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

Good morning, and welcome to the Aura Biosciences Virtual Ocular Oncology Investor 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 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 are 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 6 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 the second half of 2026. So before I dive into Bel-sar's mechanism of action, I just mentioned 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 of 2024, and then other HSPG expressing tumors in our preclinical pipeline. So 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. And what's interesting, primary uveal melanoma are most near term, about 11,000 patients per year. When we look at then going to metastasis, the cord that doubles the potential market size to $20,000 per year, then moving into ocular surface cancers out to 35,000 per year. So 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'm going to move live to Lisbon in just one moment, but I think, again, just want to highlight for everyone on the call why we are excited by and the important highlights you're going to hear today. So the first is that Phase I is complete. All patients are now at their 12-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 going to 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 Ivana, about 200 yards away from where Dr. Kim just presented the results. So that is live as it can get. So before we speak about the results today, I just wanted to help position everybody on the time line of where we're talking about in terms of melanoma, that'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, determinate lesions, these are seen by ocular oncologists, 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 where 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?

So it's my pleasure to give this encore presentation 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 is 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 the 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 2 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 these 2 injections followed by laser. One cycle, as we'll refer to, involves 3 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 micrograms of Bel-sar administered through 3 cycles of treatment. The key endpoints were tumor progression, which was defined as an increase in tumor height of at least 0.5 millimeters or an increase in largest tumor basal diameter of at least 1.5 millimeters. Visual acuity loss is defined as a loss of 15 letters from baseline and changes in tumor thickness growth rates were also evaluated. So 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 2 millimeters and a baseline largest basal diameter of about 8.5 millimeters. They are 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, and the Phase III eligible criteria just excluded one patient with a circumpapillary tumor that would not be involved 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 with 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 1 and 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, global Phase III trial is now enrolling with a target enrollment of approximately 100 subjects. The design is shown here. It's a 2:1:2 randomization with a high dose group and a lower dose group and a sham control arm. The primary endpoint is timed 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. I'm Dr. Mruthyunjaya 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 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 want to 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 nonsurgical treatment that is giving us these results. So I think it's, in many ways, we can talk about them, this is a very exciting data.

I really appreciate your synopsis of your thoughts on this. As you talk about excitement, what gets us excited is as both of you discussed, we had a continuation of the efficacy that we've seen before, but obviously, the vision is critical. I'll talk about that at length and then the safety profile, we'll also talk about. So let's talk about each one in turn. We'll save the efficacy for later, and we'll start talking about vision and safety as you were highlighting. So first, let's talk about the safety profile, and we'll go to Dr. Kim first. So what do you think about the ocular safety profile of Bel-sar that we're seeing 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 any treatment that only causes very mild anterior chamber inflammation that can be self-limited or can be easily controlled with just topical therapy more than surpasses the bar for safety, especially when you compare this to the standard treatment, which has 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 are seen with that. So maybe we'll go ahead talking with Mruthyunjaya. Can you talk about what in general you see in terms of the safety profile and 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 the patient has to go to the operating group. Sometimes we have to remove eye muscles that are attached to the eye in order to get the disc in he 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 2 to 3 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. And if I could 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 at intravitreal approach. 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 specialists, as we all are, 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 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 -- I'm talking about the safety profile. And maybe if you could comment on the vision aspect of things as well, how do you see vision results playing out?

Most of the conversation that move with patients regarding early treatment for tumors settles not on 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 the likelihood of, oh, maybe -- we just tell the patients upfront. And I tell them that within 2 to 3 years, the patient will be unable to read the biggest headline in the newspaper even with the best of glasses and erection. 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 want to give, these patients are going to lose vision and probably 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 to get even more nuance, 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.

I'm shifting to Dr. Kim, we're going to stick on the vision topic. You treat patients a lot with proton beam. And so -- because of that you referred to over hundreds of patients in these difficult locations near the optic disc or near the fovea, we've sort of discussed those -- thrown those around a little bit, but it's 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 with radiation for treatment?

Yes. 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 -- 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're -- so we know that the vision loss is 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 of -- we know who's going to 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 radiotherapy is a week, a few days out of the patient's life. If you want to maintain vision after radiotherapy, it's years of consistent anti-VEGF injections, maybe initially quarterly, but then as the macular edema and other complications develop, it can be much more frequently. So the potential for offering a therapy that 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. We probably don't have [indiscernible]. Yes, the regimen is intensive upfront, but full year saving a lot of intensive treatments and you saving the patient for acquiring 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 kind of describe to me what you tell patients to expect currently, both into the division, 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 the -- other than is the tumor going to spread outside of my eye, the next primary concern for most patients is what -- am I going to 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 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 a commitment to ongoing treatments of injections into the eye.

Because of the radiation. 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 that evolve in over time?

Yes. I think for patients that meet the criteria, the inclusion criteria in these studies is definitely an attractive option. I think we have to admit that based on the current data, possibly the tumor control rate is not going to be as high as with radiation. But if there's an 80% chance that you could have 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 longer term, it would be important to try to show whether that differential actually has any significant impact on other outcomes other than vision. We're definitely still concerned about long-term tumor control.

Yes. I think that's an excellent point. And obviously, if all patients could have that chance upfront to save their vision, then you can always keep it with you in your back pocket if you needed it, but hopefully, very few patients actually need to go on to that. Dr. Mruthyunjaya, sort of the same question. If the efficacy and safety were to hold up into 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 a form of cancer that we want to continue to watch it because we're worried about vision loss. And 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 -- for them, there's no option that they don't want to undertake a treatment that could lead to vision loss. So I think it would provide the clinician a really important tool to move treatment earlier in the time course. You showed that course of patients 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 seeking out some of those early options. Especially if this therapy meets its end points there is going to be a greater understanding about the need for screening and identifying patients at an earlier time point anyway. So that is going to change kind of the work of primary care, eye care specialists, ophthalmologists, optometrists. Knowing that there is an option, I think you'll find more patients than we've ever seen before because they're going to be identified and then they're going to want to 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 great. You bring something up that I wasn't even going to talk about, but I'll pursue your answer. So if -- so the 80% efficacy, is that meaningful to you. Again, assuming it holds up in Phase III, et cetera, is it meaningful to you in terms of what it would mean for when you treat these patients? You brought up the concept of have patients [indiscernible] would work earlier. How would you -- can you elaborate a little bit growth?

Yes. 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 we may be fundamentally altering the biology of these tumors, right? So these very small lesions which may have a lower metastatic risk than a larger tumor for sure based on many data sets, but we may be slowing down the most viable cells that are in the tumor. And that's going to bear out with long-term data for sure. So I think that the options that are -- 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 an 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...

Correct.

Let's -- earlier, you have brought up the injections and let's talk about the -- I'll 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 of minutes. I think it's a little -- it 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 retinal physicians and ocular oncologists. I think the microinjector tool really 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 injectors use 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 at 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 current verteporfin photodynamic therapy for -- it was first developed for macular degeneration. Now it's more used for other ocular oncology indication. So we're really familiar with the laser. I think it's a little bit more time-consuming than like regular PDT because we're covering a larger lesion and we have to do 2 rounds of it. But overall, it's 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. So flipping that around to Dr. Mruthyunjaya, so if you're going to place a plaque on a patient, tell me a little bit more about how that's done in terms of anesthesia and patient?

Yes. 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 that 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 disk 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 disk needs to be covering. And then we temporarily then reclose the conjunctiva, we wake the patient up. And then they keep the disk in place between 5 and 7 days depending on the institution where that radiation slowly kind of soaks in. During that time, they have eyedrops. 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 reversed 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 disk 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 counsel them on two risks of anesthesia for the placement and then the removal and then risks of infection bleeding are there. Sometimes you 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.

You talked about the oral pain medicine. Are you sometimes -- are you giving them high pain medicine or?

Yes. 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.

I always used to joke that I should be the best friend of the day. I play [indiscernible] I was best friend of day, I took it away from them. So we're going to shift gears a little bit in the last few minutes to talk about the Phase III study and the designs and the thoughts [indiscernible] like to hit for success. So we'll reverse the order. We'll go back to Dr. Mruthyunjaya first for this section. So 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 going to be able to have patients from all over the world be part of the study. They 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, it's -- they're strict. And I think what that's doing is to really enhance the population for real small melanomas. And these...

Meaning, no question of actual melanomas?

Right. They are actually melanoma is based on clinical criteria and growth at a rate that's higher than a typical standard mole or nevus. So that -- so if we fulfill the entry criteria, then I think we're all going to be much more confident that these aren't just -- we're not overtreating 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 multiple sites for 100 patients. No one clinical site would really be able to enroll 5, 10, 20 patients like you might have for other ophthalmic or other oncologic studies. And in doing so, I think that we'll see kind of real world also what the treatments are. I think patients are always going to be hesitant to enter a Phase III study where there is a control arm or a sham treatment. But I think in oncology, we know that, that's the reality for us to reach the bar. But what I tell patients is that unlike a clinical practice where you might say, come back in 4 months or 6 months because we don't have the answer as to how often these patients would be screened, even the masked, sham treatment patients are being followed incredibly close. So if there is...

Circumstances twice a week imaging?

Yes, right. So way more than what they would as part of a "standard of care." So these patients have a safety net under them. So even though they're growing quickly compared to just a molar and nevus, we would have the opportunity to intervene with standard of care radiation at the earliest time point. So that would allow us to catch patients that might fall under that 20% progression rate, but also the controlled patients as well.

Yes, that's a good point that the patients who do get randomized to sham become eligible for radiotherapies soon as they progress and 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 the Phase II in the therapeutic group matches the patients who are 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. This is the first new treatment for ocular melanoma in decades. And so I think in the early stages, we were all learning a lot about what patient population is most appropriate for this type of treatment. And so that led to 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 captured as an ideal of a population that's possible. But that highest dose therapeutic group in Phase II with 100% documented growth, basically exactly mirrors what patients who are enrolling now in Phase III.

And the patient population that we landed on being the small tumors under 2.5 millimeters, does that group do you think needs a good option or needs something to -- available?

Yes. As we mentioned previously, many of these patients because the risk of vision loss is so high with radiotherapy, we are sitting on these lesions for a few months typically before we really pull the trigger because we just don't like the thought of having to fry the macular. But -- 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 going to open up now for question and answer from our online audience.

[Operator Instructions] So our first question comes from Philip Nadeau at Cowen.

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 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, 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?

Yes. 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?

Yes. I mean, I guess we're not -- 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, we would like to not if we were to replicate the results of the Phase II where we have at least 80% tumor control. So no progression over the whole time of the 15-month study in about 80% of these patients, then we would probably consider that a viable treatment option for this subgroup of patients. Again, we're not expecting, I think, the 95% kind of rates of tumor control that we get with a very destructive, like pretty much nonselective 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 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 a 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 replacing radiotherapy in most patients in 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 is 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 going to be the majority of patients. It's really going to be the small very thin tumors in the back of the eye.

So our next question comes from Jingming Chen at Evercore.

This is Jingming on for Lisa. So we have 2 questions. So out of the 10 Phase III eligible patients the 2 who failed to achieve tumor control, can you give us a bit more color on details of these 2 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, apparently, that patient had preexisting juxtafoveal fluid under the fovea. So how common is this condition in the general patient population? And how -- do you think that's the cost of the vision control failure?