Aura Biosciences, Inc. (AURA) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Aura Biosciences Virtual KOL event. [Operator Instructions]. 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 Eli de los Pinos, Chief Executive Officer of Aura Biosciences. Please go ahead, Eli.

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 managed or the -- intervened by the PhD trained scientists, Chris Howerton, who is a former sell-side analysts, 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 3 for our LEAP 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. And as we've said in the past, we have key clinical milestones coming up this year. And 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 bind 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 but 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. So 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 reading 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'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 the -- 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, they are 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 going to 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 have Dr. Shields. Yes, 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, and Dr. Sagoo, go ahead.

Hello, I'm Mandeep Sagoo, and I work at Moorfields Eye Hospital in London. And I also practice in ocular oncology looking after patients who have intraocular tumors like melanoma, ocular surface tumors. And 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 them 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 Drug Discovery Laboratory there. And then as I mentioned, I joined Aura about a year ago.

Awesome. And yes, 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 sort of a group of diseases that together are a large number of patients, 66,000 patients among our 3 first indications. Really, this slide encapsulates why I decided to come and join Aura a year ago. Not only do we have the potential to completely change the way in the paradigm for treating the first indication, primary uveal melanoma, but really to revolutionize the way that all of the different types of eye cancers are treated, all the patients that I was seeing in clinic that Carol and Mandeep have enumerated, bel-sar really has the potential to revolutionize the way that all of these are treated. Obviously, our lead indications uveal melanoma, as I mentioned. As Eli said, we're in a Phase III trial for this, but we'll also talk about our follow-up indications. The first one being metastasis to the choroid with the 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. And then our third indication, also treated by the same focused call point to 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 2 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 EU. And importantly, all of these have a huge unmet need and we Aura believe that bel-sar can help to fill this need. Of course, looking at our first indication in 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. Go to the next slide. Great. So uveal melanomas divided into 2 main parts. There's early local disease and then late disease. And Aura is focused on the early disease side, which is by far the largest part of the patient population. So 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. And 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. So this is really one large group here of the spectrum of interim relations to small melanomas they constitute local early disease. And ideally, all of these would be treated upfront 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 melanoma, tumors that have already grown very large over time as well as metastatic disease. And late disease is a much smaller subgroup of patients in early disease.

Excellent. Okay. Well, thank you so much for the introduction, Anthony, and not sure. I guess we're ready to go to the panel discussion. I'm not sure what everyone could see right now, but I'll just kind of 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. It's less likely for it to rise 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 metastasis 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?

Yes. I'm Dr. Hakan Demirci, I work at University of Michigan at Kellogg Eye Center. I do ocular oncology full time here. I was trained under Dr. Shields. And -- so I do the -- I treat the tumors in the eye, around the eye, in the orbit and on contract eyeball.

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, those small melanomas or indeterminate lesions. In your experience, what would you say is kind of the relative split between 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 and there are late stage. So the ciliary body, large tumors, for example, or choroidal large tumors that need either radical surgery or radiotherapy. 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, there are probably 2 or threefold the magnitude of the larger ones. So way more cases that we might watch or we might offer early treatment too.

If available, right? Yes.

Totally, yes.

Okay. Actually, Carol, I forgot to clarify, when you kind of 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. Because we usually treat with radiation, but hopefully want to treat with Aura. And whereas metastatic disease is primarily -- is generally treated by the medical oncologist often with systemic chemotherapy or systemic radiotherapy. Occasionally, we can treat them focally in the eye. So different directions for treatment.

Right. And so yes, okay. So you'd have to hand them off basically to medical 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 in -- 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 lay person. So for the plaque radiotherapy, that is like where you put kind of the piece of the radioactive material right on to the eye to focus it into the tumor. Is that basically right?

Yes, exactly. Like in the plaque therapy. It's a -- think about the -- you can think about the disc in a shape of a nickel or dime and then we put this radioactive seeds like the rice seeds on it and then we plan. And when we put the patient under anesthesia under the surgery, this radioactive plaques are placed on the surf -- 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. That's it, and I guess so when you think about 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 we're efficient to operating rooms and then the staff runs. I think the -- it may vary from probably in 45 minutes to an hour surgery to 2 hours surgery. So you can adjust -- you can think about how many hours of -- or you have in a day and then maybe depends.

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 does it actually like to experience that therapy in maybe some of the sequela?

Yes. 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 2 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 every 4-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 to 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. We can work in controlling the tumor, but you got to deal with all the problems.

Yes. 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?

Yes. 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 yes, I see. So even though there could be an appearance of something that's there, again, this is a lay person's perspective, there's no actual malignant growth because it's all like scar tissue basically.

Yes. And the fluid goes away and the orange pigment goes away. These are factors that tell us if something is active. And 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.

Yes. 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 technique, 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 an hour or more and requires anesthesia. And if we're doing radiotherapy with the plaque, then 2 sets of surgeries. And 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 it's 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 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 -- 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 if you decide to do nothing and say, let's just see how it goes because we don't want to mess anything up versus let's do the radiotherapy even though there could be the sequela, I'm worried about it growing, I'm worried about it metastasizing, something like that.

Yes, exactly.

Okay excellent. And so 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 one of them is the outer layer, what we call, the sclera white layer. And under there is a vascular layer or not fully vascular, but there is a layer of what we call the uveal or the choroid. And then in the current trial or in the current technique, that's what we do, we do an injection into this -- between these 2 layers. It is -- there is a special injector is designed and approved for these purposes. So it's an office procedure. You're now the patient and then you perform the injection into this space. The advantage is it delivers the drug or what we 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 extent, it is accepted in the retinal doctors, the doctors who are using different diseases also they are using these 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 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 got to just do that, it'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 an office procedures in outpatient procedures and nothing extra for -- what's the current practice in most of the diseases right now.

Excellent. Okay. Well, great. So Dr. Daniels, I think this is a great time to maybe hear what happened in the Phase II, I guess, what's the high level kind of 12-month data that we have so far?

Yes, sure. So we're going to present the final data in a couple of months from now. But what we presented previously is 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 are in the escalation phase that got at 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, a total of 9 injections of the higher dose or full dose, the 80 micrograms. So we can kind of look at the data as the early low dose, which was very subtherapeutic and give us an idea of what natural history is like or what the sham are -- 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 care as Carol was saying. And then in the very low dose of the sham like natural history are there were only 20% of patients that failed to progress during the 1 year. So we're talking 80% versus 20% to 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 is actually related to the tumor, not the treatment. And on average, the average patient lost one letter of vision, and you compare this to what we know is the core swift radiotherapy from the collaborative ocular melanoma study and other large studies have plaque radiotherapy where the average patient is losing 30 letters. So they're talking about 30 letters with radiotherapy versus 1 letter with bel-sar, basically maintaining your vision. In terms of safety, adverse events are related to treatment. There were few and mild only grade 1 adverse events, predominantly anterior chamber inflammation that always resolved either by itself or just with a little bit of topical steroid eye drop for a week or 2, 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 may be excited you about the data profile if I might put to say that.

Yes. 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 Aura 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 onto radiotherapy, we then know that we're going to lose vision. But when we go with bel-sar, we saw in that Phase II trial, 90% of patients kept their vision. I mean, that's outstanding. Because right now, when we counsel a patient, 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 going to have reduced vision in the side. The radiation won't affect your other eye, but it will affect the vision in this side. And it's a sad day for patients because they know okay, they have a melanoma, which is a cancer and they're going to lose vision and likely go blind. We don't want that. We would rather have an effective treatment that avoids vision loss, and that's what we saw in the Phase II trial, which is that's what got me excited about the Phase II 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 II data that you'd like to share or discuss?

No. 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 II trial, considering the alternatives. So I think this is -- that's completely great. This is a very exciting like 80% as mentioned like you want to see the 100% or everything, but some of the cancer treatments, 80% is a very, very good success, actually.

Right. And the inverse basically of the other arm of the study. Yes, okay. And Anthony, I guess, we're going to move on to like trying to translate this to the Phase III 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 want to 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 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 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, the vision is related to the first key secondary endpoint -- the preservation of vision.

Got it. And 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.

Yes, with rare diseases in general, the guidance is to use what's called enrichment strategy, which means a way to include those tumors in the study where you can most efficiently be able to evaluate whether treatment is effective or not. So in this case, we're specifically enrolling those tumors that have already reached the active growing more rapidly growing phase so that when you -- it will be more obvious and the parent early on already when you treat with bel-sar that it is stopping growth. And that those that are randomized to the sham are -- and will have the ability to progress. So 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 hopefully going to stop that growth completely.

Okay. I got it. And I guess, let's just ask the question to make sure that we're 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 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, 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 yes, 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 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, 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, Phase III replicates, I think definitely, I will use it. And I think the indication will be not only for the growing ones also as Mandeep a little bit ago mentioned that the ones that were suspicious ones also will definitely 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 to 500 patients with uveal melanoma. And I would estimate that about 1/3 are small. So that's between 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 for melanoma drops significantly just by applying this medication. And I think all of us know the risk factors and all of us supply them. And wouldn't it be a great world if we could prevent obvious melanoma from developing.

Yes. No, I completely agree. And so if I -- my math was right, you would say around 50% to 60% of your patients, you would expect to use is in something like that?

Yes. At least 50% of the patients we see. Every week, I discharge patients with indeterminate lesions feeling a little bit bad because I can't justify who...

Right.

But now, I'm not going to 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. Yes, 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 I would say, 200, 250 or small that we would offer treatment with bel-sar but then there's probably another 300, 400 that have indeterminate lesions. They come in 3 or 4 a week come in with a pop-up 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, do you agree would you use the treatment? And do you basically agree with those relative splits and patients that Dr. Shields described?

Absolutely. So we treat about 300 a year, uveal melanoma is about 1/3 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 6 months for a checkup. And out of those, there will 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 hospitals, 1929. And we have been waiting almost 100 years for a new paradigm shift in how to treat melanoma and so we are really excited by this. We potentially have something totally new, new mechanism, dual mechanism treatment. So we're very interested in studying it further and carrying it on further.

Okay. All right. Well, very good. So basically, if I am able to summarize this appropriately, the bel-sar offers the advantages of being convenient 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 a sequela 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 metastasis 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?

Yes, 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 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 light issues becomes an important issue, important problem for the patient.

Yes. Well, and so then Dr. Shields, maybe you could describe to us like what would it mean to be able to kind of effectively treat choroidal metastasis in the current kind of cancer patients, you might see?