Aktiscology Inc Stock

Thank you for day three here. Really pleased to have Matthew Roden from Aktis Oncology with us. I'm going to let Matt make some opening remarks and then we can jump into Q&A.

Awesome. Thank you, Matthew. Thank you to you and the entire Morgan Stanley team for hosting us here. We're excited to be here.

And also thank you to everybody here in the audience for your interest in tracking our story. Aktis Oncology is a clinical stage oncology company focused on developing a novel set of radiopharmaceuticals or radioligand therapies. And we're very excited about this space. We think it's a large new category of anti-cancer medicines, and we're still in the relatively early stages, early era of the development of this category. We like radiopharmaceuticals in part because they're validated. We know how they work. We know why they work. We've seen that they've been successful clinically. We see that they've been successful commercially in terms of patient impact and launch ramp. But we also see that the space is, as of today, relatively early in terms of, it's really, there's only two approved, or I should say, approved products against two targets. And so the target space for radiopharmaceuticals is wide open. And so, Aktis exists to attempt to bring radiopharmaceuticals to a broad set of patient populations that have no radiopharmaceutical option. And the key unlock for that has been our mini protein radioconjugate platform technology, which enables us to hit a broad array of targets with a clinical or pharmacologic profile that is consistent with what has worked successfully in the radiopharmaceutical space.

And so from that platform, we've advanced two lead programs into the clinic. First is AKY-1189, which is targeting Nectin-4. Obviously, Nectin-4 is a validated target through Padcev, which is an approved ADC. It is now projected to have consensus peak sales numbers of about $7 billion, all in bladder cancer. Our clinical development plan is not only in bladder cancer with now what is a different payload, of a radiopharmaceutical versus an ADC, but also to develop outside of bladder cancers into breast and potentially several other tumor types. So we think this is an important and large multi-tumor opportunity for us. And then our next program is AKY-2519, which is targeting B7H3, and that, like Nectin-4, we believe has the potential to be first in class among radiopharmaceuticals. And also has a multi-tumor large patient impact opportunity and obviously commercial launch opportunity. Behind that we have several other programs that are again leveraging the Mini Protein platform. We haven't disclosed anything beyond the fact that there are multiple programs in various stages of earlier development. But we have said that we are tracking towards two additional clinical candidate nominations in the first quarter of '27. So the platform continues to produce and we're excited about the multi-product, multi-tumor clinical development plans we have.

From that we have, based on the platform technology. We do have a strategic collaboration with Eli Lilly that is worth a total value in excess of $1.2 billion. And this was really to explore or generate new mini protein radio conjugates against targets that Aktis is not working on. And so it just expands the impact potential of the platform technology. And of course Aktis retains 100% commercialization ownership of our entire pipeline including the lead programs. So beyond that, we've focused on the other critical component of the story is our supply chain. We are principally prioritizing Actinium-225 as the effector isotope. And in order to be in control of our own destiny, we have built a very robust supply chain that enables us to, we believe, ramp up to, in near term, hundreds of patient doses, and then of course deliver globally as we advance into later stage development and commercialization. So, really, it's everything under one roof that you would need to be a leader in the field, all the capabilities and components, and that's what we've been focused on because we're mostly keen to move the needle for patients. At the end of the day, if you can be valuable for patients, then you should be valuable for investors, too. So happy to dig in wherever you like.

Wonderful, wonderful. Thanks for that. So I thought maybe we could just start at a very high level on some of the components that make radiopharm attractive and how to sort of think about that. So at least in my mind, the way I've always thought about radiopharmaceuticals is the most attractive piece is you know that if you deliver an isotope to a tumor, it's going to kill the tumor, right? There's no question about that. There's not a question about resistance, et cetera, that you might see with some other drugs. However, you have to worry about accumulation in tissues or organs that could create enough toxicity that you can't dose high enough, et cetera. So, can you talk a little bit about, what you see as the benefits and sort of how you've designed your platform to be able to sort of meet that therapeutic window.

Yes, it's a great question.

The field of radiopharmaceuticals really started, well it started with of course iodine for thyroid cancers, but targeted radiopharmaceuticals started in the early days with monoclonal antibodies like for example Bexar or Zevalin. And antibodies were a logical choice at the time for delivering radioisotopes, because we know we can generate antibodies against a wide array of targets, and we know you can localize antibodies wherever that target is, and so that would be an obvious way to deliver a radioisotope. Unfortunately, one liability of antibodies is that they're long-circulating. Now, that's often an attractive facet to an antibody because you want it to stick around you want area under the curve you want target coverage et cetera. But for radiopharmaceuticals, the problem is that now what you're doing is you're just you're keeping the radiation payload in the bloodstream for a long period of time. And so what has been observed over time with monoclonals is that you have an elevated level, perhaps unacceptable level of bone marrow heme tox. And so the field has largely moved, not entirely, but largely moved to small formats. And this is due to the success of like, let's say, Lutathera and Plavicto, both are very small, peptides effectively, that are fast clearing from the bloodstream. So in other words, yes, they can hit a target with affinity, but they also are renally cleared through the kidney. They're cleared out relatively quickly in a matter of hours. And so the field has largely moved to that small format, and we have as well, because we think it's a way to maximize the therapeutic index by protecting the bone marrow. So when we're starting the company, we effectively had a whiteboard of every permutation you can imagine of all the component parts you were talking about. And we wanted to optimize for what would be an expected patient outcome. At the same time, we wanted to optimize for, well, how do we hit these other targets? And can we use antibodies or antibody fragments or other sort of antibody-like things? And where we landed was with mini proteins. And we're inspired by the work of David Baker, who subsequently won the Nobel Prize on de novo protein design, specifically around mini proteins.

So, mini proteins are the smallest polypeptides that can achieve a three-dimensional shape. And so that three-dimensional shape, and of course, the variability or diversity that comes with the polypeptide, was the enabler to hit a broad array of targets like an antibody could, but to have, because of its super small size, these are typically around 40, 50 amino acids, but then folded up into a very compact shape, they have the pharmacology of these very small formats like Pluvicto or Lutathera. So we felt like that was the Goldilocks scenario of having a binder, that could be bone marrow sparing, hopefully limit the normal tissue exposure, but also be able to achieve very high affinity and selective binding against a broad array of targets like an antibody could. So it was kind of the perfect mix of all the formats. On top of it, one of the really important things that makes this work is the diversity. So we're encoding in our libraries for over 6 billion variants of the mini proteins, and that's across 100 different scaffolds. And so that's important. And of course we're also doing generative design, which is now outside of the 6 billion. It's a new search space. It's billions of trillions of variants now that we're looking at through generative AI design. So that's been an accelerator to our innovation engine that we, when we make it, mentioned we have multiple programs following the lead to, we have multiple programs following the lead to. So that's been exciting. So the intent here was to deliver something that could really open up the target space, but also meet the needs for a patient in terms of maximizing clinical efficacy and safety. Now, on the part of efficacy, you know, there's a lot of debate about what's the right isotope, and, you know, it's our point of view that really any isotope that emits energy should kill tumors, right? So a wide array of things of isotopes should work with this kind of format. And our technology is isotope agnostic. We have used multiple isotopes in our experimental work and they all work fine, right? We did prioritize first, and it's not to say that we won't use other therapeutic payloads, but at least in our first iterations here, our first INDs were with Actinium-225. And Actinium-225 is a very powerful alpha-emitting isotope. It exerts, we think, the maximum amount of energy into the tumor if you can localize it there. And so the purpose there was to, #1, maximize the efficacy impact on patients because obviously efficacy is the unmet need in cancer. And #2, its 10-day half-life enables us to do a central manufacturing process that enables us to be, again, in control of our own destiny and supply chain, such that we can deliver at scale globally. So it was, you know, both were important components for us. It's not to say we couldn't use others later, but that's what the priority has been. So we think this is the right combination to maximize patient impact. It's not the only combination. We're sure there's other ways, other formats that can be successful. But this is a way for us to repeatedly, you know, generate as many different product candidates as we can with this kind of profile.

Just last question before we start talking about some of the programs. You talked about your choice of isotope and you talked about the supply chain there. Can you talk about from an investment standpoint where you think you are in terms of the investments that you need to make to have clinical supply through, say, a pivotal program?

Yeah, it's a great question. It's one that we're spending a lot of time on now. So what we'd like to say is at the moment, we're focused on two things principally. #1 is executing the plan we have, which we're going to talk about in a minute. And the other is planning ahead for scaling for the future, right? So we're planning for success. Right now we're utilizing multiple, multiple, we haven't disclosed the number but there are several commercial actinium supply agreements that we have. So we feel very good about where we are with actinium supply. But we've also been working with various contract manufacturers for the final step manufacturing that's a fee for service sort of thing right now. Working on opening our first GMP manufacturing facility at our 17 Dry Dock facility in Boston, and that will further verticalize our ownership of that supply chain. And as we achieve clinical proof of concept, we've already teed up various investments that we need to make. And we've looked at a combination. Would you build facilities? Would you buy facilities? Would you do some combination of both? And we've kind of mapped out what that looks like. There is investment that is required, but if you look at the precedents, it is achievable and it is not unduly burdensome in terms of the capital expense required to build out that kind of supply chain. The other part of the equation though is how many doses do you really need? And fortunately because our clinical development plans are focused on multiple large tumor types with global registration programs, we're going to need a lot of doses. We're going to need a lot of volume. And that's a good problem to have, but it's still a problem to have. And so we have focused a lot right now on sort of climbing that mountain of the capacity that we need to build. And so there's a lot of work going on. And as we go forward, we're going to stage those investments so that we can manage the cost of care capital as we build up this capacity.

Perfect. You know, we'll first talk about 1189, which is your Nectin-4 program, but maybe quickly before we do that, you know, development of radiopharmaceuticals looks a little bit different than maybe a classical oncology therapy so can you talk about sort of the value of some of the let's call it phase 0 work you can do with imaging and how you think that sets you up for a more traditional phase 1 program?

Yes, no, it's a really important question.

One of the things that we and I think many investors like about radiopharmaceuticals is that you do get added information if you can do a phase 0 like, imaging analysis of your molecule in patients. So what we did here was we were able to take the binder, which is, you know, with Nectin-4 or B7H3-targeted cold conjugate. And you can either put actinium on it for treatment purposes or, in this case, use an imaging isotope like gallium or lutetium or Copper-64. And here you're not creating the harm to the tissues because it's not at a level of activity that would cause harm to tissues, but you can do a PET-CT or SPECT-CT imaging time course to get initial uptake in various different tissues and tumors, but then you can do a time course to see how it changes over time. Then you can do a dosimeter analysis of what's the absorbed dose of activity in each normal tissue and tumor that you can look at. And this is an advantage for us and others in the field because you can quantify, you can ask a question, is a drug doing what it was designed to do? And you can see, is it going to the tumor? And in the case of our molecules, we can say yes, we see very high initial tumor uptake. We also see really nice tumor retention in those analyses. It sticks around in the tumor for a long time. At the same time, even though you may get the drug is designed to perfuse everywhere. You want to be able to find the tumor wherever it lives. It does perfuse the entire body. You do see some backgrounds into early time points, first couple of hours. You see it in the liver, you see it in the kidneys, you see it in salivary glands and other places. But you also see in the time course that it washes out of those tissues relatively quickly. And you can quantify how much is in there and you can then go on to quantify is that within a safety range that we're to be acceptable. And so this is an advantage in development because you can feel good about your safety margins going into a real phase 1 with the therapeutic isotope like Actinium, and you engage investigators, you engage the agencies, the health authorities. And the health authorities, of course, look very closely at the normal tissue dosimetry and the absorbed dose profile. And when you see our and dose escalation schemas for both lead programs, those initial starting doses of 4 megabacks and 6 megabacks supported and aligned with the agency through the clinical imaging data that we're able to gather. So this is different than like a T cell engager or ADC where you're kind of walking into phase 1 blind and you're just doing, you know, let's call it empirical dose finding based on about clinical safety and efficacy. Now once we're past that stage gate, so the dosimetry data is really useful because it's hypothesis generating. It's also in my mind kind of a stage gate. If you see untoward activity in normal tissues, you can do a fast fail approach and then reiterate and maybe come up with a different molecule. It's really nice to be able to know that you can fail something quickly without running into a year-long or two-year-long dose escalation. So we are starting with just categorically more information about the molecules than you do with other modalities. That's really helpful to us and to our investors. So that's exciting. In phase 1B, we're in a more traditional oncology dose escalation schema, right? And so now, it's all about, you know, 28-day DLT observation periods and, you know, more traditional safety analyses, safety assessments in standard dose escalation. We're using a Bowen with backfill design. And so the backfill enables you to accelerate, if you will, the dose finding through the dose escalation. So that's been an exciting thing for us. But now we're into the phase where, at the end of the day, the advancement of these molecules from here, now that we're post the dose escalation, the advancement of the molecules from here are now gated on the clinical safety observations and of course response.

So, for Nectin-4 maybe just talk a little about what's the timing of that phase 1 data, you know, the range. Maybe talk about how you selected that range of doses from the imaging data and then importantly, you know, when we see that data, you know, especially given that you have PADSEV, but what's the right comparator? What's a good outcome from that study?

Yes. Yes, so let me just first start with a few words on the design of the dose escalation. So the design of the dose escalation, there's five dose levels starting at 4 megabecquerels going up to 12 megabecquerels administration. And then you would give those, every 28 days for six cycles. Eligible for the study are, of course, Nectin-4 positive patients as determined by initial imaging with a copper imaging agent. So you have to be uptake positive in the tumor to get into the study. And that will include post-PADSEV-PEMBRO urothelial carcinoma patients. So this is, think of it as second line metastatic plus. Second line plus metastatic. But also other patients with metastatic disease that are Nectin-4 positive are eligible for the study. So this includes things like triple negative breast cancer, ER or PR positive breast cancers, colorectal cancers, head and neck, and some others, lung cancers, non-small cell. And so, Nectin-4 positive patients writ large are allowed into the study. We do have a protected number of slots for the bladder cancer patients, but we'll be moving through different types of patients, dose levels here. And we did disclose at the time of our IPO early this year that we had cleared the first dose of all and we're enrolling and the second at the time. So in terms of what do we need to see, I mean the purpose of this part one dose escalation is to establish safety at a dose, right? That is the purpose. But of course we're tracking response as well, resist response. But the efficacy question is really, more properly assessed under an expansion cohort, which is part two of the study, designed and so that said we're cognizant of as you said benchmarks what are we looking for. So since there's a protected slot of bladder cancer patients and bladder there's de-risk for Nectin-4, let's talk about that for a minute. So what we know about post-pembro-PADS-EV, there's a handful of reports that have described the outcomes and how patients after the pembro-PADS-EV combo. But probably the most comprehensive is the post-EV302 follow-up that was reported by Tom Powles at ASCO. And so what that shows is that the most common treatment course post-PADS-EV in bladder is platinum-based chemotherapy. In the outcomes there are not robust. So he's reported round about a 20% response rate in relatively short PFS, three to four months and less than a year of OS, overall survival. So, this is a difficult, you know, this is I should say, this is a patient population with not a lot of good treatment options. It's really a huge unmet medical need in our view. And so that's the patient population that is obviously one of the areas of focus for the development of the program, and potentially one of the faster paths to registration. And so this is an area of focus for us and we're cognizant of that. I just wanna double click on that notion that in dose escalation, it's going to be a mix of tumor types, it's going to be a mix of doses, it's going to be varying degrees of duration of follow up. And so the first quarter preliminary data that we're going to describe is going to be a little bit like a work in progress because backfill will not be complete and we'll be continuing to enroll patients in backfill. And so it's going to be where we are at the time and what we know about dose at that stage. But nevertheless, we're excited about what we think the potential for the program is, and given the validation from PADSEV and what we know about Nectin-4 expression and other tumor types, we think it's a really important opportunity for patients.

Great. Thank you.

Why don't we turn, just given the time, why don't we turn to B7H3 and maybe just talk a little bit about how you think about that market opportunity relative to Nectin-4. Obviously, both are big.

Yes, so the Nectin-4 opportunity is significant as we mentioned, PADSEV peak sales, consensus peak sales, expectations now are around $7 billion peak. And that's just in bladder cancer, right? And we plan to develop in bladder as well as in other large tumor types like breast cancers and others. And so we do see this as a multi-indication, multi-tumor, potentially a successful multi-billion dollar program. That said, if you look at the B7H3 program that we have, obviously B7H3 is expressed in north of 90% of prostate cancer patients, but also in high proportions of small cell and non-small cell lung cancers and various other important tumor types where there's still unmet needs. And so if you were to just, I'm going to make a comment not about the molecules specifically but rather the end markets or end patient segments we're talking about. The patient segments that could be addressable by B7H3 is just categorically larger. These are very large end markets. And so this is something that we think is a really important opportunity that we're going after. And one thing that is in common between these two programs is they're both first in class for radiopharmaceuticals. And so sometimes someone might say, well, why do I need a Nectin-4 RLT when I can use a Nectin-4 ADC, or vice versa for, um, radiopharmaceuticals for B7H3. And it's just important to keep in mind that these are totally different killing mechanisms, right? These are non-overlapping resistance profiles. These should be additive and potentially even combinable with ADCs down the line. And so we think it's irrespective of other tumor killing mechanisms, this is a unique killing mechanism that we think is going to be additive.

to the patient journey. And sort of similar question, you know obviously you're also in dose escalation with B7H3. Maybe just talk about, you know, the information you had when you picked the dose levels. Maybe how that compares to the Nectin-4 dose levels if there's any information, you know, just across that you're going to be able to glean across the programs. And then... You know, prostate cancer, obviously the sort of first key tumor type there, and sort of why you picked that versus some of the other choices you could have with B7H3.

Sure, so when we first generated imaging data with the B7H3 molecule called AKY-2519, we were excited to see the profile that we were seeing high tumor uptake in various different tumor types, including prostate, non-small cell, colorectal cancer, and some other patients. That was all reported at ASCO this year. So that was exciting. What was also exciting to us and to investigators was that the normal tissue, exposure was relatively modest. And I have to share that when you've, and we've gotten this question a lot from the posters, in the very early time points you do see a lot of liver. And that's really perfusion, not, we believe, target mediated, because it does wash out very quickly. And the total absorbed dose in the liver is actually quite low. And so that's an example of how the molecule is kind of doing what it's supposed to do, right? It's perfusing through the whole body, but it's clearing out of the normal tissues and sticking around in the tumors. In terms of the dose finding piece, what we did was, of course, you look at the absorbed dose profile in the key normal tissues. You look at bone marrow, which is almost categorically dose-limiting for radiopharmaceuticals as a category. Bone marrow, kidney, liver, et cetera, and various other normal tissues. And so then you ask the question, if I were to give a full course at a certain dose, meaning multiple administrations over time at a certain dose level, would you be below all of the emissions benchmark values of EBRT that people think about, and that's like a regulatory thing, right? So, that's what is required for a starting dose. We did, started a slightly higher dose with B7H3, not necessarily because the dosimetry data was fundamentally different than Nectin-4, it's just we asked for a higher dose and got it. And so at 6 megabecquerels, that's a good starting dose, but it's also steeper with the prostate program. It's also a steeper dose escalation curve. So we're going six, nine, 12. And so that we think is also, I think useful to us in terms of learning more about the molecule faster. So the imaging data were, exciting to us we got great feedback from the investigator community the expert community on the data because it also showed very long tumor retention in excess of six days with very high absorbed dose in the tumors relative to all of the normal tissues and we think that that sets us up for an exciting run at Prostate. So when we thought about the clinical development program, once we had those data, we took it of course to ad boards. And the prostate ad board was very enthusiastic about this profile for a couple reasons. #1, different target, right? So just categorically it's important to have a different target. #2, the very low exposure to salivary glands. And so we all know that PSMA is expressed at some level in the salivary glands and that all of the PSMA assets have some level of PSMA exposure in the salivary glands. But our level of absorbed dose in the salivary glands was markedly less than what has been reported for the PSMA agent. So that's an important potential point of differentiation versus the PSMAs, but, you know, these things are all going to live together. You're going to need PSMA agents, and we're going to be the first BCI of an H3 agent out there. And so prostate was an obvious one to go after. I would also point out that we know that targeted radiation in prostate cancers is effective. And so that's one additional layer of risk that's eliminated by this approach. #1 other thing that we explored and reported on at ASCO was the concordance of uptake with our molecule versus the FDA approved diagnostic PSMA-11. What you could see is we didn't see any evidence that you're giving something up by using B7H3 versus PSMA. So in other words, we had the same uptake writ large than what you saw with PSMA. We are doing further analysis on that for a future presentation, but we did give a glimpse of that at the ASCO poster. And so we think it's a super exciting approach, not only for prostate but in addition to prostate we have lung and in fact we have guided to opening our second phase 1B dose escalation protocol with AKY-2519 in a lung focused basket study. And that is supported by the uptake that we saw in lung and colorectal cancer patients in the imaging analysis. And that is, as I mentioned, we guided to opening it second half of this year, and that's totally on track. So this is a big, broad multi-tumor opportunity and we just can't wait to get into data. So what we've said about the.

And just remind us on the on the prostate data, when when will we see the dose escalation data there?

When we opened the prostate study, we were confident we could deliver the first preliminary dose escalation data in 2027, and we certainly stick to that. And as we get further into enrollment, we'll probably narrow that. And I would just point out that because there's only three dose levels and because there's a high degree of investigator interest in this program and priority given to this program, it has the potential to, let's say, narrow the gap in timeline between Nectin-4 and B7H3 readouts.

Great. Maybe just #1 sort of additional question. I think obviously as you get through, Phase 1B and you get expansion cohort data, I think the question will be, how quickly then can you move to a pivotal program? And is that possible versus a traditional phase 2 to phase 3? So how should we think about that?

Also great question.

So we are looking at a variety of scenarios and we're working up plans across both programs, the Nectin-4 B7H3 program, for what would it take for registration and what indications would you prioritize and how would you go about this. And so that's all part of the planning process we're under right now and obviously we're engaging ad boards of top investigators across multiple different disease areas and at the right time will engage the regulatory authorities for their feedback. But we have seen in terms of precedent anywhere from, the more traditional way for Nectin-4 would be to go into expansion cohorts because as I mentioned, the patient population, the dose escalation is a mixed patient population. So the proper way to assess efficacy and response is actually to go into an expansion cohort. And that is part of the plan, the part two of the existing Nectinium 2 protocol. But we are exploring the question of whether or not there's a different path forward to registration. And so that's one example. With prostate, we haven't, again, we haven't said anything yet about registration plans and what the development plan would be, but let's just say we're exploring all paths. And so we look forward to sharing more when we can.

Perfect. And maybe just last question. Talk about funding, capital needs, and how you think about progressing the plan from the funding.

Yeah, no, it's also critical for us because, you know, what I'm describing here are, in at least two, and maybe next year there'll be more than two multi-tumor development programs. Multi-tumor development programs are big, broad, heavy, expensive, but also very rewarding for patient impact and value. We reported $517 million on the balance sheet as of the last reported quarter with runway into 2029 under the current plan. But you can imagine. We had a very high energy IPO earlier this year. Our in the end the demand was 18 times over the initial base deal. So many times over subscribed with very high quality and we continue to engage with investors on the right time and place to raise additional capital to fund these what is really a big and broad opportunity. So we're excited about that. We are of course contemplating multiple forms of capital. There's more than one way to approach this and so we're contemplating all angles here. Also had business development as an important piece, right? We have a $1.2 billion deal with Lilly, but that really is very relatively narrow in scope. And so there's a lot of other angles here as well.

Wonderful. Matthew, thanks for being here. We appreciate it.

Thank you, Matthew.

This live transcript is auto-generated without human intervention or review.

This live transcript is auto-generated without human intervention or review.

Hi, everyone. Thank you for coming to the Jefferies Healthcare Conference. My name is [ Nora ]. I work in the banking -- investment banking team at Jefferies. I'm in the health care group. And here, we have Matthew Roden, the CEO of Aktis Oncology, and I'll leave it to him now.

Thanks, Nora, and thanks to the entire Jefferies team. It's a pleasure to be here and to present the story of Aktis Oncology. We are a targeted radiopharmaceutical company looking to transform the space by opening up the field of radiopharmaceuticals for patients who have no access to radiopharmaceuticals as of yet. Obviously, I'll be making forward-looking statements, and I invite you to our website to read our filings on potential risks and uncertainties.

So to start off, Aktis Oncology is an organization, as I mentioned, that the vision here and the goal is to really extend the benefit -- the clinical benefit of radiopharmaceuticals to new targets that are expressed in patient subsets where there's no radiopharmaceutical treatment option. And so in order to do that, we, as a team, have systematically created all of the capabilities that we think you need to be a leader in the field. And so you can see here around the circle on the slide, multiple things that we've worked on and advanced and evolved over time that we think are all important to that goal of moving the needle for patients.

And it starts, obviously, on the portfolio side, it started with our very different platform approach. We felt that in order to maximize the benefit of radiopharmaceuticals, we felt that it was needed to optimize the formats that are being used, the molecular architectures to deliver radioisotopes safely to various different tumor types. And so we created a novel mini protein radio conjugate platform, which we'll talk about a bit. And from that platform, we have thus far advanced 2 assets to the clinic. We'll talk about those today. Both of them have the potential to address multiple large market opportunities, different tumor types, which we'll talk about. I think it's certainly exciting to me to see really where we feel like we're at the foot of the mountain here with respect to an inflection point of radiopharmaceuticals becoming a large new category of anticancer medicines.

With the initial 2 programs, we do have clinical imaging proof of concept in patients, which provides a lot of excitement moving through dose escalation into expansion cohorts. We'll talk about the next steps with that as we go on. But in addition to the portfolio side, we felt from the beginning that it would be really important to be able to build the infrastructure required to deliver for patients. And so what am I referring to? We're talking about the manufacturing, the end-to-end supply chain. And of course, with that, one component of that is access to the isotopes, the payloads that you want to deliver. And so we feel that we have built an extraordinary end-to-end supply chain that has redundancies in multiple points of the end-to-end process and really a strong position on isotope supply, particularly in actinium-225, where we have announced some time ago, 3 commercial supply agreements that varied across geographies and across production methodology.

But importantly, since that time, we've signed several additional supply agreements that we believe is the industry-leading portfolio of isotope supply. On top of that, we're very well capitalized. We have, as of the last quarter, $538 million on the balance sheet, which gives us capital runway into 2029 and through multiple inflection points, which I think is really important because it just gives you the flexibility to continue investing in what could we believe has the potential to emerge as the leader in the field.

And so to illustrate the opportunity that we see and that we're working against, this slide shows really the opportunity and where our positioning is different than others in the field of radiopharmaceuticals. On the left-hand side, what you see is a representation of the total incidence of solid tumors in the U.S. and it's broken out by tumor type. And so it just gives you a sense of the size and the proportions. On the right-hand side, on the top, what you look at is, hey, how does radiopharmaceutical -- how does the modality map onto the broader oncology market? And what you can see is it's really quite targeted. It's focused on PSMA, which obviously is expressed only in prostate cancers. And as of yet, SSTR2 targeted agents are only approved in that small little sliver at the 5:00 position of the wheel. It is being developed in other indications, but as of yet, it still had relatively, let's call it, defined patient impact.

Our approach has been to work in new targets where there's no radiopharmaceutical option. We are potentially -- we're in currently first-in-class position, potentially first-in-class at launch for a Nectin-4 targeted radiopharmaceutical and a B7-H3 target radiopharmaceutical. These 2 are just the tip of the iceberg. We have several other assets in development. But as you can see here, these targets are expressed in multiple other tumor types where there is no radiopharmaceutical option. This just illustrates the differentiated positioning we have vis-a-vis others in the field. And so this is really core to our story.

So how do we do that? We employed what we call a mini protein radio conjugate platform technology. We built it from scratch ourselves. And so on the left-hand side is kind of why did we do this or what was our goal here. So obviously, with radiopharmaceuticals, you're interested in RLT because you want to drive that efficacy that is, let's say, different than other modalities of cell kill. So what we're talking about is targeting radiation in the tumors. There's multiple other therapeutic modalities one can reach for an anticancer therapy. But there are very few radiopharmaceuticals, as we mentioned, that can deliver the kind of -- that can deliver the efficacy that we're looking for.

At the same time, we want to do it safely, right? So you want to expand the therapeutic index to the maximum chance you have. And unlike other radiopharmaceutical approaches, the goal here is to open up the addressable targets, okay? And so if we can do that, we think that we're at the foot of the curve, sort of like where ADCs were 5 to 7 years ago, where format optimizations led to an inflection point in that modality. And so on the right-hand side, this leads us to why we picked and why we designed the mini protein radio conjugates. You can see here a space filling -- sorry, a surface representation of a mini protein -- a real mini protein radio conjugate. And you can see the red is the linker and the black is the isotope payload.

And what you can see here is that this is actually a very small binder. It's -- these are typically 40 to 60 amino acids, but they fold into a very compact little structure. And that very small diameter allows it to be, number one, very highly tumor penetrant; number two, fast clearing from the plasma. And so those 2 things we think are important for efficacy and safety, respectively. But unlike other small format binders like peptides, like, for example, Lutathera, Pluvicto or small peptide binders, this type of platform can be used to hit with high affinity and selectivity against a broad array of targets. Small peptide binders are very difficult to adapt to non-native peptide binding targets.

And so this would enable us we believed in the beginning when we stood up this company to really just broaden the impact of radiopharmaceuticals. So it's kind of a Goldilocks profile of the small peptide like pharmacology, fast in, fast out, but also with the ability like an antibody to hit a broad array of targets with very high affinity. And so that was the game. What we've done is we've built our own proprietary screening libraries that are encoding for over 6 billion variants of these things, right? And so that obviously lends itself to high probability of success. But on top of that, we're using the latest and greatest tools in generative AI, where we're screening effectively billions of trillions of new sequences beyond that. And so this is a very powerful way of advancing new options for patients.

So this page summarizes where we are from a pipeline perspective. Our platform technology has given rise to a whole portfolio. Our lead program is AKY-1189. It's targeting Nectin-4 expressing solid tumors. Our second program is AKY-2519. This is a B7-H3 targeting radio conjugate. Both of these are in Phase Ib dose escalation programs in patients that are expressing the target. And beyond that, as I mentioned, these 2 are just the start. We have multiple undisclosed preclinical stage assets that are on the come, and we do expect to name 2 clinical candidates early next year in addition to the first 2 that we have.

We also have separately a discovery collaboration with Eli Lilly in which we're using our platform technology that is the mini protein radio conjugate to discover novel mini protein radio conjugate skids targets that are outside of our target space, our focused target space. And at a certain stage of development, we would hand it back to Lilly for them to fully develop and commercialize. And so far, we've worked very hard to be a very good partner to Lilly in our S-1 earlier this year, we did disclose that we have hit the first milestone of that partnership. So clearly, there's been progress, and that's trending in a very nice direction. We're pleased to work with them.

In terms of the opportunity that we see here just with the lead 2 programs, if successful, we believe that these have very significant patient impact opportunities. On the top right, you can see Pluvicto and PADCEV are 2 benchmarks that we think about. These are single disease area drugs that are approved in multiple indications. And when you have a multiple indication drug like Pluvicto and PADCEV, you can get to mega blockbuster status as they are expected to do. What you see here are consensus peak sales numbers. If you look at our opportunities on the left-hand side, Nectin-4 B7-H3 targeted agents, you can see that these are expressed not only in single disease areas, but multiple disease areas. And so now we have the opportunity to have not only multi-indication opportunities, but multiple disease area indication opportunities, and we expect to fully develop these assets to their maximum extent to maximize the patient impact and certainly commercial opportunity.

As I mentioned earlier, it's been equally important for us since the beginning of our company build to have the -- to be in control of our own destiny in terms of being able to have the infrastructure to deliver for patients. So it's one thing to have a portfolio of assets, but it's another thing to be able to actually get those -- the drug product into patients on time. And with radiopharmaceuticals, there's obviously an on-time delivery piece of that, which is important. And there's very few organizations on the planet that have the operational capabilities that we have built. On the left-hand side, what you can see is we've built really an end-to-end supply chain that starts with the mini protein, the cold conjugate manufacturing.

As I mentioned earlier, the robust portfolio of isotope supply that we have. You put those together in a manufacturing process, which is the middle box, this is actually one of the key unlocks is having actually the drug product manufacturing capacity that is not only through multiple contract manufacturing relationships, but also we have our own suite, GMP suite that's up and coming and expects to be open later this year. And so this combination of capabilities, we have multiple points of redundancy at every single node of this supply chain from start to finish so that we have not only the backups to the main, but we have backups to the backups to ensure that in any given time that we can fully deliver for patients. So that's been important to us not only operationally. Obviously, it's our goal to deliver these products on time and to enroll studies on time and to eventually commercialize on time, but it's also a key strategic capability that we have. As I mentioned, there's very few organizations that have the capacity or capability to do this.

Okay. So let's turn to the program. The first program is targeting Nectin-4, AKY-1189. And what you see here is some clinical imaging data in patients. And I'll just walk you through a couple of highlights. But first, I'm just going to summarize and say the evidence that we have so far supports the idea that this radio conjugate in this format, mini protein radio conjugate can get into tumors, is retained in tumors and is rapidly cleared from normal tissues exactly the way one would hope. And so on the top row, what you can see on the top left versus the bolded numbers is the absorbed dose, that's kind of an area under the curve of our drug, AKY-1189 in the kidney and the bone marrow. Why kidney and bone marrow? Because we're renally cleared. And so it's important to measure how much activity you're leaving in the kidney in the bone marrow because bone marrow has historically been dose-limiting for radiopharmaceuticals.

And what you see is the numbers. One way to contextualize the numbers is, first of all, in gray per [indiscernible] administered activity, but that's done in that format in order to compare to what's been published for approved products like Pluvicto and Lutathera. And you can see that for the normal tissue exposure, obviously, you want as lower is better. You don't want to impart radiation exposure to normal tissues. What you can see here is it's below the numbers or I would better say, not higher than the values that you've seen with approved products like Pluvicto and Lutathera, which are judged by the FDA, is having a favorable benefit risk profile. So that was a really good starting point, and we felt that, that was -- those values and the key normal tissues would enable us to dose up to active levels in order to really push the therapeutic index.

On the right-hand side on the top is just the time activity curves that led to the numbers on the left. On the bottom, it's more about the tumors. So on the left-hand side, what you can see here is a PET/CT image of AKY-1189 conjugated to gallium. And with that, you can measure standard uptake value or SUV max in various different tumor lesions. And what we're able to measure here across 5 different tumor types is very robust levels of uptake. These values, if you look in the literature, are consistent with responses to other products like Pluvicto as an example. And generally speaking, the published thresholds that people talk about are high single digits or better. You can see here that we're anywhere from high single digits up to about 100 with central tendency in the 20s to 40s. And so these were numbers that we felt very much supported. This is initial tumor uptake very much supported moving into real efficacy and safety-based studies.

On the right-hand side, this is a SPECT/CT time course looking out to 2 days post injection. With AKY-1189 conjugated lutetium. And what you basically see here is very limited normal tissue uptake and some washout of the kidney. But what you also see is very sort of flat retention in the tumors. In fact, there's even more in the tumor at 48 hours than there is at 3 hours according to these images, which are scaled to the first time point. And so we're excited by that finding because it really was visual evidence anyway that even though the initial uptake is high, that the retention is long and that, that would correspond -- in theory, that should correspond to a heavy impact on the tumor. So all of these things taken together really supported the notion that the mini protein conjugate is doing exactly what it was designed to do, which is land the isotope into the tumor to import that anticancer activity, but also clear out of the normal tissues without causing undue harm.

So in addition to bladder cancers, which is what we're just looking at, we also looked at tumor uptake across a number of different tumor types. And you can see here patients with various subsets of breast cancer and colorectal cancer, and we have other data beyond these as well, just showing relatively robust uptake. All of the lesions you can see in the breast cancer patients in the thorax and around the thorax and in other metastatic sites, really bright uptake, SUV max values typically in the 20s to 40s, certainly, what you would want to see and similarly with colorectal cancer patients and others. This was very much supportive of the concept that this should be developed not only in bladder cancers where Nectin-4 is well known, but also in other tumor types where no Nectin-4 product is yet approved.

And so to prosecute that opportunity, we have an ongoing Phase Ib study. This is called the Nectinium-2 trial. And we're currently in Part 1, which is dose escalation. You can see here that we started at 4 MBq dose. We're dose escalating up to 12. This started later in 2025. So we're moving through the dose escalation curve. What we've said about this is that we're very much on track, very happy with the progress of the study so far and that we expect to present data on this in the first quarter of 2027. So we're excited about this opportunity. The patients are in dose escalation, not only post PADCEV bladder initially, but also patients who are Nectin-4 uptake positive across different tumor types, including triple-negative breast, HR-positive breast, lung cancers and other tumor types as well.

There is a Part 2 planned for this study, which is on the right-hand side. So once we backfill 2 doses in Part 1, we'll have a dose that we can then move forward into a dose expansion in specific tumor types, which would support, we believe, various registration paths where -- in which we'll be as aggressive as the FDA and the data allow us to be. So we're excited about that program. Everything is on track, and we look forward to sharing more information as those data emerge.

Shifting gears now to our second program in the clinic. This is AKY-2519, and it's targeting B7-H3, which is to us and others are advisers and clinicians, a very exciting target, again, a first-in-class opportunity for a radio conjugate here. We just shared data this past week at the ASCO Annual Meeting and look forward to sharing a few updates here. So again, what you're looking for in a radio conjugate is the ability to put drug in a tumor and have as little normal tissue exposure as possible. And so these are data that were in the poster presentation presented by Prof Mike Sathekge from NuMeRI South Africa.

What you can see here is one patient case study that really illustrates very nicely what this molecule is doing. On the next page, I'll have more aggregate data across a number of patients. But just to start on the upper left, you can see a PET/CT image. This is just a snapshot shortly after administration. And what you see here is already immediate uptake in tumors along the clavicle and certainly throughout the abdomen and down to the prostate bed. That's all tumor activity that you're seeing. As you would expect, and you see this with any radiopharmaceutical in the first couple of hours, you do see some -- as it's perfusing through the body in a couple of passes, you do see some normal tissue exposures, including in the salivary glands, the liver, spleen and some kidney.

And so that's informative thus far. But what you really want to do is look at the time course, get the time activity curves and understand what the area under the curve is. And so that's Section B, the SPECT-CT images, where this time we use AKY-2519 conjugated to low-dose lutetium 177, and this enables you to image patients over a 6-day period, okay? So you inject the dose and then you do the first scan 3 hours later, second scan a day later, third scan 6 days later. And what you can see is immediately the normal tissues, including the salivary glands in the liver are immediately retreating, okay? And so we believe this is due to perfusion, not target-related activity because the target-related activity is in the tumor and what you can see is the long retention out to 6 days.

And so in particular, if you look at the 144-hour time point, 6 days post injection, really all that's left is the tumor, and that was something that was exciting for us. So the machines have the capability of quantitating this. This is a standard methodologies being used by the NuMeRI team. You can see in C and D below, these are axial images of those tumors that were identified. There's 4 tumors in particular that are identified for measurement. And then on the top right-hand side, what you can see is a histogram. So what the histogram is asking is for any given dose, what proportion is going to various normal tissues and what proportion are going to the 4 tumor lesions that you looked at.

And you can see very clearly that the normal tissues, very little of the dose is actually going to the normal tissues. You can see a great number of normal tissues were assessed in this. There's probably 15 or 20 lines in there. You can see and all of them were more or less along the y-axis, which is exciting to us. In contrast, you can see much more of the proportion of the activity was over on the right-hand side on the tumors and each of those lines refer to or correspond to the 4 tumor lesions that were tracked in C and D. So then this gets quantified under F. And what you see here was very exciting to us again because not only was the dose coefficient calculated in gray per mega back of actinium-225 activity was anywhere from 0.1 to 0.3 gray per gigabecquerel administered to the normal tissues, but whereas it was anywhere from 2.4 to 4.8 gray per megabecquerel in the tumors.

There's also the opportunity to look at something called partial volume correction for tumors. This is special for tumors because there's not a pre-existing phantom that enables you to quantify in tumors because tumors are inherently -- they don't have a uniform shape. And so they do effectively like a 2D measurement and then there's a partial volume correction that looks at a way of assigning 3-dimensional activity. And so it's a bit of a sensitivity analysis. You can see that for the tumors, that means that the activity could be anywhere from 2.4 to 4.5 for the bony disease in the [ para-aortic ] lymph nodes anywhere from 3.8 to 7.5 gray per megabecquerel administered activity absorbed in the tumor.

And so we're excited about this because, obviously, it to us and our advisers and clinical experts with whom we're working, this suggests really a wide therapeutic index to step into as you think about dose escalating, which we'll come back to in a moment. These data here summarize the aggregate data across the patients that were assessed in this dosimetry analysis. You can see on the top left, again, the dose coefficients are similar to the individual patients I just shared. And the kidneys as not surprising as the organ of clearance is the one that, again, we would look at as the expected highest activity, and yet that's right in line with what you see with approved like Pluvicto. And so this, we felt very strongly supports moving into dose escalation.

On the right-hand side, this is, again, not just a single patient anymore. This is multiple patients where there's activity in tumors. And you can again see the amount of activity being deposited in the tumor is dramatically higher than the amount of activity that we're seeing in normal tissues. So this is all, again, very exciting for us as we move into the next step. So moving beyond prostate, we asked the question, and this is in collaboration with Prof. Ken Herrmann in Essen, Germany. We asked the question, how many other tumor types are we going to see uptake with AKY-2519?

And you can see here that he was indeed and able to recapitulate a lot of the prostate cancer data that we saw elsewhere. But we also saw a really nice uptake in patients -- lesions with newly diagnosed adenocarcinoma of the lung, which is the second patient you see here. Clearly, across lesions, relatively high uptake with 17 to 22 or so SUVs. Similarly with small cell lung cancer, which is typically a target for B7-H3 targeted agents, but also in rectal cancer and other patients with CRC as well. And so these are a couple of patient examples. There's more in the posters that are now on our website. But long story short or the punchline here is that in aggregate, these data with the PET-CT uptake supports the development not only in prostate, but in multiple other tumor types.

And to that end, we have 2 trials, one ongoing and planned for exploring AKY-2519 in clinical development. You can see here the Bactinium-1 study, which is in metastatic castration-resistant prostate cancer. This study is now open and enrolling. And you can see here, it's really broken into 2 cohorts. So it's almost like 2 studies in 1. At the behest of the prostate cancer experts on our advisory board, we did open not only the Pluvicto experienced cohort, which is what you would expect, but also they really urged us to open the Pluvicto naive cohort as well because they were very excited about the dosimetry findings that we had. And so this is the plan here. We have here only 3 dose escalation cohorts or 3 dose levels, I should say. And that should enable us to identify a dose relatively quickly because 2 of the 3 dose cohorts can be backfilled up to 30 patients each.

And so we're excited about this because the prostate community has given us terrific feedback. And just to go back 2 pages, I just want to highlight one additional thing that really underpins some of their excitement. I talked about the limited exposure to normal tissues, but one of the things that really stood out to the experts in the field was actually the salivary gland dose. And so what you can see here is that the dose coefficient was 0.13 gray per megabecquerel. And if you were to give like a full -- illustratively a full course of therapy at 8 megabecquerels times 4 cycles, that turns out to about 4 gray total. right? And so that is -- I invite you to look up the dosimetry data for Pluvicto. You'll see that this is dramatically lower than the salivary gland dose that is administered or I should say, delivered to patients receiving Pluvicto and other PSMA-targeted agents. So we think that this is -- or the feedback we've gotten from the experts is that this is really a key point of differentiation.

So the second study that we have now cleared regulatory review on this study is in start-up mode, is expected to start enrolling in the second half is the Bactinium-2 study, and this is a non-prostate basket study. It is going to focus to some extent on patients with lung cancers, not only non-small cell, but also small cell and we will also enroll other B7-H3 tumor types. And you can see here starting at 6, going to 9 similar dose escalation schema with backfill that will enable us to inform a dose moving forward.

In terms of upcoming milestones, we've talked about this, I think, already, but the Nectin-4 program, we expect to deliver the first of the data in the first quarter of 2027, but of course, there's going to be several following presentations hence forth from there. For the B7-H3 program, we've already hit a number of key points already this year. The next one is to start the second study. And we have committed to delivering data in 2027 for the prostate. We also talked about the manufacturing site. The manufacturing site for Aktis is expected to be open later this year. Again, a key corporate goal for us as well as advancing 2 additional clinical candidates early next year.

And so with that, I want to thank you for your time and attention, and I'm happy to take questions offline. Thanks very much.

Welcome to the Aktis Oncology conference call. [Operator Instructions]. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Alex Lobo, Investor Relations. Please go ahead, sir.

Thank you, Michelle. Before we begin, I'd like to remind you that today's remarks will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. We ask that you refer to our filings on sec.gov, including our most recent annual report on Form 10-K filed with the SEC on March 30, 2026, for a full list of risks and uncertainties.

Actual results may differ materially from those indicated by these statements. Unless required by securities law, Aktis does not undertake any obligation to update these statements regarding the future or to confirm these statements in relation to actual events. With that, I'd like to turn your call over to Matt Roden, President and CEO.

Thank you, Alex, and thank you, everyone, for joining today's call which is in reference to our May 21 press release summarizing the 2 posters on AKY-2519 to be presented at the ASCO Annual Meeting on May 30.

Joining me on the call today is our Chief Medical Officer, Akos Czibere; as well as 2 distinguished guests, Dr. Oliver Sartor, of the transformational Prostate Cancer Research Center; and Dr. Timothy Yap from the University of Texas MD Anderson Cancer Center. In addition, the entire Executive Committee from Aktis will be available for the question-and-answer session.

In terms of the agenda, I will kick us off with some introductory comments. Akos will then summarize the imaging and dosimetry data for AKY-2519, which will be presented in 2 posters at the upcoming ASCO Annual Meeting. Akos will then moderate a fireside chat with Dr. Oliver Sartor and Dr. Tim Yap. And lastly, we'll host a Q&A session with the management team and our distinguished guests.

To get us started, a reminder that Aktis Oncology aims to expand the reach of targeted radiopharmaceuticals to large patient populations that have no radiopharmaceutical option or where persistent unmet needs remain. Aktis was assembled with all the necessary elements to serve as a leader in the field. From our proprietary mini protein radioconjugate discovery platform, thus far, we've progressed 2 programs to the clinic under IND both of which have multitumor and multi-indication potential.

Today, we'll be focused on our second program, AKY-2519, an exemplar of our vision to address several important solid tumor patient populations including those where unmet needs persist, such as bladder, prostate, lung, breast, colorectal, head and neck cancers and various other tumor types. In addition to developing novel first-in-class radio pharmaceuticals, our strategy has been to be in control of the infrastructure required to deliver for patients. Our resilient, scalable supply chain, robust portfolio of isotope supply combined with a strong balance sheet and an accomplished leadership team positions us well to expand patient access to radiopharmaceuticals.

Turning now to the opportunity for AKY-2519. In prostate cancer, PLUVICTO is an important treatment option for patients. But despite its success, there continues to be unmet needs and in particular, for orthogonal treatment approaches such as ours, which hits a differentiated target in B7-H3 and delivers a differentiated payload with the alpha-emitting isotope actinium-225. Of note, PSMA expression can vary in tumors, leading to suboptimal responses to PSMA targeting therapies.

Secondly, there's required resistance to various PSMA-targeted agents, including beta emitters and given PSMA expression patterns, PSMA radioligand can be retained in the salivary glands, leading to Xerostomia that can be -- that can significantly erode quality of life with PSMA targeting therapies. This liability is not expected to be observed with B7-H3 targeting since there's no reported expression of B7-H3 in the salivary glands. Adding to that, in metastatic castration-resistant prostate cancer, it has been shown that B7-H3 is overexpressed in about 90% of patients' tumor samples, while normal tissue protein expression is quite restricted and again, not reported to be present in the salivary glands.

And lastly, while we see a compelling opportunity in prostate cancer, AKY-2519 is not just about prostate. Given the B7-H3 overexpression in multiple other tumor types and with AKY-2519 being a potentially first-in-class fast clearing radiopharmaceutical, we seek to unlock multiple white space opportunities in large patient populations such as colorectal cancers and various forms of lung cancers.

Now turning to Slide 6, which describes why we employ many proteins as targeting more of these for radio conjugates like AKY-2519. It starts with the patient. The goal here is to maximize treatment benefit by delivering powerful anticancer activity while minimizing side effects, in particular, protecting the bone marrow since hematologic toxicities have been dose-limiting for radio pharmaceuticals.

However, we also ambitiously wanted to address new targets for radiopharmaceuticals in order to broaden the patient populations benefiting beyond the PSMA SSTR2 in fab space. If we're able to do that, we believe radiopharmaceuticals are at an inflection point to becoming a large new category of anticancer medicines.

To fit these needs, we employed many proteins because we believe that they have all the right characteristics to achieve these goals as a radio pharmaceuticals. Namely, their small size enables not only high tumor penetration to deliver the potent anti-cancer activity of actinium, but also rapid clearance from the plasma to minimize radiation exposure to normal tissues, particularly sparing the bone marrow.

However, unlike other small format architectures of radio pharmaceuticals, the massive diversity of our mini protein screening as well as the 3-dimensional shape enables us to uniquely select variants with very high affinity and selectivity against a wide variety of molecular targets. So this unique combination of properties was employed to enable us to open up the target space and hence new patient populations for radiopharmaceuticals.

Turning to the pipeline page. Our proprietary platform has given rise to a portfolio of development programs. Our most advanced clinical stage program, AKY-1189 has FDA Fast Track designation and is currently enrolling in a Phase Ib clinical trial in the U.S. The trial is on track, and we expect to present preliminary dose escalation data in the first quarter of 2027.

The topic of today's call is AKY-2519 for which we have a broad clinical development plan. As you know, we recently initiated the first of 2 planned Phase Ib clinical trials of AKY-2519 in patients with metastatic castration-resistant prostate cancer, enrolling cohorts of both PLUVICTO naive and PLUVICTO experienced patients, and we expect to report preliminary data from this trial in 2027. The second Phase Ib trial is a lung cancer-focused basket trial of B7-H3 expressing tumor types and is on track to open in the second half of this year.

Now turning to the ASCO presentations that we'll be discussing today. Clinical investigators will be presenting 2 AKY-2519 posters side-by-side on May 30 at ASCO. Poster 3097 reports the imaging biodistribution and dosimetry data in 16 patients with metastatic castration-resistant prostate cancer, and the findings from this analysis informed the trial design and rationale for ongoing Phase Ib trial to AKY-2519. Poster 3098 is reporting PET/CT imaging analysis of patients with various B7-H3 expressing solid tumor types, in the tumor uptake findings of this analysis likewise informed the included tumor types for the upcoming Phase Ib long-focused basket trial.

And lastly, a quick word on the key catalysts on Page 9. Our plan remains unchanged. We're focused on executing to deliver on a variety of goals, spending corporate initiatives and program development milestones. And without further ado, I'm happy to turn it over to Akos. Akos?

Thank you, Matt. AKY-2519 is our novel, potentially first-in-class immune protein rated conjugate targeting B7-H3 expressing tumors. Like other many proteins from our proprietary rate conjugate platform, it combines high affinity with highly selective binding to its target, in this case, B7-H3 were pharmacological properties that allow for deep tumor penetration and retention in cancer cells, along with the rapid clearance from plasma necessary to limit normal tissue exposure. AKY-2519 or our second clinical stage program, further builds on our vision to bring targeted radiopharmaceuticals to large patient populations with significant unmet need.

Now let's take a quick look at B7-H3 as a target for anticancer therapies itself. I would consider biologically derisked at this point with several B7-H3 targeting ADCs in large randomized studies in small cell lung cancer and advanced metastatic frustration resistant prostate cancer. Further, we do see B7-H3 as an ideal target for rated pharmaceuticals due to its high expression across multiple tumor types and exceedingly low expression across normal tissues. It is highly expressed, as you know, in prostate cancers, lung cancers, colorectal cancers and various other solid tumor types where higher unmet needs persist. And throughout there is limited expression in normal tissues.

Clinically, expression of B7-H3 has been shown to be also associated with poor prognosis further highlighting the potential positive impact when targeting B7-H3. Before we dive into the clinical data for AKY-2519 that not only drives our excitement for the program and our platform as a whole, but also forms the basis of a broad clinical development program we are launching here in the U.S. under IND I do want to take a quick step back.

When we started to collaborate with Prof Mike Sathekge at NuMeRi in South Africa on our first program, AKY-1189, at the beginning of 2024, we were trying to understand 2 main concepts given this was the first ever mini protein to potentially enter the clinic as an actinium-225 carrying therapeutic. So first, does the rapid plasma clearance of our mini proteins translate to the desired low bone marrow exposure?

This is the important one because we do think -- and Matt spoke to that earlier, that bone marrow exposure at the end of the day is going to be what will be dose limiting for radiopharmaceuticals in oncology. And second, with our mini proteins being really cleared, what is the potential impact if any, to the kidneys. And with the capabilities and technologies available to us at the time we were able to investigate those questions and those data have been presented at the triple meeting in the fall of 2024.

Fast forward 2 years later, we have now advanced our own imaging a dosimetry capabilities and paired with the new scanners at NuMeRi, we're now together able to ask more questions like extending the number of normal tissues we can investigate and also as an access first get a look at potential tumor doses through dosimetry. So let's dive in with a brief summary of both posters before we take a look at the actual data.

First, most important, AKY-2519 in this imaging entosymegy study was generally well tolerated with no AEs or infusion-related reactions reported. Second, we observed robust tumor uptake and retention out to at least 6 days in serial imaging along with decreasing and limited normal tissue exposure. Tumor uptake by SUV on PET/CT imaging was also observed across multiple tumor types.

The robust tumor uptick and retention observed in the specie portion of the assessment translated to robust predictive tumor doses with low normal tissue exposure suggestive of a favorable therapeutic index for AKY-2519 as a therapeutic. And third, but not least, pet city imaging analysis also showed that AKY-2519 is able to consistently identify lesions that are also identified by PSMA imaging agents when using dedicated PSMA diagnostics, suggesting that B7-H3 may be indeed an excellent target for novel prostate cancer therapies.

Overall, these data suggest the potential for AKY-2519 to cure cancer cells across multiple B7-H3 expressing tumor types while minimizing normal tissue radiation exposure in patients. So in total, we're going to be presenting across 2 posters together with our collaborators data from 34 patients collected across 2 academic centers in South Africa and Germany.

In South Africa, the assessment was focused on MCRPC where 16 patients under PET and 0 spect imaging utilizing either gallium-68 or lutetium-177 as the respected imaging isotopes. In Germany, patients with different solid tumors expanding beyond prostate cancer received gallium-68 AKY-2519 before undergoing PET/CT imaging to assess tumor uptake. All in all, these data will give us a good comprehensive view of the biodistribution, tumor uptake and retention as well as the predictive absorbed doses to be delivered to tumors and a range of normal tissues. So pictures tell better stories than I ever could.

So let us first take a look at some images from a representative patient with prostate cancer who underwent serial imaging with low-dose lutetium-177 AKY-2519 and PET imaging or gallium-68 AKY-2519. We are starting with a PET/CT image on the top left than what we see here is strong uptake in extensive metastatic disease in particular node disease spread in the pelvis and around aorta. We also see uptake in the bone lesion that on the PET/CT image is actually hidden behind the liver and is the primary site of the disease as well. From a normal tissue perspective, we observed an initial blushing of the salivary glands as well as the liver here and the spline is also visible. We're not seeing much of the kidneys in this 2-hour snapshot image.

I think the more interesting to our snapshot is the captured activity over time that is pictured in Panel D here. These data -- here, where we utilize low-dose lutetium-177 with serial imaging at 3, 24 and 144 hours, what allows us to translate these visuals or the visuals into predictive or doses. And what we're seeing here, again, is a very strong initial uptake of 3 hours in the metastatic lesion that is preserved and retained at 24 and out to at least 144 hours, the latest imaging time point here.

Regarding normal tissues, have, you can see at 24 hours already clearing of the salivary glands and delivers retreating well into the background. A nice visual of how the actual dose administered to the patient is distributed between normal tissues and tumor lesions is shown in the top right panel E. So all the normal tissues, including kidney, liver, receive a small portion of the dose with the vast majority being delivered to tumors. This is the profile on to see for radiopharmaceutical and a really nice translation of our mini protein thesis.

Now looking at predictive absorb doses, putting some numbers behind the images. We see that the 3 organs highlighted here for this particular patient are all well below clinical benchmarks while the tumor doses are very, very robust. For calculation conveniences, we provide great per [ megabacural ] dose coefficients. These are data converted to potential use of actinium-225 even though lutetium-177 was the utilized imaging isotope. And we also presented total predicted gray that would be delivered to normal tissues and tumors over a typical 4-course therapeutic application of an exemplary 8-megawatt oral dose of actinium-225.

So we're seeing that tumor doses with AKY-2519 are not only very robust and consistent across various lesion types but also substantially higher than the observed doses to the normal tissues. When we assess tumor doses, we also employ what is called a partial volume correction here which can adjust for some of the heterogeneity encountered in country tumors. And I view this as a sensitivity analysis giving us a better sense of the range for the dose we may deliver to tumors.

So numbers, if we just look at the nodal disease here and the specific lesion highlighted, it is expected to receive very healthy or unhealthy for the tumor, 122 to 239 grade over only a 4-cycle treatment course at 8 megawatts. While the kidneys at the same time over the same treatment course would only receive 9.2 grade and the salary glance will only get delivered 3.6 grain. And keep in mind, [indiscernible] is a really clear trader pharmaceutical. Overall, the dissymmetry analysis in this patient predicts a fairly favorable therapeutic index for actinium-225.

Now let's take a look at the predictive dose to some key normal issues across all 12 patients with available data to do actinium conversions of the original 16-patient lutetium data set. And what you can see is that the data is very consistent with what I have just shown you for the individual patient with those coefficients coming in at 0.04 grade or mega bacterial for bone marrow to deliver and 0.5% to the kidneys and only 0.13 to the salivary glands.

So if we give this up to a full therapeutic treatment course, we are landing at 1.3 grade to the bone marrow 9.9% to deliver 16 grade to the kidneys and only 4.2 grades to the salivary glands on average here. With that, the normal dosimetry is clearly supportive of repeat dosing as clinically meaningful doses and advancement of the program. Notably, the low exposure to the salivary glands in particular could be a differentiator from PSMA carbonate therapies, especially as we think about alpha therapies in this setting.

Similar to what I just described for normal tissues, we do see that same level of consistency when we look at the population data for predictive absorbed doses to the tumors. And this is now broken down by various types of lesions. Again, I'm presenting to you the dose coefficients in [ megabacural ] also new selectivity and how that grade would look like following 4 therapeutic administrations at that exemplary mega bacterial dose.

Partial volume correction, I spoke about earlier, is not done for the primary disease sites since there is a spillover effect from the urine fill bladder, which would artificially inflate those results. But of course, we're doing it against here for the nodal and bone disease across all patients and lesions analyzed. Here, we're seeing for nodal metastases, a substantive predictive absorb dosed of 141 to 268 grade following 4 doses at 8-megawatt roles and for bone disease, we're seeing 48 to 121 gray deliver. In all of this, while the kidney will only receive 16 gray and the salivary glands as I mentioned earlier, would only receive for great studies data.

So overall, these data are quite exciting to us and really highlight the potential for AKY-2519, a very strong tumor to normal tissue ratios, and we're looking forward to start dosing patients under IND with actinium-225 AKY-2519.

Now let's pivot and take a quick look at the tumor uptake of 2519 beyond prostate cancer, of course, still including more prostate cancer patients here. And this is work now done by the team in Essen, Germany, and we can see robust tumor uptake by SUV Max in a patient with adenocarcinoma non-small cell lung cancer, a patient with recurrent small cell lung cancer in a patient with recurrent rectal cancer.

These images were taken 2 hours post injection with gallium-68 AKY-2519. And once again, similar to 1189, we can use the same binder for both imaging and therapeutic applications. These images clearly support investigation of AKY-2519 across multiple tumor clients and inform the design of this asset study, as Matt mentioned earlier. Briefly, expanding on the PET CT imaging data focusing on the core of prostate cancer patients with SUVs captured again to our post injection.

We can now look at SUV MAX and means as well as the SUV peak across different lesion types. We're consistently seeing very strong uptake highlighting that 2519, could potentially not only be utilized as a diagnostic and prostate cancer, but is potentially to be highly effective across various types of metastatic lesions, which is, of course, supported by the robust tumor dosimetry data I discussed earlier.

Further to that, here's a little bit of a teaser for you since the work in South Africa included a matched pair sampling of PSMA and B7-H3 expression through imaging with PSMA and AKY-2519. I'm showing you 2 patients here with their MIPS to maximum intensity projections and some axis of SUV MAX. When we look at the broader uptake profile for AKY-2519 and PSMA-11, which is a dedicated diagnostic agent used to select patients for PLUVICTO therapy, you can see that AKY-2519 consistently and reliably identified solutions that are also identified by PSM11, suggesting coexpression of B7-H3 and PSMA.

The way this was done here is by utilizing a thresholding approach, where all nations of ours certainly has to be cut off on colored in red. As a starting point, threshold established for PSMA were applied to both image [indiscernible], and we're going to be doing additional analysis with these data across the 4 cohort of patients, including optimization specific to B7-H3 and that will be presented at a future conference. These data, however, which are the first comprehensive imaging data of B7-H3 and prostate cancer clearly demonstrated to be a very promising target for novel therapies here.

Let us summarize again before we spend a few minutes on the development program itself. So AKY-2519 was well tolerated with no AEs or future related reactions observed to robust tumor uptake and retention that translated to strong tumor doses while keeping normal tissue exposure alone. Tumor uptake by SPV was also observed across multiple BCM regulatory tumor types.

So this data support the broad clinical development program of AKY-2519 across multiple tumor types. This is the design of the ongoing prostate cancer study that we spoke about at our last call earlier, May, utilizing copper 64 as the imaging isotope in, of course, the highly potent AKY-2519 as a therapeutic isotope. The study is now enrolling in 2 cohorts, cohort A for patients who have not received PLUVICTO and Cohort B for patients who have received PLUVICTO.

Both cohorts are independent dose escalations across 3 dose levels, 6, 9 and 12-megawatt orals, of which 2 can be expanded to up to 3 patients for each of the 2 cohorts. And now for the first time, I'm also sharing with you the high-level design of the 2519 basket [indiscernible]. It follows the same dose escalation scheme that you've seen before with backfill as well as now dedicated expansions for non-small cell lung cancer and a large one for other B7-H3 solid tumors. Protocol is now active on our IND and on track to start dosing patients in the second half of this year.

So this concludes the presentation piece of the data and now comes the fun part as I'm welcoming Dr. Sartor and Dr. Yap to our virtual fireside chat.

Thank you all for joining us. Today, I really want to take this opportunity to sit down with both of you to talk about the data just presented. And in addition, I'd like to explore with you what you're seeing in the current treatment landscape for both prostate cancer and more broadly in the B7-H3 space, where you see continuing unmet need for patients, specifically around other radar pharmaceuticals in development, when we think about prostate cancer, and how you see the treatment landscape continuing to evolve rate pharmaceuticals.

So before we dive in, I'd like to ask both of you to introduce yourselves and talk a little bit about your background and experience. And let's start in order of the studies you're going to be also supporting. So we'll start with Dr. Sartor.

Hi, I'm Dr. Oliver Sartor. I'm a long-time prostate cancer investigational dark I've been involved with ready Pharmaceuticals believe it or not, since samarium-153 back in the '90s and then going on to radium-223 and PLUVICTO. It's a pleasure to be here and delighted to be able to participate in the call today.

Good morning, everyone. Tim Yap here. Thanks so much for having me. So I'm a medical oncologist at MD Anderson. I'm the VP and Head of Clinical Development here in our Therapeutics Discovery Division and a professor in our Department of Investigational Center Therapeutics, which is our Phase I program where we're developing novel agents, including our LTs but also interesting ADCs and also T-cell engagers as well. So be involved in Phase I clinical trials in early phase studies for about 20 years.

Wonderful. Thank you. So Dr. Sartor, maybe starting a question for you. Since we're obviously at Aktis very excited about the data we just presented. Maybe you can share some of your thoughts about this data and how you see them fit into the larger prostate cancer treatment landscape, specifically in the context of our ongoing Phase Ib study in prostate cancer.

Yes. Thank you. I think the data is very impressive. Let's go back to PLUVICTO for a second because I think that's where the current money is, obviously, a multibillion dollar drug. PLUVICTO is an absolutely fantastic drug for about 1/3 of the patients. About 1/3 of the patients, it's really not very impressive at all. And then another one of the third is kind of in the middle. So PLUVICTO is obviously a very good agent but only for a minority of those were actually treated.

And I think there's plenty of opportunity to be able to look at another agent. I'll tell you what when I reviewed the data was a surprising amount of uptake even in those positive, but also extending and I know that some other data to those that are not PSMA PET positive. As a board spectrum of pipe PET positivity and B7-H3 imaging is shown here, I thought was absolutely outstanding. If you look in at the SUVs, you're looking at multiple lesions, multiple patients, above 10, which is a really nice cutoff that's been used by [indiscernible] and the Australians certainly greater than liver, member comes in with an SUV of typically around 5-ish or so.

So what we're seeing is lots of uptake and that potential rate pharmaceutical trial, the opportunity for nice activity. The other thing that I think was nice was the retention that you see in the tumor, and you see this in my sets, lutetium-177, dosimetry data where you see the retention in the tumor and the washout of the normal tissue. There are 2 items that I was watching very closely.

Number 1 was the kidney exposure because that's been an issue that has come up with the SSTR2 ligands for actinium and others and we really have to be careful with kidney. The way this mini protein works, it's not really typically cleared by the kidney, thus, the renal dose symmetry is extremely favorable. The other problem that has been encountered is with the antibodies. And we've seen the long half-life of antibodies, translate into substantial bone marrow toxicity. Here, we've seen the rapid clearance and what looks like a very tolerable bone marrow profile.

So I'm going to call it the trifecta. Really nice retention in the tumor, really minimal exposure to the kidney and rapid enough clearance to not expose the bone marrow. I think this is very preliminary but very promising data that certainly supports the use of further development.

Thank you for that, Dr. Sartor. And I wholeheartedly agree, of course. Maybe just diving a little bit deeper into prostate cancer and alpha-emitting radioisotopes and your experience there so far? What normal tissue do you typically see outside of bone marrow as the most dose limiting when thinking about alpha therapies for prostate cancer?

Yes. So let's kind of look at the landscape just for a brief moment. We had the PSMA-617 actinium -- and there, we're going to be really worrying about the salivary gland because Xerostomia is a substantial issue and can be right limiting. Next, we go to the PSMA INT from AZ, and they're also having significant salivary issues. When you go to the convergent antibody, which is 8591, you're starting to look at marrow toxicity being rate limiting.

So if you look at basically, I'm going to call it the 5 that are fairly developed. By the way, the Bayer Trillium also is under Phase III development in the not-too-distant future. There, I think it's going to be a little bit on the kidney and marrow. There's some interesting properties to the trillium molecule. But nevertheless, so far, what we're seeing is salivary and bone marrow depending on whether or not it's a small molecule like 617 or INT or the marrow, which is going to be true for the antibodies.

And maybe the last question for you, Dr. Sartor. How do you view the novel fleet of ADCs coming into prostate cancer and how they will compete with radio pharmaceuticals, not just this one specifically, but as a category at large. Where do you view physicians or yourself will prioritize ADC versus RLT or why not both?

Yes. The ADCs have so far been a bit disappointing. Most -- B7-H3 is under for the development. The BV will end up with an interesting ADC that will be presenting data here at ASCO. But so far, the ADCs have been a little bit disappointing today. The T cell engagers have been more interesting, and those are going to be looking at with xaluritamig and pasritamig coming out of the Amgen and the J&J camps. But in terms of the ADCs, I think you probably got a better mousetrap here than the ADCs have been watching so far.

Great. Thank you. Thank you for that, Dr. Sartor. Maybe now we've spent some time with Dr. Yap as we think about outside of prostate cancer. So Dr. Yap, as we are ready to initiate the Phase Ib trial, how do you view B7-H3 as a target outside of prostate cancer? What has been your experience? What gets you excited about this outside of prostate?

Yes. Thanks, Akos. So to me, B7-H3, and I think certainly to the field in general, we view B7-H3 as really an exceptionally promising target, but importantly, a near universal target for solid tumors, not just prostate cancer, but certainly plenty of other opportunities as well in addition to prostate cancer.

And it's primarily based on the data that you've already shown that it is heavily expressed across a wide range of different cancers, but minimally expressed in healthy tissues. And therefore, really can serve as a very highly specific target to go after developing targeted therapies against. And I think the data speak for themselves in terms of approaches that have been successful. And I do certainly think that B7-H3 is already, if you like, clinically derisked as an antitumor target to go after in the clinic.

Yes. Could you maybe just share with us your 1 or 2 favorite solid tumor types that are not prostate cancer for B7-H3 where you see the highest unmet need?

Yes, absolutely. So certainly, small cell lung cancer, I think it's really probably one of the most successful indications for B7-H3 targeting. And of course, I'm really referring to the ADCs the B7-H3 ADCs like [ infonezmmab], piroxicam, which have shown strong response rates and advanced, heavily pretreated small cell lung cancer. But also beyond small cell lung cancer, I really do think that it is broadly actionable in non-small cell lung cancer as a potential indication, metastatic colorectal cancer and also a head squamous cell carcinomas.

And then going even beyond that, B7-H3 is actually highly expressed in tumors like osteosarcoma, and neuroblastoma. So thinking about pediatrics on their tumors. And then going beyond that as well, it is heavily expressed as well in CNS tumors like glioblastoma. And that's the reason why there has been so much interest in targeting B7-H3 out there in terms of ADCs in terms of T cell engagers, CAR-Ts bispecific antibodies.

Great. Thank you. I think this concludes our fireside chat, and I'll hand it back over to Matt.

Great. Thanks, Akos. Thanks, Dr. Sartor and Dr. Yap. I appreciate all the insights shared here. And so now we're going to turn it over to the operator to conduct the question-and-answer session.

[Operator Instructions]. Our first question is going to come from the line of Tyler Van Buren with TD.

This is Ikenna on for Tyler. Congrats on the data, guys. My question is, given that use actinium 2025 payload, do these dosimetry results suggest the potential for improved efficacy as a relative tumor uptake compared to PLUVICTO at least similar if that improved?

Thanks for the question. I'm sorry -- go ahead.

Yes. Yes, thank you. The answer is yes. I mean you're ending up with the alpha as supposed to the beta, I think everyone would choose an alpha or beta when it comes to any tumor activity. The doses here are clearly what I think will be superior to PLUVICTO with lutetium. So I think basically, this is very promising, more so than provitamin it comes to the import doses.

Our next question will come from the line of Jonathan Chang with Leerink Partners.

This is Yiwen on for Jonathan. Congrats on the data. So how does the patient population in this Phase II study compared to the intended population of the Phase I study in terms of tumor burden disease stage and prior treatment and others.

I can answer this one. So the patient population in the South African study was primarily a trite naive patient population with only a couple of patients being PLUVICTO exposed PSMA-617 exposed for that matter. And in the EM data set, those 7 patients, it's a mix of PLUVICTO exposed and naive populations.

Our next question will come from the line of Alec Stranahan with Bank of America.

And great to see all the updates. I guess for the company or the KOLs on the call, maybe just to put a finer point and maybe some numbers on a couple of important questions that were mentioned. I guess, first, based on the literature for B7-H3 and other RTs guess what delta would you want to see an uptake between tumor and normal tissues? And then what uptake in tumor correlates with the response? And is this really that SUV Max that was mentioned or maybe a different metric.

Alex, thanks for the question. I'm going to start with Akos and we'll go to Dr. Sartor and Yap.

So I would point you to Panel E in that case study slide that we presented in this deck, if you're thinking about what ratio do I want to see, that's exactly what you want to see, right? You have all the normal tissues squished, squeezed to the left and all the tumors up to the right. And the way this plot works is it's basically the distribution of the actual dose administered, right? So what proportion of the dose goes to what tissue versus tumor. Yes. And I don't know if Dr. Sartor or Dr. Yap has a view on translation of SUV, max peak synergy data to potential efficacy.

Yes. A couple of comments from Oliver here. So number 1 is there is a huge difference in the absorbed dose that can be taken in a normal tissue and the toxicity that resolves. The bone marrow is quite sensitive. The kidney is moderately sensitive, whereas the liver is not sensitive. The salivary are kind of stuck in there in the middle. So when you think about the symmetry, you have to think not about normal tissues, but which normal tissue are you referring to? And that's why when I had my little opportunity in the fire side chat to talk about renal and salivary. This is where I think we have really exceptional data here.

Secondly, the minimum and the maximum on the SUVs that you see in the pet scan can be a little bit misleading because really, it's the retention of the isotope it matters. And I think that's what you nicely see in the lutetium-177 dosimetry from South Africa, you see the retention. So the whole game here is the area on the curve, particularly during the half life of the administered isotope. In this case, satin you can see that the absorbed dose is going to be quite large because of the retention, not the individual SUV MAX, but the retention is what counts.

Yes. I totally agree with what Oliver has just said. And in particular here, we have a massive opportunity in developing a B7-H3 targeting T which has differentiated to the other B7-H3 targeting classes of agents out there as you think about antibody drug conjugates, we do see a lot of toxicities. I think that's something that has very much been overlooked and minimized.

I think these drugs, we shouldn't forget are chemotherapy agents at the end of the day, and they do have a narrow therapeutic index and so we do see high rates of myelosuppression, 40%, 50%, Grade 3 or greater toxicities, which can be very dose levering or dose limiting for many patients out there. And so I really do think that we have a really differentiated opportunity here with the BS3 targeting RLT.

Next question is coming from the line of Alex Ramsey with William Blair.

So our question is related to the extrapolation of lutetium-177, actinium-225 and specifically, we're wondering how the translation accounts for the recoil effect of actinium-225, a potential release of isotope from the key leader upon admission of the first alpha protocol. And also how that effect could impact the calculation of total absorbed dose?

Yes. I'll take that one. So the mathematical model that we used to convert the lutetium-177 to actinium-225 accounts for all daughter emissions and the increased biological potency of the alpha emitter. So it's the full delivery of all the emissions at the site, small lesion site or organ.

I might briefly comment if I might. The first half emission is going to be purely targeted because you're still in the key. With RECOIL the second alpha mission has extremely short half-life and that extremely short halfway seconds, microseconds have to get the exact number, but it's not going to wonder at all. The third emission is from [indiscernible] and that's where some wandering can occur because it's a little over 40 minutes, but most of the data would indicate that the tumor still is retaining the majority of the alpha. And then the last alpha, which is, of course, accumulated, it's going to be relatively short-lived after that. So I think it's reasonable to take the poor alphas when you're doing the dosimetry calculations, even though only the first is actually part of the kilo.

Thank you. And I'm showing no further questions at this time. And I would like to hand the conference back over to Matt Roden for closing remarks.

Well, thanks, everybody, for joining today, and a special thanks to Dr. Sartor and Dr. Yap for your additional comments here. This will conclude our call today, and let us know if you have any follow-up questions. Thanks, and have a great day.

This concludes today's conference call. Thank you for participating, and you may now disconnect.

Maybe we can get started. I think we're at the top of the hour. Thanks for joining this session with Aktis Oncology. My name is Alec Stranahan. I cover Aktis and SMID biotech at Bank of America. I'm very pleased to be joined by Matt Roden, Chief Executive Officer of Aktis; and Akos, I'm going to try the last name, Czibere, Chief Medical Officer. I think I was in the ballpark. Thanks, guys, Akos and Matt, for being here.

Sure.

Yes. Thanks for having us. So we're excited to be here, and thank you, Alec, for the invitation and to the entire Bank of America team.

Great. Yes, looking forward to the conversation, and we'll have follow-ups at our dinner later as well today, which I'm looking forward to as well. But maybe just to start off, Matt, recent IPO, great to see the interest in that offering given the sector backdrop. I guess, this gives you cash runway into 2029.

I think just at a high level, the core thesis that you guys have built the company on is the miniprotein radioconjugates. These are antibody like targeting affinity, small molecule pharmacology, but with a radiopharmaceutical payload. I guess maybe could you talk to how this opens up the opportunity set within radiopharmaceuticals broadly? We've seen success from, I guess, the beta emitters, Pluvicto, Lutathera. What are maybe the 1 or 2 things that you think you're building upon here and sort of what you hope to prove out in the clinic?

Yes. Great. No, that's a great setup. And really, the way it starts is with us at Aktis, we had the vision, along with others in the field that radiopharmaceuticals -- targeted radiopharmaceuticals could be a large new category of anticancer medicines, right? And so it started with the new renaissance in the field with the emergence a few years ago of what is now Pluvicto and Lutathera. And what the field learned from that, in our opinion, is that fast clearing molecules, fast clearing radiopharmaceuticals can widen the therapeutic index for radiopharmaceuticals because it's bone marrow sparing.

Previously, the field was looking at monoclonal antibodies as delivering radioisotopes, which, of course, are long-lived enough in the body that it's sharing its radioactive payload for the entirety of its circulation time. And so if you could shorten the circulation time by having molecules that leave the body quickly, that you should be able to expand that therapeutic index provided that you're able to get the drug into the tumor and exert a hit at the tumor level.

So we're excited to see the emergence of Pluvicto and Lutathera because those are small peptides, they're fast clearing, but they are effective binders to their targets, and they're able to exert that payload to create an antitumor effect.

What we were interested in doing, to your point, with the miniprotein radioconjugate platform that we've built is to figure out a way of how do you replicate that success that you saw with Pluvicto across a broad new array of targets that are expressed in tumor types where there's no radiopharmaceutical option. In other words, if you think of it this way, we think of the initial movers in this field as the pioneers are the ones who did the experiments that show in a certain instance that it can work.

And we are sort of the optimizers that are looking to take over a much bigger position across the field by opening up these white space opportunities as first-in-class molecules, bringing radiopharmaceuticals into these large patient populations where unmet need exists and there's no radiopharmaceutical option.

So to accomplish that, we built this miniprotein radioconjugate platform. Miniproteins were selected intentionally because they have the properties that we felt would lend itself to that fast clearing bone marrow-sparing profile, but also by virtue of its -- they're very small size and 3-dimensional structure that we felt that it was likely or was designed to, I should say, really deeply penetrate tumors but -- and get internalized into tumors, but also by virtue of diversity in the 3-dimensional structure that it would be able to hit effectively with high affinity and selectivity, a broad array of targets. In other words, you would just be able to hit a broader array of targets.

Small peptides are great when they work. But unfortunately, they are not really effective binders against many different targets in the target universe that we care about biologically. And so this is a way for us to sort of say, all right, let's do small peptide pharmacology, but with an antibody-like ability to hit a broad array of targets with high affinity and selectivity. And so that's what we felt the miniproteins were likely to deliver. We built the platform.

And now we're screening. We have libraries that we've built ourselves that are very highly curated and selected for the properties that we want. And even those are expanding in diversity, and now -- we're now screening north of now 6 billion variants across about 100 different scaffolds or protein folds. And on top of that, we've really added on a significant effort on generative AI binder approaches where now my -- our Head of Computational Chemistry is saying that we're now effectively sampling billions of trillions of different variants in silico as we seek to expand the search space to find very high affinity, very highly selective target binders that can enable us to broaden the impact of radiopharmaceuticals to a broader array of patients.

And so the data that we've generated and have presented really -- are principally very broad, deep preclinical data sets as well as imaging and dosimetry work in patients of various different tumor types, both for the Nectin-4 program and now the B7-H3 program. Those data for the B7-H3 program will be presented in a couple of weeks at ASCO. We previewed that to some extent in our S-1 earlier this year. But these are the bases with which we've moved forward into really broad Phase Ib development plans that we are looking to convert the data that we have now, which we think are very encouraging to a more formal clinical proof of concept to come.

Great. Great. And maybe one more high-level question, and then I want to get into the different pipeline assets you have in the clinic. You framed in the past that the radiopharmaceutical space is kind of at a similar inflection point to where ADCs were roughly 5 years ago. What are the analogs here? You've got a few approved drugs. And then there's a format optimization such as your miniproteins that unlocked a much larger opportunity. So I guess what kind of format optimizations with your design do you think are most analogous to the payload and linker improvements that have sort of expanded the ADC field?

Yes. It's a fascinating topic to look across the different modalities and see where the analogies are. It wasn't just us that felt that we're approaching an inflection point in the field of radiopharmaceuticals. There was actually what we cited in the S-1 was a presentation by Boston Consulting Group at a fall conference last year, where they pointed out multiple parallels between the ADC field pre -- let's call it, pre-Daiichi Sankyo. And now the inflection point that occurred, now there's multiple ADCs now approved by the FDA and with a total TAM of about $35 billion by 2030.

And so that has really expanded, right? And ADCs are very well known and understood in terms of the opportunities that exist there. Radiopharmaceuticals, I would say, are in a similar position as ADCs 5 years ago where as you mentioned, a couple of approved products, clear clinical validation. You also have clear commercial validation with Pluvicto being the best launching oncology drug since Ibrance.

So that's about a decade that passed. That's how far back you have to go to see an oncology drug launch as strong as Pluvicto was. So there's a commercial validation. Obviously, there's strategic validation, lots of deal value generated along the way in the field of radiopharmaceuticals.

So now the question is, how do you make it just bigger? How do you open up those white space opportunities? And that's what Aktis is intended to do. And that's where we're excited about the positioning that we've created where we have 2, we believe, first-in-class or potential first-in-class targeted radiopharmaceuticals, the first one targeting Nectin-4 and the second targeting B7-H3. These targets are expressed in very important patient groups, and we look forward to moving them forward.

I'd further add that this is just the start, right? So Nectin-4, B7-H3, these 2 programs for us are really just the tip of the iceberg of what Aktis is working on. Below the surface, we have many additional projects ongoing. I alluded already to the discovery platform, but we have various programs in different stages of early development. And that was also something that we've been working on in our collaboration with Eli Lilly to leverage our platform capabilities to generate even more radio conjugates against targets outside of our scope.

Great. And obviously, Lilly stepped up in large for the IPO as well as an equity holder. Maybe we can talk about that towards the end. But maybe we can just go stepwise down the pipeline, 1189, this is your Nectin-4 targeting radioligand therapy. This is in Phase Ib. We've seen fairly derisking tissue localization data, which is kind of the first step. And maybe one of the distinct benefits of radioligand therapy generally is, you can actually see where it's going and making sure that it's getting excreted in the way that you want before you actually dose patients with the active compound.

A basket of tumor types here, a few very high Nectin-4 expressing tumors, lung cancer, CRC, cervical, urothelial cancer, which is probably the most derisked. Maybe you could just walk us through sort of the backfill design and the dose expansion, escalation and sort of the number of patients and just the design broadly of the study?

Sure. I'm going to make some opening comments and Akos will add on the clinical strategy here. So you're right. The Nectin-4 AKY-1189 opportunity is an important one for us. Obviously, Nectin-4 is a clinically and commercially validated target. So the thinking is if you can hit it effectively that you should be able to see anticancer activity. And so we are mindful of the fact that the leading compound here, which is PADCEV commercialized now by Pfizer and others is really focused on urothelial carcinomas or bladder cancers. But we -- in addition to those opportunities in bladder cancer, we also see the opportunity for several other high-expressing Nectin-4 tumor types, including breast cancers, lung cancers and several others.

So the approach that we've taken, first, as you mentioned, we have tumor uptake data. So we can show uptake of our drug in tumors of various different histologies, including bladder, breast, cervical, colorectal and lung. So we've shown that in our previous presentations. And so the clinical development plan that we've set forth is, a, focused on bladder. Obviously, as you mentioned, clear proof of concept exists for the target in bladder cancer, but also enables us to really pursue opportunities outside of that. So, Akos, you want to talk about the trial designs that we have there and what we expect to see?

Yes, happy to. And that study, the NECTINIUM-2 trial has been under IND for about a year now, right? We cleared the IND last year around this time. And it follows the BOIN backfill design. So it's dose escalation under the BOIN principle where we tend to do 3 to 4 patients per dose level as we move up through escalating doses. And then once we have identified a dose level of interest, and it could be safety, it could be some early efficacy, we're able to expand that dose level out to 30 patients, right?

And we can do that in 2 dose levels. And that helps us really find the right dose to move into the more targeted expansion phase of the study, where we'll be looking at a cohort as it's currently planned of triple-negative breast cancer patients. Post-PADCEV pembro bladder cancer patients, obviously. And then there's a large 50-patient basket for the other non-TNBC, non-UC tumor types as well.

Great. And obviously, you guided to a 1Q '27 update from sort of the Phase Ib or Part 1 of the Phase Ib. That tends to be the data card flip that I get the most questions about from investors. And from the sound of it, it's going to be a pretty substantive update kind of to the scale that we saw with RayzeBio prior to their acquisition. I guess, how do you sort of frame this in your conversations in terms of the endpoints that are most important, the number of patients that you're going to have in sort of that metastatic UC indication and what sort of good would look like to advance the program?

Yes. Maybe just to add a nuance point on the RayzeBio data set. Since that data was less dose escalation, more expansion at a given dose, right? So that was that waterfall plot at the go-forward dose. We're obviously starting a step behind that, finding the dose first that we then want to carry into that. So that data set will be built around the dose escalation, clinical safety, efficacy, right, all dose levels, all 5 dose levels that are planned once they're completed will be included and then potentially some backfill patients with varying degrees of follow-up. So double-digit numbers.

And do you want to comment on the endpoints as well?

In terms of endpoints, if you just look at the technicality of the protocol, right, the dose escalation Part 1 endpoints are all around safety, right? And it will be safety focused, and we'll obviously also present the efficacy that we observed in that. But there's no formal hypothesis testing going on in this part of the study where we have to hit a certain response rate target or anything like that. That will be following in the expansion phase study.

Okay. And I guess...

Obviously, there will be efficacy data included, right?

Yes. You're not going to push it forward just based on safety. And TRODELVY is kind of the derisking asset for the target. In the post pembro -- sorry, PADCEV is what I meant. In the -- I guess, post PADCEV failure, is that kind of the target indication? And what are sort of the outcomes for those patients typically?

So we view the post-PADCEV pembro space as sort of the low-hanging fruit quick-to-patient opportunity, right, because there's no established standard of care. And with TRODELVY, as you mentioned, having to do another lab, right? With that study not reading out until like mid-'29, I think there continues to be an opportunity to be the first new therapy in the post-PADCEV pembro setting.

I think the real question to the field and the agency is going to be what is post-PADCEV pembro, right? Is it post-PADCEV pembro in a metastatic setting? Does it include the perioperative setting? So I think there's a lot of work that can be done to really have a meaningful impact for patients. But right now, the expectation I think -- or the bar is very low. Expectation is always high, but the bar is low.

Yes. Is response a clinically meaningful endpoint for those patients? Or is it more around survival duration?

I mean the gold standard for any regulatory approval is overall survival, right? And a response is, of course, meaningful to a patient if it lasts, if it has durability, right? And I do think that a response rate can be very useful to guide the next study, right? How do you have to size it? How does it correlate with PFS, OS? Response rate is great to get breakthrough therapy designation from the agency, right, which can further expedite the development. But -- we've seen it in the past, but it's unclear at this point if response rate will be a regulatory endpoint going forward, right or if you need PFS with some OS read. I think that's all in the question -- will all need to be discussed with the agency.

Yes. Okay. That makes sense. And I alluded to before that we have the tissue localization imaging data for the nontherapeutic isotope for 1189. I guess, how does this normal tissue localization kind of compare to other RLTs in the space? I know we've seen some salivary gland accumulation for some of the beta emitters. So any expectations with the therapeutic compound now around renal accumulation, salivary glands, et cetera?

Yes. Maybe I'll start on that one. So the way we view the imaging dosimetry analysis is it's effectively something that we can use as a stage gate for development. And so the way we've described the imaging and dosimetry is supportive of the clinical plans that we've brought forward, right? And so there are instances where a certain biodistribution pattern or absorbed dose profile may give you pause in terms of moving ahead or it may inform like a starting dose, for example, may require you to start at a very low dose in dose escalation.

But in the cases of our AKY-1189 and in AKY-2519, the data that were generated were informative. They were, in our opinion, clear go signals to Phase Ib, and they did inform our dose escalation schema that we've described now for both of the lead programs. So we think that this is -- what we're seeing here is certainly something that's supportive and consistent of the go-forward approach.

What we described recently when we kicked off the initial AKY-2519 B7-H3 targeted radio conjugate program in the clinic. We now have sites open and enrolling. What we described there was an approach where the initial protocol is going to be in metastatic castrate-resistant prostate cancer patients broadly. And then there's going to be a second protocol that we expect to open in the second half of this year that's going to address lung, colorectal, pancreatic, several other tumor types.

And this is all supported by the imaging and dosimetry data that we have and that we're going to present at ASCO and that were previewed in our S-1 in January. So there's a lot to be -- that we're excited about in terms of the protocols that we have set up, and we -- and the intent of those protocols is to give us a clear go signal to the next stage of development as well. And obviously, we're thinking about various accelerated paths to registration. And ultimately, that will be data dependent, but we're trying to create as many options as possible to reach patients as quickly as possible.

I guess on the accelerated path, is there maybe precedents you can point to there? Like is that kind of the post-PADCEV pembro line of therapy that we've been talking about?

So we'll be exploring multiple options to accelerate these programs to patients once we have the data supporting that. But Akos, do you want to comment on next step?

I think more on an acceleration rather than accelerated approval pathways, which may or may not go away, right, depending on who's in charge. We shall see. I do think if you have great data, there's always a path to patients that is accelerated with the agency. They've been over the years, extremely collaborative across multiple modalities, right, and sponsors. So they share that interest in bringing the breakthroughs to the patients.

So I'm less worried about that. But I think just to pick up on your point on where does dosimetry help us, right? Specifically, it helps us bring that first therapeutic study into the clinic in a more efficient way, right? And you can see that with the 2519 program where we did disclose the 3 dose levels that we're going through in dose escalation starting at 6 MBq, which is a fairly high dose for an actinium targeted therapy. And that supported by the data that we're presenting in a couple of weeks. weeks at ASCO. So there, I think dosimetry is strong. After that, really clinical safety and efficacy, I think, will be driving the future prospects and future studies.

Yes. And I imagine that the learnings from 1189 sort of helped you plus the dosimetry you're seeing for 2519...

It's a rapidly evolving field, right? And when we set out to collaborate on the 1189 dosimetry experience, the main question we were asking is, are we staying out of the bone marrow because that's so important, right? And what is the kidney exposure. And we were able to answer that. Now 2 years later, we have different questions, right? What about the [ glance ]? What about tumor? Can we look at that? And with evolving technologies, methodologies we're not able to look at that, right, today. And who knows what we'll be able to look at 2 years from now, but I don't think we'll ever be in a position where dosimetry will replace any type of safety/efficacy evaluation.

Okay. Maybe we can switch gears to 2519. And I think that's a pretty good segue. And maybe just to start, looking forward to the presence at ASCO. We'll obviously be there for the presentation. What does this data sort of need to show to confirm sort of the early localization that you've seen in a handful of patients? And how derisking do you think this will be ultimately for pushing the therapeutic compound into the clinic?

I think the data is exciting to the KOLs, investigators and to us to go into a broad development program. We have a very focused 2 trial and 1 prostate study that's now open for a couple of weeks, clinical trials went up yesterday on that one, that study is enrolling Pluvicto exposed and Pluvicto-naive patients in parallel dose escalations and then leading also into backfill expansions, 30 patients each in 2 dose levels and then there's going to be a basket lung-focused study starting in the second half of next year. So -- but to answer your question, we'll need the clinical data to then look back, right, how derisking was it, how much of the diseases translated. And yes, I hope you stop by.

Yes. Maybe just to build on that. So at ASCO, we're going to be presenting 2 posters and very conveniently, they're side by side. So it's one-stop shopping. One of the posters is looking at tumor uptake with AKY-2519 imaging agents, principally gallium labeled AKY-2519 in a number of different tumor types. And so that's kind of asking the question, would the tumor uptake support development in various different tumor types? And so that will, in a way, link to or supported in our mind, the basket trial approach that we're describing that second protocol that we expect to open in the second half of the year.

The other poster that we are -- is going to be presented is looking at 16 patients with metastatic castrate-resistant prostate cancer patients. So this is prostate focused. And that is not only the PET/CT-based analysis like the first, but it's also going to have SPECT/CT lutetium labeled AKY-2519 that's looking at exposure of the drug over a longer time frame up through 6 days. And so that is underpinning a dosimetry analysis. In other words, what is the absorbed dose in various normal tissues and what is the absorbed dose in the selected tumors in that population.

That's -- it's due to some technical advancements even over the last 2 years that Akos referred to, we're able to provide a more expansive analysis than even we could do 2 years ago with the AKY-1189 program. So what that did is that helped us inform specifically for the prostate cancer population, what the parameters for dose escalation would be, as Akos described. And so that was really part of the basis for the excitement for us to move this into Phase Ib in that specific population as well as the feedback we got from the key opinion leaders that focus principally on prostate cancer treatment. So we invite you to the poster to have that discussion.

Great. Yes, looking forward to it. Maybe in the last few minutes here, I do want to double-click on the Lilly collaboration that you alluded to earlier. Lilly seems fairly vested in the company in several ways. It sounds like the partnership is actually advancing even ahead of schedule in terms of target ID, et cetera. I guess maybe you can just outline sort of the structure of that collaboration with Lilly and sort of the cadence that we should expect for milestones out of the collaboration.

Sure. So the Lilly collaboration started in 2024, where at that time, our platform technology and capabilities to generate these miniprotein radioconjugates were now available to us and to Lilly and to others. And based on what was broad interest, we selected Lilly as a partner for a platform deal. So what this is, is it's a discovery collaboration where we are using our platform capabilities to generate novel miniprotein radioconjugates against targets that they pick that are outside of our target space.

And so what this does is, this is a win-win all around because this just expands the number of patients that can potentially benefit from our technology. And so that collaboration, as you said, we think it's going well. We disclosed in our S-1 that we've already hit the first milestone in that collaboration. And we're gratified to see the participation from Lilly in our IPO. And there's been a good mojo all around in that collaboration. So that is, in the end, an up to $1.2 billion collaboration deal for us. And we're working very hard to serve the collaboration well. We've worked very hard to be good partners to Lilly. Lilly has been very good partners to us.

And so -- but that said, again, this is restricted to the molecules that we are working to deliver for Lilly for their development in the clinic and commercialization. But to underscore the point, all the programs that we're working on, including 1189, 2519 and the others that are still to come are wholly owned by Aktis, right? And so -- where there's no option rights or other rights by any other party to those programs. So we have the opportunity to work both for patients through our wholly-owned programs as well as expand that through the collaboration with Lilly.

Okay. Obviously, nice to get the nondilutive milestones through that partnership. I guess how do you reinvest those then back into the company, whether it's on the manufacturing? Maybe if you could just touch on that quickly at the end here.

Yes. So we are well capitalized, not only through the nondilutive sources, but also through the very strong interest that we've seen in our capital raises to date. And so we're able, by virtue of the strong cash position we just reported $538 million on the balance sheet cash, cash equivalents as of this -- as of March 31. And so that puts us in a position where we can invest not only in these broad multi-tumor clinical development programs for 2 assets with multi-tumor potential, but also invest in our own pipeline to come, as I mentioned, tip of the iceberg. There's a lot going on beneath the surface that we haven't really described as well as to service the Lilly collaboration.

You mentioned manufacturing. It's something we haven't talked about. I know we're running up against time. I'll just say that this has been a really, really important effort for us to ensure that we are in control of our own destiny by building our own manufacturing capabilities, inclusive of isotope supply, final drug substance, drug product manufacturing and delivery to patients. So all of those things are areas of focus and priorities for us because we think these are the things that are going to let -- enable us to have that significant patient impact that we're working to have.

Yes. Very good. Well, I think that's a great note to end on. I know we're at time here. But Matt, Akos, thank you so much for the conversation, and thanks, everyone, for attending and your interest in Aktis. Thank you.

Thanks. Bye-bye.

Good day, and thank you for standing by. Welcome to the Aktis Oncology, AKY-2519 Clinical Development Strategy Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Matthew Roden, President and CEO. Please go ahead.

Thank you, Didi, and thank you all for joining us this morning. Before we begin, I'd like to remind you that today's remarks will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. We ask that you refer to our filings on SEC.gov, including our most recent annual report on Form 10-K filed with the SEC on March 31, 2026, for a full list of risks and uncertainties. Actual results may differ material from those indicated by these statements. And unless required by law, Aktis does not undertake any obligation to update these statements regarding the future or to confirm these statements in relation to actual events.

Joining me on the call today with prepared remarks is Akos Czibere, our Chief Medical Officer. Also joining the call on the question-and-answer session in alphabetical order is Tyler Benedum, our Chief Technical Officer; Paul Feldman, our Chief Scientific Officer; Kyle Kuvalanka, our Chief Financial Officer; and Shulamit Ron-Bigger, our Chief Operating Officer. We're excited to discuss the announcements we made yesterday related to our second program to enter the clinic, AKY-2519, a B7-H3 targeted miniprotein radioconjugate. We see an opportunity to advance a broad clinical development plan for AKY-2519, given the high expression of B7-H3 across multiple solid tumor types and given the poor prognosis associated with B7-H3 overexpression.

First, we announced the initiation of a dedicated Phase Ib clinical trial of AKY-2519 in metastatic castrate-resistant prostate cancer. And second, we highlighted our clinical development strategy to evaluate AKY-2519 more broadly in various B7-H3 expressing tumors, including plans to initiate a second Phase Ib basket trial in lung, colorectal and other solid tumors in the second half of 2026. During today's call, we will highlight the following: the unique opportunity for B7-H3 as a differentiated radiopharmaceutical target in metastatic castrate-resistant prostate cancer and in other indications. The rationale underpinning our strategy, which we believe is significantly enhanced from what we described in our S-1 and has been informed by insights from our clinical advisory boards in the distinct treatment patterns and clinical needs of patients with castrate-resistant prostate cancer compared to other solid tumor patient groups as well as discuss the Phase Ib trial design for a dedicated prostate cancer protocol.

Before we dive into the AKY-2519 updates, I want to take a moment to remind you of our mission and the progress we've made as a company. Aktis Oncology is focused on extending the benefit of targeted radiopharmaceuticals to large patient populations that have no radiopharmaceutical option or where unmet needs persist. At present, approved radiopharmaceuticals such as PLUVICTO and Lutathera have demonstrated clinical benefit in patients, but there remains a significant opportunity to address molecular targets expressed in several other tumor types, and we're keen to extend this clinical benefit of radiopharmaceuticals to many more patients who have no radiopharmaceutical option.

Starting at the top of this page, you can see our novel and differentiated platform is designed to produce miniprotein radioconjugates to selectively deliver the tumor-killing properties of radioisotopes by maximizing tumor penetration, internalization into the tumor and retention in the tumor while rapidly clearing from normal tissues to limit unwanted exposure. From this platform, we have now advanced two distinct lead programs to the clinic, both of which are intended to address several important solid tumor patient populations including those where unmet needs persist, such as bladder, prostate, lung, breast, colorectal, head and neck cancers and various other tumor types. Aside from our two lead programs, we're further developing a pipeline of wholly owned programs in earlier development and supporting a discovery collaboration with Eli Lilly that leverages our platform for the discovery and development of additional novel radio -- miniprotein radioconjugates for the treatment of cancers.

Another major pillar of Aktis Oncology is our unique infrastructure, which includes a resilient and scalable end-to-end supply chain that we believe is paramount for us to maximize our patient impact potential. Taken together with our strong balance sheet and accomplished leadership team, we are well positioned to prosecute our mission to expand the reach of radiopharmaceuticals to patients in need. Slide 5 depicts how our miniprotein radioconjugate platform allows us to explore a portfolio of assets. Our most advanced clinical stage program is our Nectin-4 targeted radioconjugate, AKY-1189, which is currently enrolling a Phase Ib clinical trial. AKY-1189 has FDA Fast Track designation, and we expect to present preliminary dose escalation data from this program in the first quarter of 2027.

Next, AKY-2519, the topic of today's call, a miniprotein radioconjugate. We have advanced to the clinic in the past 12 months. On March 30, we announced that the FDA had cleared our IND applications for this program. We are delighted to have now achieved the critical milestone of opening the first sites for the AKY-2519 clinical program. Our two trial strategy includes leading with a dedicated Phase Ib study in patients with metastatic castrate-resistant prostate cancer as announced in yesterday's press release. This trial has been initiated and will evaluate AKY-2519 in both PLUVICTO-naïve and PLUVICTO-experienced patients. This prostate-focused protocol will be followed by a basket Phase Ib protocol, which will evaluate AKY-2519 in B7-H3 expressing cancers, including lung, colorectal and other cancer types. This study protocol is under regulatory review, and we expect to initiate the basket trial in the second half of this year.

In summary, we're working diligently to advance a portfolio of novel programs for patients in need of new and potentially transformative anticancer treatment options. And with that context, I'll turn the call over to Akos to provide an overview of B7-H3 biology and the foundation that has informed our clinical development strategy for AKY-2519.

Good morning, everyone, and thank you, Matt. So as Matt just explained, our clinical development strategy for AKY-2519 aligns closely with our vision to bring radiopharmaceuticals to large tumor types where we continue to see high unmet need. Specifically, the two-trial strategy here enables us the evaluation of AKY-2519 in a way that really allows us to efficiently generate indication relevant data for actionable data-driven decision-making as we already, at the beginning of AKY-2519's clinical journey, start to think about the next set of potentially pivotal studies. So our now initiated Phase Ib trial in mCRPC will be, to that end, enroll patients who have not been exposed or treated with PLUVICTO and those who have received prior PLUVICTO THERAPY across two separate cohorts.

The study is conducted under IND in the U.S., of course, and will utilize a mix of prostate-specific radioligand therapy centers and academics. Our upcoming Phase Ib basket trial, the second study for the AKY-2519 program will, of course, also be conducted in the U.S. under IND at multiple -- more academically focused centers. That study will focus on lung cancers as a whole, colorectal cancers and other solid tumors where we see high expression levels of B7-H3. The protocol for the basket trial has been finalized and is currently under regulatory review, and we anticipate to initiate that second study in the second half of 2026.

This two-trial approach was informed by insights from our expert clinical advisory boards and steering committees and really takes into account the distinct clinical trial landscape that is in existence for the prostate cancer -- for prostate cancers versus other solid tumors where we just haven't seen that deep penetration of radioligand therapies like we are seeing in prostate cancer. So we believe that this will enable us to more efficiently generate relevant data to inform the future studies, as mentioned before. Like Nectin-4, we do see B7-H3 as an ideal target for radiopharmaceuticals given its high expression across multiple tumor types and low expression across normal tissues. Clinically, it's also interesting, and that speaks to the high unmet need for B7-H3 expressing tumors that it's been shown to be associated with poor prognosis and lack of response to certain therapies in non-small cell lung cancer, for example.

So we do think B7-H3, like Nectin-4 has the potential to be a true first-in-class opportunity across multiple major tumor types spanning multiple lines of therapy. So let us take a brief look at the development data to date, focusing, of course, on a few preclinical highlights. First, AKY-2519 is a high affinity and selective binder for B7-H3 that was generated using our proprietary miniprotein platform with some promising preclinical data. So important for radiopharmaceuticals, we observed internalization of AKY-2519 in vitro, leading to durable tumor retention in vivo with limited normal tissue biodistribution and exposure, as you can see here in these data slides and the imager. This translated to robust antitumor effects and a dose-dependent survival benefit after a single administration of AKY-2519 in a cell line-derived xenograft model of non-small cell lung cancer.

Also of high interest, of course, as we think about metastatic castrate-resistant prostate cancer, AKY-3212, which is a sister molecule to AKY-2519, a classic tool molecule when chelated to actinium-225 demonstrated superior efficacy compared to PSMA-617 chelated to lutetium-177 in a patient-derived xenograft model of mCRPC. This model was engineered to be resistant to PSMA-617, lutetium-177. And while resistant to that particular medicine, these tumors remain sensitive to AKY-3212 chelated to actinium-225 when equivalent levels of drug were delivered or doses were delivered to tumors, as you can see in the lower right panel.

Pivoting our focus now to clinical data that we're not going to be speaking about today, but we'll be presenting at that Lakeside midyear conference, which, of course, is ASCO, as we talked about previously, we're really gratified and excited to be able to share with you clinical imaging and dosimetry data looking at normal tissues and tumors across two posters at the upcoming meeting. These two posters will have a strict focus where one poster will focus on mCRPC describing normal tissue biodistribution, dosimetry and tumor dosimetry and then a second poster that will be evaluating tumor uptake and normal tissue biodistribution across multiple tumor types, including non-small cell lung cancer and CRC.

So we do see a significant opportunity for B7-H3 as a differentiated radiopharmaceutical target in prostate cancer specifically, and of course, expanding that to other indications as well. But let's talk a little bit more about prostate cancer here. First, as you all know very well, PLUVICTO has been very successful since launch, but we do think there's a significant opportunity with a differentiated target like B7-H3 and a differentiated payload like actinium-225 because despite the success that we've seen with PLUVICTO, there continues to be an unmet need in prostate cancer for novel therapies with differentiated targets. Partly, this is because while PSMA works as a target, there are varying degrees of PSMA expression with a lot of heterogeneity across patients and some patients just lack any response to PSMA-directed therapies.

Second, there's also expression as it has been shown of PSMA on the salivary glands, which can be specifically challenging when administering high energy radioligand therapies or radiopharmaceuticals that utilize alpha emitters. This normal tissue expression liability is not expected to be present with B7-H3 since there's no expression of B7-H3 on the salivary glands. Adding to that in metastatic cancers in prostate cancers, it's been shown that B7-H3 is expressed very consistently in about 90% of all patients with low expression in normal tissues, as mentioned earlier, and most critically here, again, not present in the salivary glands. But of course, we do think that even beyond prostate cancers, B7-H3 has the potential to unlock whitespace opportunities as we call them true first-in-class opportunities in additional large tumor types such as lung cancers. And that really goes beyond just the small cell lung cancer indications.

So why did we end up splitting the program into two trials? So as we just reviewed, radiopharmaceuticals are already well established and rapidly evolving treatment modality in prostate cancer. And as a result of that, here in the U.S., we have a robust network of prostate cancer-specific RLT centers with deep expertise and experience in both patient selection and trial execution with this modality. So by spinning the prostate cancer indication out of the overall Phase Ib basket study, we now have access to these centers. And that will enable us to really optimize the dose selection process for this population and also enable us to look in parallel at PLUVICTO-naïve and PLUVICTO-experienced patients, which we think is going to be key as we think about the future positioning and development of this drug in prostate cancer. And that also really helps us to leverage the enthusiasm among those physicians working at those centers and the prostate cancer community at large as we can offer many treatment opportunities for the patients in this study.

So altogether, this dedicated prostate cancer protocol really gives us a unique opportunity to more efficiently generate indication relevant data in this key tumor type. So let's take a look at the design of this study. So this study will enroll in parallel in a BOIN dose escalation, as mentioned a few times, PLUVICTO-naïve and exposed patients across Cohort A and B. We only have three dose levels in this study, starting already at a starting dose of 6 megabecquerel and then going 3 megabecquerel increments to 9 and then 12 megabecquerel at the top dose. So very efficient. There's obviously in between dose levels if we need to go to dose, but the plan as outlined right now and active in the clinic calls for three dose levels. And then these dose levels, two of these three can and will be expanded for further dose optimization work across these two cohorts, giving us a very robust data set to inform future studies once the study has data available.

So I would now like to turn the call back over to Matt.

Great. Thanks, Akos. As you've heard today, we have designed a clinical strategy to position 2519 to demonstrate broad potential across multiple tumor types and patient populations with distinct needs. This includes prostate cancer where radiopharmaceuticals are well established. But with AKY-2519, we're delivering a new option with a differentiated target and payload and with a protocol that focuses on clinically relevant signals generated in a timely fashion. But the plan also includes addressing multiple other large patient populations such as lung and colorectal cancers, which represent whitespace opportunities for delivering the clinical benefits of radiopharmaceuticals.

And then lastly, looking ahead, company-wide over the next 12 months, we're working to deliver several important milestones, including for AKY-2519, as you've heard at the upcoming ASCO Annual Meeting later this month, we will present results from the clinical imaging and dosimetry analysis in patients with prostate cancers and other various solid tumors. And then in the second half of this year, as we've described, we expect to commence the Phase Ib basket trial in lung, colorectal and other B7-H3 expressing solid tumors. And then in 2027, we expect preliminary data from the Phase Ib prostate study to be reported. For AKY-1189, in the first quarter of 2027, we expect preliminary data from Part 1 of the ongoing Phase Ib clinical trial.

Moving to the early pipeline. We have two programs tracking towards development candidate nomination and as well as commencement of IND-enabling activities in the first quarter of 2027. And on the corporate side, we expect our in-house GMP manufacturing facility to be operational in the second half of this year as part of the company's hybrid manufacturing strategy to expand capabilities and scale and to support the ramping demands of our ongoing clinical trials. So in closing, we believe AKY-2519 has the potential to be a highly differentiated targeted radiopharmaceutical, and I want to thank all Aktis employees for your unwavering commitment to patients in bringing this forward. The strategy we outlined today reflects thoughtful positioning of the program to create value for patients and investors alike.

This concludes our prepared remarks. I'd like to open up the call for questions. Didi, feel free to proceed from here. Thank you.

[Operator Instructions] And our first question comes from Jessica Fye of JPMorgan.

This is Sylvia on for Jess Fye. You're going into both PLUVICTO-naïve and experienced patients here. For the patients who are PLUVICTO-naïve, can you speak with a bit more detail to the profile of patients you anticipate enrolling? Would they likely have low PSMA target expression? And then also, can you touch on what you expect the market to come away from ASCO having learned about AKY-2519?

Sylvia, thanks for the question. This is Matt. I'm going to take the last part first, and then I'm going to ask Akos to comment on the development in PSMA -- or I should say, PLUVICTO-naïve patients. So first, at ASCO, we're excited to bring forward the imaging and dosimetry data that we've generated. We're going to have to wait until then to go through in more detail. But in short, we believe that the imaging and dosimetry data that we have support for the development of the program as well as helps inform the clinical trial design that you saw here today. So with that, I'm going to ask Akos to comment on the PLUVICTO-naïve population.

Yes. Thank you for that question. So the protocol does not dictate or query PSMA expression levels via imaging, for example. And from an eligibility perspective, these patients could come on to our study in lieu of receiving PLUVICTO, right? So they don't need to -- and this will all be on clinicaltrials.gov when the posting goes up. They do not need to have received prior chemotherapy. They just need to have metastatic castrate-resistant prostate cancer and documented disease progression on at least two ARPIs.

And our next question comes from Tyler Van Buren of TD Cowen.

I have a couple. First, kind of a two-parter. What number of castrate-resistant prostate cancer patients are ineligible for PSMA-targeted therapy due to low target expression specifically? And how many would you say have a suboptimal response to PSMA-targeted therapy?

And then related -- the second is related to ASCO. Understanding you're waiting until the conference to discuss the data, but perhaps you can review the measurements of focus that will be most important as we think about the potential to reduce tumor burden in patients.

Yes, I can start with the PSMA-related question. So when we look at the outcomes for patients who received PLUVICTO, I loosely bucket them 1/3, 1/3, 1/3, right? So 1/3 is excellent outcomes, 1/3 has okay outcomes and 1/3 has no response to PLUVICTO. In terms of PSMA level expression, I think we are seeing many patients who have robust uptake of the imaging agent with PSMA and still not respond. And the label's requirements to receive PLUVICTO are fairly broad, right? I think it's only the presence of a lesion larger than the centimeter that's uptake negative that precludes from prescribing PLUVICTO. So I think the biology is a little more complex than just present absence when it comes to PSMA and potential response to PSMA-617 or other PSMA-directed therapies. And we're very interested in learning more about the relationship also of PSMA expression and B7-H3 expression and how that may drive differential responses for the two agents.

And Tyler, would you mind repeating the second part of the question related to ASCO?

Yes. Just understand that you're waiting for the conference to discuss the data, but I thought it would be helpful for you to kind of review the measurements that will be in focus when you report the data as we think about the potential for 2519 to reduce tumor burden in patients.

Yes. So what we are going to have in the prostate-specific poster will be an imaging and dosimetry assessment done in 16 patients that will share or show normal tissue predicted absorbed doses to key organs, including salivary glands, kidney, et cetera. And then there's going to be dosimetry assessments done on tumor as well across a number of patients. And then for the second study, it's going to be SUV-centric measurements for tumor uptake like SUVmean, SUVmax across multiple tumor types and normal tissues without dosimetry.

And our next question comes from Jonathan Chang of Leerink Partners.

First question, how did you decide on the three dose levels being evaluated in the prostate cohorts? And then second question for the Phase Ib basket study for other B7-H3 high expressing solid tumors. Given the broad expression profile of the target, what tumor types do you anticipate will be evaluated and represented in the study?

Thank you, Jonathan. This is Matt. I'll start actually with the second one. So as you heard, the basket study is intended to look broadly across B7-H3 expressing tumor types. We do see a particular concentration in high expression level in various subsets of lung cancers. And so those will be broadly included in that trial as well as other patient populations such as colorectal cancers and others. And so if you look at the expression levels of B7-H3, what's in the literature, we have some of our own data as well. You can see that there's really quite a broad opportunity to really do a signal-seeking analysis here. But of course, the key goal of the dose escalation is safety and dose finding.

In regard to the dose, I'll start and Akos may add. Clearly, both the preclinical work that we've done as well as the dosimetry work in patients informed what a starting dose would be. And so all of that was worked into our discussions with our advisers as well as with the regulatory agencies to land on this current dose escalation. But Akos, is there anything further to add to that?

No, you covered it.

Okay. Thank you, Jonathan.

And our next question comes from Alec Stranahan of Bank of America.

Walking through the latest data here. One question on B7-H3 expression pre- post-PLUVICTO. We've heard that target expression decline has been observed with other RLTs. Curious if this is something you've also seen with PSMA expression in prostate. I imagine B7-H3 expression in this context wouldn't be affected, but any thoughts there would be great. And I guess as a follow-up to that, is the reason to include both PLUVICTO-naïve and experienced cohorts more of a standard of care staging consideration? Or does this target expression piece maybe feed into that as well?

Yes, I'll start at the back end of your question, Alec. I think the splitting of the cohorts is one key -- there's one key reason to it, and that is patients who have already received radioligand therapy may tolerate a different dose than patients who are naive to it, right? Because we do have to think about the cumulative radiation that we deposit to whatever normal tissue we're depositing to, right, even though you'll appreciate the normal tissue biodistribution -- normal tissue dosimetry at ASCO we're going to be sharing it there.

There are still cumulative radiation deposits, right, just starting off with patients receiving 6 doses of PLUVICTO, sometimes more. And just to be able to really dial the right dose in for the two naive and more radiation exposed rather than PLUVICTO exposed patients, we think and our advisers think it makes the most sense to split the two. Also, we think the bigger opportunities are going to be not after PLUVICTO, right? That's something we want to do and we have to do and we are interested in, but we think this could be much more impactful in earlier disease settings.

Okay. And then -- from the expression.

So that's a bit of an open question at this point. We have a data set that we'll continue to analyze where we do have matched PSMA and B7-H3 PET/CT imaging, and we'll share when that is available. We do not expect B7-H3 expression to be lost though following PSMA-directed therapy. If anything, we expect it to be more pronounced, but there's very limited data to this end at this point. I actually think we're going to be the first B7-H3 imaging presentation in a large number of prostate cancer patients at ASCO.

Okay. That's very helpful. And maybe just one quick one for Matt on actinium supply. Great that you guys are launching the studies for 2519, and you've got 1189 as well ongoing. I guess, are you comfortable with sort of your current capacity? And how does the GMP suite coming online later this year kind of feed into your study plans for the future?

Yes. Thanks, Alec, for the question. We have been very focused on ensuring that our supply chain can scale up to what is really increasing demand from our clinical trial enrollment for this year. So I think what you see today is somewhat of an acceleration of the enrollment plan vis-a-vis what we had talked about in [ ERES-1 ] in the context of the IPO and so that did require us to really focus on being able to scale up our needs here. And so Tyler and the team have done a really nice job to ensure that we're in a good position to serve the needs of patients. And as we've discussed, both on the actinium supply side and on the manufacturing capacity side, final set manufacturing capacity side, we have set ourselves up to be able to ramp up to that increasing patient need.

And our next question comes from Alex Ramsey of William Blair.

Congrats on all the progress on this program. So maybe first, a bit of a theoretical question. So you have the upcoming data at ASCO. And so you have great SUV, great biodistribution, long-term retention. In that case, what's your confidence in that kind of translating to the Phase Ib clinical data? And how is the platform designed to mitigate risk when translating from dosimetry and imaging data to efficacy data?

And then the second question, in the post-PLUVICTO setting, we're just curious how you think about cumulative dose exposure in these patients given that they will be exposed to radiation across multiple lines of therapy? And how has the FDA kind of viewed this based on your conversations, especially in terms of renal tox and that 23 Gray limit that has been set?

Thank you, Alex, for the question. I'm going to ask Akos to comment on that one.

So those two questions really, right? So on the confidence in translating the imaging and dosimetry data to the clinic, I'd say we're obviously excited in putting a broad clinical development program into the clinic, supported by the imaging and dosimetry data and also, of course, supported by strong preclinical data. And how that will translate, we'll have to wait for the clinical data to read out, right? I don't think there's a lot of really prospective correlative analysis that's been done on that end, but we're excited with what we're seeing to this point. And what was your point on the EBRT limit?

Yes. Just for the post PLUVICTO setting for the patients that were exposed to PLUVICTO and then will be exposed to 2519 just in terms of like the cumulative tox, especially on renal tox given that the FDA has pretty strict limits for the cumulative exposure.

Yes. I think this will be more driven by clinical AEs toxicity than cumulative radiation doses. Obviously, we're collecting the administered doses as a prior therapy for patients in the PLUVICTO exposed cohort. So we can include that in all subsequent analysis. But you may have noticed that the dose levels are the same for the two populations, right? So there's no limitation in place when starting dose escalation. But we'll let the clinical data drive what dose we end up with.

I'm showing no further questions at this time. I'd like to turn it back to Matthew Roden for closing remarks.

Thank you, Didi, and thank you all for joining today. We're excited about the progress we've made and appreciate your continued support, and we look forward to keeping you updated as the program advances. Have a great rest of the day.

This concludes today's conference call. Thank you for participating, and you may now disconnect.