Good morning, and welcome to the Aura Biosciences Virtual Ocular Oncology Investor event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. 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 Jill Hopkins, Chief Medical Officer and President of Research and Development at Aura Biosciences. Please go ahead, Jill. Thank you, Tara. Thank you, everyone, for joining us today on our investor event. We're very pleased to be presenting our recent, very recent, phase II end of study data for bel-sar in choroidal melanoma, and we are excited by the consistency of this final phase II data. It's fully in line with our expectations and continues to support our phase III program, so let's get started. As we begin, we would like to note that this presentation contains forward-looking statements, which are subject to risks and uncertainties, some of which cannot be predicted or quantified, or are beyond our control. So you should not rely on these forward-looking statements as predictions of future events, so Aura Biosciences is a biotechnology company, working toward precision therapies with a platform. We're developing a novel class of viral drug conjugates. These are important new class of drugs, where we look at direct tumor cell killing, necrosis of the cancer cell, combined with immune cell activation, and we're applying a focal treatment approach in early stage disease. We are in late stage clinical development. Our phase III program in primary uveal melanoma is ongoing, and we have a SPA agreement with the FDA to support that program. We see a large market opportunity in areas of high unmet need, and our ocular oncology therapeutic area can potentially touch 60,000 patients per year in the EU and the U.S. Our urologic oncology program can touch up to 500,000 patients globally. We do have key upcoming catalysts as a company, multiple clinical data readouts over the next six to 12 months, today for phase II, that we'll review, and early phase I bladder data coming out in October. We have a strong cash position, funding our operations into second half of 2026. Before I dive into bel-sar's mechanism of action, I just mention the concept of viral drug conjugates, where we have a virus-like particle, it's an empty virus, does not contain genetic material. And it's modified and then conjugated with light activatable molecule, that we then use a standard near-infrared laser to activate after local delivery. And as mentioned, we're very compelled by and excited by the dual mechanism of action that bel-sar, our lead candidate, provides. So we can see a disruption of tumor cell membrane and a pro-immunogenic cell death by necrosis, followed by a T cell activation and immune-mediated tumor cell killing. Importantly, this is tumor agnostic. We have seen in preclinical studies, this works across a range of tumors, and as mentioned, we have near-term clinical data in both the eye and early phase in the bladder. We are currently working across multiple solid tumor indications, primary uveal melanoma being our lead candidate in phase III, and enrollment is ongoing. phase II presented today at Retina Society, that Dr. Kim will share with us shortly. We're also commencing a trial in metastases to the choroid. We anticipate that being initiated this year, with initial phase II data by year end. We're also exploring ocular surface cancers, looking toward a pre-IND enabling set of activities this year. As mentioned, we're working in bladder cancer, non-muscle invasive, where that data will be available in October 2024, and then other HSPG-expressing tumors in our preclinical pipeline. Today we're focusing on the ocular oncology potential, and we are very excited by the combination of multiple indications in this area where bel-sar could have impact. What's interesting, primary uveal melanoma, our most near-term, about 11,000 patients per year. When we look at then going to metastases, the choroid, that doubles the potential market size to 20,000 per year, then moving into ocular surface cancers, out to 35,000 per year. We see a market potential of 66,000 patients in a given year, importantly, in an area with a high unmet need for patients living with these diseases. So we are also excited by the fact that with a small core of ocular oncologists in the world, both the U.S. and rest of world, we're well-positioned to have our therapies developed and then utilized by this important team of physicians. So I am going to move live to Lisbon in just one moment, but I think, again, just wanna highlight for everyone on the call, why we are excited by and the important highlights you're gonna hear today. So the first is that phase II is complete. All patients are now at their twelve-month follow-up of bel-sar therapy. The safety profile exceeded our expectations, and the compelling efficacy that we had seen in previous trials has held up throughout phase II, and continues to inform and support our ongoing phase III program. So with that, I'm gonna go live to the Retina Society. It's my pleasure to introduce Dr. Anthony Daniels. He is our Vice President and Therapeutic Area Head of Ocular Oncology at Aura, and he was the former Chief of the Division of Ocular Oncology at Vanderbilt. So, Anthony, over to you. Thank you very much, Jill. I'm sitting here in a room with Prithvi and with Ivana about 200 yards away from where Dr. Kim just presented the results. So it's about as live as it can get. So before we speak about the results today, I just wanted to help position everybody on the timeline of, you know, where we're talking about in terms of of melanoma. There's early and late. So when patients present with uveal melanoma, uveal melanoma is melanoma of the iris, ciliary body, or choroid, but about 90% of all uveal melanoma is choroidal melanoma, and that's what we're going to talk about here today. When they present, they usually present either because this was found incidentally on a routine eye examination or an examination for another disease, or because they have a known nevus or mole in the back of the eye that was suspicious and was being followed over time to wait for it to develop into a melanoma, or occasionally they present because they're having new symptoms related to the tumor itself. But the good news is that the vast majority of these patients who present with uveal melanoma do so with early-stage disease, which ideally is what you would want in any type of cancer, to catch the cancer early, and that's the majority of cases. Unfortunately, as we'll talk about today, because the treatment options that are currently available often come with a lot of side effects, including vision loss, even though they present early, they often will enter a watchful waiting phase when they have risk factors or even with early documented growth, because we're constantly weighing the consequences of radiotherapy and vision loss versus wanting to, of course, cure the tumor itself. So this is sort of how the paradigm is in early-stage disease, and it's very important to point out that what we're talking about, early-stage disease, small melanomas, and indeterminate lesions that are in the eye, the primary tumors, this is very different than when we talk about metastatic disease, which is late-stage disease. And the physicians who see these tumors are different in both settings. In early-stage disease, when we're talking about primary ocular tumors, indeterminate lesions, these are seen by ocular oncologists, a subspecialty within ophthalmology, and of course, metastatic disease is managed primarily by medical oncologists, and the value proposition here is a little bit different. Here, we're talking about treating those early tumors with a treatment that is potentially curative and allows avoidance of radiotherapy, which of course, is the goal. When we're talking about late-stage disease, of course, metastatic disease is a completely different entity, but for other drugs that are being developed, they tend to be for later-stage disease, for very large tumors, where the goal would be to shrink them to allow them to subsequently receive radiotherapy or bel-sar, something else that could be definitive once the tumors become smaller. So just to position what we're talking about today, we're talking about the early-stage disease, the primary tumors within the eye. And really, the value proposition here would be, as we'll see when we talk about the good vision preservation in these patients, is that you could choose to treat the patients early on to treat their tumor, but also not have to risk them losing vision or decide between vision and tumor control. So with that, the plan for the day will be that since many people didn't hear Dr. Kim's presentation in the room, she's going to give a recap for us exactly as she presented it early today, so that everybody can hear the talk that she gave. And then we'll ask Dr. Mruthyunjaya to respond and give his thoughts on the data, and then we will open it up to a roundtable discussion, in a question-and-answer format here that I'll moderate. And then from there, we'll move on to, opening it up to questions from the audience. So, Dr. Kim, would you please, tell us what you told us this morning? Hey, thank you. So it's my pleasure to give this onco presentation of the final results of the phase II trial of suprachoroidal administration of bel-sar, for choroidal melanoma. I have no relevant financial disclosures. I'd like to acknowledge the very accomplished investigator group. This was a multicenter effort, and without these investigators, this data would not be available, and we'd like to, of course, thank all the patients who participated in this study. So to recap a little bit, bel-sar is a virus-like drug conjugate that consists of a viral capsid derived from human papillomavirus. It has specificity for modified heparan sulfate proteoglycans found only on malignant cells, and this capsid is conjugated to a phthalocyanine dye that is activated by near-infrared laser. You heard about the dual mechanism of action of tumor cell necrosis, as well as immune-mediated tumor cell killing. So currently, bel sar is in phase III clinical development, but I'd like to review what that treatment actually entails. Unlike current standard of care, which requires a trip to the operating room, this is an in-office procedure, and one treatment of bel-sar consists of two simple suprachoroidal injections given by a special microinjector, followed a few hours later by light activation with a standard ophthalmic laser that we're all familiar with because we currently use it for other retinal indications for photodynamic therapy. So one treatment with bel-sar involves two injections, followed by laser. One cycle, as we will refer to, involves three of these treatments, separated by a week. So this was the design of the phase II trial of suprachoroidal administration of bel-sar. It was an open-label dose escalation study enrolling 22 participants. The final therapeutic regimen consisted of a total of 720 mcg of bel-sar, administered through three cycles of treatment. The key endpoints were tumor progression, which were defined, which was defined as an increase in tumor height of at least 0.5 mm, or an increase in largest tumor basal diameter of at least 1.5 mm. Visual acuity loss was defined as a loss of 15 letters from baseline, and changes in tumor thickness growth rates were also evaluated. Looking at the baseline characteristics of the patients enrolled, we'd like to emphasize that these are indeed early stage or very small tumors, with a mean baseline tumor thickness of just two mm and a baseline largest basal diameter of about 8.5 mm. They were also tumors that would be high risk for vision loss, with radiotherapy being located very close to critical structures such as the fovea and disc. And the majority of these tumors had documented growth prior to screening. So looking at the top-line data of local tumor control, we find that 80% of patients treated with the final therapeutic regimen, and were considered eligible for the phase III study, demonstrated tumor control. The phase III eligible criteria just excluded one patient with a circumpapillary tumor that would not be enrolled in the ongoing phase III trial. Looking at changes in tumor growth rate in those patients that were considered responders, we see essentially cessation of growth among these patients, with a significant decrease in growth rate after treatment compared to prior to treatment. Also, looking at visual acuity, we see that 90% of patients in the phase III eligible group receiving the full therapeutic regimen had visual acuity preservation. Actually, the median change in best-corrected visual acuity at 12 months was a loss of only 3.5 letters. If we look at safety outcomes, they were very mild and minimal treatment-related AEs. The main and most frequent treatment-related AE was very mild anterior chamber inflammation. Most of these cases were graded as trace, so definitely grade one. The median duration of this event was about 6 days, and many resolved with no or very minimal treatment. We were reassured to see that the development of anterior chamber inflammation at one time didn't necessarily mean worsening or recurrent episodes with subsequent treatments. So based on these encouraging phase II data, a global phase III trial is now enrolling, with a target enrollment of approximately one hundred subjects. The design is shown here. It's a two to one to two randomization, with a high-dose group and a lower-dose group, and a sham control arm. The primary endpoint is time to tumor progression, with the same progression criteria as defined in the phase II study. A key secondary endpoint is a composite endpoint of time to either tumor progression or visual acuity failure, again, with the same definitions as in the phase II study. So if we present the phase II data based on these planned phase III endpoints, you see that there's a significant benefit to the therapeutic dose versus the subtherapeutic dose, as shown here in these graphs. So to summarize, the patients who received the final therapeutic dose in the phase II suprachoroidal study showed 80% tumor control rate, with cessation of growth among these patients. There was a 90% vision preservation rate, which is very significant given that 80% of the tumors were very close to the fovea or optic nerve, and we were reassured to see a very highly favorable safety profile. So we are excited to see the results of the phase III study, and we hope and expect that they'll be very similar. So thanks for your attention. Thank you very much, Dr. Kim. Dr. Mruthyunjaya, we'll go to you now for your thoughts. Thank you, Anthony, and thank you, Ivana, for that, very, clear and concise presentation. So as an ocular oncologist, this is, not only reassuring but also exciting, as, this data now gives me, as a clinician, an opportunity to, potentially offer patients with difficult-to-treat lesions, because we worry about the risk of severe vision loss in our traditional treatments. What this data tells me is that there is an adequate control rate of the tumor, there is safety in the mechanism of, delivery of the drug, as well as risk to the, the healthy eye structures, and, we are seeing an alteration in the biologic trajectory of these tumors. One of the points, Anthony, is that this is a highly selected, patient population. These are tumors that, have shown, with great rigor, growth, and that's sometimes hard to show in these smaller lesions that could be slow growing. So I think that is a key advantage, and a plus of the study design. And these were biologically getting bigger at a rate that's beyond just a normal growing mole in the eye. And we can see now that that curve is being arced in a way that is what we wanna see in any growing cancer, and I think this is the first time that I've seen this type of response in these small tumors being demonstrated. And again, this is an office-based, non-surgical treatment that is giving us these results. So I think it's in many ways, and we can talk about them, this is a very exciting data. I really appreciate your synopsis of your thoughts on this. You know, as you talk about excitement, what gets us excited is, as both of you discussed, we had a continuation of the efficacy that we had seen before. Obviously, the vision is critical, and we'll talk about that at length, and then the safety profile we'll also talk about. Let's talk about each one in turn. We'll save efficacy for later, and we'll start talking about vision and safety, as you were highlighting. First, let's talk about the safety profile, and we'll go to Dr. Kim first. What do you think about the ocular safety profile of bel-sar that was seen in the phase II study, and any particular things you'd like to highlight beyond what you already discussed in your talk? I mean, I think the safety profile was probably even better than we'd hoped for. I think, you know, any treatment that only causes very mild anterior chamber inflammation, that can be, you know, self-limited or can be easily controlled with just topical therapy is, you know, more than surpasses the bar for safety, especially when you compare this to the standard treatment, which has, you know, very significant rates of ocular morbidity. So I don't think safety is a concern with this treatment, with the current data. Fantastic. You touched on the current therapy and the side effects we're seeing with that. So maybe we'll go to Dr. Mruthyunjaya. Can you talk about what, in general, you see in terms of a safety profile or other adverse events that you see with plaque? So, placing a radiation plaque in these eyes, which are, again, highly selected for, very back of the eye, posterior location, near the optic nerve, right near the center of the vision in the fovea, these are technically more challenging to place a radioactive disc directly opposite to the front of the eye. It's prone to error, so sometimes the effective control rate is actually less in these tumors. There is a surgical morbidity that happens when a patient has to go to the operating room. Sometimes we have to remove eye muscles that are attached to the eye in order to get the disc in the accurate position. So we're looking at short-term and medium-term side effects that include double vision, pain, discomfort, local inflammation. And we talk about the long-term side effects of radiation therapy, where typically we quote vision loss in the order of, you know, two to three years after the radiation goes in. But I think we've all seen patients, especially with these more posterior tumors, that can have more short-term vision loss or vision impact due to a variety of effects that can occur during the time of surgery. Anthony, if I can also add, one of the things that I think has been very positive here is the change in delivery of the drug that Aura has taken a role in. We were involved in some of the early phase studies in which the drug was directly injected into the eye, much like we do as retina specialists for diseases like macular degeneration and diabetes, that intravitreal approach. You know, kudos that now we're using this suprachoroidal injector, which has really, I think, changed the game here in terms of the safety profile. So we're not directly putting it into the eye. It's going directly to the tissue of interest. And as a retina specialist, as we all are, you know, we've been very sensitized to the risk of inflammation in some of the newer therapeutics that have come into play. And simply by changing the route of administration, I think the safety profile is... It's very reassuring, and you know, I feel comfortable delivering it in this manner to get closer to the site of the target, but also, as Ivana mentioned, this is really manageable, low-grade inflammation. That's fantastic, and I actually would like to touch on the injections and the lasers technically themselves. We'll put that for a little bit later. I'd like to focus on what you were just talking about, about the safety profile, and maybe if you could comment on the vision aspect of things as well. How do you see the vision results playing out? Most of the conversation that we have with patients regarding early treatment for tumors settles not on, you know, the ability to treat them, that's fine, but it's this very delicate conversation about we know we are going to be blasting this eye with radiation, and that vision loss is inevitable. Like, we don't even promise, you know, the likelihood of, maybe 50, you know. We just tell the patients upfront, and I tell them that within, you know, two to three years, the patient will be unable to read the biggest headline in the newspaper, even with the best of glasses and correction. And that's impactful for patients, and it makes them very scared and very hesitant. Here we have data that suggests that patients are maintaining that vision that they came in at baseline. And again, these are tumors that are right near the optic nerve, which is critical for vision, and many that were right close to or underneath the very center of their vision. So no matter what you say, with whatever type of radiation modification you wanna give, these patients are gonna lose vision, and probably, you know, maybe to a greater degree than the overall cohort of melanoma patients. So here we have a treatment that's showing up to a year of very stable, visual results. And, you know, to get even more nuanced, these are patients that have fluid under the retina and elevations under the retina, which will all be barriers to maintaining vision regardless. Had you just watched these patients for a year, I bet their vision would continue to go down. So here we've had an intervention that's stabilizing vision, and that's way better than you would expect. Great. Thank you very much. I'm shifting to Dr. Kim. We're gonna stick on the vision topic. You treat patients a lot with proton beam, and so, because of that, you're referred an overrepresentation of patients in these difficult locations and near the optic disc or near the fovea. You know, we've sort of discussed those, thrown those around a little bit, but as people who live in this world, can you speak a little bit more to understanding the importance of those structures and vision, and the implications that those have, you know, with radiation for treatment? Yeah, I think the general principle of radiation induced complications is the higher the dose to a structure, the higher the chance of complications. And melanoma is a relatively radio-resistant tumor, so we're using high doses. And if, you know, even with the precision of protons for the tumors close to the fovea or optic nerve, these structures are essentially getting the full dose of radiation. And we know that the vision loss is, you know, predictable, and we know that to such a degree that many of us have started employing basically a prophylactic strategy. Because we're so sure that many we know who's gonna lose vision, we start giving patients anti-VEGF injections to try to ameliorate or postpone the effects of radiation-induced vision loss. So, I mean, if you think about the commitment to preserving vision in these patients, it's not just a comparison of, you know, radiotherapy is a week, a few days out of the patient's life. If you want to maintain vision after radiotherapy, it's, you know, years of consistent anti-VEGF injections, you know, maybe initially quarterly, but then as the macular edema and other complications develop, it can be much more frequently. So, you know, the potential for offering a therapy that, you know, may be a little bit more time-consuming in the beginning, but doesn't carry that kind of burden of lifelong injections, potentially, I think is very exciting. That's a really good point that we often probably don't emphasize enough, you know, yes, the regimen's intensive upfront, but hopefully, you're saving a lot of intensive treatment- you save the patient from requiring that for the rest of their life. So let's talk a little bit about how this vision loss that you were just describing fits into the conversations that you have with patients. Dr. Mruthyunjaya talked a little bit about his patients, and the conversations he has with them. Can you kinda describe to me what you tell patients to expect currently, both in terms of vision, but also other adverse events, et cetera? Kind of help us understand how that conversation currently goes with patients. I mean, it really depends—like, other than, you know, "Is the tumor gonna spread outside of my eye?" The next primary concern for most patients is: you know, "Am I gonna lose my vision?" And unfortunately, the short answer is yes, it's a matter of time. It's a little bit unpredictable. There are definitely the outliers that can have good vision for long periods of time, but, you know, our messaging is really, "This treatment needs to be done to save your life and prevent spread of the tumor." And if we can preserve some useful vision, then that's a win, and preserving that useful vision may take, you know, a commitment to, you know, ongoing treatments of injections into the eye. Because of the radiation, right? Mm-hmm. So, if the phase III data were to hold up like the phase II in terms of efficacy, safety, vision, et cetera, how would you see those conversations then evolving over time? Yeah, I think, you know, for patients that meet the criteria, the inclusion criteria in these studies, it's definitely an attractive option. I think, you know, we have to admit that, you know, based on the current data, possibly the tumor control rate is not gonna be as high as with radiation. But if there's an 80% chance that you could have a treatment that would allow you to have much better vision preservation, then I think that people would be willing to accept that slight differential in tumor control rate. And I think, you know, longer term, it would be important to try to show whether that differential actually has any significant impact on other outcomes other than- vision. You know, we're definitely still concerned about long-term tumor control. Yeah. You know, I think that's an excellent point, and, you know, obviously, if all patients could have that chance up front to save their vision, then, you know, you can always keep radiotherapy in your back pocket if you needed it, but hopefully, very few patients would actually need to go on to that. Dr. Mruthyunjaya, sort of the same question: If the efficacy and safety were to hold up in the phase III, how would you see those initial conversations going in that sense? It gives us another tool in the tool chest. I think right now it's difficult to tell a patient that has a growing tumor that we are using the word melanoma that they'll understand as, you know, a form of cancer that we want to continue to watch it because we're worried about, you know, vision loss, and you know, for some patients, that could be really significant, especially if their other eye has concurrent disease where they understand that this is going to be an issue, and to be honest, some patients will choose to watch because there isn't really... You know, for them, there's no option. Like, they don't want to, you know, undertake a treatment that could lead to vision loss. So I think it would provide the clinician a really important, you know, tool to move treatment earlier in the time course. You showed that course of, you know, patients, you know, early on versus later. Whereas right now, there's really no standard that's been set for treatment early. And I think you will find patients who are going to be, you know, seeking out some of those early options, especially if this therapy, you know, meets its endpoints, there's gonna be a greater understanding about the need for screening and identifying patients at an earlier time point anyway. That is gonna change kind of the work of primary care, eye care specialists, ophthalmologists, optometrists. Knowing that there's an option, I think you'll find more patients than we've ever seen before because they're gonna be identified. And then they're gonna wanna know, what is it that I can do? But again, the long-term data will be important, putting it into context of which patients' growth rates, things of such, which I think will be part of the conversation in the future. That's, that's great. You know, you bring something up that I wasn't even gonna talk about, but, I'll pursue your answer. So the 80% efficacy, you know, is that meaningful to you? Again, assuming it holds up in phase III, et cetera, is that meaningful to you in terms of what it would mean for when you treat these patients? You brought up the concept of, you know, have patients coming out of the woodwork earlier. How would you... Can you elaborate a little bit more on that? Yeah, so 80% efficacy is better than my current option, which is 0% efficacy by watching, right? So, it sure doesn't hit the same benchmark that we have with radiation therapy. But I'd also say that, you know, we may be fundamentally altering the biology of these tumors, right? These very small lesions, which may have a lower metastatic risk than, you know, a larger tumor, for sure, based on many data sets. But we may be, you know, slowing down, you know, the most viable cells that are in the tumor, and that's gonna bear out with long-term data for sure. You know, I think that the options that this will provide surely changes what we have available. 80%, I think, is a number that I think is meaningful for patients, especially if they are being given that opportunity, with stabilization of their current vision. So, it's a 80% with a big asterisk on it because, the quality of life that patients may enjoy, working age patients, that's not insignificant. That's a great point. So 80% might avoid radiotherapy completely, but even for the 20%, potentially, it's buying them a few more years of vision anyways until they go on to get radiotherapy. Correct. Earlier, you had brought up the injections, and well, let's talk about the lasers, so maybe we'll go to Dr. Kim first, so the actual injections, how long does it take to perform a suprachoroidal injection? It probably takes a couple minutes. I think it's a little, takes a little bit longer than a standard intravitreal injection because we typically have to use subconjunctival anesthesia, and the injection process itself needs to be slower. But technique-wise, I don't think it's a big leap for practicing retina physicians and ocular oncologists. I think the microinjector tool really, you know, facilitates finding the right space and doing it. So it's really technically not a challenge, I would say. And also now, a lot of physicians are beginning to use it. The same injector is used- for steroids and other injections out there as well. It's actually, I'm glad that you talked about the injector. And the anesthesia, you mentioned subconjunctival anesthesia, just to clarify, that's just numbing the eye, the eye itself. And the lasers, how easy or hard is it to do one of these lasers? I mean, again, we're all really familiar with this laser. We use this type of laser for, you know, current verteporfin photodynamic therapy for it was first developed for macular degeneration, now it's more used for, you know, other ocular oncology indications. So we're really familiar with the laser. I think, it's a little bit more time-consuming than PD like regular PDT, because we're covering a larger lesion, and we have to do two rounds of it. But overall, it's, you know, well-tolerated, and again, it's not a leap at all for a practicing ocular oncologist to do. And these are done in the office, and patients get up and walk home afterwards. Mm-hmm. So flipping that around to Dr. Mruthyunjaya, so if you're gonna place a plaque on a patient, tell me a little bit more about how that's done in terms of the anesthesia and the patient. Yeah. So it's a surgical procedure, so they have to come into the hospital. They come to the operating room, and depending on the preference and the safety for the patient, they may be under full general anesthesia, so breathing tube during the course of the surgery, or they'd have a local anesthetic block onto the eye. We have to use instruments to dissect away the conjunctiva, which is the clear skin over the white of the eye. We have to then manipulate the eye by identifying the eye muscles that allow us to move the eye out of the way, so we're using some strings around the eye muscles. And then we identify the location of the tumor, and then we place a metal disc. So the radiation plaque is akin to, like, a quarter that's coated in gold. So one side has gold, the other side has grains of rice, which are the radiation seeds. And they're embedded within this gold disc. So we have to get this disc all the way to the in all of these tumors here, 70% of them, into the opposite end of the eye from the front of the eye that we all look at. It's sutured into place with temporary sutures, and then we either have to move some of the eye muscles out of the way if it's in the location that the disc needs to be covering, and then we temporarily then reclose the conjunctiva. We wake the patient up, and then they keep the disc in place between five and seven days, depending on the institution, where that radiation slowly kind of soaks in. During that time, they have eye drops. It can be painful, but usually controllable with oral pain medication. And then they have to go back to the operating room within a week, where we reverse the steps, so we administer the anesthetic agent, and in a shorter procedure, we then remove those stitches that we put in, remove the disc, and then have to reposition any muscles or other tissues that we had to move out of the way to get the disc in place, and then we close the tissues, and they're discharged. So, it's more involved, for sure, because it's a surgical procedure. We, you know, counsel them on two risks of anesthesia for the placement and then the removal. And then risks of infection, bleeding are there. Sometimes we have to take patients off of blood thinners that they're on, especially older patients, that they need for other conditions, and then coordinating their care with the anesthesia team, but also their primary medical team. So clearly an office- not an office-based treatment. And you talked about the oral pain medicine. Are you sometimes giving them narcotic pain medicine, or? Yeah, so sometimes, depending on the patient and the manipulation that's involved, we can get away with over-the-counter pain medicines, but pretty regular, around-the-clock. But sometimes we have to prescribe narcotic-based pain medications, plus the medicines they're getting during anesthesia. Sure. I always used to joke that I should be their best friend the day I place a plaque, but really, I was their best friend the day I took it away from them. Absolutely true. So we're gonna shift gears a little bit in the last few minutes to talk about the phase III study and the designs and your thoughts on the likelihood for success. So, we'll reverse the order. We'll go back to Dr. Mruthyunjaya first for this section. Why is there excitement in the field around the COMPASS study? This is a global collaborative study, and I think that that's exciting because now we're gonna be able to have patients from all over the world be a part of the study. It might tell us a little bit about some differences that we know from geographic and ethnic variants of these tumors. I think the entry criteria, they're strict, and I think that what that's doing is to really enhance the population for real small melanomas and these. Meaning no question that they're actually melanomas. Right, they're actually melanomas based on clinical criteria and growth at a rate that's higher than a typical standard mole or nevus. So if we fulfill the entry criteria, then I think we're all gonna be much more confident that these aren't just... we're not over treating a mole that would never grow, right? So these are with growth, which makes recruitment challenging, right? So that's why this is a global study and, you know, multiple sites for a hundred patients. No one clinical site would really be able to, you know, enroll five, ten, twenty patients like you might have for other ophthalmic or other oncologic studies... and in doing so, I think that, you know, we'll see kind of real world also, you know, what the treatments are. I think patients are always going to be hesitant to enter a phase III study where there's a control arm or a sham treatment, but I think in oncology, we know that that's, you know, that's the reality for us to reach the bar. But what I tell patients is that, unlike, you know, a clinical practice where you might say, "Come back in four months or six months," 'cause we don't have the answer as to how often these patients would be screened, even the masked, you know, sham treatment patients are being followed incredibly close. So if there's- In some circumstances, twice-a-week imaging. Yeah, right? So way more than what they would, you know, as part of a, quote, "standard of care." So these patients have a safety net under them, so even though they're growing quickly compared to just a mole or a nevus, we would have the opportunity to intervene with standard of care radiation, you know, at the earliest time point. So that would allow us to catch patients that, you know, might fall under that 20%, you know, progression rate, but also the control patients, as well. Yeah, that's a good point, that the patients who do get randomized to sham become eligible for radiotherapy as soon as they progress, and we're following very closely for that. So, Dr. Kim, you probably can speak to this better than anybody. To what degree do you think that the patient population in phase II, in the therapeutic group, matches the patients who we're enrolling in the phase III study? I mean, I think the way it's designed, it's basically identical to the set of patients that we presented results for. So that was kind of the phase III eligible designation. I think, you know, this is the first new treatment for ocular melanoma in decades, and so I think in the early stages, you know, we were all learning a lot about what patient population is most appropriate for this type of treatment. And so, you know, that led to, you know, modifications along the way about what patients would be eligible for the phase III. So I think all the learnings from the early phase study are now implemented into phase III, and hopefully we've, you know, captured as ideal a population as possible. But that, you know, highest dose therapeutic group in phase II, with 100% documented growth, basically exactly mirrors what patients we're enrolling now in phase III. The patient population that we landed on, being these, you know, small tumors under two and a half mm, is that a group that you think needs a good option or needs something available? Yeah, as we mentioned previously, many of these patients, because their risk of vision loss is so high with radiotherapy, we are sitting on these lesions for a few months, you know, typically, before we really pull the trigger, because we just don't like the thought of having to fry the macula. But, you know, I... So I definitely think that we'll feel more comfortable initiating this treatment sooner than we would radiotherapy. Great. And I think we're exactly at time to go to questions and answers, so I'll turn it over to Dr. Hopkins. Great. Thank you both very much, and thanks, Anthony, for leading the good discussion there. And I believe we're gonna open up now for question and answer from our online audience. Great. Thank you, Jill. So at this time, we will be conducting a question and answer session with our speakers. Please hold for a brief moment while we poll for questions. So our first question comes from Philip Nadeau at Cowen. Please go ahead, Philip. Morning, thanks for taking our questions, and thanks for the update. I guess our first question is drilling down on efficacy, and particularly, how should we interpret the phase III data? I think both physicians suggested in the phase II, the 80% tumor control might be slightly less than radiotherapy. So I'm guessing at or I'm wondering, as we look at the phase III, what time to tumor progression would be necessary for you to think, first, this is actually just as good as radiotherapy, maybe the phase II underestimated the data? Second, what TTP is necessary for this to be viable, something that you'd consider in the treatment paradigm, and then, kind of what would be too little? What would be disappointing that would question whether there's a place in the treatment paradigm for bel-sar? Yeah, thanks, Phil. So why don't we go to both of our KOLs? We'll maybe start with Dr. Kim, and then we can move to Dr. Mruthyunjaya. Yeah, I mean, I guess the time to tumor progression is not something that we typically, like, we don't have a certain time in our mind, but basically, you know, we would like. If we were to replicate the results of the phase II, where we have, you know, at least 80% tumor control, so, you know, no progression over the whole time of the 15-month study in about 80% of these patients, then we would probably consider that, you know, a viable treatment option for this subgroup of patients. Again, you know, we're not expecting, I think, the 95% kind of rates of tumor control that we get with a very destructive, like, pretty much non-selective therapy. And I think we're really interested to see whether even in the patients that technically fail or progress, whether this exposure to this treatment and the potential, you know, immune priming may have some benefits down the road in terms of systemic disease control. ... That's really helpful. And then, I guess, our last question is just on where this would fit in the treatment paradigm. If we interpreted your comments correctly, it sounds like you would certainly replace watchful waiting with bel-sar, and maybe use it in some of the patients that you're currently using radiotherapy in, who are particularly at risk of losing vision. Is that a fair assessment of what you're saying, or would your use of bel-sar be even more aggressive with it replacing radiotherapy in most patients, and radiotherapy being relegated to the second line, for those patients who don't get good control? I think it would be more along the lines of the first option. I mean, at least right now, probably it's not the majority of patients that we see that have these very small tumors in the posterior pole. But I think what Dr. Mruthyunjaya and Jill was referring to is that if it gets out that there is this viable option, then we actually might start to see more tumors at earlier stages that are more amenable to this treatment because it is an option. But I don't think, as of right now, based on our melanoma population, I don't think it's gonna be the majority of patients. It's really gonna be these small, very thin tumors in the back of the eye. That's very helpful. Thanks for taking our questions. Thank you. Thanks for the questions, Philip. So our next question comes from Jingming Chen at Evercore. Please go ahead, Jingming. Hi, thanks for taking our questions. This is Jingming for Lisa. So we have two questions. So out of the 10 phase III eligible patients, the two who failed to achieve tumor control, can you give us a bit more color on details of these two patients? Like, do they have any pre-existing conditions that led to the treatment failure? And our second question is, for the patient who failed to preserve vision, and apparently that patient had pre-existing pseudophakic fluid under fovea. So how common is this condition in the general patient population? And how do you think that's the cause of the vision control failure? Thank you. Do you want me to speak to the details of those two? Yeah, so I mean, obviously, you know, these are small numbers with only two patients who failed, so I can just describe for you narratively about them in terms of what seems to be different about them. So, of the two failures, one of the patients had a very fast growth rate at entry, sort of, you know, outside the usual midpoint of the spectrum. And the growth rate did slow down significantly. So, you know, if they continued on the same growth rate for that patient, they would have crossed over at, like, two months, and they crossed over at twelve months. So there was a significant delay, but not complete cessation of growth in that patient. This is important 'cause ultimately, the phase III study is a time to event analysis, so it would still give, you know, statistical credit to the fact that the treatment, that the failures that did happen, the few, happened much later. The other patient also was a patient who had some response, but, you know, possibly, maybe, you know, would have needed one extra treatment, you know, to kind of completely kill all the cells. I think that that's all we can say about those two patients in terms of what made them interesting or unique. In terms of the patient who lost vision, so it wasn't related to the treatment itself. It was a patient who had. Often these tumors will have subretinal fluid adjacent to them, and so did this tumor. And the fluid was adjacent, but not quite underneath the fovea, the very center of the retina, where your high acuity vision comes from. And over the course of the study, the fluid did shift to be under the center of the fovea. So in tumors, like in real estate, it's location, location, location, and if you have fluid that's outside the center of the retina, it, your vision can be excellent. But if you have fluid under the center of the retina, certainly that can impact vision. And so, in talking to the PI at the site, that was their explanation for why this patient lost vision. Of note, the tumor itself was controlled. You know, the tumor itself was actually completely stopped growing, but this fluid did shift into a more sensitive location. Got it. I just wanna follow up really quick. So let's say, without the treatment, would this patient lose vision anyways due to the shift of this fluid? Yes. Okay, that's helpful. Thank you. I think Dr. Mruthyunjaya and Jill also spoke to that as well, that, you know, if you allow without treatment, the patient's probably gonna lose vision if the tumors grow, and the fluid increases, so. Jill, if I could also just add to, I think it was Chris's question about, you know, what is a number, you know, in terms of in future? Yes. We were discussing this earlier today, that, you know, there have been many attempts at non-radiation treatments for small melanomas, kind of using off-the-shelf laser-based office techniques. And, you know, we've been less than satisfied with their efficacy, but also some of the safety risks. You know, so if we ended up with data that, you know, showed us that we were hovering in the 60%-70% control range, you know, in future, I'm just, you know, hypothetically, that would not be most exciting, you know, as an option, maybe just in selected patients that would require the treatment. But all of those other office-based, very off-label treatments that are being used have the risk of significant morbidity to the structure of the retina. Thermal lasers that have been used off-label, called TTT, or transpupillary thermotherapy, basically burns the retina. It's forcing a big scar, and there's a risk of recurrence. We talked about photodynamic therapy today in the same meeting as a very off-label use, and, you know, no one can, you know, would even think of doing as many treatments as we're able to do with this treatment without knowing that there's gonna be occlusive events, you know, within the retina. So, you know, from a sense of how gentle this treatment is and how repeatable it is, I don't think we've even, you know, touched on, you know, re-treating some of these patients that, you know, may have been, you know, failures within two years and from an efficacy standpoint. But the fact that we can give multiple sessions of the drug and multiple sessions of the laser, that's very different from, you know, what investigators have tried before. So I think we're gonna learn a lot from the phase III study, in terms of how this will apply to different patient populations as well. That's a really great point. You know, with radiotherapy, you generally wouldn't give them a second round of radiotherapy. No, we rarely do. It's, you know, if ever. Thanks, Prithvi. Appreciate that. Great, so our next question comes from Jon Wolleben at JMP. Please go ahead, John. Hey, thanks for taking the questions and hosting this day. I have one for management and then one for Dr. Kim and Mruthyunjaya. Wondering, you know, if the patients who have control of their tumor growth at twelve months, how confident are you that that's gonna stick long term? Like, is there evidence, you know, visually or biopsy-wise, if the tissue is necrotized, or is there a chance that you could see growth over time? And then for Doctors Kim and Mruthyunjaya, can you talk a little bit about when do you start recommending radiotherapy to your patients? Is it a similar, you know, loss of control as defined in the phase II and phase III, or are there a different threshold that you use? Thank you. So, I didn't hear who you directed the first question to, but we can go to either of you. So Dr. Prithvi Mruthyunjaya, if you have a patient who you've treated with anything, radiation, anything like that, that was actively growing before, and then you see complete cessation of growth that persists for a year, are you... In your mind, are you thinking that tumor is cured and probably isn't going to require anything else? Obviously, you continue to follow patients, but, you know, do you- What do you think? Yeah, right. So for me, cure is a hard word, especially in melanoma. I'm always nervous, like, you know, what could happen? So long term is gonna be critical, and I think the study is designed to help us figure that out. I think that, you know, if we're talking about stabilization within a year, I think that I'm feeling pretty good about that. This is a different mechanism of action, and I think that that's what we're also going to learn. When we irradiate a tumor, you know, we know how that works in terms of its. It's targeting cells at active phases of cellular division. So the rates and the time points, you know, we can see that kind of stutter along. You know, this is, we think, a dual mechanism where there may also be immune monitoring that may help as well. So we may not see the same, you know, kind of flattening that we do with radiation tumors because different cells are being destroyed in different ways. So I think this is. It's gonna take a reprogramming, you know, for, from what I will learn from the phase III, of how the endpoints may be different in this treatment than standard radiation treatment. Yeah, so, and I, I'm not certain I'm getting to the crux of the answer, and Ivana may have more insights. But I think, you know, being able to treat a patient with radiation as a backup is always, you know, a good thing because we may have altered the biology enough with activating immune cells, et cetera, that maybe that has a role in what we're really trying to prevent, which is metastasis. And I guess maybe the same question to you with a different spin, about, you know, what absence of growth means to you at one year in your current practice, but also, maybe you can speak to tumors of this size, so, you know, under two and a half mm, et cetera. If you were to treat them even with, you know, radiation, would you really expect flattening if you were treating just the malignant cells, et cetera? Yeah, I mean, I think in terms of interpreting the results of, you know, stabilization of the tumor, for tumors of this size, you know, we also see that with radiotherapy. We don't see, you know, a lot of immediate regression or reduction in thickness just because the mitotic rate of these types of tumors is presumably lower, and that's correlated with how fast you see regression. I think we tell patients treated with radiotherapy all the time that we don't really care how much the tumor shrinks, as long as it doesn't continue to grow. I think, you know, the question was kind of directed at: What do you think is gonna happen to these tumors aft- you know, in the second year and the third year? You know, I think it would be, you know, a little bit optimistic to... I don't think we could say that we know for sure that none of these tumors are gonna progress in the second and third year. I think especially since this tumor, this treatment is, like, so targeted and presumably only touches, you know, a select population of malignant cells, that's the question that we all have. How many in the second and third year will go on to require additional treatment? And the question is, is at that point, is additional treatment more cycles of bel-sar, or is it radiation? You know, I don't think we know the answer to that, but I think I would assume that there's probably gonna be a certain population of these patients that may need additional treatment. But I think we know from the patients that have progressed, that there's really no concern about them responding to radiotherapy. There doesn't seem to be an increased risk of radiation-related complications after patients have been exposed to this therapy. So we know that if they do progress, that radiotherapy will, you know, work the same way as it does in treatment-naive patients. But whether there's an option to continue this treatment beyond what is being done in these studies, I think we'll have to see. I didn't. That's the other question. Could somebody repeat what the other one was? Yeah, so I think, John- m aybe we're getting at the twelve-month versus fifteen-month in phase III discussion on that. Is that correct? Yeah, I was just wondering. I think we touched on that, but my other question was for Doctors Kim and Mruthyunjaya, is, you know, do you use the same criteria to decide to recommend radiotherapy today for these tumors, or when do you recommend radiotherapy for patients? So, these are hard because, you know, we don't follow patients and calculate their growth rate like we do in this study. So, you know, I'm seeing them, I have a conversation, I'll bring them in, and then either we proceed with treatment, and the patient understands the risk, or we see them back in three to four months, and then, you know, another three to four months, and then have to prove to them that it's growing and or there's vision change or something because of the characteristics of the tumor, then we might proceed to treatment. But it's very reasonable that someone comes in, you know, today with a tumor of the characteristics of this entry criteria, and we'll take them to radiation. But it's a long conversation and, you know, you feel that, yes, I'm helping you, but I feel really bad that you're gonna lose vision in doing so. So it's almost apologetic to some degree, but it's not in my control that, you know, that the patient will retain vision or not. But we will take patients that fit this entry criteria to radiation today, if that's the conversation. I think that's a good point. Nobody really went and taught ophthalmology to blind patients, so. Right. I will just add, so Anthony and Jon, you know, I think where you're going with one of the questions is a question we get a lot about 12-month endpoint in phase II, 15-month endpoint in phase III. Anthony, maybe you can just clarify the situation there. Yeah. I think that there are two differences in the endpoints around time that are worth talking about. One is the twelve to fifteen, but the bigger one is moving from a landmark analysis, twelve months, to a time to event analysis at fifteen months. And, you know, sort of for anybody who's savvy with statistics, obviously, a time to event gives you a lot more statistical power, because as you saw in the phase II study, in the Kaplan-Meier curves that Dr. Kim presented, you know, it's not just that there were so many fewer patients progressing in the bel-sar, the therapeutic regimen arm, but it's also the progressions that happened much later. So both of those aspects go to support the statistics in the study. And that's also why you saw that the p-value, you know, had so many zeros, even with only 10 patients per arm. You know, because the time to event analysis really captures that. So I think that's really important to talk about, too. You know? Yeah. Great. Thank you. Thanks, Tara. I think, if that was everything, Jon, we can go to our next set of questions. Great. That's for me. Thanks, guys. Thanks, John. So our next question comes from Anshul Dhankher at LifeSci Capital. Please go ahead, Anshul. Hi, everyone. Congrats again on the update. Had a kind of a question. You know, we talked about using bel-sar to treat indeterminate lesions a little bit earlier in the call. So I wanted to get a sense from the KOLs if this is a possibility or something to consider. And then also, would you seek a label that includes those patients? This is more for the company. And then finally, if it's not on the label, do you think there could be any issues with reimbursement in using this for patients with indeterminate lesions? Thank you. So I'll jump in with the second question quickly first, which is that, you know, it's kind of right there in the study title, that is for indeterminate lesions and small choroidal melanomas. And, you know, certainly, a lot of these indeterminate lesions with growth, you know, they're all included in the population that's being treated here. But I'll leave the main question- Yeah, I think it's a semantic, Anshul. There's such a overlap between a small benign nevus, and a small melanoma, that we're talking about, you know, essentially tenths of mm that divide them and a few clinical features that come in between. I think it's smart that they've included these indeterminate lesions because that's the vocabulary that we use as clinicians, where we, you know, don't wanna say, you know, it's absolutely a melanoma. A lot of this is a clinical diagnosis in 99% of the cases, so we're not looking for, you know, a biopsy to make that confirmation of the diagnosis. I would hope that, you know, the phase III guidelines will help put guardrails around, you know, what clinicians will use, with a FDA label, eventually. But using that term indeterminate, probably, you know, will morph and, you know, it kinda gives some flexibility for us as clinicians. Because insurances could then ask, you know, "Are you sure it's a melanoma? Where is the pathology that proves it?" And the study isn't designed to have a histopathologic confirmation before going forward. So I feel actually the indeterminate, you know, is probably gonna be more beneficial for patients than just saying small melanoma because you could get into issues with what insurances will call a melanoma or not. I don't know if you'd agree with that. You raise an interesting question. So, like, in your current practice, how often do you have to rely on pathology to make the call versus this is what you do all day, is decide what the- Yeah. So it's especially for these smaller tumors, you know, less than three mm, there's a definitive risk in trying to be, you know, trying to get a histopathologic diagnosis. So we do that in the minority of the time. So this is all a clinical diagnosis. And we have, I think, you know, good clinical parameters that we use to make that call. But if you force me to, you know, prove that it's a melanoma at every time, we can have a whole discussion as to why that's not a good idea. So I kinda feel like having this indeterminate component in the label is actually important. And quite frankly, that same thing is there for radiotherapy, right? You progress to radiotherapy with an expectation that someone's gonna pay for it- without having tissue. With radiotherapy, I have to write that it's a melanoma. Like, I can't, you know, kind of, you know, tell a patient that they're gonna get approved by insurance for this hospitalization and stay, et cetera, you know, tens of thousands of dollars, on just, "Oh, I think it could be a melanoma. Like, I have to then give them a life-altering, you know, diagnosis on paper that it's a melanoma. You know, if I have an alternative for an indeterminate lesion, you know, with guidelines, that actually, I think, is better for the patient. Yeah. And I think the flip side is that even if you did have to, it sounds like what you're saying is that when you're deciding that you're going to pursue a definitive therapy, it sort of buys itself the label of melanoma officially anyways. And to the question that was asked, I imagine the same. You know, if there were to be that kind of a restrictive label, the same thing would apply there, right? You would call it what it is- and what you're treating it for. Yes. But I think it's a good precedent that currently the payers approve radiotherapy without a tissue diagnosis because that's, that's not the standard of care in melanoma. So, you know, this therapy also presumably would not require, you know, tissue. It's actually an interesting question. This would often come up with patients who had cancer insurance. And, you know, they'd say, "Oh, where's the tissue diagnosis?" And we'll just explain that doesn't really exist in the realm of uveal melanoma. That's not a thing, and they understood. Thank you. Good discussion. Tara, our next? Yes. So our next question comes from George Farmer at Scotiabank. Please go ahead, George. Hi, good morning. Thanks for taking my questions. Yeah, you know, so bel-sar has been around now for a while. I guess before the suprachoroidal administration trial was also administered intravitreally. You know, so there's been a lot of patient experience now. I was wondering if either of the docs on the call could comment on what, you know, the characteristics of these tumors after they progress. Is there? Have they, in fact, slowed down, or maybe have they become more aggressive? Do you have any feel for that? And then, also regarding, like, the semantics between growth and metastasis, is that just kind of a distinction without a difference, or are you really in fact delaying metastasis of the tumor, or are you just slowing down its growth? So to the second question first, metastasis is kind of a different beast entirely in the sense that when we're talking about control, we're talking about the primary tumor. I think that we don't know one way. You know, as much as Dr. Kim was suggesting, and I agree with her, that the fact that there's immune activation may reduce the rate of metastasis. You know, I think while it's nice to think that it might reduce it, I think we'll just have to wait and see on the metastasis issue. But again, that's totally different from the question of treating the primary tumor in the eye. Because a lot of the time, metastases come from cells that have already left the eye prior to the eye being diagnosed. Mm-hmm. And Ivona Yeah, go ahead, Ivana. Go ahead. I think the unstated assumption here, and we alluded to that before, is that there is a correlation between tumor size and risk of metastasis. So presumably, if we're able to treat melanoma at the earliest stage, you know, smallest size possible, earlier than we might wanna take the risk of radiotherapy for, then presumably, we might be lowering the risk of metastasis a little bit. But we can't. I think that's just not possible to show based on these studies. The sample size is too small, and the follow-up time is too short. But that, that's kinda the unsaid assumption, is that, like, the earlier you treat, the lower the risk of metastasis. And then in terms of the patients who have been treated with radiotherapy, I mean, after bel-sar treatment, I mean, fortunately, I don't have experience with a lot of them. But the few that I have treated don't really seem to act differently than, ones that have not received bel-sar, and I think in our light, that that's a good thing. Mm-hmm. You know? I also think to Prithvi's point, you know, the shift to suprachoroidal, right? We have a lot more experience, as it were, and particularly experience with radiotherapy after bel sar from the intravitreal. We luckily don't have all that much experience with it after suprachoroidal. There is a long-term follow-up built into the phase III study, so we'll have, you know, years of data around metastasis rates, et cetera. Mm-hmm. Great, thank you for that. Thanks, George. So our final question comes from Julian Harrison at BTIG. Please go ahead, Julian. Hi, congrats on this update, and thank you for hosting this. Dr. Kim, earlier on, you mentioned prophylactic strategies. I'm curious how often patients require anti-VEGF injections with current standard of care. Is that broadly given on a prophylactic basis now, or are there high-risk subsets you reserve that for? Yeah, personally, I reserve that for high-risk subsets, which are very similar to the subset of patients that we're treating here, tumors that are, you know, within a couple disc diameters like within three mm of the fovea or optic nerve. You know, prophylactic regimens are about every three to four months. Not everybody employs the prophylactic approach. Other people employ kind of watchful waiting, but this requires also frequent visits. I would say not less than if you're gonna do this, you know, wait and treat at the earliest signs of radiation retinopathy. You would still require careful follow-up about every three to four months with OCT because the goal is to catch the earliest signs before there's significant vision loss, because in treatment of radiation retinopathy, we're not good at improving people's vision. We can't, like, reverse vision loss as well as we can with macular degeneration or diabetic retinopathy. So we're really talking about stabilizing the vision at where it is, and so we wanna catch it as early as possible. And then, you know, if we're treating after the onset of radiation changes, then many times that can be monthly or close to monthly. For how long? Indefinitely. Unfortunately, yeah. So let me push the question a little bit further, then. With anti-VEGF injections or whatever you wanna throw at the radiation retinopathy in the long term, can you get to good vision, or is it inevitable that there's vision loss despite best efforts? I don't think it's inevitable. You know, we all have an example of, you know, patients, like five, ten years after radiotherapy, that still have excellent vision. So it's not inevitable, but by far, the vast majority, even with continued anti-VEGF treatment, have some degree of vision loss, say. Yeah, and Ivana's been a leader in trying to find strategies to prevent vision loss with radiation. But it's also clear that there's a structural destruction of vasculature, and this is. This becomes a vascular disease like diabetic retinopathy, but just a much more acute process. So, you know, what we don't know is, as she said, when to stop the prophylaxis and when to stop the treatment. And often, there's treatment fatigue from our patients, and you know, you don't know. Like, you know, if, is it fatigue from maintaining excellent vision? Probably not. But then, at some point, if there's even some vision loss, the slope is steep. Like, they can just be doing okay, and then, you know, suddenly the vision just drops significantly because you missed one injection. It's still yet unpredictable. There are clinical trials now that might help answer that in the coming years, but yeah, difficult, and it's a long-term conversation with patients as to what to do. Okay, great. Thank you. Very helpful answers. And then just back to the topic of juxtafoveal fluid under the fovea, sorry if I missed it, but is that something easily screened for, and are you excluding that in the phase III COMPASS trial? Yeah, you're talking about the patient that had the juxtafoveal fluid? Yes. We're not excluding it. It was just to say that in that particular patient, even though the tumor responded, there was... the fluid happened to move to a more vision-critical location in the eye, such that it caused a reduction in vision. We're not excluding tumors that have fluid. And I think that's smart because, especially with these tumors in the back of the eye, fluid may be one of the earliest presenting... The fact that the patient has fluid might have altered their vision, which is what took them to get their eyes checked in the first place. So I think the other markers for this treatment, which I think, you know, we've talked about, is to see the impact on fluid you know, from this treatment itself. So, I'm actually glad that we're not excluding fluid, you know, in any form because this could also help us understand some of the biology of what's happening with the treatment. So yeah, that's a good point, Julian. Got it. That makes sense. Thank you. Thanks for the questions, Julian. Yeah, so that was our last question, Jill, so I'll turn it back over to you. Great. Thank you. Well, a huge debt of gratitude to our esteemed ocular oncologists. Really appreciate the depth of the discussion and the engagement. Thank you to everyone who joined the call. With that, we'll close out and wish everyone a good rest of the day. Thank you.