Good afternoon, and welcome to the Aura Biosciences virtual KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations, and if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Aura website following the conclusion of the event. I'd now like to turn the call over to Ellie de los Pinos, Chief Executive Officer of Aura Biosciences. Please go ahead, Ellie. Hello, everybody, and good afternoon. I'm excited to introduce this webinar event. We have today a group of esteemed leaders in the field of ocular oncology from around the world, and they have all been actively engaged in the development of our drug, Bel-sar, to bring innovation to their patients. The forum will be moderated by the PhD-trained scientist, Chris Howerton, who is a former sell-side analyst, and we'll have the pleasure to have a Q&A discussion at the very end. So what is our mission at Aura? And I'm excited to introduce the mission for our company because we truly want to bring innovation to cancer patients, and we want to do that by developing precision therapies that not only improve patient outcomes, but most importantly, also preserve the organ function of the organ that's afflicted with cancer. So if we go to the next slide, we'll see what are the key investment highlights. First of all, our platform is unique. We have the opportunity to have a dual mechanism of action, by having a direct cell killing and activating the immune system. We are in late stage clinical development. We're in Phase III for our lead program in primary uveal melanoma, but we're addressing large market opportunities. Today, we'll have the opportunity to see that in ocular oncology is not just one indication, but many, many different cancers that are all treated by our ocular oncologists, that we can transform the treatment paradigm for these patients, and also in urologic oncology. As we've said in the past, we have key clinical milestones coming up this year. They're all across our pipeline, and you will be hearing some of them today on the ocular oncology in particular. So let me introduce how Bel-sar works. Bel-sar is a virus-like drug conjugate, and it has a dual mechanism of action. That's a key differentiation. The first mechanism is a direct cell kill. The virus-like particle binds selectively the membrane of the cancer cell, and it binds the cancer cell membrane through heparan sulfate proteoglycans that are highly sulfated by cancer cells and not in normal cells. Once the infrared light activates the drug, that directly kills the cancer cell by exposing reactive oxygen species. It's a very direct mechanism. It really is genetic mutation agnostic. It doesn't depend on any molecular pathway down the line in the mechanism of the cell and the malignant transformation. It really is just cell surface-based. Secondly, we have the immune activation, both innate and adaptive immunity. It's very important because we kill the cancer cell with a highly pro-immunogenic type of cell death that activates CD4 and CD8 T-cells, and that, as we think about the positioning of our drug and the impact that we can have for patients, could not just treat very effectively the cancer, but could prevent the appearance of metastasis. Finally, as we look at our pipeline, we'll all today be very focused in ocular oncology. As you can see, we have our CoMpass study, our phase III study, but this year we will also be reaching the completion of the phase II study, which is very important because it's the exact same patients, and we'll be able to see all of the endpoints that are... and all the assumptions that we're taking for phase III that are based on this phase II data. Secondly, we have metastasis to the choroid. We'll be talking a lot about what is the field of ocular oncology and the impact that we can have across this large patient population, and we are in the clinic. We will be very quickly starting this study this year and hope to have clinical data before the end of the year. And then, obviously, not today, but there, there's a lot of excitement about our urologic oncology program, and we'll be talking to you later about this program as well. So today, as I said, we have my pleasure and my privilege to introduce some of the top leaders in the world that not only have dedicated their lives to ocular oncology, their lives to the patients affected with ocular cancers, and have been highly involved in the development of Bel-sar since the early days to really transform the standard of care for these patients, which has not happened for over 50 years. So I'm gonna ask them to introduce themselves, take 1 or 2 minutes, and then Chris will lead the Q&A and the panel. Thank you so much. I will- Go ahead, Dr. Shields. Yeah, please introduce yourself. Go ahead. Sure. Hello, my name is Carol Shields. I'm from the Ocular Oncology Service at Wills Eye Hospital in Philadelphia. We run a very large eye cancer center here in Philadelphia, and we take care of hundreds and thousands of patients with uveal melanoma and metastasis and ocular surface squamous tumors. So it's a pleasure to be here, and I cherish my working relationship with Aura. Thank you. Fantastic. Thank you, Dr. Shields. Dr. Sagoo, go ahead. Hello, I'm Mandeep Sagoo, and I work at Moorfields Eye Hospital in London. I also practice in ocular oncology, looking after patients who have intraocular tumors like melanoma, ocular surface tumors. I had the privilege of training with Carol Shields almost 20 years ago in Philadelphia before going back to London, and also working with the Aura team for several years. Thank you. It's a pleasure to be here. Excellent. And, Dr. Demirci is expected to join us. It is a busy clinic day for him, so, hopefully, we'll be able to get him in here. And then, last but not least, of course, Dr. Daniels, please introduce yourself. Thanks, Chris. My name is Anthony Daniels. I'm the therapeutic area head of ocular oncology at Aura. I joined Aura a year ago, spent the 15 years prior taking care of patients with eye cancers, the last 10 of which were at Vanderbilt, where I was the chief of the division of ocular oncology and pathology, and also ran the Ocular Oncology and Drug Discovery Laboratory there. And then, as I mentioned, I joined Aura about a year ago. Awesome. Yeah, here we go. So I think maybe you can set the stage for the discussion today, Anthony, and then we'll get into the panel discussion. So go ahead. Sure. Great, thank you, Chris. So to set the stage for today's event, we want to talk about the entire ocular oncology franchise as sort of a group of diseases that together are a large number of patients, 66,000 patients, among our three first indications. Really, this slide encapsulates why I decided to come and join Aura a year ago. You know, not only do we have the potential to completely change the way and the paradigm for treating the first indication, primary uveal melanoma, but really to revolutionize the way that all the different types of eye cancers are treated. All the patients that I was seeing in clinic that Carol and Mandeep have enumerated, you know, Bel-sar really has the potential to revolutionize the way that all of these are treated. Obviously, our lead indication, uveal melanoma, as I mentioned, as Ellie said, we're in a phase III trial for this, but we'll also talk about our follow-up indications, the first one being metastases to the choroid, with a study starting later this year and with early data readout at year-end. This is a completely different disease, but it's treated by the same physicians as primary melanoma, with the exact same method of treatment. A much larger patient population, 20,000 patients in the U.S. and the EU. Then our third indication, also treated by the same focused call point of ocular oncologists that are already familiar with Bel-sar from our pivotal melanoma CoMpass study. This is potentially an even larger group of patients than the first two indications. So sort of each indication is actually larger than the one preceding it. In total, we're talking about 66,000 patients in the U.S. and E.U. And importantly, all of these have a huge unmet need, and we at Aura believe that Bel-sar can help to fill this need. Of course, looking at our first indication, melanoma, the wonderful thing is that these patients are often... at least the vast majority of them, are often diagnosed with tumors still in the early stage. But a lot of the time, treatment is delayed, sort of squandering that head start of early diagnosis. And the next slide really explains why. Can we go to the next slide? Great. So uveal melanoma is divided into two main parts. There's early local disease and then late disease. Aura is focused on the early disease side, which is by far the largest part of the patient population. Early disease includes a spectrum of indeterminate lesions with risk factors that maybe aren't yet growing, but then includes ones with frank growth documentation of small melanomas. Importantly, we know from the Collaborative Ocular Oncology Study Group that these lesions, regardless of which term we use to describe them, all contain all the genetic mutations indicative of malignant transformation. This is really one large group here of the spectrum of indeterminate lesions to small melanomas that constitute local early disease. Ideally, all of these would be treated up front, but as we're going to discuss, I think over the next hour, with current available therapies, which is largely radiation applied directly to the eye, causes vision loss and a host of other complications. So as a result, many of these tumors are monitored at first for as long as possible, and the necessary treatment might actually be delayed until it's grown enough that you can't withhold radiation any longer, and it can't be avoided. So in contrast to this early disease we've been talking about, late disease includes both local disease with large melanomas, tumors that have already grown very large over time, as well as metastatic disease. And late disease is a much smaller subgroup of patients than early disease. Excellent. Okay, well, thank you so much for that introduction, Anthony. And, not sure. I guess we're ready to go to the panel discussion. I'm not sure what everyone can see right now, but I'll just kinda go for it. There we go. Excellent! Well, there we all are. So first, I think Anthony did a pretty good job, at least in my lay understanding of describing the overview of the disease. But Dr. Shields or Carol, maybe you could help us understand a couple of things that are on the minds of investors out there. One would be: What's the difference between primary uveal melanoma and choroidal melanoma? And then, in addition to that, what's the difference between primary and metastatic disease? You're muted too, by the way. ... Okay, thank you, Chris. I'll answer the first question first. Primary uveal melanoma refers to a malignancy that can occur in the eye in different compartments, including the iris, the ciliary body, and the choroid. So choroidal melanoma is one subset of primary uveal melanoma, but it should be noted that most melanomas that occur in the eye occur in the choroid. That's like 90% of all the melanomas. Only like 6% occur in the ciliary body and 4% in the iris. So when we use the term choroidal melanoma, we're being specific to that one compartment, the main compartment where melanoma arises. Got it. It's less likely for it to arise from other sites. And then to differentiate, primary uveal melanoma means melanoma arising within the eye. Metastatic uveal melanoma means the tumor in the eye has spread to the liver, so it's metastatic to the liver. So there are different ways to treat them, different ways to approach them. Got it. And to contrast, to metastases to the choroid, that would be the other way around, which we'll get to in a few minutes. Exactly. Okay. Wonderful. Excellent, and I'll just note that Dr. Demirci has joined us. Thank you so much, and excellent to see you. We already did introductions for everyone else. If you wouldn't mind, maybe just unmuting yourself and, giving 30 seconds to a minute on your background, please. Yeah. I'm Dr. Demirci, Hakan Demirci. I work at the University of Michigan W.K. Kellogg Eye Center. I do ocular oncology full time here. I was trained under Dr. Shields, and so I treat the tumors in the eye, around the eye, in the orbit, and on conjunctiva. Excellent. Okay, well, as I said, I really appreciate you joining us, and, we'll kind of just continue with our discussion. So thanks so much. Okay, so Dr. Sagoo or Mandeep, if that's okay, we, as Anthony pointed out, Bel-sar is being developed for early stage disease. And as he defined it, you know, those small melanomas or indeterminate lesions. In your experience, what would you say is kind of the relative split between the, that early stage disease versus the late stage disease, the large melanomas and the metastatic disease? Yes. So thank you. So I think there are way more early stage type of tumors than there are late stage. So the ciliary body large tumors, for example, or choroidal large tumors that need either radical surgery or radiotherapy, are... We treat about 300 or so a year at Moorfields. And in terms of the kind of smaller melanomas, and indeterminate lesions, the lesions that we might be watching, they're probably two or threefold the magnitude of the larger ones, so way more cases that we might watch or we might offer early treatment to. If available, right? Yeah, totally. If available. Yeah. Okay. And, you know, actually, Carol, I forgot to clarify, when you kinda were talking about the primary versus metastatic disease, where is the split? Or like, what are the different kind of medical care teams that manage those different cases? Well, the primary uveal melanoma or primary choroidal melanoma would be managed by our team, ocular oncology, in conjunction with radiation oncology. Okay. Because we usually treat with radiation, but hopefully want to treat with Aura. And whereas metastatic disease is generally treated by the medical oncologist, often with systemic chemotherapy or systemic radiotherapy, occasionally, we can treat them focally in the eye. Okay. Different, different directions for treatment. Right. And so, yeah. Okay, so you'd have to hand them off basically to medical- Yeah oncology once it becomes metastasized. Okay. Excellent. All right, and Dr. Demirci, thanks again for joining us, and I guess when you think about primary uveal melanoma, what is the main treatment modality available to those patients? I mean, the main treatment modality is the radiation therapy right now, which could be mostly applied as a plaque radiotherapy, or in some centers could be applied in the proton beam radiotherapy. These are mostly for the small and medium-sized tumors, but if it is really big tumor, then the only available treatment is the removal of the eye, what we call enucleation, basically. Wow! And, just, so that, again, I'm a layperson, so for the plaque radiotherapy, that is like where you put kind of the piece, the radioactive material right onto the eye to focus it into the tumor. Is that- Yeah. - basically, right? Yes, exactly. Like, in the plaque therapy, it's to think about the... You can think about the disk in a shape of a nickel or dime, and then we put these radioactive seeds, like the rice seeds on it, and then we plant, and then when we put the patient under anesthesia, under the surgery, these radioactive plaques are placed on the surface on the top of the eye, where the tumor is, and then they stay on the eye for a certain period of time to deliver the certain amount of radiation, and with the surgery, they are removed after that. Wow! Intense. I guess so when you think about, you know, those types of procedures, how long does it take or how many are you able to achieve in a typical surgical day? I mean, I think it is. It varies from center to center and how efficient the operating rooms and then the staff runs. I think. It may vary from probably 45 minutes to an hour surgery to 2-hour surgery. So you can adjust, you can think about how many hours of OR you have in a day, and then maybe depends- But I hear you're a hard worker, so maybe you could do many, many. Okay, very good. Excellent. And so, Dr. Shields, when we think about the radiotherapy as it is right now, what is it like from the patient's perspective? I mean, I've seen some of the pictures, and it seems rough, but I guess what is it actually like to experience that therapy and maybe some of the sequelae? Yeah. So, nowadays, when we treat a patient with radiotherapy, we might see them on a Monday, and if we're lucky, we can get the radiation ready, designed, and the plaque made by maybe the next week. So, they're waiting for at least a week, 10 days, to get the treatment. And then the treatment takes about 5 days of application. Then we have to go in and do a second surgery to remove the treatment. So it's two surgeries. And the first surgery is usually general anesthesia. Second surgery is usually local anesthesia. And then we watch and monitor the tumor regressing. We usually see the patients back on a every four-month basis. The tumor slowly regresses, but then we deal with all the complications of radiation. Most common complication would be radiation-related retinopathy, where the retina gets very sick and the vision drops, or papillopathy, where the optic nerve gets sick and the vision drops. And that usually takes 1-1.5 years to occur. But then there's other complications. There's glaucoma, and cataract, and dry eye, and even some patients, it burns a little hole in their eye called scleral necrosis, and we have to put a scleral patch graft on. So there are a lot of complications to plaque radiotherapy. It's not without its problems. Uh- It can work in controlling the tumor, but you got to deal with all the problems. Yeah, and I guess we'll get to this in a little bit, but maybe I'll just address it right now. You mentioned that when you add the plaque radiotherapy, you can see the tumor regress. Is that always the case, or, I mean, would there be smaller tumors where maybe you wouldn't expect to see something like that? Yeah. Many years ago, there was a publication out of Israel where they looked at the average tumor regression after plaque radiation, and they found that it shrinks by about 60%. You're left with dead tissue. So if you have a 10-millimeter melanoma that shrinks 60%, you're left with maybe a 4- or 5-millimeter scar, which is okay. But if you have a small tumor, like a 2-millimeter-thick melanoma, and you irradiate that, it might shrink down to 1 millimeter, which is barely perceptible on ultrasonography. So smaller tumors have like a less robust appearance when you see them shrink. We know they're dead because they're not active, but it's a smaller shrinkage. But we always say, "If it remains stable, don't touch it. Leave it be, because it's probably internally all scarred down. Got it. So yeah, I see. So even though there could be an appearance of, you know, something that's there, again, this is a layperson's perspective, there's no actual malignant growth because it's all, like, necrotic scar tissue, basically. Yeah, and the fluid goes away, and the orange pigment goes away. These are factors that tell us if something's active. I see. As long as it remains stable, we're good with that. Okay, excellent. Got it. So then I guess we've kind of... Well, I'll ask, I guess. So, Mandeep, when you think about the current therapies, what would be like the challenges of the current therapies in terms of kind of your ability to see the number of patients you want to see and maybe contrast that to what a clinic day might be like? Yeah. So in a clinic day, you can get through quite a lot of patients. It's quite an efficient system. We, as ocular oncologists, have the advantage that we can look in the eye and see the tumors, and we can do direct imaging using ocular techniques, so photographing the eye, scanning the eye directly. So we're able to, at the end of one clinic visit, really have a diagnosis without taking a biopsy and have a treatment plan in the vast majority of our patients. If we're doing surgery, as has already been mentioned, that's a longer process. So that takes, you know, an hour or more and requires anesthesia. And if we're doing radiotherapy with the plaque, then two sets of surgeries. In the U.K., the patients, once they have the radioactive plaque in place, aren't allowed to go home. They have to stay in the hospital. ... So we have to keep them in the hospital. So, you know, doing a surgical treatment is very, very different. But if the question is more towards what are the considerations for treatment, then the complications that Dr. Shields mentioned, you have to weigh those up against the benefits of treatment. You look at the metastatic potential of the tumor, can you retain the eye? Can you retain useful vision? So all of these factors come into play when you're talking to the patient and telling them the diagnosis and the possible treatment plan. So that might vary between, you know, a 90-year-old patient with a very small melanoma that's just slowly growing but has poor vision in the other eye. You might then hold off from doing radiotherapy. You might watch that a little bit before offering treatment, whereas the patient who has, you know, who is young, who has a fast-growing tumor, you might wish to treat early. So, those are the kind of considerations that go both into the clinic and then into deciding on surgery. Right. No, I got you. And so then I guess, basically, again, I'll just simplify it for the simple PhD here, which would be that either it's you decide to do nothing and say, "Let's just see how it goes, because we don't wanna mess anything up," versus, "Let's do the radiotherapy, even though there could be these sequelae, I'm worried about it growing, I'm worried about it metastasizing." Something like that. Yeah, exactly. Okay. Excellent. So then, I guess, Dr. Demirci, I think this would be an excellent time to maybe interject your perspective on this, because you have actually participated in one of Aura's trials to date, and so tell us what it's like to actually apply Bel-sar. What is that like from an experiential perspective? I think the, the application involves right now injection into the eye. As we know, the eye has several layers inside it, and then the one of them is the outer layer, what we call sclera, the white layer, and under it there is a vascular layer, or not fully vascular, but there is a layer, what we call the uvea or the choroid. And then in the current trial or in the current technique, that what we do, we do an injection into this, between these two layers. It is, there is a special injector, is designed and approved for these purposes. So it's an office procedure. You numb the patient, and then you perform the injection into this space. The advantage is it delivers the drug or what you inject directly to the area that you want to deliver. It is, I think it is start to be used right now, maybe widely to a certain acceptance, accepted in the retinal doctors, the doctors who are using different diseases also, they are using this kind of injections in for other eye problems. So, the injection is easily learnable and applicable process actually. And then it also involves the laser process. The laser is a currently, I think almost all of the retina doctors or the ocular oncologists use these kind of lasers in their practice. So that involves an injection and then the laser, which is relatively common procedure in these days, basically. I mean, it sounds like science fiction to me, frankly. Like, you inject into the eye and then shoot it with lasers, right? Like, that's pretty cool. You guys get to just do that. That's pretty neat. So but like, I mean, if I heard you right, all of this is done in the clinic or in the office setting. So in contrast to what we just discussed with any of the radiotherapy, this is something that you could do in your own kind of outpatient setting? That's correct. Like, this can be... All these procedures, injections or lasers, are in-office procedures, in outpatient procedures. Nothing, I think, extra for what's current practice in most of the diseases right now. Excellent. Okay, well, great. So, Dr. Daniels, I think this is a great time to, to maybe hear what happened in the phase two, I guess. What's the high level, kind of, 12-month data that we have so far? Yeah, sure. So, we're gonna present the final data in a couple of months from now, but what we presented previously is, you know, up to having 90% of the patients completed the full study. So I'll focus on the data that's already out there. So this was a study of suprachoroidal injection of Bel-sar with laser activation, and it was a dose escalation and expansion. So practically speaking, what that means is that we have 10 patients who were in the escalation phase, that got 1 or 2 injections of a much lower dose, and then the expansion phase, that we have 10 patients who got 3 cycles of 3 treatments, so a total of 9 injections of the higher dose, the full dose, the 80 micrograms. So we can kind of look at the data as the early low dose, which was very subtherapeutic and gives us an idea of what natural history is like or what the sham might look like in the ongoing phase III study, and compare that to what the actual therapeutic regimen of the 3 cycles of 80 micrograms, which is the actual dose that we're giving in the phase III study. And what we showed in terms of tumor control is that 80% of tumors that were treated with Bel-sar- ...had complete control, which is the equivalent of a local cure, as Carol was saying. And then in the very low dose of the sham like a natural history arm, there were only 20% of patients that failed to progress during the one year. So we're talking 80% versus 20%, a very big difference between those two. But importantly, of the ones that responded, they had complete cessation of growth, as Carol was mentioning. This wasn't just that they were slowing down and gradually finding their way towards needing treatment in the future. They went, I mean, the growth parameter went completely flat, for all the responders. Only one single patient in the entire study had vision loss, which was actually related to the tumor, not the treatment. And on average, the average patient lost 1 letter of vision. And you compare this to what we know is the course with radiotherapy from the Collaborative Ocular Melanoma Study and other large studies of plaque radiotherapy, where the average patient is losing 30 letters. So, you're talking about 30 letters with radiotherapy versus 1 letter with Bel-sar, basically maintaining your vision. In terms of safety, adverse events or related to treatment, they were few and mild, only grade 1 adverse events, predominantly anterior chamber inflammation that always resolved with either by itself or just with a little bit of topical steroid eye drop for a week or two. And that was really all that we saw. No systemic side effects at all. Excellent. Okay, well, very good. And, I guess, Dr. Shields, you had the chance to present these data at AAO last year. Anything outside of maybe what Anthony just described that stood out to you or what maybe excited you about the data profile? If I might put, say that. Yeah. I think Anthony did a great job in summarizing the data. So what I really focus on is tumor control and visual outcome. And with a tumor control rate of 80%, you might say, "Well, maybe we want 90% or 95%," but we have to be realistic. We're using this novel treatment to treat small melanoma, and 80% of the growing small melanomas will have their growth halted with the Bel-sar, and those 80% don't have to go on to radiotherapy. So the remnant, the 20% that don't have complete control, we might consider a repeat application of Bel-sar or go on to radiotherapy. But once we make that step on to to radiotherapy, we then know that we're gonna lose vision. Mm. But when we go with Bel-sar, we saw in that phase two trial, 90% of patients kept their vision. I mean, that's, that's outstanding, because right now, when we counsel a patient, I'm, I'm sure Dr. Hakan and Dr. Mandeep do the same, we tell them, "We can treat you with radiation, but in the long run, you're gonna have reduced vision in this eye. The radiation won't affect your other eye, but it will affect the vision in this eye." And it's a sad day for patients because they know, okay, they have a melanoma, which is a cancer, and they're gonna lose vision and likely go blind. We don't want that. No. We would rather have an effective treatment that avoids vision loss, and that's what we saw in the phase 2 trial, which is... That's what got me excited about the phase 2 trial. Vision preserved. Okay, well said. And, Dr. Demirci, I guess, any additional thoughts? It's okay if you don't, but, any additional thoughts about the phase two data that you'd like to share or discuss? No, as, as Dr. Shields mentioned, I mean, the 80% success rate is a very—actually, is a very exciting for as a novel treatment, as a first step treatment in the phase 2 trial, considering the alternatives. So I think this is—that's—I completely agree, this is a very exciting, like 80%, as, as mentioned, like the... You want to see the 100% for everything, but in some of these cancer treatments, 80% is a very, very good success, actually. Right. And the inverse, basically, of the other arm of the study. Yeah. Okay. And, Anthony, I guess we're gonna move on to, like, trying to translate this to the phase three moving forward. So I guess let's talk about the endpoint that you have in terms of stopping growth versus tumor shrinkage or other kind of response metrics that you wanna see. So help us understand why that was chosen and maybe what's important about that. You're muted. Thank you. So our main endpoints relate to, obviously, efficacy against treating the tumor and also vision. And as Carol mentioned, for these small tumors, really what you need to see is that they stop growing. If they're actively growing, then you treat them, and they completely stop growing. With the large tumors, there's a lot more of a mass of the malignant cells, and so you may see the shrinkage that Carol described from the Israeli data. With the small tumors, where there's the underlying benign nevus architecture there, what you see is death of the malignant cells, and the tumor that was actively growing completely stops growing. And so you have a complete stability as it's replaced with the scar tissue and the necrosis. And so the primary endpoint is exactly that, that the tumors, when you treat them, stop growing, kind of dead in the tracks, as it were. So that's where the avoidance of progression is the primary endpoint. And then, of course, vision is related to the first key secondary endpoint, the preservation of vision. Got it. So then, I'll just ask you this now. So when we think about the phase III study, there was an enrichment strategy. So talk to us exactly what that means and what the rationale was for incorporating that. Yeah, you know, with rare diseases in general, the guidance is to use what's called an enrichment strategy, which means a way to include those tumors in the study where you can most efficiently be able to evaluate whether a treatment is effective or not. So, in this case, we're specifically enrolling those tumors that have already reached the active growing, you know, more rapidly growing phase, so that when you treat with Bel-sar, it'll be more obvious and apparent early on already when you treat with Bel-sar, that it is stopping growth, and that those that are randomized to the sham arm will have the ability to progress. So, you know, for the sake of the study, the enrichment strategy is those that are in the documented growth phase, so that you can, in a shorter time horizon, demonstrate that they would progress with sham, and that obviously, Bel-sar is, is, hopefully gonna stop that growth completely. Okay, I got it. And I guess let's just ask the question to, to make sure that we're all on the same page here. So, maybe I'll start with you, Mandeep. Given that this is the endpoint for the phase III study, and it was only on growing tumors, does that limit your utilization in the clinic, in your mind, or would you use it on any of these kind of early-stage disease patients, or, or those that are eligible, I guess, let's say? So, for the purposes of the study, to show that these are tumors that need treatment, that you have a subset of patients that there is growth demonstrated. But in real life, in the clinic, there will be patients with small, very suspicious lesions that look like small melanomas, where you wouldn't wait for growth. And so for those cases, you would do upfront treatment, you wouldn't wait for growth. So, the design of the study is such, with the enrichment and so on, to make it give a clean set of results and clean data. But in... The reality will be that these very suspicious lesions, the ones that have clinical features, on imaging, for example, that are indicative of small melanomas, I think we would just treat them upfront without waiting for growth. Okay. Well said. Very clear. And so then I guess let's just do a quick rapid fire here to finalize the uveal melanoma, melanoma, I swear I can talk, part of this discussion. So I'll just go to each KOL in turn. If the phase III replicated similar results in the phase II, would you use this in your practice? And if you could, estimate how many of those kind of currently wait-and-watch patients you might apply this to. So, Dr. Demirci, why don't we start with you? I mean, as you said, if the results are replicated, that what we observed in, phase II, if phase III replicates, I think definitely I will use it. And then I think the indication will be not only for the growing ones, also, as Mandeep little bit ago mentioned, that the ones that who are suspicious ones also will definitely be the candidate for this type of a treatment, actually. Okay. Excellent. And Dr. Shields, how about you? What would be your response to the same questions? I mean, so each year in our practice, we see 400-500 patients with uveal melanoma, and I would estimate that about a third are small, so that's between, you know, about 200-250, and we would probably upfront treat them with Bel-sar. And if they showed tumor control, we'd be happy. If they needed further treatment, we would probably reapply Bel-sar, and we would only go to radiotherapy only if we needed it after maybe a second failure, because we know the damage that radiotherapy does to the eye. But in addition, just as Dr. Mandeep and Dr. Hakan said, we would love to use this medication for all those high-risk lesions. We call them indeterminate lesions, and we would probably apply risk factors. There's been 6 designated risk factors that help to predict if an indeterminate lesion is going to grow into a melanoma, but maybe treat them before they grow. Hey, we may create a world where the risk for metastasis from melanoma drops significantly just by applying this medication. And I think all of us know the risk factors and all of us apply them. And wouldn't it be a great world if we could prevent obvious melanoma from developing? Yeah. No, I completely agree. And so if my math was right, you would say, around 50%-60% of your patients, you would expect to use this in, something like that. Yeah. At least 50% of the patients we see. Every week, I discharge patients with indeterminate lesions, feeling a little bit bad- Yeah ... because I can't justify treatment. Right. But now- You're like- I'm not gonna feel bad. I totally understand it. You're like: Well, there's something that's funky there, and I wish I could do something about it, but this is too extreme, so let's just keep an eye on it. Yeah, I totally get it. And that was... So you might see 400, 500 patients with uveal melanoma a year, and around 250 are in this range that we're talking about, if I- 250 or so—I would say 200-250 are small that we would offer treatment with Bel-sar, but then there's probably another 300-400 that have indeterminate lesions. They come in- Ah. 3 or 4 a week come in with a- I see. Fluid or a little orange pigment, and we don't know what that means. Got it. Okay, so there's-- I see. So, I was missing that point. Thank you for clarifying that. And then just in the interest of time, Dr. Sagoo, like, would you-- I guess, you know, do you agree? Would you use the treatment, and do you basically agree with those relative splits in patients that, that Dr. Shields described? So absolutely. So, we treat about 300 a year, uveal melanomas, about a third of small melanomas that need the radiotherapy. But we also run a nevus clinic. In our hospital, we have a system where we follow the indeterminate and suspicious lesions, and there are more than 1,000 patients in that clinic who come every year or every six months for a checkup, and out of those, there'll be some that are growing. So yes, we would then add probably several hundred more patients that we could treat if we could preserve the vision and reduce the risk of the lesion becoming a melanoma. And just to put it into historical context, plaque radiotherapy was invented almost 100 years ago in my hospital, 1929. We have been waiting almost 100 years for a new paradigm shift in how to treat melanoma. So we, you know, are really excited by this. We potentially have something totally new, a new mechanism, dual mechanism treatment. So, you know, we're very interested in studying it further and carrying it on further. Okay. All right. Well, very good. So, so basically, if I am able to summarize this appropriately, you know, the Bel-sar offers the advantages of being convenient for—from a physician's perspective, to be able to kind of apply it in the clinic setting. We're very excited about the safety profile to date, particularly in comparison to radiotherapy and just the sequelae of disease. And there's a lot of those patients right now that really have nothing that are offered to them, and this is kind of the hope of the next wave of therapies. Okay. Great. I'm seeing some nods, so I think I'm on the right track. And so let's try and talk about some of these other indications briefly, if we can. Unfortunately, we did take a lot of time there. But let's start with you, Dr. Demirci. So, if we talk about metastases to the choroid, so again, where Dr. Shields described where you might have lung or breast cancer that metastasizes to the eye, is this actually something that you treat and see? Is this a problem for you, your patients clinically? Yeah, definitely. I mean, if you look at some studies, some studies shows that the metastasis into the eye is the most common cancer in the eye, actually. So it's a common, it's a common problem. And then, the patients who have systemic cancers, they can develop metastasis inside the eye, and then affecting the vision and affecting their quality of life. This become an important problem from the tumor control, and additionally also, from the patient point, besides the tumor control, the quality of the life issue also becomes an important issue, important problem for the patient. Yeah. Well, and so then, Dr. Shields, maybe you could describe to us, you know, like, what would it mean to be able to kind of effectively treat choroidal metastases in the current kind of cancer patients you might see? Yes. So the most common cancers to metastasize to the eye include breast cancer and lung cancer. And usually, they're small, and they're limited in size, and patients come in often with metastatic disease elsewhere, and they just, they don't wanna lose their vision. They wanna get treatment. They want their eye to be saved. And so currently, the way we treat them is either with radiotherapy, either local plaque radiotherapy or external beam radiotherapy. And sometimes we'll use a certain laser-enhanced treatment called photodynamic therapy, if they're small enough. Okay. The beauty of the latter therapy is we can do it the same day we see them, and it's outpatient, so we like that. And that's what Bel-sar is. It's outpatient, and the patients like that because most of their other cancer care is going to be in an infusion center, in the hospital or even overnight in the hospital. So it's really great to be able to say to a patient, "Well, we have this one treatment. If the tumor is small enough, we might be able to do it outpatient for you. Okay. And, I had the privilege of kinda discussing with all of you yesterday, but, Mandeep, when you think about the brachytherapy, I guess, what does that course of treatment look like for your typical patient in this setting? Like, how many treatments and how long? That kind of thing. Yeah. So unlike melanomas or indeterminate melanocytic tumors, these are fast-growing. Mm-hmm. And so, if you do the external beam radiotherapy in our center, it is over 20 fractions, so it takes a month to do the treatment. And so the patients already are on systemic treatment, chemotherapy or immunotherapy for their primary cancer, and then they have to go into the hospital every day to get radiotherapy. But if you could treat locally a small metastasis, which is going to grow rapidly, they can change in a week or two. If you could treat them on the same day and preserve their vision, then that would be the ideal treatment for them. And the patients, it would make a big difference to them, just having an outpatient treatment rather than a month's worth of visits to the hospital. Certainly. Yeah, absolutely. I mean, London's a lovely place to visit, but maybe not for that, right? Yes. Uh- I think that when metastasis used to happen into the eye, it was often a kind of harbinger of doom, that you got metastasis in the eye, and that was going to signal that, you know, the patient was going to die within the next six months or so. But now, with better systemic treatment, the patients are living longer, and Carol's published on this. So patients are living longer. And so, being able to treat any small deposit that gets into the eye quickly will preserve their vision for the rest of their lives. Absolutely. Yeah, and again, maybe just in the interest of time, 'cause I wanna make sure we get to the last indication. Anthony, what is the plans, I guess, in this indication? What can you describe to us so far? You're on mute. One of these times, I'll remember to unmute myself. I got you, buddy. You know, we're planning to start a phase 2 multicenter study this year, and we expect to have early data by the end of this year. The approach that we're taking is to treat with potentially higher doses and therefore be able to reduce the number of treatments. We're looking particularly looking at 1 cycle of treatment, so it would just be 3 treatments, again, all applied in the clinic, but using the exact same mechanism of injection, exact same laser application that we're doing with melanomas. And all the sites that are gonna be in the metastasis study are also in the melanoma study, so they'll all be already well, well-versed in that. And importantly, it'll allow us to treat larger tumors, you know, with in the study, so that if you think about it, and Carol has more experience and data on this than I think anybody in the world, the tumor inclusion criteria really will include the vast majority, vast, vast majority of all the sizes of metastases that occur with we're starting with breast and lung, and then we'll spread on to other tumors after that. Okay. Very good. And then, I guess, I do wanna touch on this point because I think it's important. So, when we think about the size of the tumors that you mentioned for photodynamic therapy, Dr. Shields, what size of tumors can that typically treat? And I guess, since you may know the data, I guess, what is the typical size of metastases we might see? Yeah. So for photodynamic therapy, we usually limit the thickness, the tumor thickness, to about 3-4 millimeters in thickness. And in general, with 1 or 2 sessions of that therapy, we can get the tumor under control. Often, it leaves a little scar where you do the treatment. So the average metastatic tumor to the eye is about 3 millimeters in thickness, and that would be included in the inclusion criteria for the trial, because I think it goes up to 3.5 millimeters in thickness. So that would allow most of the breast metastatic tumors, and most of the lung metastatic tumors will make the inclusion criteria. Got it. So, the average size is kind of like 3 to 4, something like that. Yeah. I don't know exactly what they are. So, Bel-sar would be more applicable for those larger ones, but the smaller ones could use photodynamic therapy, I guess. Is there any reason you would use that over Bel-sar? We would wanna use Bel-sar over PDT, 'cause PDT is very nonspecific, and- Ah ... Bel-sar, with its attraction to the heparan sulfate on the cancer cells, would make it more applicable and more focused on the metastatic tumor. Got it. I would anticipate that we're gonna see a more robust tumor regression, because when you get a metastasis to the eye, it's probably 90% malignant cells, whereas when you have a small melanoma in the eye, it might be 20% malignant cells or- Yeah ... 30% malignant cells. A lot of the cells might be nevus cells. I see. That's why it might be a less robust reaction to the treatment for melanoma as opposed to metastatic tumors. That makes sense to me. Okay. Yeah. And then, Dr. Demirci, I guess I'll just give you the key question here. If this is similar results or as Dr. Shields maybe is hoping, better results in the metastases, would you apply it in your practice? Definitely. I mean, it will be much more practical from the patient point to, from the PDT, because they have to, like, don't go to the sun for 48 hours, and those kind of restrictions. The Bel-sar is not going to have those kind of restrictions. So definitely it will be. It will be applied. I will use it, definitely. ... Okay. Very good. And then, just trying to figure out what would-- I should ask here, 'cause I want to move to the last-- So let's say... I'll summarize this. So again, metastases to the choroid is where you might have a tumor in another location. It transfects to the choroidal area, and the reason that we treat it is because we like to see. And so, because patients are living so much longer with these other tumors, it's really important to have an effective but vision-sparing treatment in this setting. Something like that. Okay. Again, I'm seeing nods, so great. I'm on the right track again. Very good. All right, so now, maybe I'll just ask you, Mandeep, what is tumors of the ocular surface? Briefly, and I guess, do you see these? Is this a common occurrence? Like, how many of these patients do you think you might see? Yeah. So, the ocular surface is the conjunctiva. It's the tissue, it's a membrane. It's a tissue where we get conjunctivitis and infection, but also you can get tumors in that tissue. So you can get melanomas, you can get squamous-type tumors, you can get lymphomas, so all kinds of tumors. And some of them are cancerous, some are pre-cancerous, changes that you can get before they develop tumors. So, you see quite a wide variety. I think, in our practice, we've seen the number of conjunctival tumors increasing. Some of that is sunlight related, some of it is, related to immunotherapy, immunocompromise, so things like HIV and, drugs that cause immunosuppression. Some of it is viral infections, other viral infections. So we see, an increase in our practice in conjunctival tumors. Okay. Dr. Demirci, I guess, how are these currently treated, if at all? Is there-- Do you have anything to give these patients? I mean, at this point, some of them are treated with surgically, by surgical excision of them- Okay. - which is done in the operating room. And then some of these patients use topical chemotherapies. There are certain drops that they have to use. Yeah. These are the... in some different cases, you might use some radiation and those kind of things, but those are relatively smaller number of patients. Okay, so maybe you could have some surgical intervention. Chemo in the eye, that sounds pretty rough, and, like, maybe some sort of radiation intervention. Okay, well, I think given what we've heard about Bel-sar, let's hear about that. Like, that sounds better. So Dr. Daniels, why don't you bring us home here, and then we'll move on to the Q&A. Where are you at with your planning for this? And if you know anything we can hear about your plans or expectations for this indication or set of indications. And again, you're on mute. I always forget to unmute. So we're doing IND-enabling studies for this right now, but we really think that there's a potential to apply Bel-sar across the full spectrum of these ocular surface tumors. So, in all the ways that the tumors are currently treated under the current paradigm, so both in a neoadjuvant setting, to take large tumors that might require larger disfiguring surgeries and make them amenable to much smaller surgeries, or, potentially, to replace surgery with an ablative therapy, the way that we're replacing radiotherapy or hoping to replace radiotherapy for melanomas and for choroidal metastasis. But also in the adjuvant setting, you know, there's currently a paradigm to give topical mitomycin C, with all of its toxicity and things like that, to any patients who've had surgery previously but then had positive margins or evidence of residual cancer. So, you know, obviously, if you could avoid giving a toxic drop that makes patients miserable and replace it with a Bel-sar treatment applied in the clinic, that would, you know, in essence, make all ocular surface tumors amenable to treatment. So we're very excited about that. It's a large number of patients, and the tumors are right there in front of you, so it's very accessible and easy. Awesome. Well, I won't push you too hard, but I guess, like, we'll look forward to seeing some progress in ocular surface tumors once the IND-enabling stuff... And there was kind of a preclinical presentation recently, right, by one of your collaborators? Yeah. Martine Jager, who's one of the gurus of basic science research and translational research, laboratory research, actually presented two things at the large eye research convention recently, ARVO. She presented one of the award lectures, like, the top award lecture there, and focused a lot on Aura and its utility, but also specifically focused on conjunctival tumors, and preclinically demonstrated excellent efficacy with Bel-sar against different types of ocular surface tumors. Awesome. Okay. Well, very good. So I think, you know, wonderful discussion by everybody. I kind of went through primary uveal melanoma, and I think we have a good handle of that and where we are at the phase 3 program and the choroidal metastases, I think a very exciting opportunity. Certainly, I personally look forward to those data, hopefully by the end of this year. And then, of course, with the ocular surface tumors rounding out the potential franchise as it stands right now, all really good settings for Bel-sar. So, I appreciate everybody's time, and why don't... Kiana, if you're still there, why don't we try and do a few questions if we can? Thank you, Chris. At this time, we will be conducting a question and answer session with our speakers. As a reminder to the audience watching on the webcast, if you'd like to submit a question, please use the Q&A text box at the bottom of the webcast player. To our covering analysts who are joining us live, please raise your hand to indicate that you have a question, and please hold for a brief moment while we pull for questions. Our first question comes from Phil Nadeau at Cowen. Please go ahead, Phil. Good afternoon. Thanks for taking our questions and for a very interesting session. Two from us. So first on the phase 2 trial metastases to the choroid. In light of the more aggressive nature of those tumors, we're curious what the physicians would think would be necessary to serve as proof of concept for Bel-sar in that indication. Is there a rate of tumor response, rate of stable disease, or duration of response that you think Bel-sar must produce in the phase 2 in order to be convinced that it should advance in that indication? Why don't we direct that to Dr. Shields? Go ahead. Yeah. So we know the rate of regression of choroidal metastasis based on radiotherapy. In general, within 4 months or 6 months, most tumors are regressed from their original thickness, which was approximately mean 3 millimeters, down to a flat scar, so a scar of maybe 1.5 millimeters. So we know that it's a fairly rapid rate of regression, and it depends on the primary site, but let's take breast and lung, 'cause they are the most common to metastasize to the choroid. I would say in a period of maybe 1 or 2 months, they will get a little bit larger. So they grow faster than uveal melanoma, and they respond faster than uveal melanoma. I mean, I think, I think we will get answers within six months, I would think, following Bel-sar treatment, showing regression of the tumors, at least within a year. Okay. Is there a response rate that you'd want to see, like 20% tumors regressing, 50%, 80%? What, what, what is the bar in terms of rate of response that Bel-sar needs to meet? Yeah. I mean, to me, I think it depends on tumor thickness. And I would say, you know, if it goes from a mean of 3 millimeters down to 2 millimeters, that we would consider that a positive response. So maybe a 30% reduction in thickness, or 40% reduction in thickness, and the additional would be resolution of fluid, because these tumors tend to produce subretinal fluid, so we would sort of like to see resolution of subretinal fluid. Great. And then last question from us. It seems like the physician panel is very impressed by the phase 2 data for Bel-sar and looking to use it widely. As we look forward to the results from that pivotal, are there key risks to the trial that we should be aware of? What could trip up the phase 3, you know, that, that maybe we're not thinking of? Tough question. I guess, Dr. Demirci, do you have any thoughts about that? You're muted. Yeah, go ahead. Yeah, this is a tough question. I think it is really tough question. What can trip the results of it? I think the statistical enhancement strategy probably will help to differentiate and then to find the result of it and to help the results. But to reach the conclusion, but I cannot think right now what can trip the results. Like, the... If it's going to work, we will definitely see the response. And then we will replicate the results. I think I don't see any. I thought about, but I cannot, nothing come to my mind right now. And I, I guess, Dr. Daniels, maybe you wanna just remind us all what has been kind of described about the powering assumptions, just because, Dr. Demirci mentioned the statistical findings. Yeah. I mean, I think that there are two things. So, the first is that the tumor sizes, the treatment regimen, the way of applying the treatment, everything, the exact same independent reading center, everything that we used in the phase 2 study is the same in the phase 3. So it's really directly comparable, which I think really de-risks it. In terms of your question about the, the powering, you know, with our phase 2 data as the assumptions, you know, it's, well above 99% powered, both for the, the primary endpoint and the first key secondary. Actually, to the point of the statistics, even if we assume that every parameter is twofold worse than assumed, meaning that the sham does, for some reason, twice better than we saw in the phase 2, or that the Bel-sar does twofold worse than it did in the phase 2, it's actually still around 95% powered, both for the primary and the first key secondary. So, you know, any risks, I think, are mitigated by the fact that it's just so overpowered to demonstrate the efficacy. Okay. Yeah, it's very helpful. Thanks for taking my questions. Yeah. Thanks, Phil. Okay, Thank you for- Go ahead, sorry. Thank you for your questions, Phil. So our next question comes from Andrew Berens, from Leerink. Please go ahead, Andrew. Hi. Thanks. Can you guys hear me? Mm-hmm. Great. And thanks for hosting this event. A couple of questions for the doctors. ... If we consider localized uveal melanoma a spectrum of disease that ranges from indeterminate lesions to aggressive disease in patients that are candidates for enucleation, just wondering if you could give some idea of the rate of progression to metastatic disease across the spectrum and how long it generally takes for patients to progress. What I'm trying to understand is how long does it take to know whether patients out of the woods after surgery or radiotherapy across the spectrum? And the main reason is to understand how long we should benchmark surgery or radiotherapy sparing procedures versus the standard of care. Then I have one more question after you answer that. Dr. Seguin, why don't we hear your perspective on this first? Sure. So, it's hard to generalize, but if we look at the groups of melanomas, so small, medium, and large. So large will have 30, 40, 50% chance of metastasis, medium up to about 25% chance of metastasis, and the small ones are usually around 5%. This is 5-year risk. So those are the kind of the 5-year risk in terms of the groups. The average time that metastasis is detected is about 2 years after the primary treatment. But remember, the Bel-sar group are the group that have the lowest metastatic potential, and so most of those cases are unlikely to metastasize. So we've just looked at our plaque cases for small melanomas, in about 300 cases, and the metastatic rate was only about 4 or 5%. I think Dr. Shields has shown the same figure for the iodine plaque cases as well. These are quite low metastatic risk patients anyway, and so I don't think you're gonna have high numbers of metastatic patients at all with any treatment. Okay. Okay, thank you. Just wondering, at what point does an oncologist get involved with these patients, or how often do you get an oncologist involved? Shall I carry on? Yeah, go ahead. Excellent. In our practice, what we do is risk stratify the patient, either with clinical features, like the size of the melanoma, small, medium, large. And then we refer to a medical oncologist who will do a workup, and they then decide whether they need any future systemic screening and so on. And that's variable. Practice varies on systemic screening in uveal melanoma, and not only among different countries, but even in the same country. So in the U.K., practice is slightly different among different centers. But we involve the medical oncologist actually quite early, just even to give advice about systemic risk. Okay. Well, what about the other physicians that maybe would help to get there when they get an oncologist involved? We get an oncologist involved in Philadelphia in every case. So we send every single patient with uveal melanoma to a team of medical oncologists who are well-versed in metastatic risk from uveal melanoma. And in all cases, we do genetic testing or offer it, and within four months, the patient is seen by the medical oncologist. So we think it's really important for them to monitor them. But as Dr. Shields said, you know, kind of our goal with Bel-sar is to knock off tumors when they're little and hopefully minimize this risk for metastatic disease down the road. I mean, that's our goal, because as of now, there's no clear-cut, best practice medical treatment for metastatic disease. We have some contenders, but nothing is, you know, totally reliable. So if we could, we would like to knock off or minimize that risk for metastatic disease. Very good. Well, thanks, Andy, for the questions, and I guess I do wanna point out that we are running over by quite a bit. So, the rest of the team, the analyst teams that are gonna ask, please try to limit yourself to one question if you could, please. Thanks, Chris, and thanks, Andrew. So our next question comes from Jingming Chen from Evercore. Please go ahead. Hi. Thanks for taking our questions. So I'm just curious, which route of administration do you think is most suitable for metastasis to choroid and for ocular surface tumors? Thanks. Dr. Shields, go ahead, please. Yeah. So I like the suprachoroidal route because we get five times the drug using that route as compared to the trans pars plana route. So I think we know the best way to get the med to the tumor, and that's for melanoma and for metastasis. And then as for ocular surface tumors, I think the best route would be to go subtumor. So you go with your injection under the tumor, and you balloon up the tumor, and that's gonna get a real good loculated dose of medicine that can just go into the tumor from below. Very good. Got it. Thank you. You're welcome. Thank you, Jingming. So our next question comes from Jonathan Wolleben from JMP. ... John, you can go ahead. John? John's muted. Oh, sorry. There we go. Can you hear me now? Yeah, we got you. Go ahead. Thanks, guys. Question for me. You talked about bel-sar and vision preservation, but on a shorter follow-up, my understanding is brachytherapy vision loss can occur over many years. So what gives you confidence that what we're seeing, at least in the early innings for bel-sar, is gonna be sustainable, and how much follow-up would you want to see to be completely convinced? Dr. Demirci, do you have a view on this one? Yes. The radiation we see after a while—like, the effect of the radiation on vision, we see after a while, but we know that the damage happens, basically. And then, if you look at the bel-sar, it doesn't have the same kind of damage effect to the normal cells. So, in the bel-sar treatment, you don't expect that the potential damage to happen down the road, basically. So if the patient has the vision preservation, should preserve the vision the same way. I don't expect that the down the road effect on the vision, basically. Yeah. I mean, I'll make a comment if it's okay. Please. Radiotherapy is a very difficult to shield treatment modality. So when we put a plaque on the eye, you can draw a circle outside that plaque that we're getting radiation to really places in the eye we don't want to get it. And the closer we are to the center of vision, the more we're going to shed external collateral radiation to the center of vision. And it's a different effect than the laser. So when we do lasers, it's very focused, and where you put the laser is where you're gonna get whatever damage you're gonna get. But with radiation, it's very difficult to shield, and we know to anticipate side effect within the pericytes and the vascular tissue outside the radiation field. Difficult, you get a lot of collateral damage, where you don't get that with laser. We've been doing lasers for different reasons in the eye for decades now. You know, I think just to build on what Carol said, with other types of laser-based treatments, if you get side effects and you get vision loss, they happen right away. If you do, you know, transpupillary thermotherapy or another type of laser to a tumor, you know, it's in the fovea, the vision loss doesn't happen a year and a half later, or two years later. I mean, it happens right there and then. So with Bel-sar, if we were gonna see vision loss, you would expect it to happen right up front. With radiotherapy, we know, as Carol said, the, you know, the effects on the pericytes, et cetera, you start to see the damage very soon, but the vision loss happens later. But, you know, it's... I guess the point is that with Bel-sar, if the vision loss is gonna happen, it's gonna happen right away. It's not a delayed, slow effect based on this mechanism and what we've seen in patients. Super helpful. Thanks for taking the question, guys. Thanks, John. Thank you, John. Our next question comes from Julian Harrison from BTIG. Please go ahead, Julian. Thank you. Can you guys hear me? Yeah. Okay, great. Thanks for taking my question and for hosting this session. Regarding ocular surface cancers, I'm wondering how much vision is at risk compared to the other ocular opportunities being pursued with Bel-sar. Would you say the motivation to treat early is just as high as it is in primary uveal melanoma, or is it maybe more nuanced than that? Dr. Segil, I guess, let's let you answer this, if you wouldn't mind. Sure. So, ocular surface cancers can affect the vision if the tumor grows over the cornea. So that is a possibility, but most tumors don't do that. The difficulty with ocular surface cancers is that it requires a lot of treatment, and they can recur quite easily. So melanoma, for example, of the conjunctiva, you can excise it, you can do the adjuvant chemotherapy drops, and still these tumors can recur. So I think rather than vision, it would be more the tumor control, which would be more important for ocular surface. And we may immunologically see an effect away from the main tumor, interestingly, with Bel-sar, an immune response that treats any other precancerous cells that are on the ocular surface. So that's attractive as well. Very helpful. Great. Thank you. You're welcome. Thank you, Julian. So our final question comes from George Farmer, from Scotiabank. Please go ahead, George. Hi, everyone. Thanks for taking my question. A very really helpful session today. I was wondering if the panelist could comment on the phase 3 trial design a little bit more. It looks like the endpoint of the study is 15 months after the last patient enrolled. It feels that this design's a bit unconventional relative to, I guess, similar oncology trials, which would typically you'd be event rate driven and involve a disease-free survival endpoint. Can you comment on why that might be the case, and what are the advantages of having an endpoint like that would be? Dr. Shields, I guess, would you care to kick us off if you have any thoughts? Yeah, I would. I mean, I'm going to say that probably Anthony Daniels can handle this better than me, but I will say in the phase 2 suprachoroidal trial, we had tumor control at one year of 80%. So if we can achieve that, 15 months should be adequate for the study of efficacy. And as far as the complication rate, you know, we're going up to I think it's 24 months for safety, and I think we're gonna see most of our safety events, as Anthony Daniels mentioned earlier. I mean, when you do a laser, you usually see the complications right away. So, I think we're gonna be seeing them within that 24-month window. Well, yeah, and I, I guess maybe we will kick it back to you, Anthony. You know, what... We already discussed to some degree the rationale of the endpoint, but I guess, you know, what is the discussion with the FDA? I'll note that you have a, an SPA in place as well, so it sounds like it's pretty agreed upon, at least as far as it can be. Yeah, exactly. So, we have an SPA agreement with the FDA about this to make sure that they are comfortable with the endpoints. The endpoints were done in negotiation with them. So, you know, it's a time-to-event analysis, so what it says is that it's not just any events that happen as each patient hits a 15-month point, but any ones that happen, you know, while the study before the last patient hits 15 months, you know, would still count towards that. Which is important, right? Because we want and expect the sham patients to continue to progress. So, you know, it sorts of works to our advantage. We had discussions about, you know, event-driven, et cetera, and they wanted us just to use that single 15-month point rather than having it be iterative. You know, so that there's no risk of multiple looks or things like that at different time points. So, we actually felt that the endpoint that was settled on really sort of a red carpet for us to go versus sham and have the full time to see the sham event, the sham randomized patient's progress. Yeah. Yeah, you definitely will get that. All right, great. Thank you. Thanks, George. Thank you, George, and to the other analysts for your questions. I will now turn it back over to Ellie for closing remarks. Yes, thank you very much. So, as you can see, we're excited not just to impact 1 disease, but up to 3 different diseases, up to 5 different histological tumor types in the eye and completely transform the standard of care in ocular oncology. Many times, they ask me, because I'm the founder, and I have been working at the company for a few years, what is my vision? And I'm very happy to share that, because I do have a vision, and I have the vision that by 2030, we would have transformed the medical field that 100 years ago had nothing, that has been devoid of innovation, and that we will feel very proud of that, that our sons will feel very proud of that, and that the investors that helped us get there will feel very proud of that. Hopefully, we can all cheer not just, you know, an improvement on someone else's drug, but really the transformation of a medical field. Thank you very much. We're very excited, and we look forward to many more questions in the upcoming months and as we release our data.