Thanks for joining us on day two of the Leerink Partners Global Healthcare Conference. I'm Andy Berens, Senior Biotech Analyst, Head of Targeted and Oncology. We're really happy to have with us Aura Biosciences. We have Eli, the CEO, who's going to walk us through the company, their programs. They have a lot going on. Thank you for joining us, Eli. It's a pleasure. Thank you, Andy. Yep. It's beautiful weather out there. It's so beautiful to be in Miami. Yes, us from the Northeast are not missing the cold wet weather. Why don't we start with an overview of Aura for those that may not be familiar with your company? Yes. At Aura, we're developing a novel class of drugs that we call virus-like drug conjugates. This is a new way to treat cancer. It has a dual mechanism by which we can deliver a cytotoxic payload and activate the immune system. What we would say is similar to an antibody-drug conjugate, but with some key differences that make it very unique. One of them is that the potency of this drug is very high. We can deliver 200 molecules per virus-like particle, where you think an antibody is usually five to seven. The target that we're targeting in the cancer cell is something that you cannot target with an antibody. It's heparan sulfate proteoglycans that are highly sulfated, that are expressed across a variety of solid tumors. It makes it very unique. With an antibody, you can usually just target one particular type of cancer. With this technology, we can go for a rare cancer like melanoma to a much more prevalent cancer like urothelial carcinoma and not change the virus-like particle. It is a very novel class of drugs now with two clinical data sets that supports the mechanism. It's an exciting time. Great. Why don't we start with the ocular program? That was what the company was essentially founded on. You've now expanded into other tumor types. We'll talk about those. Can you tell us what you've shown so far in your ocular program? Yes. We are targeting eye cancers, and in particular, early-stage choroidal melanomas. This is a disease that starts in the eye. 90% of the time it is diagnosed early. This is a cancer where we can truly transform the standard of care. Currently, patients diagnosed with this cancer, the only thing they have available is either wait or have a very difficult radioactive treatment that mainly leaves them with blindness down the line. Obviously, it is a unique opportunity to make a difference because we have a disease we wish all cancers were diagnosed so early, a disease where it is pre-metastatic 90% of the time, localized 90% of the time. There are no targeted therapies. Basically, there is just radiotherapy that blinds patients. That is our key target. What we have seen is that with our treatment, which we give for the first three months, it's an acute treatment, we can basically achieve very similar results as with radiotherapy. These tumors that are growing completely stop growing. They are basically what the equivalent of a local cure. In opposite to radiotherapy that blinds patients, we have shown that we have 90% visual acuity preservation. Obviously, it's the holy grail of cancer, where you can treat in the eye. It's such a delicate organ. You can preserve vision in 90% of the patients where the tumors are right there on the fovea, clearly demonstrating the specificity of binding, the specificity of targeting, and then obviously having something that's very durable because we treat very acutely. Our endpoint is at 12 months. What we have seen is, again, 80% tumor control at 12 months, 90% visual acuity preservation in really difficult-to-treat patients. Exciting phase two data that supports the ongoing phase three. OK. Yeah, I think it's worth going into this in a little more detail because I know there are other companies—there are not a lot of companies going into early-stage uveal melanoma. This is different than the metastatic setting, obviously, but more competitive and a different landscape altogether. Are you guys actually trying to target the patients that are scheduled for some sort of radiation therapy, or are you actually going earlier in the treatment paradigm? I think we should walk through the treatment paradigm because it's really important. Absolutely. Let's start with the treatment paradigm. 4% of Caucasians have a nevus in their eye. That's like a mole. Obviously, that's not cancer, but that's something that already puts you in a category. We know that in the U.S., for example, there are nevus clinics where patients that actually have these moles are followed because that's something that could transform into a melanoma. It's the same as a skin melanoma. From there, these moles sometimes transform. The good news is they give signs of malignant transformation. That's what we call the area of indeterminate lesions. That's when a mole is not normal anymore. It starts having fluid, it grows a little, it has orange pigment, the patient starts having a little bit of symptoms, visual symptoms. That's where you no longer are in the category of a nevus. You are in the category of an early-stage transformation. That is right now the standard of care is just watchful wait. In fact, most of these patients are not even referred. They stay within their regular retina specialist or optometrist. They are followed for maybe six, twelve months until this lesion starts being somehow more dangerous. That is when the referrals happen. That is where you were saying at some--because there is no targeted therapy right now, some of these patients actually are referred quite late. We have seen cases where it is so late that they start to have very high risk of metastatic disease or even metastatic disease altogether. That is the three paradigms: nevus, indeterminate lesions, small melanomas. Unfortunately, there are patients that never go to the ophthalmologist. They never know that they had something and arrive with a very large lesion that basically you have to remove the eye or something that's already metastatic. Where does Aura fit and others? We clearly want to be the front-line treatment. The reason is that we believe that we can avoid the need for radiotherapy and blindness for the majority of the patients. Is a radiotherapy-sparing treatment our goal? That is why we want to go earlier and earlier. We hope that when we have our drug approved, the majority of these referral patterns, either the patients will be referred earlier or the retina specialist will treat themselves. No patient with an indeterminate lesion or something that's not normal should be watched, especially with a life-threatening disease. Now, other companies, as you know, have started in the metastatic and moved to adjuvant and neoadjuvant setting. There is a place for that because when patients are diagnosed either too late or at the moment where they have to receive the plaque radiotherapy, most likely they have a higher risk of metastatic disease. No one wants to lose the eye. Treatment around that to either lower the amount of radiotherapy or preserve your eyeball, it's kind of interesting. Although we think at the end of the day, they all have to receive radiotherapy anyways, which means that they're all going to be blinded anyways. That's the different goal. For us, it's really, really important that it's a front-line early-stage avoid radiotherapy for the majority. If some of them are not fully treated, like we have 80%, the 20% could be retreated. Ultimately, no one wants, and we don't want to see a world where patients are treated with a metal plaque inside of their eye. OK. Just to go a little deeper on this, there basically sounds like three buckets. There are the patients that have a nevi. There are patients that have risk factors that have a lesion with a certain number of risk factors. You actually cited those. I do not know that people realize that that is what you were citing. There are those patients that have these risk factors. Then there are those patients that are scheduled for a procedure, which could be radiation. If they are very unlucky and it is discovered late, it actually could be removal of the eye. You said that these patients are typically diagnosed by a general eye doctor. When you say referral, is that a referral to a retinal specialist? Or is that a referral to an oncologist? Who is the referral made to? Yes. The referral is usually the retina specialist or the optometrists themselves or the ophthalmologist that they refer to this small group of ocular oncologists, which there are only 50 in the U.S. Usually, the referrals will happen for patients that have been in observation for one year or even two years. They have this kind of like indeterminate lesion. They call it indeterminate lesions because they do not want to treat them. There is actually a genetic analysis done that all of these early lesions are malignant already. It is really semantics on what you call a small melanoma versus indeterminate lesion. It is driven by the treatment that you do. If you observe, you call it an indeterminate lesion. If you treat, you call it a small melanoma. Ultimately, we will want to treat them all. In our study, what we're saying is we are enrolling indeterminate lesions and small melanomas because ultimately, we don't want the choice of semantics. We want all of the front-line patients to receive our treatment. You're not enrolling patients that are scheduled for radiation or excision of the eye at this point? Not the larger ones. Some of this, and again, depending on the site that you go, a small melanoma or indeterminate lesion is sometimes scheduled for radiation. What we are not including is the larger ones, the ones that are going for enucleation. We do have a size cutoff for our study. That is very important. The reason for that is that the FDA allowed us to have a randomized study versus observation versus sham. You cannot put patients that are readily so big or so dangerous that you do not want to put them in a study versus sham. By default, the randomization versus sham kind of makes the inclusion criteria fall into that early-stage disease and not so much into those that have tumors that really cannot wait a day before they are treated with plaque. OK. Why don't we talk about what makes the buckets that are really important that you're targeting? That bucket of patients that have enough risk factors that the doctor or the patient are concerned that they're going to have a malignant progression, but yet not aggressive enough or big enough, enough of the risk factors to actually warrant the procedure. Correct. What patients fall into that? How many risk factors? What is it that tips the doctor or the patient towards getting the procedure versus watching and waiting? It depends. For example, now that we have the study globally, the bar may move depending on the physician. The one thing that absolutely differentiates a nevus from a melanoma is growth. That is why for us it's so important because we didn't want to say, oh, we're developing a drug for nevus. No one needs a drug for nevus. For us, it's like regardless of the numbers of risk factors, if they have a little bit of growth, it's something that should be treated. That's why our enrichment strategy with documented growth is critical. I mean, it is not a black and white science that you'll say, like if you have this, you're a melanoma. You have this. You have an indeterminate lesion. It is something that we feel like there is a very large number of patients that could benefit. At the end of the day, growth is what really, really demarks healthy from disease. Right. It seems to me one of the potentially the challenges will be getting patients referred early enough to somebody that can administer this procedure, but yet not late enough where they're too aggressive maybe. They may go on and have some sort of procedure, whether it be radiation. How many of those patients exist? How hard has it been to capture them in that sweet spot between the nevus and their schedule for? Yeah. There are a ton of patients. All I can tell you is we have a pre-screening tool where patients that actually have something that's already indeterminate, that some of them are saying, we don't want radiotherapy. We are waiting to be enrolled in the study so that we can meet the growth criteria that's required. We had a physician in London who said this is the first time in 20 years that I have patients literally disappointed that their tumor is not growing fast enough to get into your study because no one wants their tumor to grow. That's the opposite of we always want tumors to go away. That is the unmet need. We have over 170 patients that are just waiting to get into the study. This is a very large patient pool. The problem is, as you know, in rare disease when there are no drugs approved and there's uncertainty of, well, if I get treated, I'm going to be blinded, the quantification of patients is difficult. What we're seeing is that the unmet need and the number of patients that exist is really, really very high. It's a matter of having the drug approved so that we can really quantify the market opportunity properly. OK. Are we talking thousands of patients? We're talking about, yes. Obviously, now we characterize the market as 11,000 totally. We're saying 8,000 patients just in the U.S. and Europe would currently in our market research fall into this category. That is just being very, very conservative in patients that have three risk factors that are really kind of like in this paradigm of waiting six months and getting into treatment. If you think about a drug that's extremely safe, that has literally Grade 1 adverse events, that has zero systemic adverse events, that can be treated locally, that everyone can do, even a retina specialist, we think that the number of patients potentially could be larger. Initially, our 8,000 patients is very well quantified in the early stage. No one would choose radiotherapy versus something that preserves your vision. You would always choose something that preserves your vision first. Those 8,000 patients, you said three risk factors. So that's. Two, three risk factors. Two, three. OK. What about one? That's where we start saying one risk factor is an indeterminate lesion. Then you go into a very large number of patients. OK. What number of risk factors generally cause patients to actually have radiation treatment? Depending on the physician that you talk, but usually three risk factors is what and depends on which ones. Like for example, the orange pigment, fluid, and size are the three combination that makes investigators already uncomfortable and want to start to treat. If you have one or two, then maybe you watch. Again, you're watching right now, you're watching something with risk factors. That's the paradigm for me of the absolute thing that we should never do. You would never watch a mole that has risk factors. You would never do that if it's a life-threatening disease that can kill you. That's the opportunity for us, especially because we're not quantifying risk factors in our study. We're just saying indeterminate lesions and small melanomas. To your question, it's like how many exactly have one, two, or three? It will not matter. Everyone will be treated. What percentage of patients do you think you will get in your trial with one, two, or three? Do you have any? The majority of patients have one, two, or three in our study. OK. Will there be more three? Or there'll be more two or one? You don't know yet. With growth, usually it doesn't really matter. As soon as they're growing, the risk factors just don't matter. Usually, growth is associated with two or three risk factors. Usually, they go all hand in hand. OK. Let's talk about the trial. You talked about it's three arms, sham, which means that the FDA obviously feels these patients that you're enrolling are not aggressive enough that they require some immediate treatment. That's different than the trial that some other companies are running, right? Correct. OK. Walk us through the arms of the trial and the endpoints that you guys are shooting for. Yes. It really is a we had really good conversations with the FDA because this is the ophthalmology division. They really wanted to see a drug that preserves vision as front-line therapy. They allowed us to have a study versus sham. With a drug that has 80% efficacy and 90% visual acuity preservation to compare to sham is like a red carpet. Especially because we're enrolling patients that have a little bit of active growth. We are looking at time to tumor progression. What is clearly, and with 10 patients per arm, we're already seeing it in phase two, is that we have the treatment arm with high dose of bel-sar given for the first three months. Very few events of tumor progression happen. If you count of an N of 10, we have two events. In the sham arm, right now, we're comparing that to the lower dose arm in the phase II. The majority of patients will progress very quickly because we're enrolling with these actively growing lesions. Within the first 6-12 months, all of those in the sham should already receive radiotherapy. In a time to event analysis with a log rank test, we're going to have an extremely low p-value for the primary endpoint, which is just time to tumor progression. The other advantage is for the key secondary, in addition to tumor progression, we're adding events of visual acuity loss. Obviously, we have very few. We have 90% visual acuity preservation. Still, if you compare it to sham, we're going to be able to have vision as a claim because we're counting both either tumor progression or visual acuity failure. Again, very highly powered for both vision and tumor control with 100 patients or approximately 100 patients with a SPA agreement that should support registration. Again, really, really exciting to see, very innovative for the FDA to allow us to have a study front line with such a clear assumption so that it's unequivocal that we'll have a drug that should be used because who should wait for a tumor to grow? You should not wait for a tumor to grow. OK. I think it's important you also alluded to this. The doctors that will be treating these patients are the eye doctors. They're the retinal specialists, right? Correct. It doesn't require a medical oncologist. It doesn't require a radiation physicist or anyone to. Exactly. That is the advantage too, right? Usually, we say the market growth will be aligned with the physician referrals. We have right now a very efficient market launch potential with 50 specialists, which are the ocular oncologists, and 15 in the U.S. and 15 in Europe. As you see, something that is so easy to administer, why would you refer your patient to travel to an ocular oncologist when you can treat it yourself? It is one risk factor, two risk factors. You should not wait for any risk factor, right? At the moment that is no longer a nevus, you should be able to treat. We see that beautiful opportunity where we market very efficiently initially. It expands to a retina specialist. In retina, there is not a lot of exciting things except the anti-VEGFs that have been there forever. It's really nice for these retina specialists to have something that's so scary as a life-threatening disease in the eye to be able to treat it with no trade-off. I guess in terms of durability and risk for becoming metastatic, how long is the FDA going to require you follow up these patients? I know that some of the other trials that are a little later in the disease have to show the FDA that there's no risk for metastatic disease. It seems like your trial, which has a control arm with sham, that concern is less at the agency. Are they worried about that, using this could progress to more metastatic patients down the road? Right. That was a discussion. Obviously, our advantage is that we'll go so early in the treatment paradigm. The risk of metastasis is much lower. Still, we have the endpoint is 15 months, as you know, for our study. What we've discussed with the FDA is that we will have a long-term registry, a long-term follow-up for these patients so that we can look at the metastatic rate. All of the patients, even in the intravitreal study initially, all of them are followed for metastatic disease to make sure that our hope is that it's going to have much less metastatic disease for two reasons: earlier intervention and a mechanism of action that's cell mediated. We have T-cell mediated response. Both should work against developing metastasis. Hopefully, longer- term, we'll be able to show that this is the right thing to do, treat early with something that's really targeted and has a pre-immunogenic cell death, should prevent metastatic disease. It is not a requirement for approval. It is basically just a follow-up to make sure that the patients are not at risk. What have you seen in the earlier trials in terms of the durability of the responses that you're getting or the stable disease that you're getting in the program? Yeah. The patients for the endpoint of tumor progression are just followed for 12 months. In the registry, they're just followed for metastatic disease. We don't have the durability of response from 12- 24 to three years. That's something really important that we're going to be looking at in phase III, after phase III. Again, for us, it's also a great opportunity for retreatment or even for consolidation in year two and year three because there's no trade-off with our therapy. We don't have systemic disease risk. We don't have systemic side effects. We don't have the risk of losing vision. The possibility of that longer-term kind of treatment where every year you go and receive potentially a treatment to consolidate is something that we really want to explore. We don't have data beyond 12 months right now. OK. Retreatment is definitely something you think that's possible. Is there a risk or concern about potentially having more local reactions as you get more repetitions of the drug and the laser? We do not think so. This is a drug that has been extremely well tolerated with multiple administrations. There is very little risk for visual acuity loss. Obviously, we will have to do the study and look at retreatment in year two and year three to see how the patients do. Upfront, we have not seen a spike of anti-drug antibodies systemically. We have not seen any kind of side effect that would predict for any kind of toxicity on retreatment. Do you guys have a long-term extension trial in place to enroll these patients after the. Yes. Retreatment is going to be part of that? Right now, retreatment is not contemplated. We are thinking of adding that so that we can properly evaluate it in a clinical trial versus just physicians just doing it. We'll probably add that to the study. OK. Just one last question before we shift to the bladder. We can go to one of the other tumors if you prefer to talk about that. I guess in terms of the actual device and the training to do your procedure, is that going to require a big effort on the company? Do the physicians have to buy new equipment to do the procedure? Not at all. I mean, the suprachoroidal microinjector, you look at these retina specialists, they're so, sorry, the ocular oncologists, right? If they do the complex plaque brachytherapy, which is such a complex surgery, the suprachoroidal injection is like nothing. In fact, we've trained now globally all of the ocular oncologists. There has been no issue in the study of missed injections, of problems, or any type of hemorrhage, or any risk that you would foresee. It has been extremely easy to do. We don't see any risk on the microinjector. We also don't have any barrier with the light activation because this is a device that had been there for years. Even before Avastin and Lucentis came to life, these lasers had been used. Some of the lymphomas in the eyes are treated with this laser. Very little barrier on the device. Something that, in fact, for this type of physicians, these local administrations are something that they feel that they want to do. They can charge for it. They have control of the patient. I think it's a positive rather than a negative. OK. I know we only have three minutes left. You guys recently decided to branch with your drug, the procedure beyond the eye. Can you just give us an overview about what you've seen and where you're going with the bladder program? Yes. It's an exciting time for the bladder program. I don't know if you saw, but we have the late breaker presentation at the European Association of Urology, which is going to be on Saturday, the 22nd of March. I just would like to say everyone should listen in. We're going to have a KOL event afterwards. It's an exciting time. I mean, there we are foreseeing a complete treatment paradigm shift. With the mechanism of action that we have and the early data that we're seeing, we think that we could transform the treatment front line the same as we're doing in the eye, where you treat with bel-sar first, where you can have something that treats the disease and has the cell mediated immunity that really could show the durability of response. Right now, bladder cancer is treated with surgery as an anchor and a lot of adjuvant treatments. Everyone that's in the field, every single company is working towards adding durability of response with an adjuvant treatment. Our scientific-based approach is very difficult to educate the immune system towards the tumor or to remove the tumor if the tumor is removed by surgery. Immune mediated mechanisms of action need the tumor to react to. If you remove the tumor, you're not going to have durability of response unless you put chemotherapy for two years. That is the paradigm shift. We want to treat first. We want to treat the tumor. We want to generate a cell mediated immune response with a very strong CD8 and CD4 T-cell response against the tumor. Probably all the issues of durability of response are going to go away. Of course, we're early. It's a big paradigm shift. We're doing something that's completely different from anyone else with a mechanism that probably combines both the power of chemotherapy without being chemotherapy and the power of a virus without being a replicating virus. Those two are in our therapy. If you can do that first, then probably the issues for these patients will go away. Exciting times. You'll see how the KOLs will be embracing this change. There's going to be a lot of discussion. If we can position it first, then it doesn't matter what goes second. Great. I think that wraps up the session. Thank you for joining us and walking us through what you guys are doing. We look forward to see the progress in 22nd, you said? The end of the month. 22nd. It's coming very soon. Yes, yes. Stay tuned. Thanks for the invitation. It was great. Yeah. Thank you, Eli. Thanks, everyone, for joining us.