbits. But our belief is we didn't see any events that would preclude us from progressing to an IND. Next, so our Phase I trial, we're calling the [indiscernible] wet AMD Phase I study. [indiscernible] stands for Durasert in vorolanib in ophthalmology. We're on track, again, to submit the IND shortly. And if you look at the time line here, that means we hope to dose the first patient early in 2021, which means we should get top line 6 months readout by this time next year or sooner. Next. So our Phase I trial is going to enroll previously treated patients. They're going to get an injection of whatever anti-VEGF they had been receiving. And 1 or 2 weeks later, they're going to get an EYP-1901 insert. We have 3 doses at this point, and we're going to do dose escalation: 3 patients in the low dose, 5 patients in the mid-dose, 5 patients in the high dose. It's a Phase I study. So the #1 endpoint, of course, is safety. But we're going to be looking, of course, at other endpoints that are important like best-corrected visual acuity. And most important, to look at the anti-VEGF effect, is going to be that central subfield thickness on OCT. Because if we can keep these eyes dry or keep them stable over 4 months, 5 months, 6 months, then I think we're going to be able to show that the inserts are working. We're also able to do an expansion study. So we've got the potential extension of 12 additional patients. And I think we're going to do this a little adaptively and see how the 3 doses do before we decide what that extension study exactly is going to look like. Next. So at this point, I'm going to pause, and we are going to now bring in the key opinion leaders to have our roundtable discussion. So I'm joined by a trio of outstanding experts in the field of vitreoretinal disease. Each of these 3 panelists has extensive experience treating retinal disorders, including wet macular degeneration. They're all extensively published and internationally known as experts in the field of vitreoretinal disease. And together, I calculate that they have over 80 years of experience serving as principal investigators in a myriad of clinical trials. But of course, that's mostly you, Bob. So to introduce our panelists, again. Bob Avery is the founder and CEO of California Retina Consultants. Elias Reichel is the Director of Vitreoretinal Service at the New England Eye Center, and Professor and Vice Chair of Ophthalmology at Tufts. And Charlie Wykoff the Director of Research at Retina Consultants of Houston. And he's the Deputy Chair for Ophthalmology at the Blanton Eye Institute. So I'd like to thank you all for taking time out of your busy schedules to join us. I expect the discussion to be lively and productive. We do have a list of questions that we've shown the panelists in advance. And we're going to have a chance for those in the audience to ask some questions at the end. So I'd like to begin by asking each of the panelists to briefly go over little additional background on their professional experience, their current clinical practice and their experience treating and studying wet AMD. Let's start with Dr. Avery.

Thank you, Jay. Well, we've been in practice here in Central California for about 25 years. I have an academically oriented private practice. We've got 11 retina surgeons, and we were involved early on with the research in anti-VEGFs and the application of therapy using those years and years ago. So we do lots of clinical trials and -- in this field and have really -- it's been fun watching the effects of these treatments on this previously untreatable disease. But that's sort of our private practice with an academic sort of approach to things.

Thanks, Bob. Elias?

Yes. Thank you, Jay. Thank you, Nancy. I've been in practice also for 25-plus years and have seen the evolution of treatment for neovascular AMD. When we started out, in some ways, there was essentially nothing except for photocoagulation or laser. And then we went to PDT, and then the anti-VEGF era started in the early 2000s. And at this point, in my practice, we've done clinical trials. We've developed different drugs on our own. That has been quite exciting. But the really exciting thing is the anti-VEGF revolution. It's really helped so many -- millions of patients around the world for neovascular AMD and diabetic retinopathy. So these are really pivotal studies, and our treatments are really important. We treat thousands of patients in Boston here with these conditions. They all benefit from it. The patients are very appreciative of this care, and they continue to do so. They understand even in the pandemic that we're going through, how important it is to be followed and to be treated for these conditions. And it's a great service that we're doing to develop these technologies and to improve upon them.

Thanks. Charlie?

Great to be here with you. I'm a medical and surgical retina specialist based in Houston, Texas. I came out -- I've been out in practice now for about 11 years, and I lead our clinical trials group here with 14 retina specialists. We have a lot of retinal pathologies across the spectrum. And it's -- I came out when Lucentis was approved right before Eylea was approved, and it's an incredible opportunity to be able to treat patients with wet AMD with our current anti-VEGF agents. But now having had conversations with patients for years about how effective these treatments are, patients are ready for the next-generation therapeutics. And it's an incredibly exciting time. There's a lot of really exciting stuff in the pipeline. And as you mentioned, Jay, some of those opportunities are becoming close to a commercial reality. We've been talking about this for a decade. So it really is an incredible time as we pivot from our current-generation therapeutics to next-generation therapeutics, and I'm excited for the future for our patients.

Thanks, Charlie. So Bob, I'm going to ask you the first question, and it's kind of a multipart question here. Can you, first of all, for the audience, describe the initial patient experience that they have when they develop wet AMD? What type of symptoms are they likely to have? And then how do they get to your office? What does your initial evaluation consists of? And once you determine they do have wet AMD, how do you educate the patient on what to expect?

Thank you. Most of the time when we first notice metamorphopsia, some sort of distortion, waviness in their vision in that eye. And they may not notice it immediately because the other eye, if it's a good eye, may cover it up. And they may notice it when covering up the good by mistake or inadvertently notice it. Other times, people have been followed with the other eye having wet AMD or some other disease, and they'll notice it much earlier because they're looking for it. But it's usually just a waviness to the vision, lines aren't straight and mild decrease in vision as well, if it's caught early. The patient themselves, how they handle it sort of depends upon if it's the first eye or the second eye or if they're knowledgeable about macular generation. Sometimes patients have been followed by us for years for dry macular degeneration and it just progresses to wet. And so they're sort of expecting this potential thing occurring, and so they're sort of prepared. But oftentimes, they're surprised. And when you have the discussion with them that this is something that may need lifelong treatment, that is sort of a shocker. It's almost like getting a diagnosis of some chronic systemic disease that's going to really affect their lives. But when you tell them that they're not going to necessarily lose their vision as before the anti-VEGF revolution and they're going to probably improve vision, as you mentioned, Jay, the naive treatment patients usually improve in vision. And then after that first injection, which they're scared of the thought of an injection, and they realize it doesn't hurt and it actually improve their vision, then they become very, very comfortable with injections because it doesn't hurt and it makes your vision better. However, they tend to get burned out with the treatment burden as you've mentioned, and this is why we need longer duration of therapy. I'm sorry, I'm rambling, but what was the earlier question?

No, that was it. I was going to next go to Charlie, and Bob covered that kind of preamble very well. But now let's talk about medications. So you've got that patient, you've evaluated them presumably with photographs, OCT, whatever, and you've determined they have wet AMD, you've had that conversation. What do you treat them with?

Yes. Whatever I can is the truth. I prefer to use on-label agents, but more and more, we're seeing sort of decision tree made for us, whether we like it or not. And of course, we as a society, as a group are against that. We want to be able to have doctor and patient choice, but we are seeing that. We are seeing multiple payers now requiring step therapy, which is frustrating to see. But if I have my choice, I will use what I think is the best agent for the patient. And if it's my eyes, I want to use an on-label agent delivered from a prefilled glass or a [indiscernible] syringe. I mean I'll treat them as soon as possible. I'm a big believer that earlier treatment leads to better outcomes for most of our exudative retinal diseases, and the key is to begin initiation of therapy as soon as possible, ideally on the first day that they present. And it is a scary transition, as you and Bob have both laid out. You tell a patient for the first time that you're going to put a needle in their eye, and it's sort of like you're going to a what in my where? And there's a moment of shock. But as you walk through it and as patients experience the first one, we tell them that really after the first shot they're going to hopefully look at the physician and say that's it, because it really is a sort of painless procedure in the vast majority of cases. And there's some recovery time from the Betadine and such that patients might experience, but overall, extremely well tolerated and patients adapt to it quite readily. And I think that the biggest burden that we see, for most of the patients, is truly the durability. It's not the only limitation that we have. The durability is a major limitation to optimal real-world outcomes.

So Charlie, when you talk about limitations, obviously, we've really emphasized how effective they are, but what do you tell your patients about risk? I mean what is the risk of an anti-VEGF injection? Is there any?

Yes, absolutely. I definitely talk about that. I sort of talk about the fact that every intervention that we have in medicine and surgery carry some degree of risk and hopefully, some degree of benefit. And I strongly think, in this case, obviously, the benefits strongly outweigh the risks. But yes, I definitely talk about pain with the injection, and I want to talk about pain specifically because of the risk of infection or endophthalmitis. There's a rate of somewhere between probably 1 in 2,000 to 1 in 10,000, depending on the series you look at after any given injection. And of course, that's a cumulative risk. For the longer patients get retreated, higher their personal risk of ultimately getting infections. You want patients to be aware that if they develop pain or redness or light sensitivity afterward, to make sure that they're at a 24-hour phone number that they can call 7 days a week because you don't want to miss an infection after one of these injections. We also talk about the risk of retinal detachment, cataract, retinal tears that are all very unusual and much, much less of a risk. Now some of the newer agents, brolucizumab, in particular, is not FDA approved. When that's being considered for some particularly resistant patients, we do talk about the risk in that particular case of inflammation. Safety is very real issue to consider with any agent that you give, whether it's oral or intraocular, and any immune response to that can be detrimental in the setting of an eye condition. So we talk about that with certain patients also.

Yes. Since you brought up brolucizumab, I think we're going to talk about that a little bit more in a moment. But I want to get Elias' view on this as well. Elias, same question. What's your initial treatment protocol? And do you believe that 3 loading monthly doses at the beginning is required in all patients?

Yes. So I really prefer the branded drugs, and my favorite is aflibercept. I think that there's a lot of flexibility with that drug for longer duration use. So my bias is to use aflibercept. That being said, I use Avastin and Lucentis as well. And often, it is sometimes dictated by insurance and coverage. As far as how we follow these patients and treat them? There's important data to suggest that doing 3 upfront injections is important. And personally, that's not absolutely true all the time. You can sometimes get away with 1 or 2 injections for a patient with choroidal neovascularization, and they can actually go a very long period of time without treatment. But what we've learned about 3 injections is 3 injections can actually get you dry 75% to 80% of the time. It doesn't get you dry 100% of the time. So it's important to recognize which patients actually get dry after 3 injections. If you determine that a patient gets dry after 3 injections, you're probably going to have more flexibility in increasing the duration of injections, meaning that you can go out longer, say, for maybe 8 weeks or 9 weeks or 10 weeks in those patients. If a patient after having 3 injections is not dry, you're going to have to really think about being aggressive and continuing monthly injections. So that's where something where you have zero order kinetic way of delivering anti-VEGF may be key because those are the patients that really require sustained durable effect fairly frequently, maybe those that really need anti-VEGF suppression with zero order genetics.

Yes. So Elias, you're bringing up a point about pharmacology, which both you and Bob have actually written about indirectly, which is the very large dose that we deliver of anti-VEGFs now is probably way more than we need at the beginning, especially if an eye is dry, but we do it for durability. So you've published looking at, I think, subconjunctival anti-VEGFs, where you're going to get less of a level in the eye. And Bob, you've looked at the fellow eye absorption presumably systemically of the drug from 1 eye to the other. So could -- first Elias and then Bob, could you comment on that pharmacokinetic need for really high dosing at the beginning?

I mean, it's not clear that there is a need for high dosing in the beginning. I think that there -- it may be that we see too high a dose. So just to sort of temper that, low dose is probably not correct. But somewhere, there's a Goldilocks situation where you're going to have the right dose at the very beginning. There are concerns with very high doses of anti-VEGF that they cause retinal cell death and apoptosis. So it may be with these boluses of anti-VEGFs, we may induce more of that. That's possible and has been shown by some both clinically and in preclinical work. The important thing to remember about the anti-VEGFs banks though is that the sustained durability is probably what we want to see after having some kind of moderate early effect or even as high bolus and then having that sustained zero order kinetics where you have chronic suppression. The only concern that I have is that with chronic suppression over very long periods of time, again, you may see this anti-VEGF effect of cell death to [indiscernible] receptors and the retinal pigment epithelium.

Bob, same kind of question. Do we really see a contralateral effect from an intravitreal injection in 1 eye?

I think you see it most prominently, probably, on the retinopathy of prematurity baby, where they're given really whopping doses. They're using half of an adult dose, where the blood volume is so manyfold less, and the serum levels have been measured. Actually, there in Houston, at about a microgram per mil, I mean a concentration that can cause reduction in retinal leakage in diabetic vitreous. So that's what's flowing through the bloodstream in these babies after do they get these injections. And so I do think it's true that you can have fellow eye effects. And we've seen it before in adults, but it's not that common because it's diluted much more. To sort of agree with what Elias said, the initial bolus that we give is sort of wasted. I mean there's exponential decay in the eye and most of it just goes straight out into the bloodstream. And we don't need it, I don't think, at the initial stage. We're way over the dose we need to suppress all VEGF. However, we do have to get longer duration of effect because the more you put in and the longer it lasts, even with its exponential decay. All this implies that drug delivery device, where you're going to have a controlled released amount is the way to go to minimalize any potential side effects. I don't think the side effects are that common with anti-VEGF because it's such a relatively safe disease -- safe treatment, and we're using doses that are so low compared to the systemic doses. But we know from the cancer trials, when you use a systemic dose, there is an increased risk of stroke and ATEs, or arteriothrombotic events. And so there's a black-box label on Avastin for these indications at the systemic doses. We're nowhere near the systemic doses. But I do think it could have effect in, say, few babies that are developing seeing vasculature and neural tissue and such. And so I think there is a concern. But just the fact that we can give a small dose in a drug delivery device, consistently over time, we can use a tiny fraction of what's systemically absorbed or what's given with these bolus injections, and it's safer and better and last longer because you can have longer dose -- longer months out, you'll have a much higher dose in the vitreous with one of these sustained delivery devices than using this archaic bolus injection and then inject when it drops down again.

So Charlie, we did mention brolucizumab, and I think this might be a good time to just educate the audience a little bit about what the hopes were for the drug, a drying effect, length of action, and then what we've seen from a side effect profile. And second part of that is, Bob was talking about the systemic effects causing things like thromboembolic events. Do you think it's possible that the dose we're using for brolucizumab is so high, we're actually seeing that in the eye? And the last part of the question is, what are you doing in your practice with brolucizumab?

Yes. Yes, there's a lot there. And I think the challenge with the field, as you pointed out early on, Jay, is that these medications that we currently have, sort of the 3 main agents that we use regularly, are highly effective and extremely safe. But there is this huge burden of need for more durable agents, which will translate into a better long-term, real-world efficacy as well as additional targets, I think, is another unmet need. And so there's been a lot of innovation to try to bring those newer agents to market. And the first one since after Eylea's approval was brolucizumab, which was based on the HAWK and HARRIER Phase III trials, and it was -- that was an exciting medication when it was in development and still is an exciting medication. And in HAWK and HARRIER, it was found to be noninferior to on-label Eylea use for the treatment of wet AMD. But the promising aspect that we as retina specialists really gravitated towards was its superior drying efficacy. It appeared to be a better drying agent. It has a higher and more concentration of VEGF inhibition for the same injection volume versus Eylea or Lucentis or Avastin. And so the hope is that in the real world, it will be able to dry patients out more thoroughly and therefore, translate into increased durability. And we saw that a meaningful portion of patients, approximately half through 1 year and slightly fewer than half through 2 years, were able to go 12 weeks on the drug without meeting their criteria in the trial for dropping down from 12 to 8 weeks. So it was exciting when it came out of the Phase III trial and then did receive FDA approval at the end of 2019 for, of course, a market access across the United States, and many retina specialists began to use it. And the problem of inflammation quickly emerged. And looking back, I think we as a field have learned a lot about really taking a deep dive on the safety aspects from this experience because when we look back, it was -- actually, the signal was actually there in the safety package from the Phase III data set, where there was a higher rate of intraocular inflammation, potentially retinal vasculitis and retinal occlusive vasculitis in the Phase III data set. And we've learned a lot about that from real-world analyses subsequently from the IRIS Registry, for example, that was presented at AAO [indiscernible] meeting recently. And so we're still learning exactly what the incidence is, but it's probably somewhere in the 1% to 2% range of patients that are given brolucizumab experienced clinically meaningful intraocular inflammation, which is, realistically, in my clinical practice without being able to identify who those patients are a priority, is simply too high. It's too high of a bar to routinely use the medication in clinical practice

Elias, do you have patients on brolucizumab right now?

No, I don't. So...

Bob?

I do. Because one thing that sort of escapes the clinical trials is how individualized the response is to patients. I mean you have people that really, you can dry them up with 1 injection in a year, and you have people that you can't dry with an injection every 4 weeks. And those patients that are really VEGF -- anti-VEGF dependent or resistant, shall we say, or they just need a lot of it. They respond, but only for 2 to 3 weeks. We've tried alternating Avastin and the branded drugs, and those are the people that last longer on brolu. And so I've put them on that, and they've had a better response. They can go 4 weeks. They can go 8 weeks. They can go 5 weeks, sometimes. They can go 4 weeks. And so those people that have been treated that way somewhat refused to go off of it despite the increased risk. I have a discussion with them, and I have several patients that refuse to go to other treatments because of the durability of that agent despite the potential risk of artery occlusion.

Yes. And you bring up a point about the patient's response here, which is, it's still amazing to me how many patients know when they're wet. One of the reasons they're so motivated to continue to come in for injections is they really can tell that the injections work. They get immediate feedback.

That's still true, Jay, during COVID. I mean our practices -- when the whole state was shut down in March and it's shutting down again today, but -- these patients know it works and they demand to come in -- not demand, but our volumes really hardly changed because it just turned into injection clinics. And it's amazing how motivated these elderly people who are at high risk of COVID are to come in because they know it's helping.

So great segue, because my next question is for Elias. Elias, how has COVID altered your delivery of wet AMD care? And do you think when the pandemic is over and we're -- it's going to get really bad in the next month or 2, but it looks like we're going to see the end of it in the next year. Do you think we're going to see any long-term changes in the way we deliver wet AMD care because of what we learned in the pandemic?

Yes. So I mean, I think with wet AMD care right now, mid-pandemic, we're seeing our patients when we can. So when you're seeing your patient when you can, it means you better be doing an injection on that visit. So it becomes not a question of how much fluid there is and whether they're dry or wet. Generally, if the patient is there, you're going to do an injection because you're not 100% sure when you're going to see them again. And many are motivated to come in, but maybe that the clinic is closed, that we don't have the staff. They don't have a family member who can bring them in, maybe a family member can't even speak to them and see them. So when you have the patient there, you're going to do the most possible. And that, again, make -- my choice of anti-VEGF, again, tends to be aflibercept because it'll give me some latitude. The other aspect of this is telemedicine. And I don't practice telemedicine in the sense that we're observing the patient, we're doing a clinical exam, because we don't -- we can't do that in retina yet. We will get there. But what I'm anticipating is that once we're mid-pandemic and we're seeing these -- you were talking to these patients on the phone, as Bob and Charlie are saying, they are very astute. They know when they have fluid. And they say, "I need to come in" or "Hey, doc, I'm willing to wait another week or 2 when things settle down. And I'll see you." So I think that's another aspect that they really are in tune with their condition, and they can figure it out. They either check by reading a newsprint or an Amsler grid, and they're telling us that they need to be seen. As far as the future is concerned, I think that unfortunately, this awful coronavirus is not going away. It's going to be reduced. Vaccination is important. I think we're going to be wearing masks. But I think what's important is we need drugs that allow us and give us flexibility and confidence that we could extend these patients out for a longer period of time. So instead of seeing Mrs. Jones in 2 months, we'll be confident to see them in 4 months. The only caveat that I have for all these extended duration treatments is it's great to know that they extend the durability of the drug. The question is, how much do we extend observation of the patient? If we have a drug that works 4 months or 6 months, when do we see them again? Do we see them 2 months after injection, 4 weeks after injection? It's unclear. And we're going to have to learn that. We'll not have that information very soon, but we will learn over time.

So Charlie, given the number of clinical trials you're involved with, can you answer for the audience how has COVID affected the ability to first perform clinical trials for retina in general and, specifically, to recruit and keep trials going in wet AMD?

I think this has been very regionally dependent. So here in Houston and Texas, we have been able to continue our clinical trials throughout the entire pandemic, and that is absolutely not the case with many friends and colleagues around the country. So I speak of only a very localized perspective here. But in Houston, again, we've been able to continue, and it's been very disease dependent. So for example, patients with geographic atrophy have been a lot with -- from mac degeneration have been a lot more hesitant to come in for a clinical trial. They say, look, I'm going to wait a few months. I'm going to wait 6 months. I'm going to wait a year. They've had this disease for a long time. And overall, they don't see it as an urgent problem. And in many cases, I've actually agreed with them because those are many high-risk patients that are quite elderly. But these exudative retinal diseases, especially wet AMD, when you have a significant recurrence, sometimes you do not recover your vision. And we've all seen those heartbreaking cases where even if patients do want to come in, sometimes their living facility may not let them come into clinic because they are unable to simply leave. I've seen multiple cases now of wet AMD that have gotten substantially worse to the point where you cannot recover the vision because it's become fibrotic because they're unable to come in for an injection and missed a few months. So overall, we have been trying to continue our wet AMD and exudative retinal disease clinical trials and have been successful at that. But some patients have been unable to get the frequency of care that they need because of the COVID situation. But overall, that's actually a minority of our patients, and we are near to full capacity actually for research because most of these patients really do appreciate the gravity of their situation and the value of the interventions that they're receiving.

Thank you. Bob, could you speak a little bit on new treatments? And when you're trying to figure out how to integrate a new treatment into your practice, what are the factors that you look for? I mean we just heard about brolucizumab. We've got the port delivery system that maybe FDA approve soon. From your perspective, what are the important things to say, I'm going to be an early adopter or I'm not going to be an early adopter?

Well, I guess the -- it's -- it boils down to the safety, the efficacy, and I guess, the effect on the treatment burden. Those 3 things are the most important when you decide how aggressive it is to -- you're going to be and being an early adopter. I've tended to be an early adopter because everything seemed to improve in the past. Brolu was sort of a surprise how the side effects sort of were greater than we had -- I had appreciated in the clinical trials. And so that was a little bit of a setback, but -- and so sometimes, we change. And we use so much less than we would have had the -- had that side effect not been there. But I do think, you pointed out, the port delivery system is something that's going to really extend the durability, but it comes at a safety price. And the extensive safety we have now and the history we have for 15 years of injections, the endophthalmitis risk, which is the devastating complication, is real. And when it happens, it's horrible. And to go in and have something with the 1.6 chance of that and the need for surgery in this elderly population, that's going to not be for everyone. And yet, it does advance the durability quite dramatically. So it will be an individualized discussion. Some people really are more interested. They think surgery is nothing. We've done a lot of gene therapy patients, and they're not at all concerned about -- many of them not at all concerned about the initial surgery if they could get them where they don't have to have injections again. And ironically, I've had more difficulty with 2 of my patients coming in follow-up after gene therapy because they feel like they're cured because they're not getting any injections anymore. That's unusual, but these clinical trials, it is hard to keep people in the trials when all these COVID restrictions are in place, and it's hard to enroll and the ones that are not having the exudative data disease, as Charlie said. But back to what I look at, I really think it has to be a safe improvement over what we have. And what we have, bar is really high, but the durability effect is really low. And so anything that would be safe and extend that durability without sacrificing efficacy, that's what I would be looking for.

Charlie, Elias, any other comments you want to add? Do you -- would you look for anything different? Do you put a premium on safety, premium on efficacy? Are they both important?

Well, I think they're most important. The interesting thing about safety is the bar has been set so high by our branded drugs and even Avastin, which is not a branded drug, that it's created issues for brolucizumab and Abicipar. The bar is really high because those -- the 3 drugs that we mainly use are incredibly safe, and so we have to match that. It doesn't necessarily have to exceed that. And then as far as efficacy is concerned, I think the graphic that you showed where you see that inverse plateau of retinal thickness going away over time is critical. And if we have drugs that can get us into the 120 to 140 micron range of reduction, then that's great. And then the question is, as Bob said, part 3 is, what's the durability?

Yes. Charlie, any other comments?

I absolutely agree. Safety is paramount here. And then efficacy, durability, we speak of them as if they're separate, but everyone's alluded to the fact they're actually tightly connected. If you have more durable agents, you're going to get better efficacy because we're more and more diagnosing patients earlier in the disease process with good vision, and there's a wealth of data to show that better vision at baseline leads to better long-term vision. And so if you're able to have fewer shots, you're going to have better compliance, less recurrence of disease and better maintenance of vision. So I think that increasing durability is a key to [ getting both ] fewer treatments, which is what patients really want, but also improved efficacy, which -- we all have patients that are willing to come in actually more frequently if they could see better. I really do think we can have both if we get a truly durable agent.

Elias, do you think the FDA is going to be scrutinizing new anti-VEGF drugs more closely now because of Abicipar and brolucizumab?

The question is, the issue in a class effect related to anti-VEGFs. And the answer is no. Because we have so much experience with, again, aflibercept, ranibizumab and Avastin that it's not a class effect where we're seeing these increased issues of inflammation and occlusive retinal vasculitis. So I don't think it really raises the bar. I think you just -- as I said before, if we're comparable to the 3 drugs that we mostly use now, I think we're going to be safe. If it's below that bar, then there may be concerns, if there's increased risk of inflammation, if there's an increased risk of infection. So we can talk about -- we've talked about the port delivery system, risk of infection, that is something that is concerning. And the bar has been set very high with our injections where, as Charlie said, we see 1 to 2,000 to 1 to 10,000 patients with an injection risk to develop endophthalmitis, that is exceedingly low. We can't deal with 1 out of 100 or 1 out of 200.

So for the next few minutes, before we open it up for questions from the audience, I want to talk specifically now about EYP-1901 and TKIs in general. Were any of the 3, you were -- were you involved in the Tyrogenex studies at all, the oral studies? Charlie, you were?

I was. I have a very well-known patient that I have been treating for years that was in that X-82 study. And he -- I actually don't know what he got. I think it's been unblinded, so I could have looked back at that. But he had an anatomic response, but he actually did have a systemic side effect that actually led them to drop out of the study.

So based on that -- [ end of one, ] it's hard to say, but have you guys seen the data? Any comments? Have you read the paper or seen the data on -- can we tell how robust anti-VEGF effect that oral drug has? Bob, any insight?

The treatment burden seemed to drop, and that was very encouraging for such a study. I mean, I think it's proof of principle or proof of concept that these drugs do work. And I think giving it in the eye is just going to be so far superior because one of [indiscernible] you can get a higher concentration intravitreally. And I think I am very encouraged that this device work. And like you said, many other companies are looking at TKIs, from Graybug and Clearside is doing a suprachoroidal injection of one of these TKIs, the same one that Ocular Therapeutix is using. So there are many companies looking at it because it's so promising. But we have the proven treatment technology for drug delivery. And we know this works from the other drugs that have been delivered with the Durasert. So I'm really excited about this moving forward.

Anyone have any concerns, ocular safety concerns about the ocular delivery of a TKI? Elias, you've been around some of these programs for years. Any concerns?

Yes. So you're always concerned about off-target effects, and I can tell you that the PanOptica, which was a TKI, and it was a drop that was delivered to the cornea. Those patients developed corneal toxicity and epithelial changes. So that was an off-target effect. So with TKIs, you're always concerned about that because they're somewhat nonspecific in their targeting, which is both a benefit and could be a potential risk. So that's what I'd be concerned about. But the animal data looks very good. And with PanOptica, pazopanib, they had animal data that suggested this beforehand. So if your tox data is looking good, it's unlikely that that's going to be an issue. The one thing that I'd say about TKIs in general and from the early data that we're seeing from Graybug and Ocular Therapeutix is are we going to see as robust effect in changing the OCT. Looking at all the data sort of holistically, it appears that you're seeing 60 to 80 micron difference. And how does that compare to the anti-VEGFs that we're using right now? I think that's the big question in my mind.

So you mean 60 to 80 micron difference initial reduction in the thickening.

Exactly.

Yes. And so that's always been a pet peeve of mine that all of these studies for years have reported an actual number of reduction in the OCT. But unless you know where the OCT started, it's of no value. Normal OCT thickness, 300 microns. You started at 500 and you reduce it to 120, it sounds good, but you're still not dry. So that concept of either a little bit of fluid and dry long term or dry long term is really one that I think we, as retina specialists, are more interested than the actual number. Agree?

Yes. No, that's absolutely correct. But I'm looking at it from preclinical data or early clinical data, what are you looking at? And again, it's apples and oranges. Some of these patients are chronic patients. Some of them have pretty poor vision. Some -- a few of them are -- eyes that have never been treated before. So it's a real mixed bag. But the thing that convinces me is that, gee, if this drug shows you 120-micron decrease in certain patients, that's very exciting.

Charlie, Bob, any other comments about TKIs in general from a safety perspective?

Obviously...

Go ahead, Bob.

No. You go, please.

One comment I can bring up is just the role of fluid. I mean in this bolus world -- the bolus injection world that we currently live in, I am going to treat to dry a physician and maintain dry as long as I can. But that might change when we have agents like the agent that we're talking about and other agents that are able to be present for a long period of time. You're having some degree of anti-VEGF activity. If you have a little bit of persistent fluid in an anti-VEGF-treated eye ongoing that may not be detrimental, there's arguments to be had that may be a good thing. I'm not excited about fluctuations in fluid. I don't want to see the ups and downs, but if you can stabilize the eye, dry the eye but not dry it completely and then maintain stability long term, that might be equally good, if not maybe even a little better to absolute bone dry. Bob?

No. I agree with that concept in general as well. I was just going to point out, too, that by blocking all of the VEGF receptors, we may get some additional benefit, sort of like you get with the blockage from another company where they're combining it with the typical anti-VEGF to cover all VEGF molecules. And so, that may provide a little boost used as an adjunct. Let's just say a worst-case scenario, this doesn't dry it up and on, it may be a useful 6-month adjunct to anti-VEGF therapy, reducing the treatment burden significantly and attacking this other sort of mechanism of the different VEGF receptors, giving a little added boost to improve over the outcomes we see with typical injections today. So, there's still a role for it even if it didn't dry things up quite sufficiently. But as Charlie said, sometimes we don't want it to be completely dry. There's an increasing body of evidence that having a little fluid sometimes is a good thing. But I think in general, we want to suppress the VEGF, and this is something that may work by working on all 3 receptors may have an added benefit.

Yes. I think we have to consider the possibility that sometimes those little slivers of subretinal fluid that we can't get rid of may not be VEGF mediated, and that's why we're not getting rid of it. So, we've talked about TKIs in general from a safety perspective. I want to shift a little now and talk about Durasert from a safety perspective. And just so you know that 2 approved, the commonly used Durasert Technology's, ILUVIEN and YUTIQ, they're essentially the same, but they are non-bioerodible. The medication is covered in a polyamide tube that has little openings at either end in the drug elutes out, and that's how it can last for 3 years. With EYP-1901, it's bioerodible. The polyamide tube has been removed. So, there's fewer excipients. So, it's not exactly the same makeup. But the core of the drug is the same. And by removing the polyamide tube, not only do we make it bioerodible, but we can get higher doses of the drug for a shorter period of time because I don't think any of us want a 3-year anti-VEGF implant at this point. So, Elias, have you used ILUVIEN, have you ever put into YUTIQ, any particular issues around the technology?

So, ILUVIEN, a long time ago for the initial clinical trials for diabetic macular edema and really no issues in delivering it to the vitreous and no complications that [indiscernible].

Charlie?

Yes, I have used a number of ILUVIENs, maybe 20 total, and I still use it occasionally. There are certain eyes where I find it really valuable to control both DME and diabetic retinopathy, and I have not had any problems with the delivery or the long-term presence of the tube after the drug product is gone after a couple of years.

What's the bolus number you've ever put in an eye?

2.

Yes. I've got someone with 3. She was in the original study, and I've done it twice more. And I can't even see the tubes. Bob, how about you? Any experience, positive, negative?

I would say that the injector itself is clunky compared to the OZURDEX injector. So, the actual physical delivery is a little clunkier, not that, that has an impact on the outcome. But it is hard to find these guys. And one of my partners which so early on was so worried that he had done this injection and it hadn't worked. He didn't sleep all that night. He went back and he went in the sharp container and found the ILUVIEN stuck to the injector to -- and his concerns were true because you can't sometimes find it in the eye. And these are technical issues, but the actual effect is good.

They're surprisingly small. So, you just saw some of the preclinical data in general around EYP-1901. And, Elias, any initial reaction to the preclinical tox data and the program in general?

No. It looks great. I think it's very exciting. The preclinical data, the preclinical data, it gives you the go ahead. That is safe in animals, and we can go ahead in humans. Yes, the design of the study looks really good. I mean, one nuance is I personally prefer to see disease that hasn't been treated before, to have to show the best effect possible. The [indiscernible]

[indiscernible] that you were going to say that.

And that's why you asked me the question probably. But most studies are done in patients who've been treated before. So, it's a minor nuanced issue.

And Charlie, any comments?

Yes. The one point I would bring that is I'm really glad that you're targeting 6 months, 6 months or longer. Yes, I think it will be a short -- I don't want to use too strong of a word, but I would not like that it was the 3-month target or better. I really like that you're putting your neck out there and saying we're going for 6 months. I like that.

Yes. And when you think about it, 3 months, well, some of our patients with what we have now go 3 months. And especially if you're going to be doing a load, all of a sudden, if you got a 3-month drug and you loaded with 3 injections, I'm not sure it's much better than what we have. How about you, Bob?

I think, 6 months is a changer.

i agree. I think 1 to 6 is great. The Kodiak actually, it seems to me that they need that load though, because they can go longer, but then the retreatment seem to be a little earlier without the load, looking at the later data in the study in the [indiscernible]. But anyway, I agree, 6 months is much more ideal. I think it's much better because I think by the time this comes to market, I think we'll have extended from our current time so, and this is a goldilocks experience.

So, at this point, any other comments, anything we have missed that you'd like to see from my 3 panelists?

I guess the one question I would have for you, Jay. I don't know the answer to this, is when OZURDEX breaks down the palate, there's sort of a local acidic response, where with ILUVIEN, obviously, you have the permanent sort of piece of plastic, and there's no local acidic or chemical change. If EYP-1901 is going to break down, what does that local microenvironment look like as it is breaking down?

It's the same as the ILUVIEN. There is not that acidic response, it's not the same medications and excipients as in the OZURDEX, it is different.

Great. That's very positive.

Jay, without the tube, is there a component of a burst release or just instead of straight 0-order kinetics?

This is why we have you on the panel, Bob, because you're a really smart guy. And the answer is yes. There is a bit of a burst response. It turns out that there -- not only is the medication integrated into the matrix of the insert, but there is some medication on the surface. And you do -- therefore, it isn't true 0-order because you get a burst in the first few weeks, and then it goes to the 0-order.

Actually, I'll come on board and say, I like that. And I've found that one of the reasons that OZURDEX seems to still be used a lot more than ILUVIEN is that burst effect that they have. And I think on the people where it used to seeing the equivalent of a burst effect with our massive doses of anti-VEGF or the OZURDEX having a burst, and they put the ILUVIEN in the eye, huh, I didn't see much this next time.

And our scientists showed the original in vitro data, and they were disappointed that there was a burst effect. They were kind of shaking their head, oh no, it's not 0-orders of burst. I'm like, no, this is good, we like this. So, I agree. Anything else? Great. All right. I guess, at this point, Nancy, we can open it up to questions from the audience.

I'm going to ask our moderator to see if there's any questions.

[Operator Instructions] Today's first question comes from Dana Flanders with Guggenheim.

Great. Thank you very much for the questions and hosting this insightful panel and discussion. I have 3 questions, if that's okay, that I'll ask all upfront. My first one, and this is going back to, I think, a comment made, I'd love to ask the panel. Can you just elaborate a little bit on how you envision kind of observing and managing these patients on extended duration therapies as they get introduced and maybe tie that into kind of the level of response rate you would need to see out 6 months to kind of get you comfortable there. My second question and tying back to a comment made on payers pushing some therapy choices off-label. One of the topics not discussed was biosimilars. How are you thinking about the adoption of biosimilars long term that potentially alters the value proposition in your eyes? Or does the extended durability kind of offset that? And then my final question for EyePoint, can you just talk about your ability to fine-tune Durasert out to 12 months? And if that's a thought of yours in the development program and why not go out to 12 months instead of 6?

Dana, thanks for the questions. It's great to talk to you again, and thanks for listening. Elias, I think why don't you take the first one? That was, how do you get comfortable with following these patients with either EYP-1901, let's suppose it is a reliable 6-month implant or any of these new drugs?

Yes, it's a great question. I think I raised the question before. And the bottom line is I don't have an absolute answer, but the way I would approach this is, the day this gets approved, you start using the drug. And then you follow the patients more closely than you would if you're saying this is a 6-month drug. So, for instance, with this therapy, I might see the patient back 6 weeks later. If they're looking good, see them back another 6 weeks later, do this for the first 8 or 10 patients and get a sense of what goes out. Of course, it's going to be tempered by clinical trial data, and we don't have that clinical trial data. And that's going to be important, too. So, you look at the Phase III clinical trial and you look at what was -- what the study design was, how often were those patients observed and you get an idea as to what's going on with central retinal thickness on the OCT and visual acuity. And if you see -- you asked for percentage, Dana. So, if you see 2/3 of patients going out to 6 months, and you're not going to worry about them, well, that's great. Then you have to figure out, well, the 1/3, why are they requiring additional therapy or changes in their regimen. And we'll have to learn about that. I have to say, though, a priority that it's difficult to learn that we have been doing anti-VEGF since 2004, 2005, and we still do not have a very good understanding of those patients who need 1, 2 or 3 injections, those who need 12 injections in the first year. We can't -- it's very hard to define. And so, it's going to be a learning process, and it's going to rely on clinical trial data and our experience as clinicians.

And I'm going to add to that, you mentioned why not a 12-month implant, and this goes -- kind of ties into this other part of the question. One of the reasons I was so interested in this technology is I was one of the first in the world to use this technology back for CMV retinitis, the Vitrasert implant. And one of the things about Vitrasert, which I found to be extraordinarily helpful in patient care, was an 8-month implant that release ganciclovir for CMV retinitis. But none of them failed before 6 months. They were so reliable that they would absolutely ask for 6 months. So, you could put one in and reliably say, after we had the type of clinical experience that Elias talked about, this implant won't fail before 6 months. So, at 6 months, I'd start seeing them back. And if they fail, they put a new one in. If they got out to 8 or 9, I just automatically put a new one in. So, if we can get that same reliability, it's based on the same technology, the Durasert technology, out of these implants where we can tell clinicians this will not fail by 5 months or 6 months, just go ahead and reinject them at 5 or 6 months. That's what we hope for. But even if we don't achieve that, I think the potential once we get clinical experience is still very high. Bob, why don't you take the question about biosimilars? I know you've thought a lot about this and get asked a lot about it.

Well, I really don't think biosimilars are going to have as much of the overall impact in our field as it does in many other fields because we've had a pseudo biosimilar for 15 years, that is Avastin, something that dramatically lowered the price point and has been -- has had a major effect, and it's getting more noticeable just as every year goes probably with this step therapy. But they will change the amount of the branded drugs being sold. If they come in at like an 80% price point, I think the overall of -- like they do in some other oncology areas and the things. I think the overall effect on the market [indiscernible] like this one isn't going to be that different because we've already dealt with the decreased price of Avastin. And yes, it will be different to the branded drugs if they lose market share. But I don't see it really having a major impact on the need for new longer-acting technologies such as this implant. And I don't think it's going to affect the price point or something like this significantly. That's my take on it.

Charlie, do you want to add anything?

I agree. I don't see it playing a major role. I don't think it being a value-add to any of my patients. What I want to have a value-add be are the next-generation medications. I want to move forward away from Lucentis and Eylea toward the new products that are coming.

Well, and the hope is not only decreased burden on patients and society, but better visual acuity outcomes. And if we can achieve -- if we or any of these companies can achieve better visual acuity outcomes then that becomes the treatment of choice because ultimately, it's all about that. And Nancy, if you don't mind, I'll take a stab at the third question, which is how can we alter it and why not 12 months? So, it turns out, there's a lot of different things we can do to alter the delivery of Durasert, including simple things like needle size, length of the implant and actually even number of implants. We can put multiple implants into an eye through a single injection if we choose to. There's also different ways that our scientists can prepare the implants that will alter the release rate. So, what we're looking for, I've mentioned this already, we want reliability. We want the implant to last definitively around that 5- to 6-month mark. The second thing, again, about 1 year, and I'm going to ask my colleagues about this is, which would they prefer. But there -- we are still not sure, no one's really sure with the TKI working at the receptor level, that's 0-order kinetics, what is the actual dose in the eye you need to be effective? And so, that will obviously alter the things like release rate and dose and exposure to the tissue. So, Elias, if you had your choice between a reliable 6-month and a reliable 1-year implant, what would you choose?

Six months, no question. I mean, I think it sort of gets back [indiscernible] is if you do it for a year, the patients won't show up, you have to have assemblance of regularity and having patients come back. It's that you have an implant for a year, you're probably not going to see them for 6 or 8 months. If you have a 6-month implant, it sort of instills the idea that they still need to be around and observed.

And check if they are alive. Charlie, how about you?

Yes. Consistent medication that lasts for 6 months is light years different than what we're doing currently. And to think beyond that, maybe eventually, we'll get to the point where we would like a 1-year interval. But at this point, 6 months looks like a great target for me.

How about you, Bob?

I agree completely. I would rather start with the 6-month implant and get comfortable with it. And if it really does what we hope it does, and it can be extended to 1 year then I would want a 1-year implant, but not initially. I think it makes sense to get comfortable with it and make sure it works as well as you like it. But I'm not -- wouldn't be opposed to 1-year implant down the road. But if I had a 1-year and a 6-year, and I can fit in with either one, I'd probably put in a 6-month the first time and see how it works. There's also the risk of side effects and things that are, I think, minimal in this condition. But I think I would get comfortable with 6 months first before I go to 1 year, even though we have both of them available on the shelf today.

Yes. And I may be wrong about this. I'm just think the reliability of a shorter-acting implant is going to be better at the beginning. We're going to be able to get that window of when it dies, when it runs out, much tighter. And there is another analogy here. I think we mentioned the ILUVIEN implant and none of you have extensive experience with it, and you can ask the question, why, why don't we put more ILUVIENs in it? I think the answer is Paul Ashton, who designed that implant is a really, really smart guy, and he said, "I could build a steroid implant that will last 3 years. The problem is I don't think retina specialists wanted a 3-year implant." We wanted a 6-month or a 1-year implant, but that's what we got. So that -- I think it's -- you may get a variety of opinions, Dana, when you ask to the retina specialist, but I think that for now, reliability is more important than duration of action, but 6 months seems to be the sweet spot. Any other questions?

Jay, one thing I would add to what Elias has said before just because of the question specifically is, I do think home monitoring will hopefully become a reality over time. We're not there, as Elias said, we only have 1 approved agent, which is actually for before diagnosis of wet AMD. It's for screening for drying and be conversion to wet, but home OCT is coming. And I think that the opportunities there are tremendous, especially for these durable agents. We're not close, I would say, but that is a bright future. And the reason I think it's worth bringing up is a lot of people on the call, help direct funds for development. And I would encourage you to continue to look at ways to push to wheel forward for home imaging.

Yes. So, we've been working on this for a long time, too. I know a lot about it. I think the problem is not the technology. The technology is absolutely doable. It's the payers, is that you have to show the payers that the technology is actually going to save them money, not just save vision, unfortunately. And that's a really high bar. So, I agree with you. It's going to be there eventually. I'm just not sure if it will be part of my practice, I'll probably be sitting on a beach somewhere by the time it's really being used. Okay, next question.

Our next question today comes from Jennifer Kim at Cantor.

Can everybody hear me?

Yes.

Okay. Great. First of all, thanks for the presentation is super helpful and to the doctors. I found a lot of your color helpful. I have 2 questions. One quick one, and this is for the doctors. You mentioned 6 months is a game changer, 3 months isn't. What are your thoughts on 5 months? And then what are your thoughts on 4 months? And then my second question is, if a 6-month duration treatment becomes available, has that similar efficacy, tolerability and safety? Can you go through what percent of patients you would recommend to switch to that treatment? And what percent of patients who are new to treatment, you would put on the 6-month treatment? The second part of that is -- and it's related. What do you think the role of gene therapy could play in AMD when you compare that between like what's known about current treatments and maybe the expectations around the potential cost for gene therapy and questions around its actual duration of effect?

Jennifer, those are really good questions. So, starting with the first one, we've all agreed that 3 months isn't a game changer. Bob, is 4 months?

It probably depends on what the market is like when this is approved. I mean what else is out there. Today, it would be, I think, but maybe not in 3 years. I mean there may be other things that have extended it to 3 years.

Charlie?

Yes. I don't want to overstate what we said before. Maybe I think you could have a reliable 3-month drug today, I think that would be a game changer. In my practice, probably 20% to 25% of patients are getting every 4-week shots. You tell that a huge percentage of patients that we can go 3 months, they're delighted. That's fantastic for them. So, I think if you can get consistent 3 months, yes, that's a game changer. But I think 6 years is light years away -- 6 months, excuse me. And so, I just think it's incrementally better the longer you go. Going to 4 months is better than 3 months, going to 5 months is better than 4 months, et cetera.

But I think the point you made, and we've all touched on it is the reliability. is that if you've got a variable response then we don't know what to do with that. So, if you've got a implant that is a 6-month implant, the 20% of the people it fails at 2 months. We don't know where those 20% are. We got to start watching those patients every 2 months. And then we're going to say, well, why did we put that in? So, I think from an analyst perspective, it's not just duration of action, but it's reliability. How many of the patients can go 3, 4, 5 months without the implant failing? And those numbers have to be high for it to be effective. Elias, do you agree?

Yes. And one point that I want to make is it's a great question because if you go 6 months, that means 2 visits that year. If you're going 4 months, it's 3. And so, the difference there to me is not monumental. It's one extra visit, essentially. And so, the point is well taken, and it really has to do with variability. If you have a 4-month drug and there's less variability in what you're seeing on examination and on visual acuity, it may trump a 6-month drug where there's more variability.

Well, but -- I just want to point out, too, this is an $8 billion market that we're talking about. And so, if you've got one 4-month drug and one 6-month drug, I think both are going to do very well if they're safe and effective. So, the last question, I'm going to jump to the last question, which was gene therapy. And Elias, you started a gene therapy company that just had a nice exit, tell us about gene therapy for wet AMD.

Well, gene therapy is great. And actually, the focus was gene therapy for dry AMD, where there is no treatment. But gene therapy for wet AMD is great. The question is how are you going to deliver it. Is it going to be subretinal surgery? Or is it going to be intravitreal injection? I think that those are really the things that you have to think about. And one thing about surgery for macular diseases is that it will be a huge burden if we have to go to the operating room to either put a delivery system into the eye or to do gene therapy, particularly in the COVID era. Getting patients into the operating room to put an implant device in that you're not doing in the office setting is going to be difficult. Doing a gene therapy that subretinal is going to be difficult. You also have to think about the immune status of the patients who are getting gene therapy. We've heard about inflammation. These patients required corticosteroids. Do you want an 8-year-old on corticosteroids with this coronavirus around? The answer is no. So, these are the things to think about. That being said, it's -- there's an intravitreal injection that can deliver something that inhibits VEGF, which is being developed by REGENXBIO, as a subretinal injection or [indiscernible] intravitreal injection. It's interesting. Again, my concern is chronic suppression of VEGF a good thing or a bad thing. In the short-term, for wet AMD, it's a good thing. But for a lifetime, and on their slide, they wrote lifetime. A lifetime of anti-VEGF in the eye, I'm not sure that's a good thing. And so, I like the idea of the treatments that are 6 months, that kind of thing because you can change that, you can swap it out, you take it out and then if they're having some untoward effect that you don't understand or whatever, you can always switch to another therapy. But once you have a gene therapy there, it's there. That's what we think. And it's sort of very suggestive that yet long-term efficacy, but you have safety issues that may...

And so, Charlie, part of the question was about how the payers are going to respond. And so, this gets into the reliability thing. If you can say 100% of patients you treat are never going to need another injection, that's great. But what if it isn't? And how will that be, the retinal community where we do gene therapy for 80% or 60% never need another one. And how do you manage those patients since, a, priority, you don't know which one is going to be the one that does need another injection. What are your thoughts?

Yes. Gene therapy has another [indiscernible]. I think before I get to gene therapy, I'd say, even if, let's say, the EYP-1901 does not last 6 months and everybody said the proportion needed at 3 months or something. I don't think that, that's necessarily a terrible thing. Like we know from our bolus injections that the interval of which patients need retreatment is fairly consistent; once you find their dry interval where they begin the leap. We have good data. It's why treatment extend works. It's why you can go so much longer than monthly for so many patients and maintain dry retina. So, as long as it's consistent within a given patient over time, it won't bother me if some patients are less than 6 months as long as the majority are 6 months or longer. But then moving to gene therapy. I am truly fascinated about the concept of gene therapy. I'm heavily involved in those clinically trials -- in those clinical trials. I think it's really promising. I think we still have a lot to learn. We've learned a lot from both of the Phase I trials from the subretinal surgery trial with the RGX program and from the intravitreal injection program of the ADVM program. And we're still learning a lot though the additional trials that are ongoing now. So, I don't know exactly how those are going to be used commercially. I hope that we can get the inflammatory issues under controlled with ADVM-022, and I hope we can get away from surgery with RGX with suprachoroidal. But we are still -- it's still a long way to go.

Bob, you've done subretinal surgery in the Phase I trial. Any comments about that specifically or gene therapy for wet AMD, in general.

I sort of echo what I've heard from both Elias and Charlie. I mean, I think it is very promising. I do have some concerns about chronic VEGF suppression, where there were 3 trials where the monthly anti-VEGF versus PRN seem to show increased geographic atrophy. And yet, there are questions about how we measure it and not all studies have shown the same thing, but it's just an example of how really more of a drug in a more chronic fashion monthly injections for a couple of years may have had an increased effect on the side effect that we can't treat that well. So, that potential is there. There are also potentials from pigment changes we've seen with the gene therapy that may have some -- some bad effects in certain areas. And so, they're unknowns that we have to sort out. We're just in the beginning phases of this. But the promise is really great. I've had -- I've done the most RGX patients in the country. And I've had some really amazing successes where I had trouble come -- having them come back in for follow-up during COVID. They feel like they're done. So, it really is a promising thing. The trip to the OR is a hassle for the average person, but people on clinical trials are motivated. And the surgery is not that complex for most of those retinal surgeons. And so -- and we had no real complications from it, but it is a hurdle. And if we could give it intravitreally or suprachoroidally and get a similar effect, I think that would be far preferable. But the suprachoroidal delivery, I worry about the systemic blood flow from where you're putting it in, and may rinse it out and you may have not be able to do that in patients that have antibodies already to the vector, whereas the suprachoroidal -- or the subretinal is immune privileged. And so, I think we will be using subretinal for those patients who have antibodies to the vector. And so, I think there will be a role for the subretinal surgery anyway, at least in that subset, until we figure out everything. But anyway, I'm very encouraged by it. But it comes with a bit of concern that you can't turn it off. And if, for instance, we show that you get higher rates of GA, which haven't been shown after gene therapy, but suppose that happens, it's hard to turn it off once you've started the cells manufacturing anti-VEGF. So that you have to temper your enthusiasm with concerns, and we have to just watch it. That's why these drug-delivery devices, it can go for 6 months or a year, have a lot of appeal early on, in particular, and maybe for good.

Jennifer, I hope we answered all your questions. It's been so long since you asked them, I'm not sure we got to all, but anything else, Chris?

Our next question today comes from Yi Chen with H.C. Wainwright.

My question may be addressed a little bit already, but if you could provide some additional color, that would be helpful. So, when a long-acting wet AMD treatment becomes available, would you only try it on your newly diagnosed patients first? And how long a period -- or how many patients would you need to feel comfortable to start treating all your patients with the long-acting treatment?

Elias, why don't you answer that. I think Jennifer did want some insight from us, also a similar question. Thank you, Yi, about how we're going to adopt these long-acting agents?

Yes. So, again, it gets back to what the clinical trial data show. Look, if the clinical trial data show that this is exceedingly safe and there's no concerns, and there's no potential signals with respect to safety, and we're confident about efficacy, there's no reason not to start this in patients who are treatment naive, meaning that they've never been treated before. If we're a little bit more concerned, we see something there that we're not sure about then we may try some of the patients that we discussed those that need a lot of treatment, monthly treatments, they are coming in frequently, there may be a bias towards that set. But from my perspective, if this comes out and looks safe and looks good, I'll try it in potentially all comers.

And I think if you look at the adoption of Eylea when it first came out, I think most of us used it on patients who were on monthly treatment at the beginning, and then we tried it on newly diagnosed. Patients are doing well on every 3 months treatments. That's pretty acceptable for both of us and so, those are the ones that are probably going to switch last. But again, it's nice to speculate. And if safe and effective, there's no reason why you couldn't do it on everybody eventually. Next question.

I would highlight -- I'm sorry.

No. Go ahead, Bob, please.

I wanted to say I would highlight that I would do the same thing. I would do the opposite. I would start with the most needy patients first because they're the ones that are hankering for a longer duration treatment and then get comfortable with it and then use it on in the naive patients. The same way we did that with [indiscernible].

Well. And again, I think that some of the Phase I trials have done that as well, like the gene therapy trials where they've taken people who need it monthly, and you have a history of needing a monthly. And if you can do something, and all of a sudden they don't need injection for 6 months.

You know it works.

Yes, it works. And the patient knows it works. Next question, please.

Our next question today comes from Yale Jen with Laidlaw & Company.

I really appreciate the insights all the doctors has been offered. I have 3 quick questions, and I'm going to put upfront 2 for the doctor and maybe 1 for the company. The first question is that you guys mentioned variability was a great issue in terms of your adaptation to the patients. In your opinion, what will be the lowest -- highest threshold in terms of variability that will impact on your decision? And the second question is, given this is a long-lasting treatment, what if there is any problem occurred during the 6 months, what would be the remedial cost you might consider? And the last question is for the company, which is that you will report the 6-month data in probably second half of next year. And let's assume the data is robust, what will be the potential next step, whether you wait for 12 months data before you conduct additional studies? Or you will move quicker in terms of the next trials?

Thanks, Yale. So, Charlie, why don't you tackle that first one. It was variability of response. So, that's a tough one because, again, if you don't have the data in front of you about how variable the response is, it's hard to know, but what type of variability would be unacceptable to you in a sustained release?

Yes. I think I'm looking for consistent anatomic benefit, especially in a Phase I trial, I mean looking at visual acuity outcomes is so challenging. It's almost very difficult to interpret vision from a Phase I, but anatomy is very consistent with the way we look at these patients from clinic to clinic. And so, I would want to see that overall the retinal fluid status is maintained in the nontreatment-naive eyes that have been previously treated. If they're dry, I want to see them stay dry. If they have a little bit of fluid, I want to see them either dry out or maintain the same amount of fluid. But I think is most damaging to patients over time is when they do their sort of yo-yo effect, they get thicker and then thinner and thicker and thinner. And we have good data now from multiple trials effectively showing that this fluctuation in central subfield thickness is probably -- this is not one of the strongest factors correlated with decreased vision long term. So, I want to see consistent drying, multiple months of dosing in the Phase I study.

So, Bob, I'm going to ask the question a little different. Let's suppose we've got Phase III results now, and the variability response is something like 80% of the patients stay dry at 6 months, but 20%, the implant fails before 6 months. Is that useful to you?

I think it's still a very useful product. I mean, I think we're so used to the individual variability from patient to patient that -- I mean, we talk about personalized medicine, but that's what we've been doing. Treat and extend works because of how specific a patient's need is. And Charlie has done a lot of work on the treatment extend and it just shows in the HARBOR Study. I mean if you look at the spread of the PRN arm, people needed 1 injection. In 2 years, so, they needed 24. And there was no peak in that distribution that the patients are different in their need for anti-VEGF. And so, I don't expect everyone to completely respond at 6 months. I expect there to be some that do not.

When they changed the ratio, what if it's 50-50? 50% stayed dry at 6...

It's more valuable, the more -- of course, the higher the number.

I guess, give me a ratio when you'd say, you know what, I won't use this. It's just too variable.

I think this is going to be so even as an adjunct. I would -- that even if it were 50-50, I would use it because I think I would still get some additional benefit to the anti-VEGF that I might be requiring 50% of the time. I would still use it because I think it's going to be better. If the only 50% stay dry at 6 months, I bet that, that population still will have fewer anti-VEGF injections than if I didn't use it at all. So, I think there's still going to be a benefit in those who fail over just monthly or whatever PRN anti-VEGF injections. So, I think there's going to be synergy.

And so, the second 2 questions, I think I'll take. The second question was what if there's a problem, what can you do? And I would say these implants are visible the surgeon just like an OZURDEX is visible, it's approximately the same size. So, you could surgically remove it if you needed to. But I think you'd have -- you also have to think about is it the vorolanib that's causing the problems with the medication or is it a mechanical problem from the implant itself? In other words, is there a cataract present because the implant was injected into the lens. That can happen with any injection, and we're really good at removing cataracts. But if there is mechanical problems on the retina then I think the implant could certainly be removed and get a vitrectomy. I think it's highly unlikely because, again, we've seen similar implants put in tens of thousands of patients without that -- those kind of problems. And the last question is a really good one, which is how -- what are we going to do? And I think the answer is going to be, we're going to let the Phase I study inform us. And which case, what I mean by that is, if we're getting -- we're getting really significant percentage of patients lasting 6 months, we may jump right to a IIb/III, and 2 doses and a placebo with enough to be a registration study. And for me, the answer also is durability of response. And so, when we plan those out, just like Genentech planned out the refillable port in their Phase III to be refilled every 6 months, that's also a number we need to know. We need to know how long these last, and we're hopefully going to get enough of that information from the Phase I or maybe a small IIa that we can then plan the additional trials to say, okay, we're pretty sure these things are lasting 6 months or 7 months or 8 months, so we're just going to mandate a reinjection in the trial at that length of time. But this is the fun part. This is what really is exciting and interesting as you get to think about the science, you look at the data and then you go -- use the data to inform what you do next.

Ladies and gentlemen, this concludes today's question-and-answer session. I'd like to turn it back over to Nancy Lurker for any final remarks.

I want to thank everyone for joining us. Especially, I want to thank our panelists, and Dr. Duker for chairing this great discussion. I found it incredibly informative. And I hope all of our attendees did as well. Thank you very much. We look forward to keeping you updated on our progress.

And thank you. This concludes today's conference call. We thank you all for attending today's presentation. You may now disconnect your lines, and have a wonderful day.