Good morning and welcome once again to TD Cowen's 45th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen. It's my pleasure to moderate a fireside chat with Ellie de los Pinos, the founder and CEO of Aura Biosciences. Ellie, maybe I'll kick it to you to start. Can you give a brief state of the company overview, biggest strengths, biggest challenges, and how is Aura going to create shareholder value in the next 12 months?
Yeah, thank you. It's an exciting time for Aura. We are developing a new class of drugs that we call virus-like drug conjugates. One of the highlights is that we are in phase III with a SPA agreement and actively enrolling. It is obviously a time where we start thinking about pre-commercial, all of those things that, you know, initially when you are in the early stage development, you don't think about. It's a good time for the company. The field that we're going to go first is ocular oncology, which is a group of rare cancers. Our lead indication is in early stage choroidal melanoma. We're also in phase II for metastasis to the choroid. We have the opportunity of cancers of the ocular surface.
One of the key things and opportunities of our company is that it's not just a drug for one particular rare indication. Our first rare indication is like the proof of concept. We can really bring these across many other indications. One of the reasons that I feel so comfortable and confident saying that is that now we have two clinical data sets, both in melanoma and in bladder cancer, showing that the drug works. The idea is that we are late stage, phase III. We're going to launch in choroidal melanoma. We can really bring these to broader opportunities like bladder cancer.
Perfect. For those less familiar, could you maybe provide a brief introduction to bel-sar, its mechanism, and the technology platform underlying it?
Yeah, so VDCs are a very novel modality. You can imagine an ADC being very similar, right? You have an antibody-drug conjugate. In this case, it has a virus-like particle that's conjugated to a cytotoxic payload. That's the concept. Why it's different and we think it can provide really an advantage for the treatment of early stage local cancers is that it's extremely potent. It's very safe. It has a dual mechanism of action. The way it works is that the virus-like particle basically binds the cancer cell. We have a cytotoxic payload. In our first VDC, it's a light-activated cytotoxic payload that really very, very fast kills the cancer cell. We have a second mechanism of action, which is an immune activation. If you think about treating early stage local cancers, what do you want?
You want something very efficient that can preserve the organ. What we want is a cell-mediated immune response. Because if we can do that, we potentially can actually achieve those local cures because we're not treating metastatic disease. This is an ideal approach for those early stage local cancers. We've shown it in the eye. With early melanoma, we've shown it in the bladder. The opportunity is very big, but there's not a lot of competition. Everyone is in metastatic disease. The early local treatment of cancers with this novel modality is something that we're truly pioneering and we think can make a big difference.
Maybe we'll start with bladder cancer. There was some news yesterday morning. Can you maybe briefly outline the news?
Yeah, so in bladder cancer, we presented some early data in the fall. It was the first time that we were presenting data in such a large indication. It showed incredible results. In a phase I, you do not really expect to see complete responses, and especially when you start with a single dose with an ocular volume. That was our initial kind of like presentation. Now we have the full window of opportunity study completed with the full immune staining, evaluating the full mechanism of action in this particular indication. We got the late breaker presentation on Saturday at the European Academy of Urology, which is the equivalent of AUA, the American Academy of Urology. Big, big attendance, one of the top ones globally.
The fact that we were able to get the late breaker is because we think we have a paradigm-shifting approach that's very different from anyone else in this field and that can really have a dramatic impact. That is why you get this kind of late breaker. We are excited. We are going to be able to present additional data than what we presented in the fall. We will also have a research forum. We will have a KOL event on Monday with American KOLs to discuss why this is a paradigm-shifting approach and why the data is so meaningful.
Could you describe the study design and what does it mean to be a window of opportunity study?
Yeah, so a window of opportunity study is a unique study where you basically are giving your drug right ahead of standard of care. You are offering the patient standard of care, not a delayed standard of care. In the case of bladder cancer, where the standard of care is surgery because it is local early stage disease, what we discussed with the FDA is an approach where we were able to give just a single treatment of bel-sar and then perform a standard of care surgery 7-14 days after. This provides an advantage. You know, obviously, it is the first time that we were doing this in bladder cancer. It is safe for the patient. For the company and for us, it was very important because the surgery allows us to have tissue after treatment. In tissue after treatment, you can do immunohistopathological assessment.
You can look at the immune response. You can actually see the drug works as it had worked and we've seen in over 10 different animal models. Do we see necrosis? Do we see the cell-mediated immunity? That is the advantage of this study. The disadvantage is that, obviously, even if the drug works dramatically well by design, you have the surgery. You can't evaluate durability of response. You can't look at this as from the perspective of a phase II because we were allowed to jump very quickly on the heels of our ocular data. That was kind of like the agreement with the FDA. That is the pros and cons. It is very exciting for us for the first time when we presented the data in the fall that because we have this tissue, we could do the IHC evaluation.
When you look at a single dose having complete clinical responses, like the tumor's melting away, and then it's not just that you don't see the tumor on cystoscopy, which is the normal case in a phase II, you actually, even if you don't see it, you go and do surgery, you look, and you see that there was not a single cancer cell left behind. It was full of infiltrate of CD4 and CD8 just in seven days. That's the exciting thing of this study. Of course, acknowledging the limitations that what's next and what's the durability, but really to have that assessment, it was something that we could never do in the eye. You can't remove the eye and say, see, there's nothing there. In the bladder, yes.
It was very, very reassuring for us that we have a drug that works really well across very, very different types of tumors.
In the initial five patients you saw, four had absolutely no sign of tumor. We're going to get an update at the end of the month. Can you give us some sense of the number of patients that will be in that update, differences in dosing, and kind of anything that will be new and incremental versus what we previously saw?
Yeah, so the majority of the patients that we had presented were intermediate risk. The study did not obviously just enroll intermediate risk patients. It was all comers. We could actually have high risk, even CIS. Unfortunately, we did not have any CIS. We wish we could have shown it. We have five patients with intermediate risk and five with high risk. Now we will be able to provide the full data, especially the high-risk patients, because we want to make sure that this drug should work across the treatment landscape. This is not a drug only for the early ones. When they get bigger and more malignant, it should not work. It is good for us to be able to show the full spectrum of different types of patients.
We'll have high-risk patients that have been treated with BCG, that have failed BCG, that have failed gemcitabine, and that come into the study, much more bulkier tumors. I mean, the same design, single dose, 14 days removed with surgery. If there is nothing left, still do surgery to see what is the immune response. What is very exciting is with this, we can also look, we're only treating one lesion, but some of these patients have two or three lesions. We can also see a field effect. That is also part of this full data set, like, okay, can you really see the immune response having a cytotoxic effect on lesions that are not treated by your drug? We're going to be able to provide that full evaluation. Exciting times, obviously, a new modality.
We could look at this as being the first immune ablated. We know that you can kill with chemotherapy, especially if you put chemotherapy for a long time in the bladder. That comes with trade-offs too, safety. If you can actually treat with your immune system, especially frontline, where your immune system is very potent and bladder responds well to the immune system without side effects, that would be the optimal approach. More to on the treatment paradigm and paradigm shift coming up in this presentation.
Okay. So it'll be 10 patients in total, five that we've already seen, five new?
Yes.
The five new are high risk?
Yes. We presented a few, but in the high risk, everything is now fully confirmed with full histopathologic assessment. We will have also more immune data. In the prior, we had early data on CD3, CD4. Now we have a full panel of immune markers to really see how is the immune system really getting these lesions cleared with such a single dose.
Got it. Okay. You have gotten into meeting with regulators this year to discuss next steps for the program. Can you give us some sense of when that meeting could occur? What are the key elements of the program that you want to get the input from the regulators?
Yes, that meeting has recently occurred. In the KOL event that we will have on Monday, we will provide the study design that's fully endorsed by the FDA. We wanted to wait to have this regulatory interaction because obviously, we had just done, again, a very, what it's called a phase Ia, right, the window of opportunity. The data was so good that it encouraged us to really have that interaction on how can we speed up this development. We had the meeting. We incorporate the feedback from the agency. Now what we're going to present to investors on what's next has that kind of regulatory endorsement, which is, as you know, very important.
Any teasers about what the study is going to be like?
I can't say. You know very well I can't say. But we don't have to wait long, right? It's right there around the corner.
It sounds like you, or at least in the past, you were looking at low-grade, low-to-intermediate risk as the target population. Is that still likely to be the case?
That's where we have seen and we've presented the data, such a strong result, right? If four out of five patients respond so well with a tiny dose and no safety events, right, we had grade one adverse events, we definitely think that there is a very big role for the drug in that patient population. Again, I mean, there is no reason why this drug shouldn't work across the disease spectrum, even in muscle-invasive bladder cancer. We are excited to be able to present more data at the conference. Still, I think that the development path could potentially be different, as you know, for intermediate risk and high risk, that the paradigm shift could be also different. I think we could see a role. Hopefully, the data will be clear about that.
Could you provide an overview of how Aura views the bladder cancer market? How would you segment low-grade, low-to-intermediate risk versus high risk? Who are the potential competitors in each area?
Yes. It's so interesting. Look, early stage local disease in general is treated with surgery and radiotherapy. Those are the mainstreams. If you know anyone that has even stage one breast cancer, it's immediately surgery. In bladder cancer, it's not different. You're diagnosed, you're blood and urine. The first thing is a surgery called TURBT. That's the anchor of this treatment paradigm. The problem, if you ask, so what is the problem? You have a tumor that's visible. You have surgery. Why do you need drugs? Well, the problem is recurrence. Recurrence leads to progression. Progression leads to you losing the bladder. A cystectomy is something that no one wants to go through, plus an increased risk of metastatic disease. What is the competitive landscape? What has been done? Fifty years ago, BCG was the first immune modulator to add after the surgery, right?
Can we reduce this recurrence rate? Everyone else in clinical development, including the latest approvals, are in this kind of like adjuvant treatment, meaning that you do the surgery, and then you try to add intravesical treatments to see if this recurrence rate can reduce. The less options you have before cystectomy, the more opportunity to get drugs approved. That has been the kind of like if you see the latest approvals, ImmunityBio, all of this coming to this late stage adjuvant treatment, let's try to do something after surgery. What's the problem? The problem is that if you remove the tumor, you cannot possibly have an immune response against the tumor. You're basically treating the disease with chemotherapy, and you need long-term contact of that potential new recurrence with the chemotherapy to be useful.
That is why you have the TAR-200, where it is like long release of chemotherapy or many, many cycles of adjuvant treatment. The paradigm shift that we want to bring forward is if you have the tumor, treat the tumor first with something that can have a cell-mediated immune response, because that is your best chance to prevent recurrence in a disease that is known to respond to the immune system. Do not do it after the tumor is removed. Because if you do it after the tumor is removed, like BCG, you basically have a pro-inflammatory response in the bladder that is unlikely to have a T cell response against a tumor neoantigen or when the tumor comes back again, the immune system is not educated. For us, the paradigm shift is we have something so unique that you can treat frontline when the tumor is there.
We have shown that with just a couple of those, right now it is single dose, but even single dose in 14 days, you have such a strong CD4 and CD8 that is capable of removing lesions that are not even treated. Do that first. You can obviously do the surgery or not need the surgery. For example, for intermediate risk patients, you may not need the surgery. You do not need it for staging. For a high-risk patient, you may even do the surgery, but if you have treated an educated immune system first, we think that long-term, that is going to make that durability of response. Instead of seeing these curves that everyone starts at 70, 80, and by 12 months, everyone is 40-50, that is because you have not primed the immune system first. Our hope is that everyone will be treated first, treat the tumor first.
That is the key paradigm shift. We're going to have biomarkers that show that our CD4s and CD8s are highly activated. We can do that throughout the study. Hopefully, instead of curves going down, you'll see curves being flat. You don't have to replace anything that you were doing before, just primed the immune system first. Hopefully, that across many early-stage cancers, because what we think is that we humans, we love repetition, right? We feel comfortable with doing the same thing that we've been doing for 50 years. You have a tumor, get the surgeon to remove it. If we think a little bit before, it's like maybe you get your immune system to treat it first, then get the surgeon in.
Let's shift gears to choroidal melanoma. Updated data has been presented actually several times, most recently, I think, at the Retina Society. For those less familiar, can you outline bel-sar's phase II results?
Yeah. In early-stage melanoma, it's very similar, right? We have a lesion. It's not yet treated. Standard of care is remove the eye or leave you blind with radiotherapy. Again, humans coming with surgery and radiotherapy. In the eye, you want to preserve your vision. And we can. In the phase II study, we showed that with an acute treatment, not forever, not every cycle until it progresses, just an acute treatment of three cycles early on, we have 80% of these tumors completely arrested, not growing anymore. In the eye, we have durability at 12 months because we treat for the first three months. We look at 12 months, and these tumors are completely dead. They are not.
The nice thing is that we can do that the same as radiotherapy does, but radiotherapy leaves you blind, and we have 90% visual acuity preservation. In fact, only one patient lost 18 letters. That's not the dramatic vision loss that happens with a radioactive plaque in your eye. We can feel very comfortable to say that we have an incredible unprecedented level of visual acuity preservation, even when the tumors are on the fovea. You can have the tumor in the worst, in the macula, in the fovea, in those areas where vision is so critical, and still keep your vision and treat your tumor. If you are diagnosed early, why would you choose radiotherapy? No one. We have patients that do not want to. They rather have the fear of metastatic disease than to be blinded. We are very excited.
We think that for the first time, we can treat early-stage cancer with something that does not have the trade-off of a surgical intervention or a radioactive intervention that really piggybacks on that immune system on a very targeted cytotoxicity. There are many, many of these early-stage patients. That is the problem with a rare disease. We start and we say, like, oh, how many patients are there? It is really an opportunity for investors. It happens that we have 4% of Americans with a nevus in their eye. Then we have a small number of small melanomas. We have seen that this group of patients with indeterminate lesions are having the exact same mutations as the small melanomas. Why not treat early? Right now, we do not do it because we do not want to blind so many patients.
With a drug like us, we could do it a little bit. That is the opportunity. We are excited. phase III with the SPA agreement, 100 patients, we should be able to get this drug approved.
Actually diving into the phase III trial, what is the design of the study? And can you talk about the key elements that are outlined in the SPA trial?
Yes. The SPA agreement, as you know, is very important, especially when you do a new indication for a type of tumor that has never had a drug approved. I wanted to make sure that the endpoints were very clear and aligned. The study has three arms. It is a randomized mass control study. The key is that it is a study versus sham. Why? In early-stage cancer treatment, actually, we observe these patients. They have a small lesion in their eye. Before we treat them with radiotherapy, we watchful wait. Because watchful wait is a standard of care, the FDA basically gave us a red carpet. It is like, okay, you can compare to watchful wait. At the moment that these patients progress, treat them with radiotherapy. The study will look at events of progression.
It's a time-to-event analysis, obviously, with a drug that works 80% of the times in phase II versus sham that basically doesn't have any effect. Tumors that are actively growing should progress very quickly in the sham. Tumors that are treated should not progress, giving us a great separation of the arms. In the phase II study, we have a p-value with, I think, three or four zeros. I can't say it because there are so many zeros, but it's a very, very good result. Those are comparing the therapeutic to the subtherapeutic, meaning that we're giving one or two injections of treatment. Imagine if you're not treating at all. We've powered the study very high so that even if the sham did not perform and all of them grew within 12 months, we would still have a highly successful study for approval.
What is the powering of the study and the assumptions for the treatment arm versus the sham arm?
Yeah. If you look at the phase II data and you look at 80% response in the treatment arm and the subtherapeutic, which is 20%, right? In the case of sham, we would assume zero, but let's say 20%. It gives us 99.5% power for the primary endpoint and 95. Now, we obviously have taken a very conservative approach. It's like, what if we were not 80%? Where if we were 60%-65%, right? We think it's going to be much better. Even if we were to drop the efficacy to 60%-65%, we would have 95% power. Highly, highly powered with a very robust phase II data and with an enrichment strategy. Every single patient that comes into the study is actively growing, meaning that the sham is going to fail, right? Because if they are growing, they're not going to stop growing.
That is how we risk mitigate the study by having these enrichment strategies, especially for the sham.
The key secondary endpoint is a composite of time to progression as well as visual acuity failure. Can you talk about the significance of that endpoint from a regulatory perspective as well as a commercial perspective?
Right. The big advantage for us, the big value proposition, is to treat while preserving vision. Obviously, if you're comparing to sham, you're not going to show that you're better than doing nothing in terms of vision. How could we do that superiority analysis so that vision is in the claim? Actually, this was an idea from the FDA because it's like, really, you have such a beautiful visual acuity preservation. You should be able to have it in the claim even when you have a sham study. The idea was to have it as a composite, meaning that it's exactly the same as the primary time to event, meaning time to progression, but also it will be either/or, any event of progression or visual acuity failure. Obviously, in the sham, we assume very few events of visual acuity failure, some but not many.
In the treatment arm, some but not many either because we have 90%. By adding that, we still preserve the powering of the study, which is mainly driven by events of tumor progression. We are allowed to say that we were able to look at vision in the secondary endpoint, and vision was really good. It is a way for us to have a superiority analysis in a key secondary endpoint to talk about vision. We are excited about it. The secondary endpoint is highly, highly powered because it is mainly a duplicate of the primary.
How is enrollment going, and when could we see data?
Yeah. We have earnings coming up very soon. We wanted to wait to earnings to give an accurate guidance. As you know, we haven't been providing numbers of enrollment every month to investors and analysts, but we will give guidance on where we are at the next earnings call. We're excited. As you know, Europe was a little slow getting the EU CTR process. I'm European, and I love Europe, but Europe is always slow with the regulators. Now we have all Europe open, and they're very excited. It's actively enrolling, and they're, I think, coming up very quickly. I think we've risk mitigated a little bit of that delay, but we'll be able to give some guidance.
Could you provide an overview of the market?
Of the market opportunity?
Yeah, the market opportunity.
Yes. In early-stage disease, and this is very important, as I said, we have patients with nevus, 4% of Americans. That's not our market. You have a small number of patients with small melanomas. There is this big number of indeterminate lesions. The key for us was that those indeterminate lesions should be treated. We talked to the FDA. We brought KOLs to the FDA. In our study, it includes indeterminate lesions. It really is like semantics because a lot of these indeterminate lesions are indeed small melanomas, have the same mutations. The key for us is that the label will include indeterminate lesions and small melanomas. That's where our market opportunity comes into a beautiful place because indeterminate lesions, you can count as 4,000 in the United States and 4,000 in Europe.
You start talking about 8,000 early-stage lesions that you're not going to treat with systemic treatments. You don't want to treat with radiotherapy. You want to treat locally with something that doesn't have side effects and preserves vision. The earlier you go, the more local you want to go, right? These patients, we've talked to many that had an early diagnosis of an indeterminate lesion. They said, like, "I wish we had this opportunity." We waited and waited. Some waited for two years, and then it was too late. They came back, and it's like, "Oh, now we have to radiate you. You have micrometastasis. It's too late." That's the opportunity. Again, we think there's really no competition there.
Actually, could you spend a minute on competition? We do get questions from investors about the IDEAYA trial as well as ChemIntra's development program in choroidal melanoma. How would you compare and contrast the patient populations and opportunity of bel-sar versus those other agents?
Yes. It's so important. All we're doing with bel-sar is treating early. If you think across the board, right, we're treating early in melanoma. We're treating early in bladder cancer. We're treating local. These patients are all pre-metastatic. Let's talk about Kimmtrak first. Kimmtrak is an excellent drug. Once the disease has gone outside of the eye, metastatic, then if you have that particular HLA subtype, Kimmtrak has shown to increase your survival chances. Actually, we've seen the success commercially. The exciting thing to talk about Kimmtrak and us is like, if they exist, did that metastatic disease need exist? Imagine how many patients early-stage exist, right? Because these patients take a long time to metastasize, and most of them, hopefully, will never metastasize if they are treated early. There should be four or five times more patients than the patients in metastatic disease.
That's ChemIntra. Very different. Metastatic disease versus local. Now let's talk about Darovasertib and IDEAYA. Now, a lot of these patients, the majority, come early, right? Indeterminate lesions and small melanomas are the majority. Unfortunately, there are patients that, as the one I mentioned, they keep waiting, waiting, and then the tumor is medium to large. What do we do? Surgery. Surgery, enucleation is really tough to lose your eye. What IDEAYA has shown is that by giving something systemic, they can have a little bit of response locally, 10%-20%, enough to potentially rescue these patients. Instead of having an enucleation, having their definitive treatment, which is radiotherapy. They do not replace radiotherapy. We replace radiotherapy.
They are trying to give it either to avoid a surgery or to give less radiotherapy, like neoadjuvant, so that you give a little bit less dose of radiotherapy with the goal. The clinical benefit there would be, well, potentially, if you give a little bit less radiotherapy, you preserve a little bit more your vision. The tough part of that value proposition is that, unfortunately, when you give radiotherapy, it does not matter how much you give. Little radiotherapy, a small amount or a large amount, that kills the blood vessels in the retina. Radiation retinopathy is very, very tough to treat. That leads to blindness, two to three years down the line. To show a benefit with a small amount of radiotherapy, it will take two, three years in a large number of patients, still in a met need.
I think that it's worth pursuing, but very different than treating frontline and avoiding radiotherapy altogether. We don't want to give surgery and radiotherapy in early-stage disease when we can preserve the organ. We should really try to avoid that.
Perfect. With that, I think we're out of time. Thank you.
Wonderful. Thank you.