Good afternoon, everyone. Andrew Berens, Senior Research Analyst at Leerink Partners. It's day two of our Global Healthcare Conference in Miami. We're very pleased to have with us Aura Biosciences CEO, Elisabet de los Pinos. Thank you for joining us.
Thank you. It's a pleasure to be here.
Why don't we start with a brief overview of the company?
Yeah. Aura has a novel class of drugs called virus-like drug conjugates, and we're leaders in the development of ocular oncology drugs. The VDCs that we're developing are in phase III for early choroidal melanoma, and we have also the opportunity to develop them in other two ocular oncology indications. Overall, ocular oncology represents one of those therapeutic areas that has had no innovation in 100 years, and our novel approach with a dual mechanism of action is ideally suited to transform the standard of care. Now, that's our lead therapeutic area. We have also initiated development in bladder cancer, and we can talk a little bit more about that. This is a year where we have the end of enrollment as one of our key milestones.
The phase III in early choroidal melanoma has been our value driver, our flagship to get the drug approved. It has an SPA, so that end of enrollment is so important. That's for us has been the central focus, but it's an exciting year on multiple clinical readouts.
Great.
Good to talk about it.
Good. Well, congrats on the progress. Yeah, why don't we start with bel-sar and choroidal melanoma. Can you just describe, I guess, the process, what the drug is? I mean, you mentioned it's a virus conjugate, but there's also a procedure associated with it, which I think is a big part of the commercial proposition.
Absolutely. A virus-like drug conjugate is a virus-like particle that it's targeted to the cancer cell membrane, and it's conjugated to, in this case, in our first VDC, a photosensitizer. We have 200 molecules of the photosensitizer conjugated per virus-like particle. When you inject this VDC, let's say for example in the context of an eye cancer, when you inject it in the eye, it really is. It has no cytotoxicity. It's like a prodrug. It's extremely safe, and it will bind just the membrane of the cancer cell. As you were saying, it requires light activation with infrared wavelength to activate the photosensitizer. When you do that, there is a very robust generation of reactive oxygen species right at the membrane of the cancer cell. The cell goes into necrosis due to an ablative mechanism that's highly reproducible.
It's genetic agnostic, stage agnostic, and tumor agnostic. A secondary mechanism because we're, like, profoundly changing the TME. By breaking down the membrane of the cancer cell, we release damage-associated molecular patterns. There is this big influx of CD4 and CD8 T cells that now react, not to the virus, but to the tumor neoantigens that are exposed with long-term durability of CD8 T- cell memory. That dual mechanism of action is ideally suited for early frontline intervention of early local disease. In cancer, usually that's surgery or radiotherapy. We aim to either replace or highly improve the toxicities associated with those standard of care.
Okay. You've seen it is stimulating the immune system because you have seen some activity in the tumors that are not actually injected or subjected to the laser, correct?
Absolutely. We have not just in preclinical setting, which we saw this great abscopal effect, but in the bladder study in a very early setting, where we were not aiming to see that, and we were just treating one lesion, and we saw lesions outside of the treated area completely go away in a remarkable way, and we were able to do full immune profiling showing that that was absolutely an adaptive immune response, a CD4, CD8 immune response getting rid of the, untreated tumor. If you think about that, the opportunity of treating early in the context of any early cancer and generating that strong immune response, that should prevent metastasis, should prevent recurrence, and should treat very effectively with a lot of safety.
Okay. Let's talk a little bit about the opportunity. Uveal melanoma, it's a spectrum of diseases, right? It's, I mean, it starts on one hand, it could just be a pigment in the eye, and on the other hand, it could be a aggressive malignant tumor that has metastasized and the patient needs to have their eye removed. Can you just circumscribe the area that you guys are targeting for us?
Yes. Early choroidal melanomas are diagnosed very early. In fact, there is the opportunity for imaging diagnostics. You don't even have to do a biopsy. These are lesions that are highly pigmented, and ocular oncologists have a high level of confidence in diagnosing these lesions when they have symptoms of malignant transformation. Because they can see them. For example, they have orange pigment or fluid in those lesions, or a little bit of growth. Those are no longer just pigmented lesions that are benign. Those are. It's a life-threatening disease that should be treated as soon as possible. The problem with the current standard of care and why there is a lack of treatment intervention early on is because the current standard of care for 100 years has been radiotherapy, and that blinds patients. The choice between an early-stage intervention or blindness is a really hard one to make.
The question whether they're easy to identify and whether they can be identified early by ocular oncologist, 100%, and that's something that's to our advantage. The early diagnosis and the interest for early intervention is there. It's just that there has never been a vision-preserving therapy to intervene early.
There's some patients. They see their doctor. They get an eye exam. They see something on the eye. They get referred to retinal specialist. The retinal specialist looks for the risk factors, and if they have one or two or three, it determines kind of the options that they may get. You guys are looking at the patients that have one or two of the risk factors, more or less, that aren't definitive, that if they have too many of the risk factors, they will get radiation, right? Either a plaque or
All our patients in the phase II and in the phase III are early choroidal melanomas that would be deemed eligible for observation for a while. They have documented growth. They have some of these risk factors, but it's okay to watch them for a few months. That's the critical. They would ultimately be treated with radiotherapy within six months, but they're eligible to be in observation. That's very important because in our phase III study, because of that, the FDA allowed us to randomize versus sham. With a drug that works in 80% of patients to be randomized versus sham was a red carpet for us. That's because those patients that have early choroidal melanomas, because of the risk of being blinded with radiotherapy, have that watch and wait period that allows us to put them into the study.
Okay. How many of these patients are there in the U.S.?
Our estimate is that the early choroidal melanoma in the U.S. and Europe is 8,000 patients. 4,000 in the U.S. and 4,000 in Europe. Now, a fraction of those are treated today. If you look at how many patients with early choroidal melanoma are treated with radiotherapy, they're not gonna be 4,000. It's gonna be more like 2,000. The reality is that there is a equal number of patients that are now in that watchful wait. They're not coded as melanomas just because they are not treated, and you don't wanna have a patient with melanoma just in observation. Instead, they code them as high-risk indeterminate lesions so that allow themselves to have this period of observation. This is purely semantics. It's known and it's published that the same genetic mutations exist early on ahead of documented growth.
The fact that they are high-risk indeterminate lesions is just because they don't wanna treat them early enough, and that's why, you know, we have this kind of like semantics of number of patients versus choroidal melanomas. In the future, when there is a drug that's approved, all of those 4,000 will be early choroidal melanomas, and that's one of the key things that we're being very, very clear with ocular oncologists. They want to treat. They want to call them early choroidal melanomas. If there was a drug for those, they would all be treated.
Okay. I guess one of the things that we've been looking at is just how much of a time period is there between when somebody would be considered for the trial or the treatment, and then when they might progress beyond when, you know, they would get something more aggressive, like, you know, when they would get like a plaque or external beam. Like, how long is that window of finding the patient and then getting them referred to the doctor?
For some patients can be 9-12 months. We've heard patients that are two years kind of like around the ophthalmologist, retina specialist, like they are in observation, and then they get referred, and it's too late. Usually the referral patterns are between nine and 12 months.
Okay. A big part of the commercial success will be getting these doctors to realize there's something available now, and they shouldn't just watch and wait and be slow to tell the patient, you know, next available. They should say, "You really should get in because you might be.
Absolutely. Especially because first of all, we're enrolling these patients in the study. It's gonna be unequivocally that the drug works. Most importantly, we have an impeccable safety profile. There's no trade-off with a drug that has such good safety. We clearly see this going from ocular oncologists into the retina specialist. In our phase III, we're seeing that's where the early-stage patients are being referred. These practices, they have high volume patients. Patients may not want to travel to an ocular oncologist if the retina specialist can do the light activation and the suprachoroidal administration. The safety is so good that you don't have to worry about the medical oncologist, you don't have to worry about systemic toxicities. You can just treat locally instead of just observing or sending it to the ocular oncologist.
If that's the case with a buy and bill model, with a rare disease pricing, we see the opportunity really expanding nicely, so that every single early-stage choroidal melanoma will be treated.
Okay. Now what about this criteria for to have some growth? When you add that into the 4,000 + 4,000 patients, what percentage of them actually have that?
Yes. That's actually something that it's so inherent to the study design, and it's critical for the study design, but it's just a fraction, right? We are waiting for patients to meet a certain threshold of active growth so that if they get randomized to sham, we guarantee that those patients in the sham will progress within 6-9 months. It's critical because then we have a highly powered study. We want those patients to be growing. In the real world, none of the ocular oncologists will want to have patients waiting for growth. All the opposite. What they want is to treat ahead of growth because they already know that they have the genetic mutations and the malignancies there. It's really an artifact of the study. It is an enrichment strategy that we're following.
It's very well documented in the regulatory side of like the FDA and EMA that like these type of enrichment strategies are ideal for rare diseases where you don't have the advantage of having so many patients to unequivocally show that it works. We hopefully will be able to make the drug accessible to many more patients. In fact, we have 400 patients that already with the restriction of the enrollment, they're waiting just to have that, like, threshold of active growth with the hope that they will get into a randomized study, with the hope of one of three arms will have bel-sar. That's the unmet need and the fact that patients really want to avoid the blindness associated with radiation.
How confident are you the FDA, if they approve the drug, won't have that requirement in the label for there to be growth since that's the way the trial was designed?
Look, we're basing our assessment in terms of precedent, and that's the best we can do with FDA. There is so much precedent, and there has been discussions with them when we were discussing the SPA, for example, on the need broader than just for the actively growing patients. Tepezza is a clear example of a drug that had exactly an enrichment strategy for the phase III and then was given a broad label. We discussed with Dr. Wiley Chambers, who's now is our advisor outside of FDA, whether that would be something that would be followed in our case. He said, "Absolutely." We feel, like, comfortable as much as one can be based on the precedent and the guidance that we've been given that that's the case. But mostly because that's where the physicians and the patients will want to use the drug.
That's obviously something that we're seeing already now in the study and that we hope to, you know, discuss with the FDA upon approval.
Okay. That trial now, the guidance is for it to be fully enrolled by year-end?
Earlier than that. What we've said is that top line data is gonna be in Q4 of 2027.
Okay.
That's 15 months. The timeline of the study is when the last patient is enrolled, then you count 15 months.
Okay.
Because it's a time-driven analysis. That doesn't mean that all patients will have 15 months. In fact, most of the patients will have between 15 and 24 months. When the last patient meets 15 months, that's when you call the study. It's an event-driven analysis, but at a particular time. If you'll count back from Q4 2027, 15 months, that's where, like, our guidance was given in November, and that is a very, very conservative guidance. It says like, we said, like, "Let's not assume any acceleration of enrollment. Let's be conservative. What we're seeing in the fall, like, the steady enrollment rate, let's project it linearly." We feel really, really good, because we've seen a lot of enthusiasm. The momentum is great.
All I can say is that we're reaffirming guidance of end of enrollment much earlier than year-end.
Okay.
Yes.
Great. Well, that'll be a big, big readout for you guys for sure.
Yes. Absolutely. Yes.
Between now and then, you're gonna have some more data in the eye too. Can you talk a little bit about those programs?
Yes. That's exciting because it's a drug that, again, can truly transform, as I opened this presentation, truly transform ocular oncology. It's probably the only drug that's tumor agnostic for a group of rare cancers. What are these other rare cancers? We're having a phase II study in metastasis to the choroid. These are primary tumors that do not start in the eye. They're metastatic patients, mostly with metastatic breast cancer, whose mets go to the eye. For those patients, despite being treated with systemic medications, today they're all treated with radiation in the eye. They're all being blinded by the radiation, even more so because sometimes these mets are in both eyes, are bilateral. For those patients, having a vision-preserving therapy is really, really critical. That is a study that we're running now.
For any metastatic cancer that has mets to the choroid, we can treat them, and we can treat them safely, and we can preserve vision and treat the tumor effectively. That's a proof of concept study that will read out before the melanoma in 2027. Actually, this is a proof of concept study that we'll provide this year. The second one is cancers of the ocular surface. You can have actually melanomas in the front of the eye as well as you have melanomas in the back of the eye, and also squamous cell carcinomas of the conjunctiva. Well, those are really difficult to treat, although you can see them. The surgeries are tricky, and there's really nothing. They sometimes give chemotherapy as drops of chemotherapy in the eye, mitomycin or 5-FU. Imagine how that feels in the eye.
The recurrence rates are high, and most patients actually end up losing the entire eye. That is another study where we can show a very rapid proof of concept. The same as we did in bladder cancer. Instead of giving suprachoroidally, in this case, we can give intralesional. We can do a biopsy, give the treatment, and see how the tumor responds because we can have a surgery afterwards. It's a window of opportunity, kind of like we did with bladder. Really exciting because there's a very low bar because there's nothing there. Any benefit in terms of preserving the eye, preserving vision, and avoiding the recurrence of these tumors, or even having less of a surgical intervention, that would be fantastic.
As you can see, if we compound all of those indications in ocular oncology, it's one of those medical fields that really it's 66,000 patients without even anyone in preclinical for mets to the choroid or cancers of the ocular surface. The same physicians, the same safety database, the same drug. It's a very easy value proposition to go to the FDA with a successful phase III for melanoma and say, "Hey, can we expand this other proof- of- concept studies so that they serve as pivotal studies and then have the approval as a supplemental BLA on year two and year three?" Then we own the entire ocular oncology space.
Okay. How many patients did you say the whole addressable market could be?
It's 66,000 patients. Each indication is bigger than the one before. We said in early melanoma, we're talking about 8,000 between the-
Yeah
U.S. and Europe, while for metastasis, we're talking about 20,000, and for cancers of the ocular surface, 35,000. In fact, today to our head of the therapeutic area, one investor said like, "So you're practicing at Yale. How many ocular surface cancers do you see per one melanoma?" And he said, "1-5." It is a really good opportunity because again, the same physicians are gonna be so familiar using the drug. Now they can use it in any of these rare cancers. On a standalone, it would nobody has gone for 100 years. us collectively, we have the best drug to tackle them.
Okay. No, that's exciting. Why don't we switch, and I don't know how much time. I want to make sure we have time to talk about the bladder. About 11 minutes. Okay. Yep. Let's switch gears and talk about the bladder program. There's some similarities between that and the ocular program.
Yes, 100%. As I said, this dual mechanism of action is ideal for diseases that are early, local regional, where there's not yet a metastatic disease, but that we can have a dual mechanism of action and prevent the recurrence and metastasis. Bladder cancer, pre-metastatic, what is the number one problem? Recurrence. Especially in intermediate risk, which is the same as in ocular oncology, the earlier you go, the larger number of patients. In those patients, to put them through surgery and multiple rounds of chemotherapy for a disease that can be treated much more efficiently if you had something that was immune mediated versus chemotherapy mediated, it's a big deal. Not replace the surgery. The surgery is something that these physicians love to do, and it may be necessary to do, but you could do it for only neoadjuvant. Why that matters?
Well, it matters because you still have the tumor. You can have the highest exposure of tumor neoantigens to the immune system with something that it's fast, it's easy to do, it's safe. We've developed a formulation that it doesn't require any refrigeration, doesn't require BSL-2, doesn't require general anesthesia. You can just diagnose a papillary lesion, open the fridge, treat it right away, two administrations, and then by the time that you've done that, you have them scheduled for the surgery. The surgery can be either confirmatory that the tumor is gone. The surgery can be staging, making sure that it doesn't progress into the bladder, and the surgery allows you to have a biomarker of response with immune profiling. All of that puts the neoadjuvant as like the novel. We don't compete with any adjuvant treatment.
You can have seven different companies, gemcitabine , docetaxel, mitomycin, whatever you can put in the adjuvant setting, that we're still gonna be in the neoadjuvant as a standalone.
Okay.
That's the differentiation.
You're trying two different approaches around TURBT. One is to eliminate TURBT and the other is in conjunction with it, or have you changed the strategy?
Look, even if we had 100% complete response rate, we think that physicians still want to do the TURBT as a confirmatory step. That provides the most flexibility. We are evaluating immunoablative because we think that the contribution of the drug is very robust. Only with two administrations, we think that we're gonna have a very high understanding of how much the drug contributes to the efficacy. Ultimately, the neoadjuvant provides the most flexibility commercially and also the best ease into the urologist practice because it doesn't replace anything. It's just adding something without adding any safety with something that doesn't require going to the OR that can be value added with a biomarker obtained at the TURBT.
That's again, while we're exploring both and we think that both will have very good data, the neoadjuvant seems like the best suited for a commercial success and to provide patient benefit. In addition, the neoadjuvant allows you to move from non-muscle invasive to other settings where neoadjuvant is clearly established, like muscle invasive, for example. Now you have the first drug approved in neoadjuvant. It's easy. A urologist may easily see that in other settings, like even upper tract or even prostate. Neoadjuvant allows us to really have a positioning that's unique across the disease stage.
Will you remind us what you've seen so far in the bladder setting?
Yeah. We actually in the first study where we didn't even have this new formulation, it was basically the drug from the ocular study in a single dose. We treated single lesion, and we saw in intermediate risk, four of the five patients with intermediate risk lesions completely go away, not just the lesion treated, but also lesions that were not treated. That was a very, very strong, like for a feasibility study where you're trying to see, like, is it safe? Can the physicians do this? That led us to really accelerate development, especially in intermediate risk. In high risk, we also saw a number of complete responses and also abscopal effect and also like a very strong tolerability, so that it's potentially a drug that could be used in high risk equally well, and that's why we're also evaluating that.
From a value proposition and where we see the majority of patients, intermediate risk just makes a lot of sense.
Right. Okay, what are the next updates? What are we gonna learn?
Yeah. In the next update, we have the study with not just single dose, but we have optimized the regimen to be two treatments, so two cycles to really boost this immune response that's probably the biggest value proposition that we have for the patients, like, can we boost the immune response? It's a two cycle followed by either TURBT or just observation. That's the immunoablative versus neoadjuvant in intermediate risk and high risk. In high risk, we only have neoadjuvant. There's not immunoablative cohort. We'll have of these, all of these cohorts with a total of 21 patients, three months data by mid-year. That's in a recurrence-free survival kind of approach, where we're gonna be able to compare to other approaches like adjuvant, but in a very distinctive positioning as a neoadjuvant.
You know, obviously, the value will start accruing as we have longer follow-up because at 12 months is where we're clearly gonna differentiate. With biomarker data and good durability at three months, it's already a drug in a new positioning that should get investor attention.
Okay. The goal will be, after the TURBT, you should see a benefit in terms of the duration of not needing another.
100%.
Okay.
Yes. Yes. Our hope is that in intermediate risk, we don't need all those heavy adjuvant treatments. We don't need to expose patients to chemotherapy. In intermediate risk, with a neoadjuvant approach and a good TURBT, you should be able to have very long durability.
Okay. Okay, very interesting.
That's a lot of the patients, right? Those are the patients that would benefit the most, and that's only, you know, we only have Gemcitabine there for patients.
Right. Okay. Let me see if there's any questions from the audience. Any questions, Grelli? Anything else that we, you wanna cover?
No. It's an exciting year. I think that, a lot of investors is like, "When is that end of enrollment?" Obviously, as you say, we're not updating enrollment monthly, but I would say pay a lot of attention.
Good. Yeah. Now the clock will be ticking then for the data.
Yes, exactly.
Okay.
All right.
Well, congrats on all the progress.
Yes, thank you.