Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to our R&D Day. For those of you I haven't met, my name is [ Annie Kasperian ], and I lead Investor Relations and Corporate Communications across U.S. and Europe. It's a pleasure to welcome you today. Our presentation today includes forward-looking statements that are subject to substantial risks. Actual results may differ materially. You are cautioned not to rely on the forward-looking statements, which are made only as of today's date, and recommend -- and we recommend you refer to these statements along with the risk factors across our ASX and SEC filings. Today, you will hear from Telix management, Dr. Christian Behrenbruch, Managing Director and Group CEO; Mr. Kevin Richardson, CEO of our Precision Medicine business; Mr. Richard Valeix, CEO for Therapeutics business; Dr. David Cade, Group Chief Medical Officer; and Dr. Michael Wheatcroft, Vice President for Discovery Sciences. I also wanted to point out or acknowledge that we have our recently appointed Chairman of the Board, Mr. [ David Gill], joining us in the audience today. In addition to hearing from our management, you will also hear from prominently opinion leaders, including Dr. Alicia Morgans, Associate Professor of Medicine at Harvard Medical School and Director of Adult survivorship program at Dana-Farber; Dr. Varun Sundaram, a surgical urologist and advanced prostate cancer specialist at [ Urology Austin]; Dr. [ Sumanta Pal], also known as Dr. Monty, Professor and Research Co-Director of Kidney Cancer Program City of Hope; and Dr. Arthur Braat, associated at University Medical Center [indiscernible]. Our agenda today will begin with a strategic overview by Dr. Behrenbruch, followed by an update of our R&D capabilities and pipeline. We will then move into prostate cancer portfolio, where we will hear from both management and our clinical experts. Dr. [ Morgan ] will provide an update on the [ 591 ] program, while Dr. Sundaram will discuss the study. We will take questions specific to 591 program immediately following Dr. Morgan's presentation since she will join us virtually. All other questions will be reserved for the dedicated Q&A session. Our renal cancer portfolio -- on renal cancer portfolio, you'll hear -- you'll get an opportunity to hear from Dr. Monty and on brain cancer portfolio, you'll get an opportunity to hear from Dr. Braat. Dr. Behrenbruch will share some closing remarks, after which lunch will be served. We encourage you to stay around for lunch. Today's event is being webcast live and available for replay. So with that, I'd like to introduce you to Dr. Behrenbruch.

To get you up to speed on what's going on in the company. Very grateful to our KOLs, who are here today, managed to find -- carve time out of their really valuable clinical time to be here. So extremely grateful for that. Thank you. I was going to say next slide, and then I realized I had to drive it myself. So first of all, this slide is Telix in a nutshell in terms of our corporate strategy. As we've built the business over the last 10 years, these different pillars of the business have come into real focus. Today, we will talk about the Precision Medicine business. It's an incredibly important part of what we do. It's the way that we finance our R&D infrastructure growth, but there's going to be a strong emphasis today on the presentations around our therapeutics pipeline, which given the historical investor focus on the revenue-generating part of the business is perhaps received less attention. So part of our goal today is to get you up to speed with what the latest activities are across some of the really exciting data that these programs are generating and to sort of help you to understand the disease focus areas that are important to the company. One of the things that's also evolved over the last, I guess, 2 or 3 years is really a purchase price premium on early-stage assets in the radiopharma space. When I started the company over a decade ago, didn't really have the appetite to do really early stage stuff. It felt like there were enough assets and opportunities out there without having to sort of go into the lab, but we now feel that there are opportunities and reasons for looking at novel targets, looking at novel targeting methods. And so we'll touch a little bit on that today. And we've -- obviously, in the last couple of years, we've made some transactions that are around building that in-house capability. I'm grateful to be joined today by Richard Valeix and Kevin Richardson, who really represent the commercial drivers of the business. Kevin, in particular, leads our Precision Medicine portfolio. But we see the commercial organization that we've built as an asset to our organization just as definitively as our infrastructure or our pipeline. Nuclear medicine products are not typical pharma products, right? And the way that we sell them, deliver them, educate. It's really about delivering a clinical workflow all the way from a dose being delivered to the loading dock of a hospital through how do you calibrate a scanner, do dosimetry, manage a patient, radiation safety and even waste recovery. So this is a really unusual business. And that's why the emphasis on supply chain and manufacturing is so important. Can't reliably deliver a dose, whether it's a diagnostic or therapeutic product every single day and manage the whole delivery process of getting that into clinical practice, you actually don't have a business. And it's astonishing how few people in radiopharma really understand that. Today, we have 3 approved products. Really excited, and I realized there was a little time coming, but really excited to have gotten Pixclara approved last week. This is an important product for neuro-oncology patients in the United States. We do intend to expand the availability of this product globally. Pixclara builds on the very vibrant franchise that we built in prostate cancer imaging. We were second to market, but we really believe that we are delivering as the market leader in this space. You're going to see some fantastic discussion today around what we're doing with bypass, which is a step change in prostate cancer. And our track -- our 2-product strategy has proven to be very successful in terms of managing the reimbursement dynamics in the United States. And this is really how the growth of the business has evolved over the last couple of years. As you can see that we've really built a vibrant business, but the growth drivers for our precision medicine business will continue. And I think, in particular, I think a particular note aside from getting the resubmissions and commercialization launch of Pixclara or [indiscernible], the step change in our business that you're going to see come out of bypass and the operational and margin benefit of running our own nuclear pharmacy network is something that's really starting to take shape for us. You would have seen in our half year results. RLS went from being the fifth largest distribution partner that we had at the time that we acquired to the second largest. And when we put product volume through our own our nuclear pharmacy network, we not only have greater control over customer delivery, but it has a beneficial margin impact as well. And so you're going to see as the company matures and evolves, there are going to be a lot more selective about how we manage our distribution strategies in key markets. This is the company today. We are commercially active in 22 countries. We do supply product beyond that. But as a regulatory approved product, it's 22 countries today. We are expanding in 2027 into China. We have an NDA that's in review right now. We have agreed with the Japanese regulators on an accelerated approval pathway in Japan for Illuccix, and we are commercially active in terms of preparation for commercialization in Korea as well. So really, if you look at the supply chain infrastructure, clinical capabilities that we built inside the company, it really is about servicing all of this. Now today, I'm not going to talk very much about the ITM transaction, of course, in the breaks and what not, I'm happy to take your questions. But just to note that this transaction really expands this footprint. [ ITM ] is commercially active in 65 countries, and we see the opportunity to push our product pipeline and slip stream that isotope availability and reach a whole lot more patients as well as deliver to the next level of standard in the key commercially critical markets that we already serve. And so our tag line is creating a global radiopharma powerhouse, and I couldn't be more excited about what the combination of the 2 companies will deliver, of course, subject to closing conditions. We are a company that has grown through execution on our development pipeline, building a commercial team, but we also have been a company that has grown inorganically through strategic investment and partnerships. These are some of the key ones. I can tell you that all of the transactions that we have undertaken as a company have really led to the growth in our revenue and global reach. I'm particularly, as I said, excited about the ITM transaction, but you'll obviously be aware that we have a partnership with [ Regeneron], which will get a little bit of air play today in the R&D day. As well as some of the enabling technologies that we've invested in like ARTMS and IsoTherapeutics group. These are acquisitions that are actually enabling these next generation of assets that you're going to hear about today to come into fruition. So when I think about the future, we believe that we are creating a radiopharma company that has really no peer. I think that there's a growing appreciation in the investor community that radiopharmaceuticals are melting ice cubes. The supply chain and distribution is incredibly complicated. And that customer delivery excellence matters, and you only achieve that if you have that vertical integration. Supply chains are -- there's no magic radiopharmaceutical or radioisotope store in the sky. So if you're committed to delivering a pipeline, you have to have that infrastructure coming in behind it. I'm not going to go into all the details, but between isotope supply chain pipeline augmentation and really the talent that comes through in this merger, I think that there's a really bright future for what the combined organization looks like. And so just to kind of wrap it all up and bring it back to my opening strategy slide, as we think about what is a business that has global supply chain reach, the best therapeutics pipeline in the industry, a cash-generative business now on the precision medicine and the manufacturing piece. If you think about what the combined businesses look like, essentially, it's a book ending of a therapeutics pipeline with precision medicine and manufacturing. Their isotope business is very profitable. It's cash generative. It's highly differentiated. There isn't another radio pharma company that has scaled to deliver [ terribecral ] level of production output. And then when you see those 2 commercial businesses supporting the pipeline, you can see that the combined company has a very bright future indeed. So yes, exciting future and a lot to talk about and to understand over the next few months as we close that transaction out. That's it for me today. I just don't want to again reiterate, thank you for coming. And now I get to hand over to a very special guy in the Telix organization. Mike actually was employee #1 of the company. So he's been here from the very beginning, and we've all aged appropriately commensurately. But I'm really appreciative for might to come out today and give you a little bit of an overview on what's happening on the early stage and innovation side of the business. So Mike, over to you.

So I'm never quite sure when Chris says a special guy. I think is a positive thing, right? So you'll see that VP Discovery Sciences, somebody have been running the R&D efforts in Telix for a number of years. what goes into the design of a radiopharmaceutical and hopefully not too much of a science lesson, but more of a guideline to what we think about, which is kind of slightly differentiated in the industry we see. So I'm going to spade the slide where we've got a targeting agent and a radioisotope attached to a Kat and those things. But this audience knows that we have a targeting agent, which is the cancer-specific part and the radioisotope, which is the payload. But I think one thing that really doesn't get enough airtime, if you like, is around target selection. The actual cancer target you deliver to is probably the principal feature of the actual drug in terms of the therapeutic window of that particular drug is defined by that target, both in efficacy in terms of making sure you deliver enough radiation to that cancer cell but also making sure it's selective enough that actually you're not hitting kind of off-target tissues and creating a safety issue. And all the good things we like in targets, so we want to have a high expression. We want to be very specific. You want to have a high prevalence in the disease you're going after. But one key thing as well, we really look for in a target is the ability to internalize the flip inside and drag the radiation inside the cell. That's how we get really great efficacy by retaining that radiation inside the cancer cell. So Telix has got in its late-phase portfolio, we have a number of really well-validated targets with [ PSMA, CA9, and LAT-1 ] and [indiscernible] list as well. We're also starting to explore those novel targets in our early-stage research as well. So there are many different targeting agents you can use for delivering radiation. And I think the thing -- key thing we believe is that each one has a different properties. They have a different set of properties, and it's somewhat of a trade-off of things like pharmacokinetics, how quickly does your delivery vehicle get into the tumor? How quickly does it penetrate? How quickly does it clear from the blood and also how well does it internalize? And I think this kind of approach, we value all these different approaches. It is a trade-off of these sort of parameters. So that's why Telix has this kind of unusual targeting agent agnostic approach. We think that antibodies and small molecules all have their place, and it's about how you use them and for what purpose that really matters. So for example, sort of small molecules and peptides on the left-hand side of the screen, very small. They actually penetrate tumors really rapidly, and that's great, but they also wash out really quickly as well. and may not be as specific as, for instance, antibodies, which have a great specificity to cancer. And they may be -- because they use slow kinetics, they can -- they do take some time to get into and saturate that tumor with radiation. But once they're in that sort of sustained circulation alongside this ability to internalize and get into the cancer cell means that the cancer cells exposed to radiation for a long period of time. So we get kind of length of time, length of exposure to irradiate that tumor is really a beneficial thing. So [indiscernible], we're starting to also look at -- we're always looking to optimize, and we're now looking at sort of what we think might be a sweet spot in the middle somewhere in this diagram with engineered antibody fragments called miniibodies. So essentially, these are sort of cutdown versions of full IgGs. They're slightly smaller and they clear quickly, et cetera. So we're starting to look at these as a new delivery format in the research and early clinical studies. So we have 2 miniibody programs in early development, one targeting [ AVba6 integrin ] and another targeting DLL3, both in different forms of lung cancer. And again, this smaller format, we think, is really exciting because it can -- not only has it kind of clear quickly, but it actually is shown in clinical studies that were done just down the road in Memorial Sloan Kettering Cancer Center. We've already validated this early-stage minibody with -- this has already been clinically validated in studies where you've shown really quite a faster -- much faster uptake into tumors in this red line here on the tumor compared to IgGs. So when you think about the targeting agent, you then think about which payload are you going to choose. And obviously, like diagnostic versus therapeutic is a key one, the mission profile. And really, the secret sauce here is matching your radioisotope with the properties of your targeting agent. So often you would choose your pharmacokinetics of your drug to match that of the sort of the decay properties of the radioisotope. And this freedom to choose different targeting agents means we could -- we have much more freedom to choose a complete array of radioisotopes. And I think, again, matching the targeting agent with the disease with the isotope that agnostic approach to not just sticking with one thing being best, but actually thinking what's best for this situation you're using it in -- and it really underpins that strength of that approach. And so while clinical studies have really shown the benefits of [ Alpha's ] in potency, in terms of potency. It does also have a very short path length. It doesn't penetrate very deep into tissue. So we think the optimal use of those alpha emitters will be around that early disease or small-volume disease, micrometastatic disease. And that can -- we hope will have a real great benefit in those sort of diseases. But we still see value in beta emitters in those bulkier diseases or diseases where you may have heterogeneity, so patches of cancer and healthy tissue. So the ability to crossfire radiation across those bulky tumors is actually a real benefit. So the answer really here is that no one isotope is going to be best. It's really about what's the best application for the actual disease. And so when you come -- when you designed your molecule and you may have the best radioisotope, best radiopharmaceutical therapy in the world, but it's no use unless you can make it and deliver it. So it's no secret, as Chris showed before, that we've been developing the Telix Manufacturing Solutions network, a [ TMS ] network, which is a global network of sites, both serving radioisotope production as well as -- so acquisitions such as [ ARTMS ] help us do that. That's a technology that adds to any cyclotron to produce radioisotopes that are consistent and reproducible and reliable. So no matter where you are in the world, you're getting reproducibility of that radioisotope raw material, which is something that often gets overlooked if you're using multiple different providers. We also have our own in-house production of certain isotopes such as [ LED 212], a generation initiative so that we can fully support the full range of radioisotopes. Within [ TMS ], we also have dose production and radiopharmacy dose production and delivery. And obviously, our RLS network across the U.S. as an extensive network to actually make our products and deliver them to sites, reproducibly and reliably that reliability and reproducibility of delivery is really important for both clinical and commercial success. And I'm very pleased to also announce that we've added a new facility in Melbourne, [indiscernible] Australia, where we've run a lot of our clinical studies where we actually have a clinical manufacturing and imaging sites. So actually now straying into sort of the clinical utility, clinical dosing. And so just to wrap up. One thing we wanted to talk about is that Telix's core strategy is about theranostics. It's about the interplay of the diagnostics and the therapeutics. And so while imaging is powerful on its own, it really has a synergy with the therapeutics, both in terms of showing clinical proof of concept, the ability to look at dosimetry to estimate dosing for the therapeutic, also looking at are you dosing the right patient population. But as this slide shows, showing disease response to a therapeutic is supremely valuable. They work in synergy together as a theranostic. And so while we have a lot of emphasis on our commercial pipeline being diagnostics, it's really what we're very pleased to be able to show is the progress we're making in our therapeutic pipeline. And with that, I'll hand over to Richard Valeix, our CEO of Therapeutics. therapeutics business.

Hi, everyone. It's my pleasure to be on stage with you today. And my role today will be to present to you an overview of the therapeutics late-stage portfolio that we are currently developing. So probably you're familiar with these slides, but what I wanted to bring to you today is that Telix has probably the largest and the deepest portfolio under development currently in the radiopharma world. So we can say that, as mentioned by Mike, we are a diagnostic company because you will see that in front of each there compounds, you can find a diagnostic one or a [indiscernible] as we used to call that because it helps to diagnose some disease, but it helps also to select the patients as patient selections, eligibility for therapy and also monitoring the efficacy of our therapeutic compounds. So that's really a good synergy that you can see there and it's illustrated with the pairing of therapeutic and diagnostic compound. If we look at the disease areas that we are working on, you can see that we have a huge [indiscernible] and a huge focus on the urology oncology. And namely, we have the prostate cancer treatment that we are developing heavily. But we have also some compounds in the kidney disease area. So we will come back on these compounds in the -- during the presentations today. But really, what I wanted to highlight there is it's the urology is really one of our core disease area and focus. We are also working in neuro-oncology, where, as you know, recently, we obtained the marketing authorization for [ EpixLAa], our precision medicine compounds. And we are developing 2 assets in the treatment of neuro-oncology disease. The first one is in recurrent glioblastoma. And as you know, it's a really debilitating disease where no recent approved drugs have demonstrated a huge value for the patients. And third, we have the [indiscernible], an indication compounds and targets. We just used on the [ 400 ] that it's, in fact, a fab compound that we acquired a year ago. [indiscernible] is currently under the sunlight, as you saw in the press recently, but I really wanted to focus the fact that we have here 2 compounds that we name the fabs with a diagnostic compound and also a therapeutic compound. These 2 compounds have probably the most data published on the field. So if you are interested with you, we can provide you the latest publication on these 2 compounds, which derisk the development of that because we have already proof of evidence with expanded access programs in various centers. The attention I wanted to bring to you, it's not illustrated there or perhaps, yes, we have 3 Phase III trials ongoing. in urology with [indiscernible] in prostate, with [ Luton ] trial in kidney and with [indiscernible] recurrent glioblastoma. That's amazing to have 3 Phase III trial running in parallel with this portfolio. What I wanted also to highlight is something that Mike said that with the recent acquisition of ITM and all the vertical integration that we have done recently, we have a platform that authorized us to deal with antibody peptide and also more recently with minibodies and nanobodies. So that's for the targets. And with ITM, we have also now secured the access for all the isotopes that we are dealing with in this portfolio. So you can see that it compares us probably a unique capability that even some competitors and big competitors that don't have yet. I wanted also to highlight some partners that we are dealing with. So you're aware about the Regeneron deal that we made earlier this year. It's very interesting to develop antibodies with Regeneron, which is probably one of the most well-known company developing ADC drugs, and they have a pipeline of antibodies that it's difficult to imagine. So we are currently dealing with 4 initial programs under development in a codevelopment, copromotion deal. Right. So that's very exciting to be capable to launch these new assets in [indiscernible] tumor, it will authorize us to start to work in therapy with these new compounds for the treatment of the [ neuroendocrine ] tumor. So that's very exciting, and I can tell you that the team internally are extremely attached to that. Now I will hand over to Dave Cade, our Chief Medical Officer, to introduce the topics related to therapeutic compound in prostate.

So it's now my great pleasure to introduce the first of our 4 key opinion leader presenters, Dr. Alicia Morgans, who's dialing in virtually and [ Annie ] tells me that we might be just a couple of minutes early. So tell me if you'd like me to flip the order, [ Andy]. But Dr. Morgans is an Associate Professor of Medicine at the Harvard Medical School, She's a [ genitourinary ] medical oncologist and the Director of the Adult survivorship program at the [indiscernible] Institute. And as a clinician and investigator Dr. Morgans has very extensive expertise in trials in prostate cancer as well as patient-reported outcome measures, which we sometimes forget as a feel. This is an emerging area that's critically important to the way we design our Phase III trials these days, the way patients flow through a trial and what's important in terms of other measures that we don't think of. So as well as that, Dr. Morgans is very focused on incorporating our patient preferences and the beliefs into clinical decision-making outside of the trial context when she's seeing patients in the clinic at the Dana-Farber. So have we got Dr. Morgans online? Yes, go on. Okay. All right. So let's change the order slightly. Dr. Morgans is going to cover our [ TLX 591 ] program. And I will cover our [ 597 ] program. But before we go into discussing our small molecule candidate [ TLX 597], I think it's really important to understand and appreciate why we have both a small molecule and an antibody in our pipeline. And it's critically important to understand to do that, it's critically important to understand the main prostate cancer disease states. And of course, it's a spectrum, but I think it's reasonable that we can categorize early and late prostate cancer in the implications for how we best manage our patients. Let me just go forward to -- okay. Perfect. So while the pictograms here are highly simplified, they do illustrate the baseline characteristics of the 2 main populations of patients that we see in clinic. And on the left-hand side, we have patients with early metastatic disease. That's typically not always, but typically of smaller volume typically responsive to androgen pathway suppression with ADT and RP drugs. These patients are usually newly diagnosed, so they otherwise fit apart from early prostate cancer. And so really, the objectives of treatment are to maximize quality of life to delay progression into the androgen pathway modulation resistant state. And to prolong overall survival as far beyond 5 years or 6 years as we can. So they're really the objectives in this early population. On the right-hand side, we have patients with later metastatic disease. The tumor burden is now increased. They've got bulkier disease. The disease has now become resistant to androgen pathway suppression. And so our objectives of treatment evolve in this group of patients really to now optimizing the combinations of therapy that are remaining for us to use and controlling bulky disease and ultimately really prolonging the remaining usually 2 or 3 years of life that these patients have with acceptable quality of life. And so this slide summarizes our portfolio approach to metastatic prostate cancer, utilizing 2 distinct mechanisms of action that are really adapted to each of those 2 categories of disease state within the continuum of care. And as the first-in-class radio antibody drug conjugate, [ Telix 591 ] mine is administered in 2 doses, 2 weeks apart, which really enables it to be layered on top of a backbone of conventional RP or [ taxane ] chemotherapy. The patient with metastatic APMR disease would typically receive. And so far, we've confirmed the safety of this approach from Part 1 of our [indiscernible] study as well as having confirmed the encouraging early efficacy of [ 8.8 ] months of radiographic progression-free survival in the earlier prostate [ SELECT ] study. [ TLG 597], which is our next-generation small molecule on the other hand, is really designed to enable dose intensification and adaptive dosing. And these are 2 very important points that I'll go into in a bit more detail in a moment. So dose intensification and dose adaptation is really suitable for patients with earlier metastatic androgen pathway modulation sensitive or naive disease. These are the new terms for metastatic hormone-sensitive and metastatic castrate-resistant prostate cancer. We use the new terms now. And really, the aim with dose intensification and dose adaptation is to delay progression into the [ APMR ] state, while at the same time, maximizing quality of life. Now delving into [ TLX 597 ] in a little bit more detail, you'll see here on the right-hand side, what's a very highly favorable biodistribution and pharmacokinetics of the small molecule. And what you can see is that there's very, very low uptake in the salivary glands. That's the top smaller football there, and also very low uptake in the kidneys, which is the lower football. And low uptake at 5 hours in the slower lands and kidneys, but very prolonged residence time in both the soft tissue and the bony compartments of the tumor -- of the tumor volume. Now this pattern is quite remarkable. It's really not what we've come to expect from the earlier small molecule radioligand therapies. And this is unsurprisingly reflected in the resulting dosimetry. With [indiscernible] impacting about 1/2 the dose to the kidneys and about 1/3 of the dose to the salivary glands while delivering about twice the dose to the tumor target compared to the current first generation small molecule [ RLT], so these are very attractive properties of this small molecule. Now some very interesting work, go forward. So a very interesting work of the past, I'd say, 2 or 3 years has highlighted 2 very important factors that may enable us to improve on what we've already achieved with the small molecule [ LTs ] to date. Now firstly, [ PSMA ] receptor density the density of PSMA expression is an important factor in treatment response with lutetium PSMA therapy. And then secondly, your hand, [indiscernible] in the U.K. has shown that this PSMA receptor density can be manipulated. We can markedly upregulate that density in response to ionizing radiation, like that from [ Lutetium]. And you can see this, I think, very clearly on the right-hand side, I think the pictures are crystal clear. This is a patient who's received 2 doses of [ TLX597 ] on day 1 and day 3. And you can see that in the post-treatment imaging after the day 3 fraction, there's much higher total tumor volume on spec imaging. And this is due to the upregulation of the PSMA target. So the first dose has caused upregulation of the target. And when we dose again with the second dose on day 3, there's much more target to hit. So this is a very attractive property that we aim to exploit with dose intensification. And this is the overall concept of dose intensification using both a higher injected activity of lutetium. So 8.5 gigabits is substantially more than we would typically give and it's given in what I would describe as a compressed schedule on days 1 and day 3 and day 15 instead of the usual schedule of very 6 weeks. And this is to that upregulated PSMA expression and the incomplete tumor DNA repair in the first early period after first dose. And so to evaluate the potential of dose intensified TLX597, we undertook the optimal PSMA Phase II randomized trial in men with metastatic [ APAMA ] disease. And this has been led by Professor Louis [indiscernible] in Sydney. And this is a multicenter study that enrolled a vision like population of patients who had received prior RP and chemotherapy. And we completed the enrollment in the study back in June and anticipated the initial top line readout around the time of [ ASCO GU ] in early 2027, and that data is very eagerly anticipated. So let's now look at a couple of case studies, which really illustrate why the optimal PSMA data will be so interesting. So this is a 71-year-old patient with very diffuse skeletal metastases, who previously was treated with [ ARP ] and 2 separate lines of [ taxane ] chemotherapy. And there's 2 important points that you can see here. So firstly, the question is, can a dose intensified regimen be undertaken safely. So with [ TLX 591 ] in a highly favorable dose symmetry profile, it appears that the answer to that question about can it be done safely is yes. Specifically, we can see that this patient's kidney function remains normal and his bone marrow function remains normal. So they are 2 very sensitive indicators of the tolerability of an intensified regimen. And then secondly, it does a dose intensified regimen seemed to deliver clinical benefit. Well, here, we can see a 97% PSA response at week 10 and serial spec imaging performed after each of those first 4 doses demonstrates very clear disease shrinkage. So in this patient, this is a very nice example of the apparent viability of dose intensification. This is a second case with even more pronounced skeletal metastases as well as infiltration of the bone marrow. And in this patient, that's -- the bone marrow has been infiltrated to the extent that these patients become both anemic and thrombocytopenic, low platelets. And he was anemic and thrombocytopenic at baseline. So this is a very delicate and fragile patient to treat. But encouragingly, he tolerated the dose intensified regimen very well. And not only did he tolerate it through the reduction of the disease burden infiltrating his marrow, he's anemia and his thrombocytopenia improved in the absence of blood transfusion. So he's overall health state improved from a dose intensified regimen. And then from an efficacy perspective, this patient had a 99% PSA response out to week 20. So a very durable reduction in his PSA expression. So again, I think these patients are really nice example of the viability of that dose intensified approach. It's going to go forward. Thank you. So in summary, we believe the unique profile of [ Telx 597 ] fundamentally enables 3 important development pathways. So the first of those is dose intensification, which is being evaluated in optimal PSMA, as I described. Secondly, the use in earlier metastatic hormone-sensitive prostate cancer, where safety and quality of life are critically important given the patient's relatively longer life expectancy. And then thirdly, I think it's quite evident that this favorable small molecule could be an ideal candidate or an ideal delivery vector for alpha isotopes. And so to close out, this is optimal [indiscernible] and this is a Phase II study with [ TLX-597 ] in early metastatic APMS disease that commenced enrollment back in July and which we anticipate will generate some very important clinical data about the earlier use of this small molecule in the coming 12 months. Now [ Andy], would you like to switch to Dr. Morgans. Keep going? Okay. So let's go beyond [ Lutetium], and we'll have a quick tour of our assets further in the disease journey. So let's move really briefly to our targeted alpha therapies for prostate cancer. And I think the clinical experience we've gained as a field with the first-generation small molecules has probably taught us 2 basic principles. And the first of those is that alpha isotopes like actinium-225 and led [ 12 ] must be kept away from the salivary glands as [indiscernible] dry mouth is the main dose-limiting toxicity, which really markedly impacts and degrades the patient's quality of life. So we've got to avoid the salivary glands. And then secondly, [ alpharocetopes ] must be kept away from the kidneys as renal injury is a significant safety concern. And so while their early stage, [ where ] evaluating a reengineered radio antibody drug conjugate approach with [ TLX592], which, like TLX591 is a highly specific antibody to the tumor expressed PSMA, as my colleague, Dr. Wheatcroft pointed out very nicely. It keeps away from PSMA expressed on endogenous tissues like the salivary gland. As well as [ TLX 597 ] due to its biodistribution profile, which I've gone into a bit of detail, it really makes it an ideal candidate we believe probably the most attractive small molecule for targeted alpha therapy development because it keeps away from the salivary glands in the kidneys. So I think this slide summarizes our approach very nicely. I wanted to provide some brief insights on our -- on our [ TLX 90 ] asset, which beyond [ Alpha ] aligns to our approach of really serving the patient across their disease journey. So [ Telexis ] it's a novel candidate that we're developing for actually quite late-stage patients with the palliation of metastatic bone pain, which is a very common hallmark of late-stage disease needs to be addressed. So [ TLX90 ] employs [indiscernible], which is a bone-seeking small molecule that uses that novel chelator that we're developing as an alternative to the main stays, which are opioids and targeted external beam radiation therapy for very specific [ fosi ] of bone pain. And each of these opioids and EBRT do remain suboptimal for different reasons. And so on the right side, we can see here from an earlier Phase I study at both dosing levels of [ TLX90], there are significant reductions in the pain scores achieved quite early at 6 weeks, but these are durable reductions in pain out to 4 months following treatment. And these are patients with a relatively brief prognosis in terms of survival. So this is a meaningful improvement in pain scores and improvement in quality of life. So to conclude, while I won't spend too much time here, this, I think, really nicely summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are really tailored to both the disease state itself early in late disease as well as the condition of the patient. And the way I would summarize it is that [ Telx 591], which Dr. Morgans, I think we'll talk about in a moment, yes, good, it utilizes an antibody targeting vector to deliver the therapeutic payload, which really enables ultra-specific and prolonged tumor retention with very limited radiation to the healthy organs. And then furthermore, that short 2-dose regimen is intended to be combined with the other standards of care that the patient would otherwise be receiving in the metastatic [ APMR ] setting. And this is really the intent of [indiscernible], the Phase III trial that's ongoing in 7 countries. Whereas there's a very significant opportunity in early metastatic PMS disease for TLX59 due to its potentially best-in-class symmetry profile that really makes it uniquely suitable for earlier use as well as the dose intensification to achieve those further efficacy we're looking for. So with that, can I invite Dr. Morgans. Okay. Thanks, Andy. All right. Dr. Morgans, can you hear us?

Yes, I can.

Good, good. I have introduced you and I've just done 597. We've changed the order for you. So I'll hand the floor over to you, Dr. Morgans.

Thank you so much, David and wonderful presentation. I really appreciate being here with everybody, and apologies that I am virtually here because I am also in clinic today, as you may see from my coat and background. I am an Associate Professor of Medicine at Harvard Medical School and the Director of the Survivorship program for Dana-Farber Cancer Institute or I'm also a GE medical oncologist, they take care of patients with prostate cancer. And let's go on to the next slide, please. And I think I'm very grateful that everyone is here to think and learn a little bit about prostate cancer in the way that Telix is trying to address it. I'm not sure that the slide is advanced, but hopefully, we can see the slide that shows the prostate cancer disease overview, which is the next slide -- thank you. And apologies if there's a delay on my end. Prostate cancer is the most common cancer in men, and it's the second leading cause of cancer death in the United States. This is actually something that's true in many countries around the world where we see the incidence of prostate cancer actually increasing in many, many countries. Importantly, 1 in 8 men will be diagnosed with prostate cancer during their lifetime and 1 in 44 die from it, but actually many become long-term survivors after a diagnosis with prostate cancer, many actually living with metastatic disease. And metastatic disease remains associated with certainly poorer outcomes than cured disease, the 5-year survival rate is 30% versus 90% for earlier disease that's curable. And despite all of our therapeutic advances, prostate cancer remains a substantial unmet need. As we can see on that incidence chart for the United States on the right-hand side, there's actually been an increase in diagnosis of prostate cancer, particularly in the advanced and metastatic settings over the last number of years. And so this is something we are actively trying to combat. If we go to the next slide, we can see the prostate cancer patient journey through various spaces of advanced disease. And just to orient everyone, I think we've heard from David, about the newer nomenclature that we are now using to be, I think, more sensitive to avoiding the use of certain things like the word castration. But let's talk about this broader landscape because the standard care prostate cancer absolutely has been evolving in the last number of years and importantly, incorporating radio pharmaceuticals into that into that landscape and into having quite an important role within this algorithm. For patients with metastatic disease, they typically would start in what we used to call the hormone-sensitive setting or metastatic hormone-sensitive prostate cancer that we're now calling [indiscernible], androgen pathway modulation naive or sensitive. And this is where we are commonly using antigen receptor pathway inhibitors or ARPI as the backbone of our treatment in combination with ADT and [ docetaxel ] sometimes added in there as well for patients with high volume and very aggressive metastatic disease. In July of 2026, Lu-PSMA-617 also received approval in the states in this earlier setting. But I think it's important for everyone to recognize that although we do have that approval, and we think in clinic, we're certainly grateful to have options. There's definitely been some caution around that and whether we should really jump on board and absolutely integrate that immediately into our algorithms because there is not yet a demonstrated overall survival benefit, and there is moderate acute toxicity. And importantly, just to level set for today's discussion, we don't know the late and long-term toxicity that might be associated with this regimen as we use it in this early disease state. So just moving along to the next settings, as patients do have progression of disease and that occurs in the setting of usually medical castration or pharmacologic castration. They move into first, second and then third line plus metastatic APMR or androgen pathway modulation resistant settings. In the first and second line treatment settings, we do have options, including AR pathway inhibitor or ARPI switch, [ text ] in chemotherapy, Lu-PSMA-617 that we can use before or after tax in chemotherapy and PARP inhibitors for certain patients who have HRR alterations. And by third line and further than that, our options tend to narrow down to things like [ cabazitaxel ] chemotherapy or perhaps [indiscernible] PSMA-617 [ post-taxane ] setting if patients have not already received it. But I think also importantly, just calling attention to the bottom of the slide is that throughout all of this, particularly in the earlier settings, renal toxicity and quality of life considerations are something that are increasingly important to us in clinical decision-making and important as we move radioligand therapy into these early disease settings. And this is really critical because you think about these earlier-stage patients as typically being healthier, being more active, and certainly having a longer life expectancy and things like renal toxicity or salivary gland toxicity are things that we need to address with our newer generation of radiopharmaceutical agents as we're hoping to incorporate them into the earlier settings, but we really need to balance that with cautious optimism that really considers those adverse events and the potential there. It looks like the slide that we're seeing now is the slide that's looking at advancing past first-generation PSMA-RLTs. This slide is really thinking about our toxicities here. And 177Lu-PSMA-617 has transformed outcomes for patients with metastatic prostate cancer and the clinical trial data from things like vision, [indiscernible], the registration trials have been practice-changing, as we've mentioned. But as we're moving into these earlier settings, patients are thinking about being really conservative or at least thoughtful about those toxicities that I mentioned, xerostomia and renal impairment. And if we look at this slide, this is the U.S. package insert, the adverse event data across those clinical trials is presented and xerostomia occurred in somewhere between 39% to 61% of patients in the studies and in most cases, we're categorized as low grade, but they can still have an impact, a severe impact, in some cases, on patient quality of life. I think as we think of xerostomia, I think many of us who gave these toxicities don't necessarily realize that grade 2 xerostomia means that patients are already altering what they eat. Even though the number seems low, there is a real impact on patients, and they are relying on things like mouth lubricants and live substitutes, and they're often having to alter their diet to we'd be more focused on pureed food or soft food, moist foods in order to be able to safely swallow and get enough nutrition. But Grade 3, again, the number seems low or at least in the middle of the range when we think of all the [ CTCAE ] adverse event grades here. But Grade 3 is quite serious, and this is the highest grade for xerostomia, this means some patients are unable to adequately nourish themselves and they do need tube feeding or IV nutrition. So we have to -- even if the numbers look relatively low in terms of the grade, we have to be aware that they can affect patients. On the REIT side, we are definitely thinking about and concerned about long-term nephro toxicity, especially, as I said, is those agents move into earlier lines of therapy when patients are going to be on treatment and exposed to the cumulative risk of renal toxicity for much longer, and they do need good kidneys because they're going to need further therapies for their disease over time. Going to the next slide. This is really going to be an opportunity to focus on TLX591, which I think is an exciting novel therapy for patients with prostate cancer. We can go on to the next slide. This is a radio antibody drug conjugate, and it's meant to really address some of these key unmet needs. Just to lay those out as a recap here, TLX591 is a differentiated PSMA-targeted radiopharmaceutical that's using a monoclonal antibody to target prostate cancer that's expressed PSMA on its surface, and it targets that with high specificity, enabling a really precise delivery to the cancer tissue of the radioactive payload. And it addresses a number of these clinical needs that have been unmet, especially having a nice 2-dose, 15-day cycle that helps us in clinic by facilitating a more feasible integration with our standard of care AR pathway inhibitors or chemotherapeutic agents as we often need to deliver those as well. It has a very low radiation dose that's imparted to the salivary glands into the kidneys. And these are, as I just mentioned, the 2 main organs that can be injured when we're using small molecule agents to target PSMA. And it's really a transient and mainly self-limiting hematologic profile, which is also something we're thinking about in clinic, especially as we think about bone marrow suppression being something that could limit later lines of therapy for our patients. There's also a specific internalization and prolonged retention of the agent within the prostate cancer cell, which is going to be visible clearly on post treatment imaging, which helps us in clinic make sure that we're really getting the drug to where it needs to go. And there's also the potential for real-world advantages from lower administration activity and lower radiation doses to normal tissues, especially to the kidneys. And as we can see on the slide, we can see this mechanism of action where drug is binding to PSMA and then it undergoes receptor-mediated endocytosis, coming into the prostate cancer cell where it is then taken into the endosome, it undergoes lysosomal metabolism and ultimately is broken down and excreted primarily through the liver. We go on to the next slide, we can see the schema for the ProstACT Global, the Phase III study of TLX591. Part 1 has been completed. The FDA is aligned to advance to Part 2 in the U.S., which is also important. So this is the overall design. ProstACT Global is a Phase III study, as I mentioned. And you can -- as you can see, the part is the randomized treatment expansion that's going to enroll 490 patients. And this is currently enrolling patients in 7 countries. They include Australia, New Zealand, Canada, Singapore, South Korea, the U.K. and Turkey. And the study also has regulatory approvals for Part 2 in China and Part 1 in Japan. On the left-hand side of the slide, you can see Part 1, which was performed for safety and dosimetry and this part has been completed. This is a prerequisite of the FDA that was required before commencing Part 2 in the United States. And just to show we can see that Part 2, which is a randomized treatment expansion. It's a 2:1 randomization to TLX591 plus [ abiraterone enzo versus abiraterone, enzalutamide or docetaxelan]. As I said, 490 patients currently enrolling. And patients can get into the study if they have metastatic APMR, and they've had exposure and progression of disease to the to on prior AR pathway inhibitor or ARPI. Let's go into the next slide. Here, we can see the primary objective of Part 1 outcome here. The primary objective of Part 1 ProstACT Global was to assess the safety of TLX591 when it was given [ concomitly ] with standard of care [ abiraterone or enzalutamide ] or followed by standard of care docetaxel chemotherapy. And overall, the 3 cohorts showed an acceptable safety profile. There were no new safety signals when compared to prior studies, including their most recent ProstACT SELECT study. The most common treatment-emergent adverse events were things that we might expect or would expect fatigue, nausea and dry mouth, and almost all of the nonhematologic adverse events were Grade 1 or 2, which, as I mentioned before, is really on the mild side with the exception of 1 Grade 3 dizziness event. Hematologic adverse events comprised grade 3 and 4 thrombocytopenia, which is a low platelet count number. This occurred in 13 -- 14% and 31% of patients, respectively, Grade 3 and Grade 4 as well as Grade 3 and Grade 4 neutropenia, which is a lowering of the neutrophil account, a type of white blood cell, which occurred in 22% and 25% of patients, respectively. And these hematologic events were actually in line with the profile expected for one of these radio antibody drug conjugates and are transient, manageable, and we're going to go into that in a little bit more detail on the next slide. So let's go to the next slide. This slide shows the platelet kinetics across all 3 cohorts. You can see the blue is the patients receiving [ abiraterone RNG red is enzalutamide], and green is those patients who had docetaxel. What we can see is that the platelet level, maters around 43 days after dose 1, and there's recovery to Grade 1 adverse event or better roughly 15 days later. So again, short-lived and quite predictable. And the recovery patterns were consistent across -- generally consistent across the cohorts. And I think this is important, too, because docetaxel, obviously being a cytotoxic, it's reassuring to see that we still see that nice recovery. As I mentioned in the prior slide, the hematologic events are the main adverse events of interest for this class of therapy. And in terms of thrombocytopenia or that low platelet count, we can see that they were consistent, the near occurring 43 days after 6 weeks after that first dose of TLX591. No patients experienced any febrile neutropenia, which is a relatively common adverse event that can occur when patients get treatments like chemotherapy that cause low neutrophil counts and no patients experienced any spontaneous bleeding, which is something that can occur when patients have low platelet counts. So in summary, these hematologic adverse events are quite well characterized. They're well understood from prior clinical studies with the agent. They were self-limited and they resolved spontaneously without intervention in the majority of patients for Part 1. If we can go into the next slide, while we can see that the safety was the primary objective of Part 1 of ProstACT Global. The main secondary endpoint was to look at the PK, the biodistribution and the radiation dosimetry of TLX591, when it was given concurrently with standard of care. And overall, these 3 cohorts receiving different agents, [ abiraterone ] in green, docetaxel in pink are and [ enzalutamide ] in sort of a teal color, we can see 3 cohorts demonstrated a predictable PK profile and if you think about where you want the radio activity to be, you do want that to either be circulating in the blood pool so that it's available to bind to and be taken up by the tumors in the tumors themselves were in the liver where the drug is going to be cleared from the body as we saw and talked about earlier. So for these 2 graphs, the importance is that the graph on the left shows the blood radio activity concentration and that's sustained but declining over time. And in the right-hand graph, we can see that it's basically the reciprocal of that, demonstrating that the tumor radio activity or the lesion activity is increasing early and then sustained over time because the antibody has been internalized and it has a prolonged retention within the tumor. So the exposure and washout kinetics were quite consistent across the 3 cohorts indicating no evidence of TLX on interacting with any of the ARPI agents that it was co-administered with, which is very important. If we go on to the next slide, this is, I think, really importantly, demonstrating normal organ dosimetry. So this is making sure that our normal tissues are not being exposed to large levels of radiation that will exceed a threshold of harm. So these are the organs that we certainly want to keep the radiation away from. And we can see quite clearly that Part 1 confirmed that the radiation exposure, which you can see in the dark blue to these normal organs is quite low and well below the safety limits that have been determined for external beam radiation therapy and radioligand therapy literature. And those are outlined in the gray and the orange-colored hashed marked bars that we can see on the same -- overlaid on the same graph here. So in particular note, you can see that with TLX591, there's very low radiation dose in part to the kidneys and the salivary glands. We've talked about these being 2 normal tissues that the small molecule [indiscernible] therapies tend to hit actually quite hard. And this reduces the risk of developing kidney impairment and dry mouth, when you have that low exposure to those organs as we can see here, and each of these that we already talked about can really affect the patient's quality of life during treatment and certainly, their lives over years to come. So on the right-hand side of the chart, you can see the liver which is relatively radio tolerant in terms of organ tolerance. And this is the primary clearance organ and so it has clearly received the highest dose. And from there, the activity is going to be cleared from the body via the right and left colon, rectum and via stool ultimately. We can go on to the next slide. I am happy to share 3 cases of patients who have enrolled in the study so far. Just to illustrate the biodistribution and tumor retention characteristics and also, I think, to illustrate some cases where we might consider use in the future. What we can see here is the case of an 83-year-old gentleman, who has known a metastatic APMR disease with metastatic disease in the chest. He was actually diagnosed with prostate cancer in 2012 and had a prostate removal of radical [ presetectimi ] at that time. He was treated with enzalutamide therapy starting in November of 2023 in combination with ADT. And he unfortunately had progression of disease in June 2025. And he had a baseline gallium PSMA PET that identified metastatic disease and the thoracic vertebra bodies and ribs as we can see here illustrated in that baseline or posttreatment specs is showing some of this. So TLX591 treatment was started on August 5, 2025. You had a second dose on August 19, 2025. And he experienced a transient grade for thrombocytopenia or low platelet count and did recover. He received his first dose of [indiscernible] chemotherapy about 10 weeks later on October 28, and he completed 6 cycles. His current patient status is bilateral peripheral neuropathy. This is something nerve damage or irritation that can happen with [ dosadaxyl ] chemotherapy. But he has had no progression of disease reported during his last patient visit, and that was the time of data cutoff, 341 days after his treatment. If we can go on to the next slide, this is a patient -- the second patient, and he has also known a metastatic APMR previously exposed to ADT [indiscernible], and he received [ abiraterone ] in combination with TLX591. And you can see the sustained tumor-associated imaging signals over 15 days after the first administration really demonstrating, I think, so clearly, to me as a clinician at least at that 15-day mark, we can see those areas of uptake in addition, of course, to the liver. This is something that I think just shows the way the drug hangs in those tumor cells and hopefully is able to provide a long and prolonged radiation to them. So this patient was diagnosed with prostate cancer in 2019. He was treated with ADT and received his first ARPI enzalutamide in the first-line metastatic APMR setting, and he progressed on that treatment and the treating physician or investigator in this case, determined that he should [indiscernible] standard of care in combination with TLX591. [indiscernible] baseline [ Gallium PSMA ] pad that identified metastatic disease in the chest, apnea and pelvic lymph nodes. And he was treated as we can see and he ultimately had stable disease for 339 days but did have progression of disease on March 13, 2026. That is very actually impressive and quite reassuring for him, not something we would expect with second-line ARPI treatment, abiraterone being something that we've used after enzalutamide has minimal expected value there. So if we go into the next slide, this is a patient case -- a final patient. He's a 62-year-old gentleman with known metastatic APMR previously treated with triplet therapy in the metastatic APMNRS-setting with ADT [ darolutamide ] and docetaxel, diagnosed with metastatic disease in 2017, high-grade disease, [indiscernible] 9 started docetaxel in October 2017 through February 2018. [ Darolutamide ] started in February 2022 and the progression of disease in May of '25. His baseline PSMA pet on gallium PSMA 11 was demonstrated to show uptake and the investigator initiated concurrent standard of care. [ Enzalutamide ] on June 30, 2025, 14 days before TLX591, had the first dose on July 9 and the second dose of TLX591 on July 23, and -- and as you can see, starting on the left, in the darker green, early vascular hepatic distribution, then to the right in lighter green, persistent uptake in the metastatic sites. Out to 15 days, representing that signature of TLX591 rather than a small molecule ligand, which we would not expect to see there. So the patient was on study, an extended follow-up as a data cutoff, imaging out to day 337 with no treatment discontinuation recorded and no progression of disease through day 337 and that was the time of data cutoff. So the message here is really that TLX591 plus enzalutamide was well tolerated after previous docetaxel therapy and achieved a durable response in a posterolutamide setting, again, post ARPI, that second ARPI is expected to have minimal benefit. So that concludes my presentation. I appreciate your time, and I'll wrap up here, David, and hand back to you.

Hello. So since Dr. Morgans is joining us virtually, this is Anne. We can take a couple of questions. If you do have any questions, please raise your hand, and these would be specific to Dr. Morgans. There will be a broader Q&A session a little bit later after the conclusion of all the presentations. Please raise your hand if you have any questions.

Of course, Laura here. Laura, Nice to see you here in New York.

I was wondering if you could talk a little about your experience with PSMA-617. And in particular, your view on some of the real-world evidence that was presented at ASCO on whether or not rather how much the real is a problem? And what considerations you think we're really trying to solve for in this population that's post at least [indiscernible]?

Sure. So I have used quite a lot of Lu-PSMA-617. This is something I've used in clinical trials as well as in standard of care in various settings. And I think that from a treatment opportunity standpoint, patients are very keen to get radioligand therapy or these targeted radioactive drugs. But I would say we are still defining the potential renal toxicity. I think that there are -- there's likely an underrepresentation of the renal toxicity that is likely occurring. It is not something that is as big of a concern when you're only using these drugs in the very late lines of therapy because patients don't have an extended time to live and to need additional therapies over time. But especially as we move things into earlier settings, I would say that despite the real-world evidence that may be coming out, I think we have an incomplete characterization. Often, this renal toxicity is thought to be somewhat delayed and maybe incompletely captured. So I think we, as a field, are continuing to try to work to put some of that forward. And then can you just repeat the last part of your question was really around, I think, RPs?

Sorry. The last part of the question was, what do you think the main toxicity considerations we're trying to solve for [indiscernible] in that population?

Okay. Thank you. Yes. So I think that these are the main toxicities that we're trying to solve for [indiscernible] as we just discussed this Xerostomia as well as the renal toxicity. I had -- just as an example, I had a patient who was on [ PSMA 4]. I suppose the -- our apologies, I was on PSMA addition. This is the metastatic APM NS or formally metastatic hormone-sensitive prostate cancer setting. He has had excellent disease control. He has been followed -- and follow-up actually at this point, probably 4 years. And the challenge that he has faced, he's an older Italian gentleman, loves getting fresh tomatoes. He and his wife make a beautiful fragrance sauce. They've even brought somee into us. He he's not able to taste sauce in the same way after having his treatment. So it is -- and this is something that he noticed and he brings up and talks to me about in clinic, and it's been upsetting to him. It is not to the point that he is unable to eat and needs a feeding tube. That's really not the issue for him. But his life has been altered in ways that we think are meaningful to him and hopefully are contributing to his disease control, but it's something that I think he would have liked to avoid if this was going to be possible. [indiscernible] toxicity also something, as I said, difficult to pin down. But if you don't have highly functioning kidneys you're not able to necessarily treat your other medical problems or potentially get other therapies for prostate cancer which can limit you over time and absolutely affect the longevity and certainly the quality of your life. So I think any time we can reduce toxicity and ensure that the trade-off that patients are making in terms of having activity against the cancer and maintenance of themselves and there are opportunity and ability to take care of the rest of them, it's going to be a win for patients and something that's going to be helpful in terms of therapeutic development.

If there are no -- okay, it looks like we may have one more.

Just wanted to hear about your perspective, like what kind of patient baseline characteristics would make a patient not very ideal or ideal for [indiscernible].

Sure. So I think the biggest barrier to getting treatment is if I were to say a patient who could not get treatment is a patient who has preexisting bone marrow suppression. This might be a patient with a myelodysplastic syndrome or who has low platelet counts for some reason or some suppression of blood counts. This is relatively rare. These are going to be the same patients who are not going to be able to take things like chemotherapy or other radiopharmaceuticals, things that cause low blood counts. And again, it's relatively rare, but that would be the main patient population, I would think. Luckily, these agents are well tolerated and things that even patients who have functional limitations and mobility troubles, or other medical problems are generally able to take in this agent. So TLX591 importantly plays well with other medicines that we use commonly, these AR pathway inhibitors and can precede chemotherapy. So it really opens the door for most patients to be able to get this kind of a treatment, do it safely and well.

Thank you so much, Dr. Morgans. I think with that, I'll transition to David Cade, who will introduce us to Dr. Sundaram. Thank you.

Yes. Just on behalf of the 40-odd folks, I think, in the room, I'd just like to thank, acknowledge and thank Dr. Morgans for dialing in. She actually has a very busy clinic this morning at the Dana-Farber. She had a patient prior and a patient after. So obviously, the next patient will be very fortunate to be being cared for by a clinician of that capability. So now we're going to switch from, I think, a very comprehensive review of prostate therapeutics to prostate precision medicine. And this is a very important session. We've obviously got a majority of men in the room. And while I'm very fortunate with my colleagues to be the developers of this next approach, many of us unfortunately, are likely to be customers of the next approach. So it's my real pleasure to introduce our next key opinion leader presenter, Dr. Varun Sundaram, who moved to Central Texas as a surgical urologist after originally practicing as a urologist in [ Gresham ] Oregon, I think, is your original hometown. He completed his undergraduate studies and his medical degree at Washington University in St. Louis and subsequently went on to finishes general surgery, internship and urology residency at UT Southwestern in Texas, where my Texan colleague is also educated. Dr. Sundaram is now a very busy urologist at Urology Austin, the largest private urology practice in Texas. And the last thing I would say is it's always entertaining to invite a surgeon to the stage, so for obvious reasons. So welcome up.

All right. Thanks for the intro. So I brought a little prop and we'll get to that in a second. But thank you guys for having me today. My focus is primarily on the BiPASS trial, the use of PET scans to help minimize the biopsies and the risks of biopsies. So currently, as a urologist, when we're evaluating patients with prostate cancer with elevated PSA, we rely heavily on a biopsy. This is typically done with a probe transrectaly. The biopsy can be their transperineal or through the rectum itself. And it will sometimes require 15, even 24 samples to obtain all the tissue that we need. It really depends on where the lesions are seen on the MRI and even if a lesion is seen, we typically sample the rest of the prostate because there's a chance that there's clinically significant cancer elsewhere. So a lot of our technique and our prior thoughts were kind of a blind shock on approach. Let's hit this with a bunch of needles. Hopefully, one of them will land and we'll detect something. And there are risks to that. Infection, urinary retention, leading, people can develop clots in their bladder afterwards and then they can't urinate. [ Hematospermia ] is a relatively benign thing, but it is very, very shocking to the patient and their partner. And people recover over the next couple of days, if they end up getting admitted for sepsis, it can be even longer. So here's just a quick video of this -- what you see here is the ultrasound probe. This would go in a patient's rectum. So I'm about to show you the needle as well, but the entire time we're doing this biopsy, which is somewhere between 10 and 20 minutes, depending on how you do it, there is this probe in the rectum, which is probably the worst thing for the patients. That's the biopsy gun that we use. And Kevin was nice enough to get one delivered here. This is not a small needle. The patients will hear this 15x to 25x as we're biopsying them. And it's hard not to jump every time you hear this click. Once they've had it and they come back for another one, they're sort of primed for it, but that can actually make things worse than they're expecting this click and worrying about the pain. So if we can avoid these things, we should avoid them. And that's where the BiPASS study, I think, has shown a lot of light. Typically, when we get an elevated PSA, we'll order an MRI of the prostate, and that's a multiparametric MRI, 3T MRI. That's a very complicated study, and we'll get to that in a bit, too. And then if that shows a lesion or if the PSA is too big -- sorry, too high for the size of the prostate, so the PSA density is elevated, we'll do a random biopsy as well. And so -- this is 800,000 biopsies every year, some sources say 1 million, and a lot of them are negative. We do this biopsy because the PSA is elevated, the PSA [indiscernible] elevated or the MRI showed something and a lot of them could have been avoided because they're negative, patients had a spurious elevation. They don't have a true lesion or tumor and there's a large percentage of patients who refuse a biopsy. And there have been a lot of tools that have been developed in a post PSA setting saying, "Hey, you got an elevated PSA, let's do some tumor marker. Let's do a biomarker. Let's see if we need to go on to a biopsy." Unfortunately, those weren't developed in a post PSA post MRI model. So the second you get an MRI, a lot of those are fairly useless clinically. And so using Telix BiPASS, that would be a post MRI model, and that would allow us a certain level of diagnostic accuracy we don't have right now and we can avoid these things. We talked a little bit about the risk of biopsy. But again, hematuria, rectal bleeding, sepsis is the biggest risk. And there's about a 3% risk of sepsis with a transrectal biopsy, about 1% or less with the transparent biopsy. The other issue is false negatives. You can do a biopsy, see no cancer and then subsequently a year or 2 later, you [indiscernible] the patient with cancer. It's probably not because they didn't have it at that time, but that you missed it because you're doing a -- partially blind approach. So the primary 1 and 2 studies helped develop a sensitivity and the specificity in the scoring system for the PSMA. And what you see here is that the sensitivity of a pet scan plus the MRI is much more than the MRI alone. The idea is that this will allow us to reduce a lot of these unnecessary biopsies, right? So ideally, about 50% of them are unnecessary. If we can reduce those patients benefit significantly from that. But before each study or before each biopsy, pet scan can help us say, okay, this lesion is a little bit more aggressive. This lesion is a little bit less aggressive. [ Primarily ] established the proof-of-concept and [ primary 2 ] showed that it can safely reduce biopsies while still maintaining a clinically significant detection of prostate cancer. And so then comes the BiPASS trial. This was a Phase III trial, which I got to give a little shout out for Urology Austin. We were the leading enrollers in this study. And it took a look at patients who had an MRI of the prostate, had an elevated PSA, and we're going to go on to biopsy already. And the patients then got a PSMA scan before their biopsy and then the biopsy was then random or guided towards PSA or MRI targets. And there's a 6-month follow-up. So we're still in the process of that follow-up. But the primary objective was to detect clinically significant cancer and to help identify which patients we can avoid a biopsy in. And we talked about that. I think, again, the most important thing is this will likely be utilized between MRI and biopsy for almost all patients. So even if not everyone is spared a biopsy, everyone can have the diagnostic benefit of getting a PSMA scan and the target population for that is somewhere between 800,000 and 1 million patients every year. The idea is, after the publication of the study is that patients with either symptoms or elevated PSA, they get a PSMA scan. They get a multiparametric MRI and then we stratify their risk. If they have a [ hired 5 lesion ] or a very high risk on PSMA, we go straight to biopsy. If it's a little bit less than [indiscernible] 5, 1 or 4, but the pet is still positive, you still go to a biopsy because of the really high specificity. And then finally, if you have [indiscernible] 1 or 2 or even a [indiscernible] 3, but the PETs negative, you can really talk about avoiding biopsy in those patients, which there is a significant population in the U.S. that wants to hear you say anything, but you need a biopsy or you need another biopsy. You'd be surprised at how many urologists are out there in the community, mostly in sort of rural settings where they don't have access to an MRI, they don't have access to a PET scan. So you'll get patients from there who've had 3, 4, maybe even 5 biopsies, and we still can't find out why they have an elevated PSA. Those patients love it when you say, "Hey, we don't need to do this." And so we can reduce the amount of biopsies. We can eliminate the need for biopsy, and we really affect patient care by reducing anxiety and worry over a procedure that can be invasive and can cause significant harm. Ending up with sepsis in the hospital is a huge issue, and it drives up health care costs to the millions every year. The other benefit of the [ Gallium PSMA ] scan is it is less likely to show an indeterminate bone lesion than [indiscernible]. And this is really important because when we do these scans prebiopsy, preradiation, if we detect a bone lesion, that drastically changes our treatment course. We now go from talking to somebody about carrying their cancer to talking to someone about keeping them alive as long as possible. And so even if we don't suspect or have a high likehood of belief in their bone lesion, finding this creates a lot of anxiety and stress for the patient, creates a lot of unnecessary workload. And frankly, it will delay treatment by quite a bit in the time it takes to get another MRI of the area, get CT scan, specifically at the spine or the chest. So having a tracer that is more sensitive and specific to bone lesions. And so it's less likely to give us false positives is huge. And here's an example of an anterior rib lesion. You see on the CT scan on the FDG, you see a little light up or activity. But on the gallium scan, there's nothing there. And this -- the reason for the false positives can be numerous things. They can be small benign bone lesions. They can be prior trauma fractures. There were numerous causes in somebody's 70 years of life, why they can have a little bit of imaging findings at a bone. And so having a tracer like gallium is extremely important for minimizing the concern. So currently, we use a multi-parametric MRI. And what you see are 3 different phases. You see the T2 weighted imaging, the [ DWI ] and the [ ADC ] and these are very complex. They don't look very similar. One of them looks like a radar scan from the 50s. And the quality of the MRI is not the most important thing. It's the quality of the radiologist or the urologist reading those MRIs. And I'll be honest, most urologists don't know how to read these. We rely heavily on our radiologists. And the vast majority of literature for MRIs and prostate cancer was developed using a single site and a single radiologist. So a person who read thousands upon thousands of scans. That is not the truth in everyday practice. These are not the people we have access to read MRIs they read -- they have to read less than 5% of all the MRIs done in the U.S. So that means 95% of the MRI is done in the U.S., you can't use the pivotal studies and the excellent diagnostic accuracy of MRIs based on papers because that was one person reading every single study for all of those papers. And so I'm lucky I have a guy that is very good, and I have patients drive just to see him for their MRI, but not everybody has that, and I only have one of those in the town of Austin, Texas. So I think that says a lot.

Well, thank you for that highly effective and visceral presentation. We appreciate it. So we've just heard a lot of great science up here today. And now I want to talk a little bit about translating that science into really highly effective patient experiences for the technologies that we're bringing to market. So this is the way we see on the diagnostics side. This is the way we currently see the PSMA pet market. You can see the biopsy. So right now, everything that we that we look at is from the biopsy behind that. So if you look at our current indications, it's initial staging, it's biochemical recurrence and then radioligand selection -- treatment selection. So you can see that we've also targeted and have ambition to go after response to treatment on APM resistance as we think about what that looks like in non-metastatic disease. And then, of course, progression for that and then monitoring progression. So we are ambitiously chasing a lot of indications further down the line. But all of them, all of them are after the biopsy. So what I'd like to kind of think about is that there's really nothing more frustrating than an idea who's idea whose time has not come yet, right? So you've got this idea. You're trying to bring it to market. But really, the confidence in the scan was not there. So we've been working through how to do this with [ Primary One, primary 2 ] and now BiPASS. But really, what we had to do is get some experience with it, and we've done that. So now that we've done that, imagine if you will, a world where we have the confidence in PSMA PET scan, and then you can see nothing is really more powerful than an idea whose time has come. So when you think about that shift, so if you look at what happens before the biopsy, this 800,000 scans that he was speaking of, and the 200,000 men that say no to biopsy each year. So really, if you just look at it before and you look at it after BiPASS, imagine if you will, this world, where every patient that needs a biopsy that is indicated for a biopsy gets a BiPASS first. And so what you see is this capturing of over 800,000 scans or 800,000 patients that are indicated for biopsy, get a scan first. Now we believe there's another 200,000. If you look at that little gray area above that, that actually say no to the biopsy. And from his demonstration, you can see why you might say no to that. And so we think that just that market is approaching $1 billion. Just getting the people who said no to biopsy is about $1 billion. But when you look at the 800,000 scans that we can capture because of the increased sensitivity and specificity, then imagine if you will, a world where BiPASS gets approved by the FDA. As we've said, we've aligned with the FDA on a new NDA for BiPASS, and we attend to address that indication. And so what happens after? So the question that we pose through our strategic advisory boards is what happens if we get a BiPASS indication for the pre-biopsy setting? Well, then you get an initial staging even with BiPASS. So you have this baseline and initial staging immediately pre biopsy. So that will most likely decrease. And then because of the imaging that you're getting and your surgical selection that you see now with the bypass image that you saw a few minutes ago, you'll see that even biochemical recurrence may decrease as well. And then as you look at response to non-metastatic, we start thinking about how to really assess that response using the primary scores. And we really think about what that may do in terms of why wait, why wait for your PSA to increase, and we go after that indication as well. And so you can see the redistribution, if you will, of what we see in PSMA scans today with what may be tomorrow if bypass is approved. So some really exciting things that will happen for men around the world and a big part of what we're trying to do as we look at what we can do for men in this area. So we -- you got to hear from a urologist about his experience and the way he views it. And one of the things that, as we talk to the Austin urology group in this trial is that when they get a biopsy and it's negative, you can't necessarily tell a patient they don't have prostate cancer. You just tell them that we didn't find any prostate cancer. And so that patient while he was indicated once, they will still track is PSA every 6 months and though bringing back in again on a watch and way to get another biopsy. So that could be another BiPASS. But as we start thinking about the patient side of this, then we surveyed over 1,000 patients that got a biopsy, and it comes out just like you would think when poised the question, would you rather have a PSMA scan first and possibly avoid a biopsy then, of course, 95% of the men said overwhelmingly that they would rather do that. Now it kind of makes you wonder about the other 5%. But I think that as we are really kind of understanding and educating this. We have not started any education at all on the patient side of this. So this is just a patient advocacy group that we work through and did the study with. And just position this or propose this idea to them. And you can see that it's overwhelming. And so much so that as we know now that when patients get educated about other alternative methods, especially for something that they're trying to avoid in general, then they are more than willing to either discuss it with their doctor or ask to discuss it with their doctor. And you can read some of the comments as well about the experience they've had. Now what does that do for -- what does that really do for our TAM, we call it, or our opportunity? We see that overall, we're approaching a $20 billion opportunity in the -- and this is U.S. only. So we have the initial 670,000 scans that we're working with in the current state. We believe there's another $800,000 in BiPASS, another 200,000 that we can activate that are saying no. And then when you net that out, we see that the TAM in that first 3 indications really just about doubles or a little bit more. And then as we progress in our indication expansion strategy, then you'll see we've got another $250,000 or $0.25 million that we're going to chase down. Now because of what we're doing in the [ theranostic ] area, and you got to hear some great presentations on our therapies, we look at that TAM in general, remember, our idea is to really derisk the targets by having the initial tracer in the diagnostic area, really understanding that the [ theranostic ] strategy does a couple of things for us. It derisks the tracer, but also over the past 3 to 4 years, we've built relationships as we prepare for therapy, we built relationships with regulators, with customers, with payers, not just here in the U.S. but globally. And that's a really important part of the theranostic strategy as we have that both commercial, regulatory and payer experience. So as you combine those 2 TAMs and you look at metastatic APM, both naive and sensitive, and about 16,000 patients, we believe, when you look at first line and second line and resistant, then we think it's about 22,000. And then, of course, in second line plus we see it over 12,000 patients. So when you look at the entire portfolio on a theranostic perspective, then you can see that we're approaching $20 million and we think that the portfolio and pipeline that the team put together for you enables us to achieve that. So thank you very much.

Thank you, Kevin. We're going to open it up for Q&A. So if I can please ask all the speakers to go to the stage. And if you have any questions, please raise your hand. Let's just for them to get situated. All right. Please go ahead, Andy.

This is Tsan-Yu Hsieh, William Blair. Kevin, you mentioned about the NDA submission based on the BiPASS study. I'm curious if you can elaborate a little bit just about kind of how you can achieve that. Obviously, we're in this game every 3 years, you've got to have something -- something new, but it would be helpful for the investment community to know how -- what's the detailed strategy there?

Yes. I would say that we've aligned with the FDA that we want to pursue a new NDA. And of course, in pursuing a new that would allow us to get an NDC and [ HIC Pix code ] and then ultimately work for a transitional pass-through code. So while it's not necessarily part of our life cycle management overall, broadly for the portfolio, it is. But we believe this as a more of a disruptive technology in the way that we're going to redistribute and move pre-biopsy versus post biopsy. So it ultimately fits into that, but having that as a -- the FDA agreed that it was a big enough change in the product and the indication that they believe we could pursue an NDA. So that's what we're doing.

Any other questions?

So there's new PET MRI systems from GE in 2022. You got FDA approves the [ Siemens Healthineers ] got approved in January 2026. So is the roll out of these new, better, more sensitive MRIs going to help the diagnostic pathway?

Well, I think I would manage that from where the market is today and where it may go. Now if you think about how that combination between a pet MR and BiPASS and how those could work together, I think we see a lot of synergy in that. And we believe that the sensitivity and specificity of bypass will achieve our end points. And then so we see that as a good thing for the direction we want to go. And just based on their rollout and how we manage that, we would be happy to help support and drive that.

Can you speak to the cost impact in the physician office in regards to current biopsies in practice versus a pet approach?

Sure. The health economics, we believe is somewhat neutral in terms of how we approach that from either a PET CT, PSMA versus a biopsy. Now each and every one of the clinics, of course, have a different RBU system on the facilities -- on the technical side for what the physician does. But as you know, including Dr. Sundaram's practice is there's many of the private practice urologists that are -- have scanners now, and that's an emerging -- that's really a part of the emerging part of what we're doing. So we believe it's at worse and net neutral. And because of what we think that is going to happen downstream and the overall complication rates is going to be net positive for BiPASS. And if you wanted to comment?

I can say for the urologists, those who own their own pet scanners, it's net positive. The revenue from a PET scan is far outweighs that of a biopsy. But the other thing you have to think of is we're all at capacity right now. I don't think I can add another 10% of biopsies on to my schedule or any of my partners. And so -- if anything, we need avenues and ways of evaluating things that don't directly tie up our clinic, our time and our biopsy machine. So I think I would say that I think it can only be that positive net positive. And in those settings where they don't have their own PET scanner, again, they're also at capacity. We're not making more urologists in a timely fashion.

Any other questions? All right. If there are no other questions, I'll hand it over to David Cade to go to the next session.

Okay. Thank you. No break?

Let's keep going.

Let's keep going? Okay. So I think we've had a very comprehensive tour through both our therapeutic and prostate cancer pipeline. So let's switch now to kidney cancer. So prostate and kidney are obviously the main parts of our urology franchise. Our next speaker, I'm delighted to say is Dr. Monty Pal, globally, and Dr. Pal is a very much globally recognized leader in the research and management of kidney cancer. He's the co-director of the Kidney Cancer Program at City of Hope. So thank you for coming all this way. And he serves as the clinical trials, medical director at its comprehensive cancer center, which is a very busy comprehensive cancer center. Over the course of his career, he's led and contributed to many, I would say, practice-changing clinical studies that have advanced the standard of care in kidney cancer, publishing more than, I think it's 500 papers of your career and really leading a significant portfolio of clinical trials. So please join me in welcoming Dr. Pal up.

Thank you. Thank you. Perfect. Perfect. Well, really delighted to be here, and thank you for the very, very kind introduction. Really excited to share with you some of the latest developments in this space. But before we jump into that, just a quick disease overview. So with respect to kidney cancer, it's really a disease that's been rising in prominence. The estimates suggest by about 3% per annum for several decades now. It represents the 14 most common diagnosed cancer worldwide. And if you look at the age standard incidence and mortality, it tends to be highest in North America as well as in Europe. This is a male predominant disease with about a 3:1 to 2:1 ratio. And when we think about kidney cancer in that vernacular, about 90% of cases are going to be renal cell carcinoma. And within that, about 85% are going to represent clear cell renal cell carcinoma. So that's by far the most common histology and it makes up the lion's share of what I tend to see in the clinic. Now I will point out, and we highlighted a bit of the disease burden that incidence rates are rising, as I mentioned, 3% per annum for several decades. A lot of that hinges on better imaging techniques. A lot of that also hinges on the fact that we have exposure to more carcinogens in the natural environment. And what's really quite strange is that despite the increase in the available imaging that we have to diagnose the disease. Unfortunately, still about 30% of patients are diagnosed with metastatic disease in the get-go. And despite the many advancements that we'll highlight momentarily, 5-year survival remains rather dismal for this disease and there's about 180,000 deaths that occur worldwide. As we shift to the treatment challenges, I think the one thing that I'd really emphasize is that at this point in time, kidney cancer therapy is really maybe a one or two trick pony. When we think about the different therapeutic modalities that we have, we have checkpoint inhibitors. We have VEGF targeted therapies. And typically, those are tyrosine kinase inhibitors. And although there are a certain subset of patients, I'd estimate it around 10% that can have durable complete responses to these therapies. The vast majority of these individuals inevitably progress primary and acquired resistance occurs across the vast majority of these therapies. And truthfully, when we get beyond frontline management of this disease, we have very little in the third line and fourth line to offer patients. And in fact, many would argue that second-line therapies as they stand currently can actually be very redundant. And I'll make that point in some of my subsequent slides. There's certainly a need for better tolerated therapies. It's estimated that about 4,700 patients per year in the U.S. are going to need third-line options and at this point in time, the management strategy tends to be use of another targeted therapies. So I'll put the patient in front of you who has received a regimen like [ nivo-ipi ] upfront, maybe [ cabozantinib ] in the second setting. What we have are just more targeted therapies to offer that after that, [ lenvatinib, tivozanib], et cetera, and we'll discuss this in subsequent slides and intellectually and frankly, logistically, the clinic is not very satisfying to rechallenge the patient with a very similar class of options. I will say that adverse effects tend to really sort of plague the third and fourth-line settings. Patients have already been exposed to treatments and have significant incurred toxicities like diarrhea, fatigue, et cetera. And this only gets magnified as you get into later line of therapy. So it would be ideal to have therapies that can provide durable disease control with manageable to I'm really in the mindset that we're only going to get there if we really introduce novel mechanisms of action in this later setting. So what targets can we exploit that we haven't to date ironically, it's actually one of the entities that we use to diagnose renal cell carcinoma, that's CA9, or carbonic and [indiscernible]. So this is a transmembrane glycoprotein. If we think of it is physiologic function, it works in oxygen sensing. It's a pH regulator as well. And as we'll highlight in the next slide, it's really induced by [indiscernible] tumor gene in many cases, but also by [ Hypoxi ] as well. And we see this in about 95% of cases of clear cell renal cell carcinoma. Pathologists routinely use this. They use PACS and a handful of other stains to really classify clear cell renal cell carcinoma. And when we think about the mechanism here, I'll start with the mutations that really sort of underlike clear cell RCC. And as I've mentioned in the previous slide, that's this VHL alteration. When we think about VHL and its native function, it's ubiquitous [ ligase], it tends to sort target certain elements for destruction. When VHL is altered and this happens in a somatic fashion in about 55% to 60% of patients germ line setting as well and a small fraction of patients. What we see is that there tends to be accumulation of one of the products that really sort of drives kidney cancer growth and that's hypoxia-inducible factor HIF. Now HIF is actually -- CA9, as I mentioned before, is a transcriptional target of HIF. And when we have this accumulation of HIF in the context of VHL alterations, you tend to see increased transcription of [indiscernible]. And again, we've described the function of [indiscernible] important element to really bear in mind is that [ CA9-expression ] has really seen minimally on normal tissues. And that's, I think, one of the key elements that lends itself to being a therapeutic target. So let's talk a little bit about the different targeting approaches to CA9, an agent that's maybe well known to some of the audiences [ gerentuximab]. This is an IgG1 capital light chain chimeric monoclonal antibody. And actually, it's very highly specific for CA9, it leads to internalization. And one of the elements that I'll point out is that geretuximab has been very heavily studied many may remember a presentation ASCO several years ago, the [ RISER ] study, in which there was an extensive look at gerentuximab in patients with renal cell carcinoma. So there is extensive safety data around this. We know that this entity is hepatically cleared. Moving on to the developments based on gerentuximab. We have the 89 zirconium payload, which is useful in the context of imaging. This is a [ positron bitter ] with a half-life of 3.3 days. And again, this is suitable for pet imaging. What I'm going to be focusing on those listed on the right, and that's the 177 lutetium payload. And this is a medium energy beta emitter, half-life of 6.7 days, and this is really suitable for antibody-based therapy. So I'm going to get into the development plan that we have for this in just a moment here. But before I do that, let me just sort of articulate the standard pathway for management of advanced renal cell carcinoma. So after the time of diagnosis and surgery, we have more than a modest fraction of patients who develop disease recurrence usually with metastatic sites, including lung, bone, liver, lymph node, et cetera. And there's a small fraction of patients. I'd estimate about 5% to 10% who really fit in the top of that first-line graphic. Those are patients with oligometastatic disease who have maybe limited sites of spread in those situations, we can target patients with site-directed radiation or [indiscernible] surgery. That's not the lion's share of what I tend to see in clinic. About 20% of frontline patients have what's deemed to be favorable risk disease. These are based on prognostic factors, including time frame diagnosis to treatment or hemoglobin levels, calcium levels, et cetera, et cetera. But those patients are generally approached with a combination of VEGF TKI and association with checkpoint inhibitor. About 70% to 80% of patients are going to have what's termed to intermediate [indiscernible] disease. And these are patients with certainly a briefer prognosis and poor outcomes even in the context of therapy. Most of these patients are approached with us a combination of TKI with IO or with a dual I-O/I-O regimen such as nivolumab [indiscernible]. There's a very rare subset of patients in this day and age who would get TKI monotherapy. Those are patients with absolute contraindications to checkpoint inhibitors, and that's a fleeting population. As we move to the second line setting, this is really where the challenge arises. There's so much redundancy in what we do. even for the patient who's been frontline treated with a TKI and I-O-based regimen, you're oftentimes just going to rechallenge with another TKI-based strategy. I'm happy to chat about some of the more recent developments of the landscape. But if you think to really what has been introduced perhaps over the course of the past year or 2, we have therapies that target a hypoxia-inducible factor, HIF, like [indiscernible]. We most recently have under consideration for approval, a combination of [indiscernible]. I find that these options are maybe a little bit less palatable because, again, many of these therapies fall along the same signaling access as VEGF and therapies that we use in the frontline setting. So again, patients are already facing substantial toxicities that they've incurred in the frontline setting from those therapies. In the third-line setting, the problem gets magnified, where, again, there's a lot of redundancy we're again rechallenging with VEGF inhibitors, mTOR inhibitors, largely a pool of drugs that can maybe be envisioned as almost cytostatic. So I wanted to outline some of the rationale that belies the [ Ludian ] studies that I'll be highlighting in just a moment. And this hinges on, again, the use of 177 lutetium bonder entuximab. And what I'll point out here is that there is data from previous studies. These were investigator-initiated trials in a Phase I study that included in 23 patients, in a Phase II study that included 14 patients, there's a couple of really important lessons learned. The first is that patients who receive the maximum number of cycles were actually those who had received lower doses of therapy. So you can see that it was those individuals who received less than [indiscernible] rolls of treatment. That we're really able to sustain a greater extent of dosing. There are none, in fact, if you'd received in excess of 4,000 megabecrules. More treatment, frankly, correlates with better outcomes. So if you look to patients who received 3 cycles of therapy, median overall survival was 49.3 months. That falls down to 22.2 months amongst those that received 2 cycles you're down to 18.7 months if you just received 1 cycle of therapy. So there really seems to be some diminution of benefit if you're not receiving 3 cycles of treatment in the course of these early studies. There also seem to be, and this is perhaps expected an increase in hematologic toxicity with higher doses. We didn't really see any grade 3/4 leukocyte or platelet toxicities in patients that received the dose of 1,887 megawatt rolls. And we'll talk about that dose in just a moment. This dose is well tolerated. It allowed for multiple cycles of therapy. Now beyond these observations from initial studies, there's also a bit of pharmacologic rationale that belies our approach and the studies I'll highlight in just a moment. And that's the fact that if you look at [ TLX250 ] tumor residence time, there seems to be little or no relevant therapeutic activity that's maintained after about 3 weeks or so. So with that in mind, if we fractionate therapy, we feel that we may potentially really maximize efficacy and reduce those intervals, which the patient is really receiving no therapeutic benefit. If you're spacing out at 3-month intervals, 4-month intervals, et cetera, you have a long period of time in which tumors aren't exposed to sufficient dose of therapy. Using the strategy that we've suggested here, each fraction stays low enough to avoid dose-limiting toxicities as well. And moving forward, there's 2 strategies that we'd like to assess. The first use is, again, that dose of 1,887 megabecrolls every 2 months for a total of 3 cycles, and this is really based on activity seen in previous studies. And we're taking the further step of assessing 1,258 [indiscernible] every month for a total of 6 cycles. So how is this incorporated in our forthcoming study? So there's 2 studies I'd like to highlight here, but very similar in premise, [ Motion ] and [ Ludian ] Atlas. And I'm the principal investigator for Ludian Atlas. Some similarities, this involves the same patient population, patients with advanced or metastatic renal cell carcinoma. These patients should have had disease progression on or after 2 to 3 prior lines [indiscernible]. So again, this is an area of unmet need as I think I've painted a picture of my previous slides. And these patients have to be C9-positive by 89 zirconium TLX250 pet. Now lending itself to some of the differences between these designs. In the U.S., there is a safety lead-in that's mandated. So there's 3 patients in each of the 2 dosing cohorts. These patients can be sort of melded into the dose optimization scheme that you see that's running both in the [ Ludian ] study in Australia and the [ Ledeo ] ATLAS study in the U.S. So you can see the 2 schedules that we're evaluating. I've already highlighted that dosing strategy on the previous slide, but you can see this comparison of monthly dosing as well as look at every 2-month dosing. Now again, one of the differences is that in the design of [ Ludian ] in Australia, we have the flexibility to actually migrate directly into a Phase III design, and I think that's quite unique. You can see here that the randomization proposes either to our drug versus investigators' choice of therapy, sample size is still to be determined. I think it's a very pragmatic design in this setting. And with that, I will pass it on to , I believe, Dr. Cade. Thank you.