All right. Good afternoon, everyone. Let's get started. I'm Andrew Berens, Senior Biotech Analyst at Leerink Partners. Thank you for joining us on day two. We're winding down the last few meetings, the conference, today in sunny Miami. I'm very happy to have with us, Aura, and Eli, CEO of the company. Thank you.
Pleasure to be here. Thank you.
Great. Why don't we start with a brief overview of Aura for those who don't know the story?
Yes, absolutely. So Aura is an oncology company developing a novel class of drugs that we call virus-like drug conjugates. And we are in a field of medicine, ocular oncology, that has a big unmet medical need, starting with primary choroidal melanoma, where we are in phase III. We have the opportunity to bring value to these patients across all indications, which involve melanoma, choroidal metastasis, cancers of the ocular surface. And then the other exciting thing for us is that besides being in phase III for, in ocular oncology, our technology and drug can provide value in the exciting field of non-muscle invasive bladder cancer, and muscle-invasive bladder cancer. So we have data coming up in that space, and I'm eager to tell you more about that.
Great! No, I think we will definitely cover both of those. Why don't we start with the ocular program, with bel-sar, and what have you guys shown so far, the latest updates?
Yes, absolutely, and I have a few slides on our phase II data to show you. So there are two key things, in this drug as we think about the approval in primary choroidal melanoma. One is, does it has efficacy in terms of stopping the tumors from growing, which in early-stage disease, that's the equivalent of a local cure. And the second, can we do that with visual acuity preservation? Because the standard of care blinds patients. So let me tell you about those two in phase II, which supports the endpoints that we have discussed for approval in phase III.
So if we look at tumour control, which is a key primary endpoint for us, we can see that in our phase II, we have 80% tumor control with the, you know, therapeutic regimen, with the dose that we're going to use in phase III. Whereas in patients that have been treated subtherapeutically, the tumor control is very poor, meaning that these are tumours that grow, and if you don't treatment, they would continue to grow and metastasize, and we're very effective at the equivalent of a local cure. If we look at patient by patient, the spaghetti plots, you can see very relevant effect, right? On the right-hand side, you see the patients that have been treated. The arrows show the different cycles, and most patients consistently respond, and that's something that really relies on the mechanism of action. We have something that it's genetic agnostic.
It doesn't matter if the cell has a GNAQ mutation or is BAP1 deficient. We can grow across multiple tumors and across different genetic mutations, and that's why you have that consistency of response. On the left-hand side, you see patients that have been treated subtherapeutic, and that's what a sham in a phase III study would look like. Patients continue to grow, right? These are active melanomas, life-threatening, and as such, if you treat them subtherapeutically, that's what it would be in a sham-controlled study. So again, this phase II data is very strong, and it enables us to have a very high-powered study. In phase III, as you know, we only have to treat 100 patients, and we have a SPA agreement. So very good data and obviously paired with very good safety.
So if you look at the visual acuity, especially for patients, if you think about it, these are patients that have tumors right on the fovea and the macula, and with radiotherapy, they have very poor options of keeping their vision. They would lose not just 15 letters, but 30, 40 letters. They would have the definition of blindness. And with our therapy, we only have one patient that lost and was very close to the 15-letter, 18-letter, but the majority of patients, as you can see, 90% preserved vision. So then, if you pair the efficacy, which is very close to radiotherapy, but with the big advantage of having a safe therapy, obviously, that gives you the positioning of frontline.
For all of those patients that right now may be hesitant to receive radiotherapy, we can really provide a novel treatment option that can work just as well, but preserving your vision.
Great, and just to be clear, can you describe the, the way that bel-sar is administered in the procedure?
Yeah. We're talking about treating choroidal tumors, and we have the opportunity to treat with a suprachoroidal microinjector, which means that we give the drug in the layer where the tumor starts, and it just goes directly to the back of the eye. So it's a very targeted way where we can have the maximum efficacy without barely side effects. I mean, the side effects that you can see here are grade 1, a little bit of inflammation that can be treated with topical drops. That's because we're giving the drug with suprachoroidal administration, and we give that in 3 cycles. Cycles are injections on day 1, 8, and 15, and so every month they go 3 times, and it's an acute treatment. This is not a PRN treatment. It's basically for the first 3 months, you'll receive these treatment cycles, and that's it.
You're supposed to have, as you've seen in the spaghetti plots, a cure for 80% of the patients. And for the two that didn't respond just as well, they actually delayed the growth so that you could spare radioactive treatment for a full year. So overall, you know, a great opportunity to avoid radiotherapy for the vast majority.
Okay, and it's combined also with using the laser?
That is correct. There is a light-activatable drug... and it has the power of what we call the dual layer of safety. The virus-like particle is very selective to the cancer cell-
Mm.
But you're only activating the drug where the tumor is. So, that opportunity of treating so selectively with something that in ocular oncology is so standard of care, these type of light treatments are very available. The lasers are already there, so it's not a barrier for adoption, but a big, big opportunity for safety.
Okay, and this will be, eventually, when it's commercial, will be billed as a procedure?
Right. So you have the opportunity to build a procedure and a drug, right? Which is something, again, we're treating a local disease locally, by ocular oncologists that are used to do this kind of procedure. So it actually is something that can be done in the office versus a plaque radiotherapy, right, that you have to pair with radiation oncologist or even the proton beam facility. So there's a high incentive, for adoption, to be done in the office and, and yes, with different procedure codes.
Okay. Why don't we talk a little, I mean, you mentioned this a little bit, but why don't we talk about the commercial opportunity that you see that could be treated with this intervention?
Yes, absolutely. So this is how we look at the commercial opportunity, right? A lot of us are so used to metastatic disease and understanding the number of patients that, you know, are treated for metastatic disease. But in this particular disease, the opportunity is in the early stage disease, and here exemplifies it. We know, you know, the launch of KEYTRUDA actually has been very successful. For us, it represents that there are so many more patients front line that could benefit from this, and it really is a very large market opportunity just with choroidal melanoma. So our label is supposed to be for indeterminate lesions and small tumors, which, as you can see here, is 8,000 just in the U.S. and Europe.
So all of these blue patients are those indeterminate lesions that really are in watchful wait and could benefit from an early treatment intervention. But that's just our first ocular oncology indication. If you look at choroidal metastasis, that's 20,000 patients. Cancers of the ocular surface, 35,000. So collectively, you put all these numbers together, and you think, like, the only alternative is radiotherapy that blinds patients. The commercial opportunity is one of those, and it's rare to see, in 2024.
Right. What, in terms of, I guess, the indeterminate lesions, what percentage are indeterminate and right now watch and wait, versus those that are actually treated?
Yes, there's a large percentage of indeterminate lesions, and that's why we were so eager to have them included in the study. The definition of an indeterminate lesion is that of a very small lesion, usually 1-2 millimeters, that has some risk factors. The risk factors are, you know, diagnosed with imaging diagnosis, so it's clear to identify if a patient has fluid in the subretinal fluid, it's usually called orange pigmentation. It starts to have features that are not normal, that that patient doesn't have a normal nevus, and there's clear now publications that show that melanoma cells are present at that early stage. And so the bulk majority, two-thirds of these blue patients are those indeterminate lesion category that right now is—they're just called indeterminate because they are not treated.
At the moment that they would be treated, they would be very likely melanomas.
Okay, and in the watch-and-wait protocol that they use, what percentage of the indeterminate lesions eventually then become malignant and need further intervention?
Yes, if they have two or three risk factors, within one or two years, they are ultimately all treated. It's rare that, you know, they just defer treatment, and it's a difficult discussion. Actually, we have one of the ocular oncologists that joined the company this year, Dr. Anthony Daniels, that says, like, "This is a dilemma when I was talking to patients. I usually say, 'Well, you know, we should wait because we don't want to blind you. We didn't go to ophthalmology to blind patients,' but it's a life-threatening disease, so we don't want to wait too long." So it's usually one to two years, and it's something that we absolutely shouldn't do.
With a life-threatening disease and a target product profile like the one we have, we actually think we can prevent all the litany of problems that come afterwards if we could treat everyone upfront.
Okay. Why don't we talk a little bit about the registrational path of the trial that you have. How does it differ from what you already showed us in the early trials?
Yeah. So, we're very happy that we got an SPA agreement with the FDA. Actually says in writing that this supports registration, right? And, and it's one of a kind because there's never been a registration study or a drug approved for early-stage disease for these patients. So one of the key things for the SPA was the definition of the endpoints. What you can see here is time to tumor progression, and I'll show you the percent of the percentage of patients in those spaghetti plots that actually didn't progress, and the ones that did progress in subtherapeutic doses. So this is where we're gonna look, not just at the number of events of tumor progression, but at the time of those events to occur.
And that gives a log-rank test between the treatment arm and the sham arm in a very low p-value. We've actually plotted using this endpoint, our phase II data, and just with 10 patients per arm, we have a p-value of 0.0012. So, and that's just with 10 patients, right? So we feel strongly that this is a study that's highly powered, that it's we're shooting for success. And, obviously, we want to involve the majority of the ocular oncology community, not just in the United States, but globally. So that that is like a pre-marketing launch, that everyone feels they are part of the study, and they were part of the first-ever drug that will be approved, potentially.
Okay, and to get the approval that includes lesions of indeterminate size, would you—how many do you think you'll be enrolling in there, and how do you... I mean, I would assume that they have to be more rapidly growing to see progression in the control arm?
Correct. One of the key things, and that's normal in rare diseases, we're using an enrichment strategy. So basically, most patients will have a criteria of a little bit of signs of growth so that they are not in the very far left of that blue chart that I was showing before, and they're all coming at a very similar stage of growth. So the idea would be that those in the sham arm that are not treated and have a little bit of growth, continue to grow and meet the progression definition within 6-9 months. That will give those events of tumor progression in the primary endpoint, you know, very early, so that they differentiate the curves between the sham and the treatment arm pretty early.
It is a key inclusion criteria, that, again, it's something that, has guidelines for rare diseases, and even in ophthalmology, it's been very successful to use a smaller sample size to get the drug approved.
Okay, and what's the rationale with the half-dose bel-sar?
Yes, that's a requirement from the FDA to optimize the masking of the study. It's not unusual if you look at visual acuity as an endpoint and the fact that we're going through the ophthalmology division. So, as you can see, vision is just part of the secondary endpoint, the time to composite event. But for the FDA, it was very important that we optimize the masking. So it is something that's not gonna be part of the statistical analysis, but it's important to protect the study.
Okay. And what do you view as a bar for success in this trial?
Really, it's incredible that we don't have to meet a minimal clinical benefit. There's nothing approved. We're comparing to sham, so just a statistical significance is what's needed, and as I said, we're very, very highly powered. So it is one of those that we have to run it to show it, but we have a very, you know, the probability of success we think is pretty high.
Okay, and the timing?
The timing, so we are actively enrolling. The sites in the US are mostly all activated, and there's excitement in the community. But we've been conservative. We've given 18 months for enrollment because this is a global study, and it's a phase III. It's not unusual for a phase III to take 18 months. And then, as you can see here, the primary analysis will be at 15 months. So, so yes, now it's a, you know, full execution game, as you know.
Okay. And the three treatments, is there any reason why patients couldn't go through that, the cycles again, if they had recurrence or it started growing again?
Absolutely. I mean, you cannot do that with plaque radiotherapy. You literally, the side effects of radiotherapy are so harsh that the problem is that you have to remove the eye. But with us, there's literally grade one adverse events. So the phase III is very clean. We don't want to add retreatment, not to confound it. But yes, this is something that we will absolutely look at.
Okay. And then you mentioned choroidal metastasis previously. Just to clarify, that's where tumors from elsewhere in the body metastasize to the eye?
Correct. Yes. As you can see, ocular oncology is not just choroidal melanoma. Some, you know, investors think that, "Oh, it's just primary choroidal melanoma, not metastatic." But here is the picture. We have 11,000 patients with choroidal melanoma. As I said, choroidal metastasis is twice as prevalent, and there's a huge unmet medical need. In fact, the KOLs were the ones who came to us and said, "Eli, you should really, now that we see that the drug works, we would love to try it in metastasis because these patients really need a vision preservation therapy." So we're very excited. We have sites in waiting list even, if that happens. So we're hoping to launch this study this year and provide some data before the end of the year.
Okay, and which tumors are the ones that metastasize to the eye?
Yes, it's usually lung and breast. And the majority of breast cancer, which, as you know, we've been so successful with, metastatic breast cancer. And I just can't imagine a woman that has survived and endured a metastatic breast cancer, that now has a metastasis, a tiny lesion in the eye, and has to be blinded after enduring that and having long-term survival. So I'm passionate about this indication and really hoping to see the data.
Right. Okay. Well, great. Why don't we talk a little bit about, commercially, you did mention that, physicians already use a lot of them do these procedures, so there shouldn't be a barrier. But do you foresee, will there be a period that there are some physicians that will have to be educated and have to get new equipment?
Well, you know, that's why I said it's so important that our phase III is global. And look, there are 100 ocular oncologists between the U.S. and Europe. We're hoping to open 85 sites. So hopefully, that education happens in phase III, and there's nothing really unusual. Suprachoroidal administration is really very easy to do for these highly trained and very specialized ocular oncologists. And laser and light activation is something that has been mainstream of... You know, before the anti-VEGFs, everything was verteporfin. So I think that there's not really a barrier from the device perspective. There is an education to now, yes, there is a drug, and actually, you know, hopefully everyone say yes, and I was part of COMPASS, so I know how to use it.
Okay, great. Well, it definitely sounds like there'll be a lot of demand from patients as well as the providers once it's available.
Absolutely. We really hope to make a difference, and, you know, really, when I started the company, and it's one of those that you try to make a difference in fields of medicine that really have had no innovation, where pharma companies may have overlooked the need for patients. And you come with a technology that can so profoundly impact the field, it becomes very, you know, a sense of purpose is very high, and that actually is something that across the company, we're all really, really excited to get the, the drug approved.
Great. Why don't we talk a little bit about the bladder cancer that you guys have recently announced going forward with? And there's some similarities between what you're doing in the eye and the bladder, and the doctors that treat the patients, although the urologist instead of ophthalmologist, but-
Yeah.
Like, you know, what is the protocol that you're testing in bladder cancer?
Yeah. So the key uniqueness of our drug is that it's tumor agnostic, right? We've already shown data in melanoma, and now obviously we have a CR in urothelial carcinoma. They couldn't be more different types of tumors, and yet the drug works consistently in both. So tumor agnostic and disease stage agnostic. That's something that, you know, very few other drugs can do, and it's because the mechanism of action doesn't really rely on a particular genetic mutation or a defect of a particular type of cell. As long as the drug binds the surface, it should work. So in bladder cancer, it makes a lot of sense.
The similarities, as you said, is like, it's diagnosed early, it's local, it's already treated with procedures that urologists actually are very similar to what we're doing, and there is an opportunity to treat better versus just using the mainstream, which, as you can see here, really, a patient goes through a surgery called TURBT. The problem is there is a lot of recurrence. So our vision was, well, you know, there is a tumor. It's diagnosed early. We can treat it. We can be tissue-specific and tumor-specific, and not only have an ablative type of therapy, but an immune ablative. Can we use the immune system to really generate a T cell response early on, so that later, you know, everything else is much better? Less recurrence, hopefully less need for multiple cycles of adjuvant therapy. That would be transformative in this disease.
So that was the goal, and as you said, I mean, it's a, you know, it's a first phase 1 window of opportunity where we're treating, and the advantage here versus the eye is that we can treat ahead of the TURBT, ahead of this surgery, and that allows us to be able to get the sample and see what happens. And so I'm just gonna walk you through our first patient, which actually was a complete response, something that is very exciting now because we can absolutely undeniably say that it works in multiple tumor types and with a novel mechanism that I'll show you now. Because when you treat, procedure-wise, something very easy through a cystoscope, urologists actually do this all the time with, by the way, Botox for urinary incontinence, nothing very difficult to do. Light activation, the same. This is something for imaging diagnostics.
It's very easy to do. And then the patient came back on day seven to do the TURBT, but guess what? There was no tumor to remove. The entire tumor had disappeared, and it was a complete response. So the beauty of it is that we were able to, you know, see... I don't have the histology here, but we were able to see the response using, you know, histopathological assessment, and we were able to see that not only there was no carcinoma left behind, but there was a massive immune infiltrate.
Now, if we can show, and we have the rest of the study coming up, if we can show consistently across disease stages in muscle-invasive and non-muscle-invasive, that we have this result, necrosis, focal activation, and strong immune activation, that could be something that then could be developed in many different ways and provide value for these patients. And obviously, when we report the data, we'll tell, we're gonna do this for this population and potentially that study for approval in that other population. But initially, for this first study, it's just to show that it works consistently in the same way across all of these types of patients.
So in this single patient, when they went back to do the biopsy, the tumor was gone, but they went, and they biopsied the tissue that was still there?
Correct, and that's why they did it because just as a confirmation that there was no carcinoma left behind, right? Visually, when they did the cystoscopy, there was nothing, but they still were able to, you know, remove some, and just for safety, and we could see no carcinoma, not a single carcinoma cell left behind, a massive immune infiltrate. Like, as I look at this, and if you look at the available therapies, you know, other chemotherapies like gemcitabine have been there forever. They're not immune-stimulating. The surgery is not immune-stimulating. So if you have the, something that's not just overall immune-stimulating, like BCG, but specific to the tumor neoantigens, that should translate into a much better response down the line for these patients.
Can you go back to the slide before this one? So the area that you are going to change or the treatment paradigm potentially would be eliminating BCG?
... Correct. Eliminating BCG and potentially, we have the data will play out. For this first patient, the patient really didn't need a TURBT, so it was immune ablative, right? We were able to eliminate the tumor and stimulate the immune system with a single dose. So in that particular case, potentially, you know, patients could either forego TURBT and have something frontline that's much better, much faster, doesn't require six or nine administrations, and can be done in the office. You remove the need for the OR. That's something that for these older patients would be a huge benefit.
Okay, and then potentially cystectomy if it comes back, is that?
Absolutely. I mean, you could. First of all, there's no way why you couldn't do this at any stage of the disease, even in CIS or later on in MIBC, as you said. Like, for the muscle invasive, the risk of cystectomy or metastatic disease is much higher. So in those patients, if we could prevent cystectomy and, you know, prevent or modify the risk for metastatic disease, that would be incredible.
Okay. I think one of the benefits here would be also potentially preventing recurrence. Are you going to be able to show that in the phase I trial that you planned?
Not in this phase I, because it's a safety study. We were surprised to see complete responses with a single dose, so it's not even part of the endpoint. But it's not a very long study to show an impact on durability of response or recurrence. Because, as you see, others have shown it at three months. A complete response rate at three months in some of the other, you know, drugs in the space has been well accepted by the FDA. So I think that there is a clear path to get a drug approved in this disease stage, where we could see the advantage of just doing it instead of the surgery or in addition to the surgery.
Okay, and do you think that eventually patients might not need the TURBT if the tumor's gone completely when they go back in, or you think that they're still going to wanna?
Well, it depends on the type of patient and the type of risk, right? But for example, for an intermediate-risk patient, if you can avoid some of the procedures or even the risk of anaesthesia going to the OR, and you consistently show not only that it's better than surgery, but you're better protected because now your immune system is educated. The surgery doesn't educate the immune system. You're going to blunt the immune system down the line. Now that you're healthy, you can treat the tumour and have a response to, to the tumour antigens. That's the benefit that if it can be conveyed to the patient, the patient may see it as a double benefit, avoiding the OR and getting the immune activation.
Okay, and I mean, it seems like recently, there's, obviously, BCG's been around for 50 years, but there are a number of new interventions coming in. You know, what are your thoughts about some of those and where this bel-sar procedure might fit in?
Absolutely, and we love that there's more innovation in this space because patients really need it. But mostly everyone else is an adjuvant treatment given intravesically, and you can see that there's a clear path for that for CIS plus minus papillary lesions after BCG refractory, right? There's a high need there, there's guidance from the FDA, and there are five players there for a population that's somehow small. But that's a clear path for an adjuvant treatment once the, you know, the tumor is removed or there's a little bit of tumor behind. We are not adjuvant. We are actually a tumor-targeted treatment. We actually want the tumor to be there. We don't want the tumor to be removed and just take care of what's left. We want to treat the tumor and have a strong immune activation against the tumor.
Very distinct, as you can see. For that frontline position with something, something very safe that can work with a small number of interventions and can have a strong tissue-specific immune response, I don't think that we compete with anyone.
This would be one injection and one laser versus the eye, which is three, correct?
That's correct. In the eye, we're giving, you know, a cycle. We can't say yet. This was just a phase I window of opportunity with single dose. It happens that, you know, in this particular disease, it works extremely well. It could be 1 or 2 injections. Still, that would be much less than if you look at the adjuvant treatments, we're talking about 14, 15 administrations. Seventy-year-olds going through, you know, so many administrations, if you can provide the value upfront with 1 or 2, that would be, you know, highly preferred.
Okay. Well, great. Congratulations on all the progress. We look forward to the updates.
Yes, absolutely. We're happy to be here, and thank you for the invitation.
Thanks, everyone.