Aura Biosciences Aktie

This is my first fireside chat in this job.

Oh, is it?

Yes.

Oh, fantastic. All right. I guess we're all good.

Are we live?

Yes. Good afternoon, everyone. I'm Sean Laaman, Head of U.S. Mid-Cap Biotech Equity Research at Morgan Stanley, and welcome to Morgan Stanley's Global Healthcare Conference. Before we commence, to make you aware of some important disclosures, please see the Morgan Stanley Research Disclosures website at www.morganstanley.com/researchdisclosures, and if you have any questions, please reach out to your Morgan Stanley research sales representative.

For this session, we have the pleasure of welcoming from Aura Biosciences, their President and CEO, Natalie Holles. Welcome, and thank you for your time today.

Thanks very much, Sean. I'm happy to be here.

Okay. Congratulations on the, I guess it's a relatively new role, and you've been in the seat for a few months now. And what excited you most about the opportunity to lead Aura at this stage?

Certainly. It's been 4 months since I joined the company, and I'd say what got me excited on my way in was that Aura represented a late-stage clinical opportunity that was as de-risked clinically and from a regulatory perspective as anything that I'd seen. The Phase II data for our investigational product, bel-sar in early choroidal melanoma, it's a small N, but I think you can't argue with the magnitude of the effects and the consistency of the finding across the subjects.

So I was intrigued, but what really got me excited about the opportunity was the true unmet need in the field of early choroidal melanoma and the untapped commercial opportunity that it presented for us. We can talk more about that as we go on. But it was not only the clinical de-risking, but the opportunity to build a really important company around a special product.

Wonderful. Thank you. And you recently refined Aura's strategy to focus the company's resources on ocular oncology. Can you discuss the vision behind that decision and your priority for Aura over the next 12 to 18 months?

So when I joined the company, as I said, we were actually just finishing enrollment in our Phase III registration study of CoMpass for treatment of patients with early choroidal melanoma. And the evidence around the potential for efficacy and impact was really overwhelming and exciting. I believe, though, that you've got to decide, you've got to pick 1 thing that you're going to be best in the world at and sort of go all in.

And from my perspective, there's the opportunity to really impact patients' lives, build a valuable business focused just in ocular oncology. We had previously had a program ongoing in bladder cancer, a Phase II study. We committed to the community that we're going to finish that study. We'll follow the enrolled participants through 12 months, but really focus the company's resources and attention in ocular oncology going forward.

Awesome. Thank you. And what does the real-world treatment journey look like today for patients with indeterminate lesions and small choroidal melanoma?

So we really -- one of the things that's happening in the field is that this delineation between indeterminate lesions and small choroidal melanomas is really sort of going away. And the group is more broadly being defined as early choroidal melanoma. And the reason for that is that the treatment choices for these patients have been dire to date.

You receive this diagnosis, you have melanoma growing in your eye, you have 2 really bad choices. Number one is do nothing, leave it alone and let it grow. Or we can treat it, but the treatment, which is plaque radiotherapy, is going to put most patients on basically irreversible paths to blindness. And so the delineation between indeterminate lesions and small choroidal melanomas is really based on, am I going to treat or not? If I'm not, I'm not going to say you have melanoma and do nothing, I'll call it an indeterminate lesion. If I am going to treat, I'm not going to blind you because you've got an indeterminate lesion, I'm going to call it melanoma.

So what bel-sar represents is a whole new treatment paradigm. What we saw in the Phase II data is that we got excellent tumor control. 80% of patients saw cessation of tumor growth, which is considered a functional cure in this disease, and it's our primary efficacy endpoint in the ongoing study. But also importantly, 90% of patients had vision preservation. So now you have the opportunity to treat the tumor without losing your vision. And so that is really the opportunity that we have to change what is currently a pretty dire diagnosis for these patients.

Right. Thank you. And I guess moving on to the trial, could you briefly review the design of the Phase III CoMpass trial, including the patient population, the primary and secondary endpoints, and the anticipated timing of top line data?

Yes. So CoMpass is a randomized Phase III registrational study being conducted under a Special Protocol Assessment with the FDA in patients with early choroidal melanoma. And we have delineations around the size of the choroidal melanomas, and importantly, for reasons that we'll talk about, the patients coming into the study need to have documented growth. So they need to have tumors that are growing.

There are 3 arms to the study. The first is the therapeutic arm, which is bel-sar treated at an 80-microgram dose. We have a sham arm, a randomized 1:1 between the 80-microgram dose and the sham arm. But then we also have a 40-microgram dose, which was designed -- it was designed in collaboration with the agency to ensure that our investigators were masked to treatment arms.

So the investigators know they're giving an injection, but they don't know if it's the therapeutic dose or the subtherapeutic dose. We ended up enrolling 108 patients in the subject. Primary efficacy analysis is tumor progression or cessation of tumor growth. That will be analyzed 15 months post-enrollment of the last patient enrolled in the study. The key secondary endpoint is a composite of tumor progression and vision control -- or I'm sorry, and vision preservation.

And we really expect that most of the power of that secondary efficacy endpoint will be driven by tumor progression or cessation of tumor growth. But to us, it's really important to have that measurement of vision preservation as we think forward to an eventual label and commercial launch for the product. So as I mentioned, the study is fully enrolled. We completed enrollment in May, and we are guiding to top line data from this study in the second half of next year.

Okay. Thank you. And what gives you confidence in the trial based on the Phase II results? And can you talk about the significance of the Special Protocol Assessment agreement with the FDA?

Yes. So the Special Protocol Assessment is important to us because it signifies that we have alignment with the division that this study, if conducted and if we see results as we expect, should be supportive for registration of the product. And so the time that the company took, and this was before my time, to get alignment and agreement on the SPA was really important in terms of increasing our probability of regulatory success if we hit on the primary endpoint as we very much hope to.

And so -- and I should mention that we also, while we don't have a formal written agreement with the EMA, we also aligned on the strategy and the design of the study with EMA as well as being supportive of approval in that geography. So it is, from our perspective, we feel like we're in a really good place from a regulatory probability of success.

And then in thinking about overall confidence in the study, as I mentioned, the Phase II was small, only 10 subjects treated at the therapeutic dose, but the magnitude of the effect was really profound. 80% of patients achieved tumor -- or maintained a cessation of tumor growth out through 12 months versus a sham arm where we saw most progressions occurring between 6 and 9 months. The safety profile was excellent in that study. No serious adverse events. All of the adverse events were milder and resolved.

And importantly, we saw 90% of patients in that Phase II study preserve vision. So we've made sure to have good concordance between the inclusion-exclusion criteria in CoMpass versus the Phase II study. We have good confidence that the baseline demographics are consistent between the 2. And importantly, as I mentioned earlier, we agreed with the FDA on this inclusion criterion around documented growth, meaning that participants who enrolled in the study need to have actively growing tumors.

And the reason for that, it was really an enrichment strategy to ensure that we would see enough progressions within the 15-month time period to be able to delineate between treatment and control. And that's a precedent that's been set with other drugs that have been developed in concordance or in collaboration with this division.

And so it made the enrollment a little bit slower than I think anyone would have liked, but we got there eventually. And what it does is it gives us a nice, rich patient population in which to explore this effect and gives us good confidence in hitting our primary endpoint.

Great. And what Phase III outcomes would cause oncologists to immediately change or think about changing away from the current standards?

So I think the most interesting element of the bel-sar, the potential bel-sar treatment paradigm, is that we saw 80% tumor control in the Phase II study in the ballpark of what you see with radiation, but we're enabling vision preservation.

So now where you have this big group of patients who -- they're -- this is no longer a benign freckle in the back of the eye, this is a lesion that looks suspicious. Now that you have a treatment option that can treat the tumor but preserve vision, we believe that, that will really drive usage earlier and earlier.

Right. And how much in the investment thesis is dependent upon demonstrating vision preservation and showing tumor control? And what proportion of patients, ultimately, avoiding radiation altogether would constitute a meaningful clinical success?

Yes. So tumor control and avoiding radiation are essentially the same thing, because when patients progress, they'll roll over to standard of care, which is radiotherapy. The vision preservation, I think it's a really important element of the profile. Because plaque radiotherapy works great for stopping tumor growth. It just comes with real consequential downsides.

If we can match or nearly match the tumor control that you're seeing with radiotherapy without blinding patients, that's a really important advancement in the treatment. So we have good confidence around that, certainly based on the Phase II data. We have good confidence that vision preservation is going to be achievable with bel-sar, and that'll ultimately be a key driver for moving the treatment paradigm forward in the disease progression.

Wonderful. Thank you. And what are the most important assumptions investors may be overlooking in the sham control arm event rate?

Yes. So 2 things, I would say, with respect to the sham arm. So number one, as I mentioned, the inclusion-exclusion criteria for CoMpass very closely match the patient population that was enrolled in the Phase II study. So there are more of these subjects, but we expect them to look very similar to the patients that we enrolled in the Phase II, where we saw this really profound treatment effect.

And then the other important consideration in the sham arm is, again, and this was also the case in the Phase II study, the documented growth, enrolling patients whose tumors are actively growing gives us confidence that we are going to see the progression events that we would expect to in the sham arm that will drive the p-value on the primary efficacy analysis.

Thank you. And what is the minimum duration of tumor control required for physicians to view bel-sar as disease modifying rather than merely delaying radiation?

So I think importantly, the primary endpoint in the study is cessation of tumor growth, and that is considered in early choroidal melanoma, that is considered a functional cure. So I think in and of itself, it is a disease-modifying therapy, if you will. We have a few time points that we'll have the opportunity to look at in the CoMpass study. As I mentioned, the top line efficacy analysis will be conducted at 15 months. However, it is a 24-month study, so we'll get another look at durability of effect at 24 months.

And then as patients complete enrollment in CoMpass, we're enrolling them into a 5-year long-term follow-up study where we will continue to follow all patients for safety, tumor control, and vision preservation. And we think what's going to be really interesting in the out years is that we know with radiation that the vision loss is -- it can be slow, it can be anywhere from 2 to 5 years, but it is very prevalent. 95% of these patients eventually lose their vision. So the longer we follow, we believe the more pronounced an improvement in the treatment options that we'll see in bel-sar versus plaque radiotherapy.

Sure, sure. And how should investors think about retreatment rates in commercial practice versus those observed in clinical development?

Sure. So we haven't studied retreatment in the clinical program thus far. The current treatment paradigm is 3 cycles of 3 injections followed by laser activation. There's no reason that you couldn't retreat with bel-sar. It's just not something that we've studied to date. We'd expect that to be part of life cycle management.

I think another thing that's reassuring to physicians as they are becoming familiar with bel-sar in the commercial setting is that there's nothing about treatment with bel-sar that obviates the option to move to radiotherapy if for some reason their patients don't respond. So we're really not taking anything off the table by treating with bel-sar. Again, we're just providing the opportunity to control tumor growth without losing vision and therefore driving earlier adoption.

Sure. And if you could just size the market today and then how that could change or expand if you began treating lesions earlier.

Yes. So we generally believe that between the U.S. and the major European markets, there are about 8,000 patients a year that are diagnosed with early choroidal melanoma. A fraction of those, if you go pull the ICD-9 codes trying to identify these patients in the medical records, it'll look smaller because again, early choroidal melanoma is currently more or less defined by whether or not a patient receives radiotherapy. So the expectation is, rather than the subset of that 8,000 that is currently captured now by radiotherapy, it's the entire 8,000 that would end up being available.

And just to put that in perspective, another uveal melanoma drug that is used in the metastatic setting, KIMMTRAK, maybe 1,000 patients a year, 1,500 patients a year that are treated using that. So this early choroidal melanoma space really represents the majority, the vast majority of the uveal melanoma patients that are out there at any given time. So it's really an interesting and underserved element of the patient population that we're excited about bringing this therapy to.

For sure. So in Phase III, you must be thinking about the other side, and like, what percentage of prospective patients are currently managed by a relatively small number of high-volume ocular oncology centers? And what infrastructure would be required for a center to become fully operational with bel-sar, assuming approval occurs?

Yes. So there are approximately 100 ocular oncologists between the U.S. and Europe, 90% of whom are involved in our program in some way. So it's a very tight community that we know quite well, and who are quite excited about bel-sar. So we're starting from a pretty defined set of physicians who -- the radiotherapy is performed exclusively by the ocular oncologist.

Some of the early choroidal melanoma patients who are in watch and wait mode are currently managed by retinal specialists. The expectation is that we would start with ocular oncologists. They're really sort of our core partners in this development program, and that's where we want to put the emphasis of our early launch efforts. And that can be achieved with a very small commercial footprint. I mean, if you're talking about just split it down the middle, 50 in the U.S., 50 in Europe. If we're just focusing on the U.S., 50 physicians means a very focused commercial call point.

Now, this is a rare disease drug, and we want to make sure that we make it as easy as possible for physicians and patients to access the therapy. And so there'll be a lot of, sort of, support wrapped around that. It's not just sales reps in the field, but it's doing everything you can to make it as easy as possible for the drug to get adopted. And then in terms of infrastructure in a standard ocular oncology practice, they're used to these ophthalmic lasers. Many of them already have them. They've used them for photodynamic therapy.

And so we're not imposing an undue infrastructure burden. They don't need a special room to administer bel-sar or the like. And part of the work that we'll do in preparing for launch is, again, making it as seamless as possible for these physicians to administer this new therapy when it becomes available.

Sure. And what do you see as the most important hurdles to adoption? Is it reimbursement?

Most important hurdle to adoption is getting the drug approved. So we are in heads down. And we will have a registration process in front of us. And I think we've made some changes to the team recently. I've brought in some outstanding leaders in regulatory and technical operations and people leadership. So it's really sort of scaling our organization and our capabilities to get to this next stage.

And I don't at all mean to be cavalier about the complexities of launching a rare disease drug. I've done it a couple of times, and I know what's involved. But I really think it's incumbent on us in the lead up to launch to do the market development work to, again, drive this -- support this movement towards calling all of these patients early choroidal melanoma patients, getting as much exposure to therapy through the clinical programs as possible, which we're doing not only in early choroidal melanoma but with our programs in metastases to the choroid and ocular surface, so that when we launch, we've got sort of as much of a ramp going as possible.

Sure. Thank you. And Aura is developing bel-sar metastases to the choroid and cancers of the ocular surface. What clinical proof points would provide the strongest validation that bel-sar can address multiple ocular cancers?

Yes. So I mean, what's really interesting about bel-sar and the mechanism of action is that these HPV-derived virus-like particles, which are sort of the delivery backbone of bel-sar, have excellent tropism for these modified heparan sulfate proteoglycans, which are fairly ubiquitously expressed across all solid tumors. And through work that was done primarily by our collaborator, John Schiller, at the NIH, there's an enormous amount of in vivo and in vitro non-clinical data demonstrating the breadth of the potential utility here.

So -- and I should mention, we presented 3-month data from our bladder program in our Q2 earnings last month where we saw really encouraging efficacy and durability in a completely different tumor type than what we're studying in early choroidal melanoma. So when we think about metastases of the choroid, the 2 most common solid tumors which produce choroidal metastases are breast and lung. We have excellent non-clinical data there supporting the tropism and the potency against those.

And so we would expect -- and these are fast-growing tumors versus an early choroidal melanoma where they're slower growing. So we would expect to see in our dose escalation study, once we get into the efficacious dose range, we'd expect to see tumor shrinkage in these tumors. And in ocular surface cancers, these are cancers, as the name would suggest, on the surface of the cancer, we'll be injecting intratumorally there.

It's really more of a Phase 0 study at this point where we are treating this as a window of opportunity. We identify the participant, enroll them in the study, we inject bel-sar, and then as part of the surgery to remove the surface tumor, we're taking some histology. And we're looking essentially at, are we seeing evidence of immune activation, tumor shrinkage, how feasible is this? This is the first time we're doing intratumoral delivery in the eye. And then the results from this study will inform where we would go in terms of actually sort of clinically meaningful endpoints later in development.

Sure. Thank you. And looking forward over the next 6, 12, and 24 months, what does the pathway look like? What does the catalyst pathway look like?

It's really exciting. It feels like 2027 is we're sort of perched on the launch pad now, and to me it feels like 2027 is really the blast-off year. So we have top line data from CoMpass that we're guiding to the second half of next year on that program. And then as I mentioned, we'll have a 24-month endpoint in that study as well, which we'll have in 2028.

And then the work that we're doing internally right now is we've recently, with the shift in focus to deprioritize bladder, the resources that were focused on that program have now been redirected to the choroidal metastases program, the ocular surface program. Those teams have just sort of been given, like, full empowerment and full resources to see what you can do with these studies. The teams are heads down on those efforts now.

We plan in the first quarter of next year to provide updates on both of those. And the goal is really to have, over the next 3 years, which is the time horizon in which I think about the business, really set up a nice cadence of clinical catalysts, not only in early choroidal melanoma, but in the earlier-stage programs as well to really engage investors, drive interest as we move towards launch in early choroidal melanoma.

Sure, sure. Wonderful. I've got a couple of macro type questions for you.

Okay. I'll do my best.

No, that's fine. They're hopefully pretty easy. So we're really focused on what's going on in China and China-originated innovation. So just your view on the landscape, even from a competitive perspective, or do you think about it much in terms of a BD and R&D strategy sense?

Interesting. So I'll answer the latter question first. From an R&D perspective, I mean, the CoMpass study is fully enrolled. We have our sites sort of in the chute. Easy for me to say. The team is very much in heads-down mode, but now it's kind of execution there. So there's really no rationale for expanding into China there. For the earlier stage program, I suppose it's a potential. However, that being said, we have this outstanding network of ocular oncology investigators between the U.S. and Europe and Australia, actually, which is where we're running the ocular surface study. I'm not sure that we have the need.

From a competitive perspective, I think we all worry about that in this field. One of the things that was unique about bel-sar, when again, I was contemplating where I was going to land for my next gig, was that the product presentation here is elegant/complex in a good way. We have an HPV-derived virus-like particle that is conjugated to a small molecule light-activated dye, which is injected via proprietary suprachoroidal injector that we have exclusive ocular oncology rights to, and then activated with an ophthalmic laser. That is not an easily knock-off-able product presentation.

And so when you think about the size of the market, well, first of all, let me start with my sort of base IP. I've got market exclusivity out through at least 2040 based on my IP and regulatory exclusivities. But then even beyond that, when you think about the size of the opportunity versus sort of the activation energy required to pull together a drug and generate the evidence of a biosimilar, I think it is a higher barrier to entry than you see in other more standard small molecule or biologics fields.

And frankly, that was one of the things that I liked about this opportunity. When I thought about the terminal value of it, I'm like, this could be valuable for a really long time. It could help patients and drive value for a really long time. Part of what got me excited.

Sure. Awesome. Second macro question, just on AI. So are you adopting AI across your business? And if so, can you point to a specific example where it's changed a cost assumption, an output, a POS, anything?

So I'm based in the Bay Area, so I'm sort of technically biased. I'm very AI curious, I guess I would say. We haven't used it. I mean we're in late-stage development. We're not a discovery organization, so AI-driven discovery isn't relevant to my business. Where I see it being relevant to my business is, I have a big document that we've got to write in the coming years. And using -- and I think the tools for document generation from primary data are getting better and better.

And that could be a huge time-saving, resource savings for me if I can adopt AI to help me draft my BLA, pull together the necessary supporting documentation. I mean, we're already sort of doing little test balloons on it, and it's an incredibly powerful technology. And what is, to me, a very high-yield, low-risk use case.

Sure. Great. Wonderful. Last question for you. Is there anything that I didn't ask that I should have? Or is there a message you would like to leave investors with?

I think you asked all the right questions. I think I would say 2027 is going to be a big year for Aura. I joined this company because I'm excited about getting to do another rare disease drug launch that very positively impacts patients. It's something I feel really passionately about. And I think the opportunity here is immense and frankly underappreciated. So I look forward to continuing my education about Aura to the market as we get closer to top line CoMpass data next year.

Wonderful. Thank you, Natalie.

Thank you, Sean.

And thanks, everyone, for listening. Thank you.

Thank you.