Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Okay. All right. Good morning, ladies and gentlemen. My name is Kyahn Williamson, and I'm the SVP of Investor Relations and Corporate Communications at Telix. I'd really like to thank you all for taking the time to join our session today, both to the people attending here in person and via the webcast. Today's session has been designed to give our shareholders a deeper look into Telix's urology pipeline and understand how we are building on the Illuccix, prostate cancer imaging agent to build a truly unique end-to-end offering for our urology and urologic oncology customer base. Being here in New York is a great opportunity to bring together some of our U.S.-based senior leaders, our external clinical experts, and provide this unique opportunity for our shareholders here in North America and around the globe to hear about our pipeline and some recent company news. Can I ask you just to take a note of our standard disclaimer? And now to move to the agenda. As you'll see, we have a really great lineup of presentations for you today. This will take you through the commercialization of Illuccix, our first commercial product, and how we are leveraging that investment in preparation to launch TLX250-CDx, our renal cancer imaging agent, and TLX101-CDx, our brain cancer imaging agent. We will also be providing scientific and clinical insights into the CA9 program and our 250-therapy program and TLX591, our prostate cancer therapy program. We will also talk about the acquisition of Lightpoint Medical, which we announced on the ASX earlier today. This acquisition brings a new late-stage urologic asset into the pipeline for radio guided surgery. For the order of presentations, we will start with presentations from the Telix team. After this, our 2 KOLs will come to the stage. Their presentations will followed by a fireside chat with Mary with time for a few questions from the audience. We'll conclude today's program with a Q&A panel session with the Telix team. And at this point, we will take further questions from the floor and the virtual audience. For those participating via webcast, you have been provided with an e-mail address to submit questions. which is also on the screen right now. For those in the room, we do have scheduled breaks, but we please ask you feel free to help yourself to refreshments throughout, and join us for lunch at the conclusion of the formal presentations. I'd now like to introduce today's speakers. As I said earlier, the value in this event is bringing together some of our senior leaders, many of whom are based in the U.S. to address our shareholders. With us today, we have Chris Behrenbruch, our CEO; Kevin Richardson, CEO of Telix Americas; Ted Stephens, our VP of Marketing for Americas; and Tom Fromm, VP of Sales. I am also really pleased to welcome our medical leaders, Dr. Colin Hayward, Group Chief Medical Officer; and Mary Jessel, our VP of Global Medical Affairs. Joining us today will also be 2 key opinion leaders, Dr. Brian Shuch, a principal investigator and lead recruiter in our Phase III ZIRCON study, who will today share his insights on the clinical utility of our renal cancer imaging agent; and Dr. Scott Tagawa, who has been heavily involved in the initial development and clinical program of our lead prostate cancer therapy asset, TLX591 for prostate cancer therapy. He'll be giving insightful presentation to the clinical data on this asset and the role he foresees it playing in the therapy space. Mary will introduce both of these in more detail prior to the respective sessions, but we just want to pass on our appreciation now for them being here today. I would now like to hand over to Chris for his presentation.

Thanks very much, Kyahn, and welcome to everyone. It's a real privilege to have you come and join us this morning. Just before I start on with my presentation, just a little bit to state the obvious, like a lot of forums of this nature, this is an investor conference, it's not a clinical positioning or a sales exercise from a product perspective. And so part of our goal today is to make sure that you walk away with some understanding of how we view the evolving market and landscape, competitive landscape, in particular, and also that you understand what our viewpoints are on product differentiation. As Ky illustrated by the invitation of our 2 key opinion leaders for renal imaging and for prostate cancer therapy, we are really deeply committed to discussing the evolving scientific data as part of this forum. Also, we're going to talk in quite a bit of detail about our commercial strategy against what we see as a growing body of evidence around the comparative use of gallium and F-18 based PSMA agents. I think when the field started, there was a degree of viewpoint around parity of these products. And I think as clinical data starts to become more available, it's clear that there are differences in the way that these products will be used and interpreted in their clinical impact. So again -- and we'll certainly be doing that with reference to the science. So I encourage you to note that whenever we make a scientific statement, there is a footnote corresponding to a publication, a peer-reviewed publication, and we are certainly mindful of how the practice guidelines are evolving around the PSMA space. So I just wanted to outline that a little bit in advance. So without further ado, I thought I'd give a bit of an introduction and an overview of the company. I know there's a good deal of understanding in the room from some people, but it is variable. And I thought to give you an outline of what our current strategic priorities are would be a good backdrop for the rest of the morning. So first of all, we take the view that we are one of the really leading companies in this space. And there's principally 4 kind of categories of basis for that statement. The first one is that we are a commercial stage company. You could be mistaken for believing that we're an imaging company. We're actually a therapeutics company that believes in the concept of precision medicine. But the imaging products in our portfolio give us an early commercialization revenue generation opportunity. And these are really important unmet medical needs that we think are well worth pursuing, both clinically and commercially. Our lead product, Illuccix, in prostate cancer is selling well. We'll certainly talk more about that over the course of the morning. And we have regulatory filings, as Ky mentioned, underway for 2 more imaging products, BLA and NDA that will be filed this year. And those will meaningfully augment our Illuccix revenue stream. We think we have one of the most exciting, if not the most exciting pipeline in therapeutic radiopharmaceuticals. We have over 20 clinical trials running around the globe, demonstrating the utility of that pipeline. That pipeline is going to generate super exciting data over the next 12 to 18 months. We think there's some significant commercial catalysts. And so there's lots to watch out for as the company executes on its mission. Supply chain and manufacturing is something that I think the market now understands as a really critical area of focus in this field. As you will appreciate, we develop products that have an incredibly short life span sometimes a few hours in the case of Illuccix, maybe out to a week for some of the longer products. And so manufacturing and supply chain is critical to integrate into the commercial execution strategy for the business. And we've invested a good deal of shareholder capital and making sure that, that is something we have command over. A couple of weeks ago, I was in -- seems longer than that. But a couple of weeks ago, I was in Belgium for the opening of our European manufacturing facility. In some countries around the world, in some markets, we are fully vertically integrated, developer, manufacturer, and we are increasingly focused on taking charge and command over our supply chain. I think that's, by the way, a trend certainly for the more mature companies in this space. And certainly, we can talk more about that in Q&A if there's interest. Last of all, we're a well-funded company. We're cash flow positive, which I think is a bit unusual for a company of our market cap. We're currently underwriting about $100 million of annualized R&D expenditure from earnings of our product sales. So we really feel that puts us in a very strong position, particularly in the current market conditions. Now I'm not going to spend lots of time giving you potted history lesson although in the hallowed walls of the Yale Club, the wooden panel sort of tend to make you a bit nostalgic, but I just wanted to point out, and you can read the slide in your leisure, but this is a field that's been sitting in dormancy for a long time. And we can go back to amazing discoveries by Roentgen and Marie Curie and that's historically interesting. But it does start to fire up a little bit, about a century ago when we started to use brachytherapy therapy to treat prostate cancer. I think prostate cancer has always been kind of the focal point of the potential of this field. And it's -- that's what makes it so amazing to see it come to life at the moment both for our products and for the field overall. There's just some exciting momentum. One key catalyst, I think, was really back in 2013 with Algeta, they demonstrated that if you run the study and you get the clinical evidence, big pharma will buy into radiopharmaceuticals, even though it's an unconventional asset class in many ways. And I think that trend has really continued in the sort of roughly a decade since then. So I think the key take-home message here, we have a ton of momentum in this field. And that momentum means that this is an exciting place to be. I'm not so concerned about things like Inflation Reduction Act and where will pharma focus their next attention in terms of asset class, but I really do care a lot about -- we care a lot about the clinical outcomes that we're trying to achieve as a business. And that's really manifest in the momentum that we're seeing in this field. Just a little bit more about the company, so you can understand and I think it contextualizes as well. The team that's here today. We have kind of 4 pieces to our business globally. First of all, clearly, we're a drug developer. So we do develop our pipeline, run clinical trials. We don't have an appetite for basic drug discovery. Our general model is we like to find things in academia or repurpose things that have been developed elsewhere in pharma. An example was our acquisition of the Lartruvo pipeline -- Lartruvo asset from Lilly last year. We just think that as the space evolves, there's a ton of asset real estate out there that could be repurposed into really useful radiopharmaceutical products. So that's really what our early-stage development and translational team is focused on. We have a number of centers of excellence around operations, manufacturing operations, clinical operations. Mary and Colin represent those teams today, to a large extent. So you'll be able to engage with them on their functionality. And then we are bifurcated into 3 distinct operating regions: EMEA, Americas and APAC region. It's great to have Kevin who represent Americas, who's the leader of our U.S. and well, wider Americas business here today. It's clearly from a commercial perspective, the dominant operating region in the business right now although we do expect that to change and grow over the coming years. It's a fair bit of competition between the CEOs in our group structure. So it's good to see that appetite to win inside the company. And then we have a global services group under -- led by our Group Chief Financial Officer, really covers all of our internal services, and we're becoming quite self-sufficient in that respect. And so those teams are all distributed across the globe. We have kind of 3 major concentrations of activity, the Australian Eastern Seaboard, which is where the company was started and founded. Despite my accent, I am an Australian originally or an Australian by naturalization. We have a very strong R&D cluster in Belgium, augmented by great clinical and commercial team in Geneva. And then we have a huge focus in Indianapolis, which is really our kind of biggest hub for the company now. And I think it is fair to say that we are a U.S. company kind of disguised as an ASX-listed company. The majority of our growth in employees now are really on this side of the Pacific. And again, that, I think, just brings the relevancy of this meeting together. You're really going to have a chance to see the outstanding caliber of people we have in our U.S. team. As I mentioned or I alluded to sort of peripherally in the history of radiopharma slide, this is a really rapidly growing area, very -- the near-term drivers of growth are the diagnostics business. There's quite a significant pipeline of new products coming forward. Clearly, diagnostic imaging products have a more straightforward regulatory pathway. The clinical trials that we run are typically less demanding than therapeutic trials. Often, we're taking patients on their way into the operating theater, taking a resection specimen comparing it to the imaging, that's your histologic ground truth. The ZIRCON study was a nice example of that. But there are -- there's a ton of really exciting products and targets coming down the pathway that are going to give good growth to this field over the next few years, but it's also strategically important. I think from an oncology stakeholder engagement perspective, these are marketing tools of our science, right? These are -- when you can show a map of a patient's disease from their toes to their nose, all right, and then sit down and take a fresh look at a treatment strategy for that patient, that's a game changer. Now clearly, radiopharmaceutical therapies will become embedded into that dialogue. But actually, we take a really open-minded viewpoint. We think theranostics, which I have to admit I'm personally not the biggest fan of that word. It's kind of bastardization of the English language in some respects. But I think the fact is, is that combining any kind of therapeutic intervention where the diagnostic imaging agent is a good outcome for patients. And I think that speaks very much to our strategy. We are developing therapeutic radiopharmaceuticals. But as you can see from things like the Lightpoint acquisition, we're really interested in what can the role of molecular imaging bring to the operating fear. And clearly if we're targeting a specialty like urology, we are working with a surgeon, right? And so that's an extremely relevant customer touch point for us to have. So the diagnostics business is important, but clearly, the biggest growth over the next few years is going to be in the therapeutics business. We're starting to see the first kind of next-generation products coming online, moving beyond bone-seeking agents and microspheres into things that are truly molecularly targeted radiation. We've got our first product approvals. And these -- there's no doubt that these products are going to change the practice of medicine for the better. So that's where that growth is really going to come from over the next few years. And I think that this growth profile is being noticed by big pharma. I think that this is going to become a field for M&A and consolidation over the next 3 or 4 years, even more than it has been in the past. So in terms of our company's growth aspirations, we really feel that we have built all the elements and organs of a commercial stage pharma company. We're pretty good at identifying assets and building pipeline. We rely on very strong partnerships and supply chain to deliver really our products globally, not just in clinical trials, which we do in about 30 countries around the world right now, but for commercial product delivery as well. We've been able to show that we can deliver on complicated late-stage Phase III trials. I think many of you would agree, that's an important bar to jump over for a biotech company because it's hard to run Phase III trials, especially in pandemics, which wasn't, I have to admit, the most fun I've ever had in my entire life. And then to be able to get product regulatory approvals not just in the U.S. but in other countries, I think that, that shows, again, an execution maturity, that's a little bit unusual in this industry. And then it's really nice for me to be able to show off the strength of the commercial team that we've built and you're going to really see that today. We just have an outstanding -- I think we have the best sales and marketing team in this industry. And I'm just excited about how the commercial team and clinical team work so well together to deliver the outcomes that we've been able to demonstrate for shareholders. And so I think just to kind of wrap it up, what we feel is that with Illuccix. Illuccix, it was a test case for us. In some respects, it was our training wheels. Illuccix has a different meaning to Telix than it might do to a competitor because it's just the beginning of a really deep pipeline. And so we learned a lot of lessons from Telix. We learned how to take a product to market. We learned how to make it clinically relevant and position it. We learned how to engage with practice guidelines. We learned about manufacturing the supply chain. And I think this is a kind of an engine that we're going to be able to use for really a lot of long-term growth in the company. And I think that when bigger companies look at a company like Telix, they really recognize that we've built 3 incredibly powerful assets in the company. We've got a pipeline of great products that are slowly unlocking value over time. We've got a manufacturing and supply chain understanding that can really deliver those products globally. And the fact that we are able to do things like partner with Bayer in their recent Phase III trial, and we're delivering Illuccix in -- I can't remember how many countries for that study but from the U.S. to Japan and, more or less, everything in between. That shows that, that commitment to delivering our products globally is strategically important. That's what's going to make a big difference. Being a domestic market actor is not enough to demonstrate the value and the potential of this field. And then the commercial team. it's not probably going to be surprising to you, but it's hard to sell radiopharmaceuticals to oncologists. It's a really high bar of commercial execution. And so we're positioning a new asset class to people that haven't traditionally used radio activity, haven't traditionally engaged with it, and that requires a lot of talent and multidisciplinary interaction to make it work. That's an asset, building that commercial team as an asset. So I'm really excited about that. So just to wrap up, our near-term strategic opportunities and priority is really focused around that leadership position in urologic oncology and we're really going to be clearly showcasing that today. We haven't probably talked that much about our neuro-oncology program, but you're going to see that come really to the fore over the next 12 months. First, with the filing of our glioblastoma imaging agent and then the acceleration of our GBM therapy program, which has started to get some really nice data. And then, of course, more broadly to unlock the value of that therapy pipeline. That's really -- now that we've started to get those revenue streams moving and we've got some wins under the board, we can really focus on delivering that. And so just to summarize, we really feel that we are delivering on the potential -- the clinical potential and the commercial potential of targeted radiation. Our mission as a company is to go all the way from diagnosis and staging to therapeutic intervention. We think there's some interesting pit stops in the middle, which is why we do things like look at the role of molecular imaging in the operating theater. And so as Ky said in her opening comments, this is really about how do we look at the end-to-end utility of radiopharmaceuticals. And that's a really exciting commercial and clinical question to ask. And of course, there's some platform technologies that underpin all that things like artificial intelligence and clinical decision support. I think most people in this room understand that with theranostics, if we're really going to make theranostics work, we have to take the data from, imaging and diagnostics and staging and also ancillary information like genomic profiling. We need to integrate that with a therapeutic plan. And this doesn't happen by physician eyeballing. There's a ton of data science that has to go behind that. And if we don't build those clinical applications to link the diagnostic and therapeutic pieces together, we actually don't have a solution. What we're going to do is we're just going to give doses to patients. That's not going to be the best outcome at the end of the day. So anyway, I'll come back around to some of those -- so higher-level trends at the end of the session in my concluding remarks. But I think -- whilst this slide is very simple -- I think it's a very compelling vision for where we're taking Telix and why this company is so exciting to be a part of. Thank you very much for your attention. I'm going to now move on to my esteemed colleague, Kevin Richardson to talk about building our U.S. commercial team. Thanks.

Thank you, Chris. So good day, everyone, and thank you for being with us. I'm excited to talk to you about the impressive commercial organization that we built here at Telix. And really, how the success of the Illuccix launch has set the stage for the launches of TLX250-CDx and for TLX101-CDx. You'll also get a chance to hear from Ted Stephens, our VP of Marketing; and Tom Fromm, our VP of Sales, who will provide insight into this growing and exciting market and how we've successfully positioned Telix to take advantage of it. So as you can see, Illuccix has demonstrated strong quarter-over-quarter sales growth since its launch in April of 2022. We've developed a solid customer base across all segments of the market, including IDTF, hospital outpatient, VA, DoD as well as physician offices. Patients are being scanned with Illuccix in all 50 states in Puerto Rico. And because of our 200 points of distribution, we can bring our product to key metropolitan areas as well as suburban and more rural communities. Our goal is to make Illuccix easily accessible for our customers and their patients in the markets that they serve. So I'm pleased with the team's accomplishments to date, and I'm excited to share with you how we built the team that delivered these results and how they are preparing for the next assets in our portfolio. But we didn't just build the organization to launch Illuccix. We built it to take a leadership position in urologic oncology. The commercialization of Illuccix has had a great foundation for our urology business, and we'll use our ever-expanding footprint and growing relationships with urologists and nuclear medicine radiologists to introduce new products into the market across several disease states and along the continuum of diagnostic imaging, surgery and therapy. As Chris mentioned, we also have a team of dedicated scientists working on the AI platform to bridge reader and clinical decision support to eventually disease prediction. And with our commercial team driving broad adoption of Illuccix in the urology offices around the U.S., we continue to move closer to this vision. One of our best differentiators is our leadership team. So if you're going to hire great people, you must first hire great leaders. And then with those leaders develop a corporate culture that attracts the best people in the industry. Using this approach, we've assembled a world-class executive leadership team and a group of customer-facing leaders organized to penetrate these complex markets that we serve and scale then as we grow our portfolio. While it's my responsibility to set the strategy and deliver on our objectives, each leader is responsible for working cross-functionally to deliver on the [Audio Gap] Integrated business plan objectives. Our VP of Medical Affairs, Dr. [Audio Gap] Medical strategies for Telix products. She is an integral part of the U.S. customer-facing team and works with the commercial leaders to align her objectives and her activities. Now our Chief Operating Officer, Darren Patti, is a nuclear pharmacist by education and has over a decade of experience in pharmacy and nuclear pharmacy operations. Darren is responsible for making all the trains run on time and making sure that we maintain a high level of customer service and satisfaction, from our imaging center customers to our radiopharmacy distribution partners. Tom Fromm, who you'll hear from later, is a highly qualified energetic sales leader. He honed his leadership skills in the competitive medical device space of transcatheter heart valves as well as interventional oncology. Now these leadership and recruiting skills have helped him assemble an outstanding sales team with Telix -- here at Telix with a strong track record in nuclear medicine, medical device, interventional and therapeutic oncology as well as medical imaging. Our VP of Net Strategic Accounts, Tony Zinno is a 20-year veteran in nuclear medicine with a vast network of relationships Tony's expertise is in building partnerships through the integrated delivery networks around the country. This is a really important strategic arm of the commercial team, and it gives us access to hundreds of cameras, PET-CT as well as tens of thousands of patients. Another of today's speakers VP of Marketing, Ted Stephens, is really fundamental to our business strategy. In a market-centric organization, marketing is really the Rosetta Stone that pulls all functions and our customers together. Ted has over 10 years of experience at the marketing executive level and turning customer requirements into successful product launches. As the leader of our go-to-market strategy, Ted is central to the successful adoption of our product, and is the creator of the commercial playbook that's led to our success. As we scale our business, we've taken a measured well-planned approach to building our commercial capabilities. People and processes are the key ingredients to a high-performing organization, and it's critical to understand where you're going what your competencies are really your areas of expertise that you need and then you develop those into your commercial function. So first and foremost is understanding these required competencies or expertise in the segments that we operate. In other words, what do we need to know about our customers, the diseases they treat, and then the tools they use. While we operate in a multidisciplinary market where we need to understand urology, oncology and radiology across several disease states. And then they use several types of tools or agents, including pharmaceuticals devices and even medical devices or radioisotopes. Second, building these competencies into each commercial function. So each customer-facing function must understand the nuances of our customers in this segment so they can be effective in their role. Third is bringing in the right people and the previous experience in subject matter expertise and then leveraging that experience to raise the knowledge and understanding among everybody on the team. So to pull together this group of all stars and then turn them into a high-performing team, we started with the corporate culture of teamwork and put in a process in place to allow team members to utilize their skills and their expertise of each other to achieve this best outcome. Now this has really been crucial in developing the high-performing Americas team, and then really attracting and maintaining some of the best talent in the industry. So finally, we must foster high-performing teams through operational excellence or operational discipline. This means planning, executing, the briefing, and then repeating this process again and again. High-performing teams do this together, so they learn from each other and their shared experiences through the debriefing process. We do this monthly and quarterly at the management level to ensure that we're attracting to our plan. This ensures that our tactical execution drives to the objectives that we set for the business. So once you've built this world-class organization, and then you need to deploy them. So while Tom is going to cover this in a little more detail, we -- this slide is going to provide a high-level look at the customer-facing team that we put into place to drive growth and then support our customers. This broad and deep structure covers all 50 states and can be deployed to launch 250-CDx in the urology business and 101-CDx in our specialty neuro franchise with minimal incremental additions. Our functional leadership is focused on creating a customer experience that sets us apart from the competition and demonstrates our clinical differences in the market. While our sales team leads the frontline relationships, we operate in a very complex medical environment. And we have invested heavily in our customer-facing team. We often hear from our customers how much they appreciate the medical support. And we also -- are also able to leverage our vast network of distributor partners to support our customers and grow Illuccix. The Telix team makes everything runs smoothly for them. This is why our customers tell us that they love the support they get from Telix and Telix makes this us the easy-to-use PSMA. I'll now turn over the podium to Ted Stephens, our Vice President of Marketing, who will tell you more about our go-to-market strategy.

Thank you, Kevin, and good morning, everyone. We believe PSMA PET-CT continue to be an exciting and growing market. We hope to demonstrate that not all PSMA agents are created equally and that we expect to continue to increase our market share over the coming months in this growing market. That growth will come from both increased awareness and utilization of PSMA driven by expanded indications and support -- continued support from our medical societies. Our commercial strategy is to stimulate demand and grow Illuccix and it breaks down into 3 fundamental areas. First is to increase awareness by educating urologists, referring physicians and patient advocacy groups about the specific benefits of Illuccix. Second, our commercial team will continue to add volume at the account level as we see growth in both de novo and existing accounts. Finally, we'll leverage the growing amount of emerging data, highlighting the clinical advantages of gallium, allowing us to clearly differentiate Illuccix due to its unique accuracy, precision and availability. So we call this the Illuccix difference, and its foundation is our clinical data, as illustrated in some of the customer-facing material that you see here. This translates to superior clinical accuracy for our customers. We're able to achieve high-quality images that our customers can trust because of our product's higher sensitivity compared to competitive F-18 imaging agents. Our reliable distribution is due to our partnership with over 200 radiopharmacies and distributor partners across the United States. This allows us to deliver Illuccix doses at all times of the day, offering unprecedented scheduling flexibility and -- to both our customers and patients. Lastly, we built a commercial organization to provide end-to-end support for our customers from training and education to onboarding, image optimization, market access and clinical support. We've also expanded our medical team enabling them to provide what we believe to be is best-in-class and industry-leading levels of clinical support to our customers. So as we go a little deeper on this, the heart of the Illuccix difference is our robust clinical data and the growing number of scientific publications illustrating that our product has the most validated accuracy compared to other PSMA imaging agents. That means high true-positive rates of detection for both regional and distant metastatic disease, including bone, unprecedented diagnostic performance even for micrometastatic disease, accurate interpretation with high inter-reader agreement. So I've mentioned the emerging clinical data suggesting that clinical differences between gallium and F-18 based images -- based agents. And these differences are now being recognized by multiple societies in recent guideline documents and scientific publications. Emerging trends are focused on nonspecific bone uptake where, in some cases, gallium PSMA has 6x less. Gallium and Illuccix PSMA has great detection of pelvic lymph nodes, greater reliability and identifying PSMA-positive lesions across a broad range of patient populations. [Audio Gap] that are being developed with our distributors and local radiopharmacies. Earlier, I mentioned our network consisting of over 200 local radiopharmacies. This means that we have Illuccix doses stocked and ready to go in radiopharmacies throughout the country and in close proximity to imaging centers. In addition, we have a motivated local team in these markets with local knowledge and deep account level relationships that, frankly, creates a significant competitive advantage and enhances our ability to deliver service and products to the market. We can actually deliver doses within hours of ordering to customers in major metropolitan areas as well as suburban and rural areas. And nuclear medicine departments can use all 8 to 10 hours of their imaging day to accommodate patient schedules. With our model, we've been able to deliver and achieve an industry-best 99% on-time delivery. This simply is not possible with a centrally manufactured product with large distances between manufacturing and end user create challenges with reliable on-time dose delivery. So as we look forward, we believe this commercial and operational capability is a valuable asset, and it uniquely positions Telix to efficiently commercialize new assets and products in the coming months and years. So let's shift now to a few comments about our marketing organization and process. I'm very proud to say that we've built a great team as we've recruited individuals from highly successful companies with strong marketing skill sets that have experience in oncology, medical device and nuclear medicine spaces. We've also developed our marketing organization, ensuring that we have the skill and experience to amplify our brand messages through multiple channels and -- while we're able to scale and accommodate a pipeline of products. So here's how our process works. At the top of the slide and then moving down, you can see that we start with a very thorough understanding of the patient journey and all of the stakeholders involved in the decision-making process. We go from awareness and screening to diagnosis and treatment and through ongoing patient management. With this, our brand manager then develops a strategy and marketing plan to influence and accelerate product adoption both effectively and efficiently. This plan is developed to leverage our marketing channels as we engage the target customers through digital marketing, patient education, disease awareness, KOL and society engagement, targeted physicians. And finally, they deploy tools that enable Tom's team to build preference for Telix products with our customers. Because of these functional capabilities we've built, we're prepared to bring our product portfolio through our marketing process and accelerate product adoption. With our renal and brain cancer imaging products on the near horizon, we've initiated 3 different simultaneous processes. Our product development teams are focused on delivering what we call a "launch-ready product" while our downstream team is responsible for both preparing the market and preparing the organization as we approach launch. These initiatives involve cross-functional collaborative teams working on specific activities to ensure a successful launch in each region of the world. Throughout these processes, we'll leverage relationships, call points and distribution channels that we've already built. So with that, in conclusion, it's a very exciting time at Telix, and we look forward to keeping you updated on the launch of our new products. I'll now turn the podium over to Tom Fromm, our Vice President of Sales.

Thank you, Ted. I'd like to start off by introducing you to my sales organization reporting directly to me are the area vice presidents and the area sales team. The area vice presidents have overall responsibility of their assigned areas, including recruiting and managing their teams. Their accountability for achieving their objectives and leading and executing the commercial playbook. The sales training team are tasked with training the organization on everything from disease states and treatment options to clinically differentiating our Illuccix to our customers. The training continuum ongoing sales effective in Australia to maintain the most productive sales team in the industry. Our training team will also prepare the organization for future product launches. We have strategically placed our current sales force to maximize our coverage of the pet scanners and the hospital imaging centers around the country. The first map shows the sales force we put in place to launch and grow Illuccix. As you can see, we have great coverage in the U.S. We believe we will need to make only minimal additions to our density to our coverage in a few areas to launch TLX250-CDx, approximately a 20% increase. For 250-CDx, it will be added to existing sales team's bag as it's the exact call point that they are currently focused on, the urologist and the nuc med radiologist. To enter the neuro market, we'll add a small, focused sales team integrated with a focused, cross-functional medical and marketing team. While the call point will be the neurologist that treats these patients, they'll also be scanned at the imaging centers where we have relationships and technical medical expertise. So how do we build a world-class commercial team? It's about the people and the process. We began by recruiting some of the best talent in the industry. Our sales organization is built with sales award winners from some of the most competitive companies in medicine. They have a track record of proven results and understand how to fully optimize the hospital system and build a preference for Telix products with our physician customers. Underlying any successful sales team is a great culture. We worked hard to have a great place salespeople want to be and maintaining the Telix culture continues to be one of our top priorities. Our patient-first and teamwork mindset makes the sales organization the best-in-class. Once you have recruited them, you must train them up before and after you send them out. Sales training and effectiveness is an essential part of our growth strategy. A professional sales organization must have a training continuum that facilitates field success and continues to challenge the territory manager to get better at their tread. Having a well-trained professional sales organization that can quickly expand to support new product offerings as efficiently as it supports existing products is a strategic asset here at Telix. Now that they are hired, trained, and ready to go, they need a plan to be successful. The AVP and the territory manager work closely to ensure that the territory plan will result in targeted sales. Based on a marketing-driven strategy and local market dynamics, the AVP gives direction and account prioritization and sales tactics and works with the territory manager to ensure their success in the area. Our competitive incentive strategy is also best-in-class and allows our team members to maximize the opportunity in each region. Our incentive plan helps Telix to recruit the best commercial talent in the industry and gives employees long-term incentives to stay, growing with us personally and professionally. As you've heard today, process and the Telix commercial playbook has delivered great results, moving customers efficiently from initial contact to revenue generation and ensuring customer stickiness along the way. The territory account manager is responsible for making initial contact with the customer, and the AVP quarters back the cross-functional care team, which supports our customers at any given time and make sure they're set up for ongoing success. The cross-functional support team positions us as the easy-to-use PSMA with a clinical advantage. A central element to our support team that is involved with all our customers as our local pharmacy model. They have been selling nuclear medicine products to the pet imaging centers for years and their local knowledge and strong relationships, extend and reach and enhance our ability to execute our sales strategy. They see our customers every day when they deliver the patient dose and ensure a great customer experience with Illuccix. That is why we partner with the industry's best. When account has a high level of strategic value at Telix, they are part of our strategic portfolio and the strategic accounts teams will engage with the C-suites, at the same time, our territory managers are working with our doctors and staff. The strategic team is working to open access to a larger integrated delivery network of hospitals and imaging centers. Sales success is because of good sales process. In the Telix and the commercial playbook is how we execute our plan. Final initiation of contact, our team educates the potential customers on the Illuccix difference. Once the account has decided to move forward with Illuccix, the AVP brings in the other functions needed to move the customer through the process. With any hospital or imaging center, a new product can sometimes feel overwhelming for the staff, which is why we offer end-to-end service in addition to our product. Our medical and marketing access teams arrived prior to the first dose. We want to make sure that the account is ready to go from reimbursement in a medical perspective. Then of course, our field-based team is at the first dose is to make sure everything runs smoothly. This is a big reason customers view us as the easy-to-use PSMA, and it will be a huge advantage as we introduce them to additional products. After the account is up and running, our territory manager begins to educate the referral base and increase patient awareness to drive patients to the Illuccix imaging centers. I'd like to now turn it over to Kevin for a few closing comments.

Well, thank you, Tom, and I hope you've all gotten a good sense of where Telix is as a company, where we're going and how we're going to get there. The high-level takeaways are what makes Telix different. And that is really that we have the best -- we think we have the best PSMA product on the market. Our people and processes in the commercial team are what have made us successful. We can attract the best people in the industry by function and area of expertise because we have an exciting team culture that nurtures and develops team play and involves the leadership team and the planning process and decision-making process. So I will close with this. We have a formidable but scalable customer service customer-facing team, and we're really ready for the imminent launch of 250-CDx and 101, as well as the addition of future products. We continue to use our products, our people and processes to differentiate Telix and tackle this large and growing market. And I believe we're uniquely positioned for success. So thank you for being with us today. I'll turn it over to Colin Hayward, our CMO, to talk about the future of PSMA imaging.

Thanks, Kevin. So I'm Colin Hayward. I'm the Group Chief Medical Officer. I'm responsible for the medical affairs and the clinical development of Telix. Now as you've just heard from the U.S. commercial team, the clinical momentum and the commercial momentum behind Illuccix is huge. And I want to show you some of that clinical momentum. I want to bring us back to those tangible benefits that PSMA scanning, especially with the benefits discussed of Illuccix, can offer patients throughout their prostate cancer journeys. In this presentation, I'll give you a quick tour of some of the more recent publications for PSMA imaging and show you how Illuccix imaging will expand over time to become a holistic mainstay of patient management. First, I want to make it clear that Illuccix is more than just a diagnostic. It helps physicians every day manage patients by better understanding the location, the extent, the biology of the disease of the prostate cancer. Our goal is to be part of the patient's prostate cancer journey from that initial diagnosis to future management, including surgery, radiation therapy and radiopharmaceutical therapy, ultimately helping people with prostate cancer live longer and better-quality lives. Many of you know that our current indications are in the early stage for newly diagnosed patients with suspected metastases and patients with biochemical recurrence. These indications have been expanded in March to include patients with metastatic disease for whom PSMA-directed radioligand therapy is indicated a current differentiator for our product also. Our opportunity is to continue growing Illuccix, increasing the frequency of use and expanding the indications eventually encompassing the patient's entire journey throughout prostate cancer. We still have a long way ahead to realize the full potential of our current indications, but I will show you how the use cases for Illuccix are expanding. Let me start within our current indications with a case study of a patient who -- with prostate cancer after their initial radical treatment, after surgery it was, had a rising PSA. What would have happened in a pre-Illuccix era? Well, in many cases, that patient would have gone to whole body pelvic radiation, antiandrogen therapy would be recommended, both of which have potentially severe side effects. For pelvic radiation, for example, urinary incontinence, bowel problems, fatigue, sexual dysfunction. Some of the side effects for antiandrogen therapy are the same. Lots of muscle mass as well, increased body fat, erectile dysfunction, hot flashes, I could go on. There's an extensive list of side effects. So this patient was imaged with Illuccix finding a single pelvic lymph node. This node can potentially be addressed by targeted external radiation delaying or even preventing the use of whole pelvis radiation and antiandrogen therapy. And this immediately shows the use for increased imaging for any one patient from the newly diagnosed setting to recurrence and then potential follow-up. Innovation with Illuccix, though, doesn't just come with new indications. It comes with working with the innovators in the imaging field, for example. Here are images of a prostate cancer patient taken on the uEXPLORER PET/CT. These pretty exquisite images with the Illuccix produced by our friends at BAMF Health, they were done in a matter of seconds and minutes compared to the usual 20 to 30 minutes in a normal scanner. Obviously, with fast imaging, more patients can be scanned in a day, and that time saving is a big quality of life improvement for patients. Research in PSMA-PET and Illuccix continues to grow across the world. In Telix sponsored studies, for example, in our collaborations with academia. And also driven independently with researchers around the world driving and expanding the evidence base for utilization as demonstrated this growing list of publications. This evidence has the potential to result in potential new indications and continue to evolve PSMA-PET into new normal standards of care like the recent AUA guidance that's come out. As I mentioned earlier, we want to be with a patient throughout their prostate cancer journey. What comes before even our existing indications. Well, before a high or medium risk diagnosis for many patients like my dad, who are diagnosed with a low-grade prostate cancer, the current standard of follow-up is to assess PSA values over time, repeat imaging, repeat biopsies at different intervals. What if those patients could receive more accurate imaging and eventually avoid the need of biopsy altogether? So this is an example from an Australian study of 291 patients, the primary study. In this cohort of patients, a primary score was given based on their PSMA imaging, the higher the score, the more likely the patient was to have clinically significant disease. And the results of the -- well -- the study correlated well with that histology. And clearly, the interpretation of that imaging can be quite subjective. So could be enhanced with new AI tools such as our recent acquisition. So subsequent to finding clinically significant disease after patients will progress to surgery or other radical treatment. Here, you'll see highlights from a publication by our collaborators at Indiana University who use PSMA imaging routinely to help them plan their surgical procedures. In this study, they're identifying patients with extra prostatic extension, or EPE, PSMA-PET has outperformed MRI resulting in change of surgical plans in around 30% of patients. It helps them conserve those nerve bundles that are close to the prostate and avoid potentially debilitating effects post-surgery. Could Illuccix and gallium images also be used in the operating room? I mean historically, it's unlikely because of the short -- half-life of gallium, but here is an ex vivo proof-of-concept study. An Italian group dosed 7 patients with a relatively low dose of gallium PSMA prior to surgery. And the surgical sample, a prototype probe with the drop in beta was used on the specimens approximately 2.5 hours post-injection, showing it can detect positron emissions. In patients where cancer occurs, re-irradiation is a treatment option. A bit like our case study where we highlighted precisely that PSMA positive lesion was and therefore, minimizing exposure to normal tissue and focusing the external regulation on that PSMA-positive lesion. Of course, using Illuccix helps to reduce the possibility of false positives and irradiating healthy tissue. On this slide, you'll see results from 2 studies in which PSMA-PET was used for patients with prostate bed recurrence to plan those radiation fields. Using PSMA-PET to guide that leads to intensification in treatment for over half of those patients. And this has the potential to result in better outcomes. Again, proving that Illuccix is more than just a diagnostic. We, of course, have an ongoing collaboration with RefleXion where Illuccix will be used on their innovative biologically guided radiation device, and we're excited about generating data in the very near future there. So you've seen the potential of Illuccix in active surveillance, potentially surgery, biopsy, radiation planning, et cetera. The next step is to help manage and define treatments throughout their journey as they change treatments, as the disease evolves. This slide features 3 2023 publications that address patient management. First study showing gallium PSMA imaging, detecting recurrence even in that very low PSA setting, again, showing the benefits of Illuccix in low PSA recurrence. And how PSMA can affect those patients with that salvage therapy. In the second study, PSMA expression is shown to be a potential prognostic factor and maybe even a better prognostic factor than PSA. So it can help guide in terms of management and understand what outcomes you might expect. So not just for radioligand therapy but other treatments as well. And thirdly, in a large metro analysis with over 4,000 patients, we see how PSMA imaging has potentially changed management in over 50% of patients. So again, throughout that continuum. Now as we discuss managing patients, I'd like to briefly just remind you of our collaboration with Bayer and their largest study, the Aricept study using Illuccix. In this case, Illuccix is being used with a global study of nearly 800 patients from the U.S. all the way to Japan, demonstrating that flexibility and ease of use case for Illuccix. Patients who are negative on structural imaging, but positive on PSMA scans are randomized and their response to therapy assessed over time with ongoing PSMA-PET imaging every 24 weeks or until progression. The fact this study is underway is a sign that big pharma who potentially drive those new imaging standard of care with Illuccix being used not only for ablation selection but also to monitor that ongoing response. In fact, in this study, RPFS or radiographic progression-free survival, through PSMA imaging is the primary endpoint, maybe putting an end to less sensitive imaging like bone scans that have much less clinical value. I showed you this earlier version of the PSA time line chart with the blue areas calling out the current indications of Illuccix and where they lie on the prostate cancer continuum. As you've seen today, in just a very small snapshot of that publication in PubMed that have come out in the last few months. This growing body of research shows that Illuccix has the potential to address many other points along that cancer journey, shown in pink, including surgical planning, the active surveillance, biopsy planning, radiation planning and ongoing disease management. So although the PS in PSMA stands for prostate specific, it's a little bit of a misnomer. It's a market of neoangiogenesis. It's in a number of other tumors and in the literature described several tumors, such as glioblastoma, salivary gland tumors, hepatocellular carcinoma, and so on. The image on the right clearly shows cancer in a location in a patient with liver cancer after a long history of cirrhosis. So as a diagnostics, Illuccix has set the stage for our commercial development pipeline. And through our various collaborations, it's already being used in many other parts of the patient journey. Our depth and commitment to urologic oncology starts and has started with Illuccix, continues into surgery with our recent agreement to acquire Lightpoint Medical. And they're very exciting since a gamma probe that can be used in combination with our technetium agent. And of course, our commitment to therapeutics with ProstACT GLOBAL and TLX591 in start-up right now. Illuccix is just the start. Telix has an unprecedented commitment to urologic oncology. After the break, we'll take a deeper dive into GU oncology with the story of CA9, as well. So we're now going to take a break. I'm happy to speak to anybody during the break as of my colleagues, apart from any Australians about cricket, of course. And then we'll start again at 9:45. So thanks very much. [Break]

Well, thanks for living up to my expectations and not discussing sport and rubbing my nose in it. Thank you very much for that. Welcome back. When I joined Telix, the CA9 or carbonic anhydrase IX program was the target I was most excited by. Why? Well, because of its potential to affect the tumor microenvironment and its potential pan tumor applicability. CA9 is associated with hard-to-treat tumors and poor clinical outcomes and thus, major unmet clinical needs. The antibody girentuximab, has demonstrated the ability to target CA9 in a very sensitive and very specific way, particularly in the recent ZIRCON Phase III study. While CA9 is expressed in almost ubiquitously in clear cell renal cancer, it's also expressed in a large number of other tumors and is a marker of potentially tumor aggression and hypoxia. CA9 has the potential to show pan-cancer applicability both diagnostically and therapeutically. And this is what we're exploring in the STARBURST study, which I'll come to at the end of this presentation. But I want to briefly go over the science and the background of CA9 expression. In normal oxogenetic conditions, HIF-1 alpha hypoxia inducible factor I alpha is degraded. However, under hypoxic conditions, as seen in many tumors, that HIF-1 alpha is overexpressed. And this leads to our regulations in other genes such as CA9. So what does that mean to the patient? The CA9 expression may lead to treatment resistance of the cancer and the poor prognosis because that tumor microenvironment, that ecosystem, it creates hypoxic conditions that can help a tumor survive and develop resistance to therapy. The CA9 within the tumor can also potentially further the tumor growth and increase the metastatic potential of that tumor causing the cancer to spread from its existing site to new tissues. So we know we can effectively target CA9 with TLX250-CDx or zirconium girentuximab, the antibody imaging target for CA9. Girentuximab is a monoclonal antibody and thus cleared by the hepatobiliary mechanism allowing for optimal renal visualization. The zirconium links well with the antibody and has a half-life that's suited to antibody uptake. It's residualized into the tumor cell, giving it better tumor to background ratios for imaging, particularly those small tumors. And in previous studies, we've shown that girentuximab has the ability to effectively target CA9 expression. Dr. Brian Shuch will be going into further detail about the ZIRCON study, but I just want to touch on it because really the results are exceptional. ZIRCON was a Phase III study, looking at the sensitivity and specificity of zirconium girentuximab in clear cell renal cancer in patients with renal masses less than 7 centimeters. The headline, hopefully that you're all familiar with, is that it demonstrated exceptional sensitivity and specificity as well as very consistent intra-reader agreement. And if we compare that to some recent imaging agents that have been approved, it's considerable. These results were even shown in small and very small renal masses of less than 4 and less than 2 centimeters, respectively, which can be the most challenging renal masses in terms of diagnostic dilemmas. We see the potential not only to benefit clear cell renal cancer, but to stage patients monitor those on active surveillance, monitor high-risk patients and analogous to the Illuccix development, monitor and change management throughout their clear cell renal cancer journey. We're excited by the broader applicability that girentuximab could have in targeting CA9. We know CA9 expression can be found in numerous other cancer types with head and neck cancer having the most evidence CA9 expression in the literature. We can also see pancreatic cancer, ovarian cancer, to name but a few. You'll see an example of CA9 expression in breast cancer on the right and how its expression is associated with the worst overall survival. We have an extensive development program both in imaging and of course, therapeutics. And all of these studies are active. We have the STARLITE studies. STARLITE 1 is in that first line clear cell renal cancer in combination with standard of care, cabi and nivo, cabozantinib and nivolumab. STARLITE 2 here in New York is in second line with nivolumab only in those patients who have been treated with prior immuno-oncology therapy. The concept behind these studies is to evaluate the potential of the lutetium girentuximab to enhance other agents, in particular, that potential immune priming effect of targeted radiation. The STARSTRUCK study is the collaboration with Merck KGaA and looks at the lutetium girentuximab in combination with a DNA damage repair inhibitor. Antitumor activity of lutetium girentuximab has been shown in these original studies of rapidly progressing metastatic renal cancer and patients -- in these patients are progression-free survival of 8 to 11 months were seen. Actually, it was not too similar to the original Avastin studies in a similar population. You'll see on the screen some early images from the STARLITE 2 study that has lutetium girentuximab dosing in it. The image on the left, the PET zirconium girentuximab scan, so like in the ZIRCON study, but here clearly showing metastatic disease. It shows tumors in the skull and other sites around the body. The second image is this PET scan. Lutetium dosing, showing how that therapeutic antibody is targeting those metastases. We use antibodies, as you've probably seen in a lot of our therapeutic prostate and renal programs to deliver the radiation. And this data shows why we use those, the preclinical data behind our STARSTRUCK study. The antibodies are internalized into the tumor and the activity stays in the tumor for a lot longer. This combination, therefore, has the potential to lower the dose of radiation, avoiding potential side effects and demonstrating enhanced activity over a period of time, and in this case, with the DNA damage response inhibitor peposertib in this preclinical model. So I promised to talk about the STARBURST study. And let's talk about that Phase II STARBURST study, one of the studies I am most excited about this year. It's investigating the ability of radiolabeled girentuximab to target CA9 expression tumors. This is the beauty of theranostics. Using a relatively simple imaging study, we can assess potential dosimetry. We look at the therapeutic dose as well as that targeting ability in multiple tumor types. This work will complement some investigator-initiated studies where we've already seen CA9 expression such as in triple-negative breast cancer and urothelial cancers, including bladder cancer. The first STARBURST study was dosed last week actually and in patient with colorectal cancer and will be image later this week. We know that girentuximab is an excellent targeting antibody with unprecedented sensitivity and specificity. We've seen that lutetium antibody has demonstrated antitumor activity. We're taking this to the next level with different therapeutic combinations and look at the potential to target multiple tumor types. I'd now like to turn it over to Dr. Brian Shuch, who's joined us from UCLA today. Thanks, Brian. And as promised, he will be going into greater detail about the ZIRCON study and the potential clinical utility of TLX250-CDx.

It is my honor to introduce Dr. Brian Shuch, expert surgical urologist in renal cancers. Dr. Brian Shuch is a Director of the UCLA Kidney Cancer Program and the Alvin & Carrie Meinhardt Endowed Chair in. He completed his urology training at UCLA, followed by a urological oncology scholarship at the National Cancer Institute. He serves in leadership positions with various kidney cancer research organizations such as SWOG, NCI and [indiscernible]. Dr. Shuch is a leader in translational research with over 160 peer-reviewed papers in prestigious journals, including Nature, PNAS and JCO. He was a leader in -- he was our lead investigator on Telix ZIRCON Phase III study of TLX250-CDx in clear cell renal cell carcinoma, which reported positive results in November 2022. I welcome Dr. Shuch.

Okay. Great. Thanks, Mary. I'm happy to be at the Yale Club. My first job as faculty was at Yale, and they were kind of upset that I for warmer weather, so I'm surprised they let me in the building, but good to be here. So I'm excited. This is a seismic shift in California, so I have to say that. This is really an earthquake in our field of urologic cancer. Kidney cancer has been really stagnant. So I'm really going to just talk about some treatment perspectives coming from a surgical minded person and also talk about the imaging quality here, and this is really -- going to really be a paradigm shift over the next few years. So just some disclosures. So just to briefly go over the ZIRCON study. The ZIRCON is really designed to have 3 independent radiologist review imaging before patients went to the OR. So these are 3 independent radiologists who are not colluding, trying to say, hey, is this positive. These were independent. And the lower bar set by the FDA to have a threshold of 70% and 68% sensitivity and specificity were met by both readers. It really was significantly destroyed in the performance. And you see the pooled sensitivity and specificity were outstanding, 85% and 87%. This blows CT and MRI out of the water in terms of the accuracy. And then the positive predictive value here was 93%. And I'll also kind of share that 93% is considered the positive predictive value at predicting clear cell. There were some very aggressive malignancies, just as Colin mentioned, the STARBURST study is looking at other cancers. I had a patient with the renal sarcoma very rare and it was very positive on that -- on the imaging agent. And that patient, unfortunately, had brain metastases and died 6 months later, okay? So am I upset that it was a false positive? No, I want to know about that. So I think the data is actually better than what will be published. Then looking at the 4-centimeter cohort, everyone wants to know is this going to work well for the smaller renal mass. Yes, the data is even better. Again, the sensitivity and specificity are a little bit better with 90% specificity. And then everyone said, what about the very small lesions. These are the ones which pretty much are enriched for more benign lesions. And depending on if it was centrally sized or locally sized, the data is even better, smaller cohort, but you see that the performance is outstanding. So really, this pivotal Phase III study have really exceeded primary end points, which were both sensitivity and specificity set by the FDA. There is really good intra-observer variability. And then the safety profile is outstanding. This is an agent which has been used in hundreds of patients on an adjuvant study, on prior imaging studies. And in this 300-patient imaging study, there were really no safety signals. The only safety signal that was seen -- as surgeons, we sometimes harm patients. So this is an agent which hopefully will kind of decrease the unnecessary burden of surgery in some patients. So just going over our patient journey, we do see more and more patients. This is not the kidney cancer era that was seen 20, 30 years ago. We have a lot of patients that are really incidentally diagnosed, and you consider it maybe there's an epidemic out there. There's 3 or 4x more kidney cancer today than ever before when you look at the rate per 100,000 people. And that's because you sneeze and you're in the ER and they'll scan you. You had chest pain and they'll scan you, and it catches your kidney. And actually, the increased use of imaging is directly correlated to a nephrectomy. And in -- people in the Medicare population, about 43% of patients in a 5-year period will get imaged in their chest or abdomen. So if you go to the ER, you probably want to not be imaged unnecessarily. It's hard. We are in an era of defensive medicine. We call it CYA medicine. And a lot of patients get scanned and lo and behold we're found with something which maybe we want to know about and a lot of times, maybe we didn't want to know about it. And this led to a massive stage migration. About 70% of our kidney tumors today are T1a or T1b, meaning less than 4 for T1a or less than 7 for T1bs. And most patients will be seen by a urologist and most of the patients we see may require other imaging. A lot of patients come in with a scan. They got seen in the ER. They got a chest CT, it catches part of the kidney. Or maybe a patient had lower back pain and they got an MRI of their back and lo and behold, something seen in the kidney. So we always have an opportunity to say, "Hey, should we order more imaging to get more work up?" And that's really a point where the scan if available will be -- the urologists will say, "Hey, I have an image showing a kidney lesion. Let me get more information." And then there's really high variability of management, really depending on who you see. Some people just cut everything out, other people will be more thoughtful. And if you have an agent like this, you're kind of forced to be thoughtful because just like the advent of the robot to surgical technology, patients want more information, patients want the latest and greatest technologies that will help them improve their care. So why girentuximab, why zirconium imaging? Well, this detects clear cell kidney cancer, which is really the elephant in the room. I would probably say, how many of you have an iPhone. Well, iPhone is probably the most common phone in the market. Well, clear cell kidney cancer is 75% of the kidney cancers we see clinically. And it actually is about 90% of the kidney cancer deaths that we'll have in our patient populations. And while there are 20 or 22 different types of kidney cancers, really, this is the one which is the big guy, which is hurting most of our patients. And a lot of these non-clear cell subtypes are more indolent. The second most common one, papillary, while it can behave aggressively, especially when small, it's usually more indolent. Chromophobe, there, we estimate maybe only about 50 patients a year who will die of a chromophobe kidney tumor. So most of those are indolent. And just looking at -- not looking at anything like size or stage, just histology, you see that clear cell is going to have worse prognosis. And a lot of these other less common subtypes we're talking about maybe less than 1%. So they're going to be rare and usually when they present, they're usually much worse and not localized. So why not just biopsy it? Well, we stick a needle into almost everything. Almost every type of tumor clinically, we stick a needle, and we get information. But in kidney cancer, we have not done that, that often. And some of the reasons why, our radiologists despite being very good, a lot of times they swing and miss, okay? About 10% to 15% of patients will have a biopsy, they'll have a large needle put probably 10 centimeters deep into their back, and there will be an insignificant amount of tissue. So it will be a non-diagnostic biopsy. And then there are a lot of errors. There's some sampling errors. Sometimes part of the tumor might be necrotic or there might be part of the tumor, which they say it's purely differentiated, we can't tell or the immunohistochemical profile will be unclear. So sometimes the pathologists are not willing to make a call. And then we do know that the negative predictive value is not wonderful. One of our kidney cancer is called an oncocytoma, it's pink, and it kind of resembles the third most common type of kidney cancer, called chromophobe, which is pink. So a lot of times, urologists say, "Why am I going to do this if it's going to be nondiagnostic and it's not maybe going to change management." So for many years, we've just not done biopsies. And we've -- we head to this wise tail that is really super harmful. But in reality is there are some complications, but when we need to do it, it is safe, but the complications we have to discuss, hematomas transfusions. Transfusion is 1%. It's rare, but most patients do get a small hematoma. Pneumothorax, patients are breathing. They're breathing, the needles going in, well, their lungs could move and they could get a collapsed lung. And then there is seating, a needle can come in and pull some tumor out into the fat. So patients can get upstaged that's called T3, where a tumor is seen in the fat, and that's about a 70% higher risk of upstaging in those who get biopsied. It may not oncologically cause cells to spill and change their outcome, but patients don't like knowing that the tumor can be pulled along a needle tract, and there have been some rare horror stories. And about 10% to 15% of people in the United States do biopsy. In other countries like Canada, there are some centers which biopsy everyone. Now what about our guidelines? Well, our clinical guidelines right now are just based on the suspicious mask, maybe do a biopsy, get some imaging, a CT or MRI. There's no mention of PET scan here yet. But we have all our management, which is based on really location and size, okay? I'm looking for a house, it's location and size, but I want to see the inside. I want to know what is inside that house before I make a purchase. So what about tumor biology? And I would tell you that biology often is destiny. It's going to determine who's going to go and be in the NBA draft in 20 years when they're born, okay? If I'm 7-foot-4, I have a good chance to be in the NBA. I'm, unfortunately, 5-foot-10. And the draft tomorrow, if you guys want to watch in New York. So in terms of our kind of where we see this fitting in, instead of just rushing everyone off to the OR and cutting tumors out, we do believe that in a patient with a suspicious solid mask, there's an algorithm to move forward. If I do the girentuximab, zirconium PET/CT, it will clearly either be positive or negative. They're very -- there are really no equivocal kind of cases here. You'll see later on the imaging is very strikingly bright or strikingly absent. So if you do have a positive scan and you're a candidate for treatment. Why would I want to watch that tumor, if I'm a young and I'm healthy, I potentially want to just have it removed. If I'm older and maybe not as healthy, maybe I'd want to have some less invasive modalities. We have other treatment modalities, ablation or steroid tactic radiation, new treatment modalities, ultrasonic treatment called histotripsy. A lot of these new or other technologies are effective. And we know that clear cells grow on surveillance. And patients always ask me, "Why would I want to watch it when I'm just going to get older and sicker when I need treatment? Why wouldn't I want to treat it now?" And now I have that capability of getting more information. If it's negative, we know we've taken out the elephant in the room, the clear cell kidney tumor. And it does enrich now for more benign, more indolent histologies. And maybe those are the patients I would want to get additional information on. Maybe I'd want to consider biopsying those patients because I want to try to find an excuse not to operate on them. Now we do have a large number of patients who have cystic renal masses, and these are patients that are -- we call Bosniak IIF, IIIs and IVs. We used to just cut a lot of these tumors out. We do know that we can observe some of them. But some of them are cancers and some of them will change and patients do want to get more information. And in those patients I can't even biopsy. I can't stick a needle and try to catch a little small fragment of a wall or a small, tiny nodule. The rate of a diagnostic biopsy there is probably less than 25%. So biopsy is not even an option. And in those patients, if it's positive, I'm going to probably consider treating that patient with the treatment modality. And if it's negative, those patients who have a higher risk of benign disease, I'm probably going to follow them. So clearly, having this imaging agent available upfront on most of these patients is going to be quite useful. Now just to summarize, what we do have an agent now, which is very highly specific, highly sensitive. And it will be practice changing for urologists if we have this in our tool kit. We do believe this improves the identification of clear cell kidney cancer compared to the current sensitivity and specificity of CT and MRI, this is clearly better, and it's very safe. And more information is going to lead to more appropriate treatment. We remove about 5,000 to 7,000 benign renal tumors a year. And a lot of those patients have derived no benefit. They get to hang out with me and spend a day or 2 in the hospital. But other than that, they really may not have benefited from surgery. And then it's not invasive. Who wants a large needle shoved 10 centimeters into their back? I don't. If I have this tool available, I'm going to try to do it rather than offer patients a biopsy. And I think it will help us risk-stratify patients and decide who really is most appropriate for management. And then moving on to the imaging, everyone says, "Well, how good is this imaging? Does it give you what you really need? Is it going to make more -- give you a quality information?" And I just want to kind of put it out there what our current imaging does and doesn't do. So what do we want to know as surgeons? Well, we want to know about stage and size, okay? And our current treatments -- our current imaging agents do that. But what about aggressivity. Well, if I have a tumor which is invading into another organ, clearly, I know it's acting aggressively. But again, we told you there's significant stage migration. A lot of these tumors today have moved into smaller, more localized setting. And I don't really know about the aggressivity on our imaging, okay? And our current standard imaging besides the MRI and CT, there are things out there like FDG or other nuclear medicine study, one called the SPECT/CT, not really that great. And the FDG, it gets taken up by the kidney. The whole kidney looks bright. So this is not really useful in looking at localized kidney tumors. And then the ability to give patients information on benign and malignant is not that reliable. So about -- looking at the sensitivity and specificity, about 1/3 or 1/4 of our cases are clearly going to be mischaracterized. And the sensitivity at best, 65 to, one study, 85. It really doesn't compare to the data in the ZIRCON study. Now these are 2 of my patients that I treated. Now imaging does not tell you it's malignant. So these are 2 patients. One is a 2-centimeter mass, 1 is a 30-centimeter mass. Clearly, you would know which one you probably wouldn't want to have in your body. But the imaging doesn't tell you that both of these actually are malignant. And again, the imaging anatomically just gives you a level of suspicion and doesn't give you to the information about what's inside that house. Okay. Now here's just 3 patients that were on the ZIRCON study. And basically, this shows you 3 different examples, looking at the coronal PET/CT with a very bright uptake of the agent. The CA9, again is upregulated in clear cell kidney cancer, which is really is an easy bar for entry with this other, obviously, tumors can be imaged. If you look at the 3D MIP image, there is very, very outstanding high signal to noise. Garituximab binds CA9, there is very minimal uptake in biliary epithelium. It's not enough that even on a therapeutic study, there was any concern of any GI toxicity on this study, there was no toxicity other than really surgical toxicity. So this is really a really high-quality imaging agent and our nuclear medicine says -- docs says, this is among the cleanest target that they've worked with, and they're very impressed by the image quality. Now what about the high performance. So these are 2 patients that I took to the OR on the trial. One was an oncocytoma. As you see, it is cold negative, there is no uptake. And of course, on your imaging it really confirms that it is going to be a non-clear cell kidney tumor. And then if you do immunohistochemical, there's no CA9 expression. The other patient, this was a patient with chromophobe kidney cancer. We took to the OR, we removed it. And again, it was cold, negative, not equivocal. It was just negative. So clearly, it's either going to be very, very bright with uptakes -- the [ sEV ] uptakes on the trial anywhere from like 30 to 80 -- and then the negative, there were just -- there was not even a question. So this leads to very, very high inter-reader reproducibility. Again, on the trial, you have 3 independent readers and the outcomes were outstanding. Now what about FDG? You might say, well, what can we use FTG? Is that something that's available? Well, yes, FTG is widely available. But if you see here, the whole kidney becomes bright. And on this patient over here, you could see maybe there's a little lower uptake in that area, but it can't really be used to say malignant or benign. And as you see on the patient on the study, they got the TLX250, and clearly, there's a clear cell kidney cancer there and a patient went for a partial nephrectomy on study. Maybe if the patient -- in the future would go in active lent, that lesion would grow and maybe they would not be a candidate for active -- for a partial nephrectomy. So I think it's getting the patients the information they need and their surgeon the ability to make more informed treatment decisions. Now from an imaging perspective, again, the high lesion to background ratio is outstanding. They're very easy to read. Even I can read them, and I'm not a nuclear medicine specialist. And then it allows our nuclear medicine people to give us really insight into the tumor biology. I know which ones are clear cell. The occasional false positives, the sarcoma, the aggressive papillary kidney cancer. I don't consider that a failure of this imaging. I think if you look at the ability to predict cancer, it's going to be nearly 100% accurate in diagnosing cancer. And the -- I think the performance in the very small kidney tumors to 1, 2-centimeter masses are going to be -- we showed that before, it's outstanding. It's just as good as the large lesions. So I think this is a game changer in the field that I'm really excited to get my hands on it clinically outside of the trial. And we just need our folks to get this approved in the next few months. Okay. Great. Thank you.

Wonderful. This is -- thank you so much, Dr. Shuch for your insightful presentation. I'd like to get your thoughts on the potential impact of the zirconium trial results. What is the scale of the renal size potential patient population that could potentially benefit from the scan?

Yes. So that's a moving target because, unfortunately, people are not getting any smaller. Okay? If you go in the airline, it's a more crowded space because people are getting bigger and bigger. And the obesity epidemic and the aging population is actually making a rate rise. It's going to be about 80,000 new diagnosis a year of kidney cancer. But we have a large number of patients with cystic renal masses, which we really have a hard time capturing that number, but we estimate another 25,000, 30,000. So if you put them all together, it's going to be at least 110,000 patients a year are going to be diagnosed with the renal tumor. And again, you have an opportunity to impact them once. But these patients -- there's a large number of them, the prevalence of kidney cancer is much, much higher than just the incidents.

This is great, great thoughts on that. And you mentioned a little bit on the patient journey. So how are patients being referred to you through the clinic?

So a lot of patients get referred from the primary care. They go to the ER for something randomly and they get diagnosed with a renal mass, where they go another doctor is doing the work up and say, "Hey, I just did a workup for chest pain. I did an imaging of your chest, and lo and behold, it cuts -- the lower cuts show a mass on the kidney." I've had neurosurgeons do a back workup and they see a lesion and they send them to me. It kind of dictates what insurance they have. If they have an HMO or PPO, sometimes they have to go through their primary doctor. But it could be through the ER, it could be a direct referral from their primary care or it can be another specialist who's doing a workup and finds a lump on the kidney. And those, they usually need to send them to a urologist for further characterization.

So the referrals can come in from all sorts of different directions?

Yes.

And then what happens to these patients once they come to you? What's the next steps? And how do you think the standard practice of managing these patients might potentially change?

So it's very variable. I mean, there are some doctors who just take everyone to the OR right now with the absence of very reliable tools like the TLX250 imaging agent. But in my office, I always try to give them the information a biopsy is available. We don't want to do biopsy in a lot of patients, and these are the reasons why. And then we offer patients the ability to get this more information versus go right to treatment. When I go right to treatment, we talk about partial or radical nephrectomy or ablation. So -- we try to give a lot of patients information. Again, it depends on who you see. I spend an hour on a new diagnosis. Some people might spend 10 minutes and get them booked for the OR. I think people, if they have this agent available, it's going to be something that are guidelines. If you member of the NCCN guidelines, I'll tell you that people are hungry to give patients more information to make more informed treatment decisions. And I think this fits in nicely on our diagnostic workup before treatment decision algorithms.

And you mentioned that some folks will undergo biopsies or the surgeries. Now how do you think that this would change? I mean, for example, are biopsies 100%? Are they always accurate? And is surgery always the right path forward?

So biopsies, I would -- again, I said -- they're not 100% accurate. There's a lot of limitations in the U.S., it might be 9% to 15% of people biopsy. But my good friend, Tony Finelli in Toronto, he biopsies everyone, and he says the era of biopsy in his hands now is over, okay? So he is no longer going to biopsy someone. I mean, again, who wants a 10-centimeter needle shoved into their back and knowing that they're going to be awake for that? I wouldn't personally. So I'm going to offer this to everyone where I feel that a biopsy could have been undertaken. And then for treatment, again, I think this is going to give us more informed, not every patient needs surgery. Other patients be followed by active surveillance. Other patients may be followed by ablation. And really getting better risk stratification of the tumor before treatment is going to be very helpful in trying to have us tease out what's the best treatment modality. And I'm going to probably do more less invasive modalities if I feel like a tumor is not going to be very aggressive, and a patient wants treatment.

And you mentioned the treatment stratification. And from your perspective, from a surgeon, what is the information that you're looking for that's going to help you better inform?

Yes. I mean, again, we get size and location, but the idea we get some biology and biological information before treatment is going to help. There are some tumors that are going to be deep and central. I can't take a margin. And if I know a tumor has more aggressive biology, I may not want to kind of shelve it out getting very close to the edges because sometimes when you get very close to the tumor edges, maybe you leave something behind, okay? So it's going to help me decide maybe who should have a partial nephrectomy, who's going to have a radical nephrectomy. So even in those cases where I'm going to take someone to the OR, the more information I get about the biological potential is going to make me make a more informed treatment decisions. So even for you might say, "Hey, this patient is going to be a surgical candidate," I still want to use it. And I also have added potential that I can maybe stage patients a little bit better. That wasn't part of the trial, but there is massive potential to stage patients. And as you see some of the images Colin put up on that STARLITE trial, metastatic kidney cancer is still kidney cancer, clear cell kidney cancer, and we can use this to help stage patients for lymph nodes for distant sites. We have a lot of patients who have indeterminate lesions outside the kidney, and we take a leap of faith operating on them. Maybe we shouldn't operate on them.

You mentioned -- what do you think the overtreatment or unnecessary surgeries that happen previously in the standard of practice of medicine, currently?

So for small renal masses, it's kind of embarrassing that about 25% of the partial nephrectomies we do in the United States are ultimately for tumors that are found to be benign, okay? 25%. So that comes out about 5,000 to 6,000 cases a year in the United States that patients have a partial nephrectomy for -- or a radical nephrectomy, God forbid, for a benign tumor. And I really -- those benign tumors are not destined to spread. They're not destined to usually cause any harm. Those patients probably could have been followed. If patients were anxious, maybe they could have had less invasive treatment modalities. But that's a lot of patients. And we actually estimated there's about 20 patients or 30 patients who are actually dying from surgical complications from unnecessary treatment. And that's pretty outrageous when you come to think of it. And the cost to U.S. society, we estimated about over $150 million in U.S. charges for removing benign tumor. So I think we have probably more we can invest that money with rather than on unnecessary surgery.

And then following up on that, what do you think about the ZIRCON results and how that can impact this overtreatment with unnecessary surgeries?

I mean, again, the data speaks for itself. I mean, the positive rate to value, I think 94% is awesome. And again, if you consider that it also -- the false positives were actually really cancer, some of them very aggressive. I mean, I'm going to use that on everyone. The ones that are negative, I'm going to feel a little bit more confident that it's either benign or indolent. I probably will do more biopsies in that select patient population where they really want to know and they're anxious watching it. And I have other scans that we could use that are occasional [indiscernible] sestamibi, or I could actually -- once I know it's not a clear cell kidney tumor, I'm pretty good at picking out the papillary. The ones that are left over are probably chromophobe. I feel more confident in a small mass known that I probably can observe those patients or treat them with less aggressive treatment modalities that are pretty effective.

Do you foresee surgeons stopping biopsies or...

So biopsies -- yes, we're not the ones who do the biopsy. So we'll probably do less referrals for biopsies. So at the end of the day, urologic surgeons like to operate, but we also don't like to do unnecessary surgery. And again, sometimes we take a lesion out, and it depends on how you spin things, like you can say, we got it all and it's benign. I think of it as I did unnecessary surgery and I may not have helped you. I do think that when our guidelines change and we say this should be incorporated, I consider in our field we may start considering these things as never events. It's clearly a never event to remove the wrong kidney, okay? I'll get fired for that. But I think in the future, when you take a whole kidney out, and it's ultimately benign, I think it's going to be a big paradigm shift over the next few years that says, well, you didn't order this scan. You'll probably go to your hospital board and say, "Hey, you just removed an organ unnecessarily. Why -- how can you justify that when you have a tool like this?"

Where do you see the other potential for this imaging agent?

So I think staging is going to be incredibly different instead of just doing serial CT scans, MRIs, having this in high-risk patients for surveillance is something you can do over and over and over again, and you can find disease potentially a little bit earlier. We have an investigator-initiated trial, which is now being -- going through IRB, which is going to hopefully show that this is better than conventional CT scans of the chest, abdomen and pelvis. Bone imaging is not great. It's just -- it's good in prostate cancer. We have other -- just as PSMA has revolutionized prostate cancer, this is really -- we're on the cusp for improving it. I do think for patients -- we have a lot of patients who have 1 or 2 sites of disease, we irradiate them, we cut the lesions out. We try to make them to the state called NED, no evidence of disease. I think we'll realize that a lot of those patients probably have more disease than we really thought. It's kind of like the Will Rogers effect. We're going to be reclassifying patients into different buckets and giving them more appropriate management. So I think for staging and for treatment, again, the theranostics, Colin just touched upon it, I mean it's a whole new era, just like in prostate cancer, where we're using lutetium based, alpha emitters, beta emitters, to kind of treat patients. I'm about maybe not even operating on some patients that maybe I can give them this in the localized setting and potentially give it to patients, and then I only operate at the ones who are not doing well or progressing. I can go to the beach. I don't go to the beach enough.

Yes. And what do you think about the guidelines currently? How -- where do you think it will fit in? And do you think that this will change rapidly once decision gets approved?

Yes. I mean our clinical guidelines don't have much about PET. It's actually nowhere, but I do see -- for NCCN, I can only speak to some on those guideline panels, also AUA, they're very rigorous to look -- they need to look at the data. And the data from ZIRCON study is really quite remarkable, but it's really in the localized T1 -- renal mass. So I see that first panel being the work-up of the renal mass, it's probably going to be a no-brainer. This is an agent which has very high sensitivity and specificity for the workup of an indeterminant renal mass. And that will be something, I think, will be looked at very favorably because the data is there. It's a positive trial. In other areas, we'll have to accumulate more data, and I know the team is planning on doing staging, theranostics. As all these trials move forward and hopefully are positive, there are going to be different things added hopefully different parts of the guidelines. But right now, in the workup of the indeterminant renal mass, clearly, that is ripe for change.

Great. I'd like to open some questions to the audience. We have time for a few, and from the webcast.

Can you hear me?

Yes.

Just -- you mentioned just a minute ago that with a negative scan, you're increasingly confident that it's indolent. But then what's your next go to in terms of wanting to screen out, say, papillary or sarcoma?

So in terms of -- a lot of it depends on the patient. So if I saw Mary here who is healthy and fit, I would probably want to get more information because I wouldn't want to miss it. But if you look at it in a patient who's like my mother, my mother has a small renal mass, I'm following her, okay? And I do love my mother, okay? If she had a negative scan, she's 75, and she has had a stent in her heart, I'm going to feel more confident probably just doing active surveillance and not getting more information. But if someone like Mary, who probably ran 8 miles this morning and is fit, I don't want to kind of just sit tight on something that has a chance of being malignant. So I'd like to use the scan in her. And if it's negative, I probably want to get a little bit more information, whether it's a multi-phase MRI, multi-phase CT, I can pull out the papillary lesions. I may want a biopsy and then I can assure Mary she has another 60 years of life ahead of her that I know what I'm dealing with.

Thank you. I felt very good about that. Are there any others?

What about your colleagues in this field? As you said, there's no PET in the current NCCN guidelines. How do you feel the adoption curve will progress assuming that the -- we get an approval in this product?

I mean, there are companies that submit very often try to say, "Hey, we'd like you to reconsider this." So every year, there's submissions to the NCCN to look at the data. But really, the data is what leads to people saying is this something which they approve and then the level of approval category 1, 2a, 2b, there's different levels. But I mean, again, if -- once this becomes available, I think submission to the NCCN and AUA, the data is there. It's a positive study. I don't know how that you couldn't consider this, whether it's level 1 uniform consensus versus level 2 majority consensus, I see this being something which will be -- people will be hungry for adding to the guideline because it helps us improve care with -- and maybe spare people unnecessary treatment.

We have time for one more.

I think from the emerging data from ZIRCON, the key message is that histology is probably more important than size alone, and then the data really addresses the current clinical concerns around the overutilization of nephrectomy. So my question is that by looking beyond the initial stage in diagnosis, would you see the role of the PET on some of the use cases, such as post-systematic therapy monitoring?

Yes. So there are -- this is -- no data in this area, but I think this is extremely exciting and an amazing opportunity for our patients with clear cell kidney cancer. Unlike any era before, we have actually really effective systemic therapies. About 10% to 15% of patients now get a really good, either a complete response or a very deep partial response. So they go on their cabo/nivo, their axi/pembro, their len/pembro, or ipi/nivo. Now triplet therapy there, again, we'll see where that fits in. Patients have a really deep response. What do you do with those patients? After a year, after 2 years, there's always a discussion clinically, do you stop therapy? Patients are scared to death. They're doing well on therapy. Do you stop their therapy? Well, again, a lot of the lesions even if a lot of patients have a really deep response and there are a couple of spots here and there, do you still biopsy lesions to see if they're actually live or active? If I -- if this tool was available, it would be an agent where you would imaging -- image patients, you'd be able to probably say what is their actually disease burden. And if you see very little left on your scan you potentially could consider and maybe whether it's making the treating oncologists feel confident about stopping therapy or that the patient who is scared to death that they're going to stop therapy and then their disease is going to become resistant. I see this as a tool that you can potentially use to reassure everyone that you can get them off therapy. I don't know the proper endpoint to do that study other than the willingness or make treatment decisions, but the cost to keep a patient on therapy for a month -- a month of like pembro is like $20,000. So just to get patients off therapy would be a huge cost-saving thing. And I see this as an opportunity to get some of those really deep responders off therapy.

Thank you, Dr. Shuch. I'd like to now introduce our next key opinion leader. It's honored to introduce Dr. Scott Tagawa, a leader in prostate cancer theranostics. Dr. Scott Tagawa is a Professor at Weill Corne Medicine, and led the early phase trial -- clinical trials of the anti-PSMA radioimmunotherapy J591. Dr. Tagawa's research is focused on clinical and translational investigational in GU and thrombosis malignancy. Additionally, he has led pioneering research in drug development in prostate cancer, in particular, using antibodies against PSMA. He leads clinical trials using radio-immunotherapy to fight metastatic prostate cancer to prevent or delay metastatic disease in men with rising PSA and targeting tumor vasculature in advanced solid tumors. He is also a fellow of the American Society of Clinical Oncology. Thank you, Dr. Scott.

Thanks, Mary. And thanks for the invitation. I'm going to make one -- I was going to say several, but one final comment in terms of CA9 targeting. The end users, the doctors that order these tests are the same for PSMA. So we're used to already ordering the nuclear medicine tests. So I think that's going to be one extra advantage as well as getting prior approval from insurance, which is painful, but we're used to it now. Okay. Switching targets, PSMA. Disclosures will be up for a second. It does include Telix and everyone else, kind o. Okay. So I think that it's highly unlikely that most of you have not heard of this, but just kind of an introduction because there are different terminologies. So PSMA, I think you know what that is, a self-service protein are expressed on the vast majority, but not all of prostate cancers, normal expression, normal prostate tissue as well as the luminal surface of salivary and lacrimal glands, breast border, the small intestine and proximal tubules. TRT is one of the terms that we use for targeted radionuclide therapy. So when we talk -- with PSMA. So we're targeting PSMA, give a systemic infusion intravenously. And then there's 2 main components. There's the radionuclide, and there's different characteristics. Some can be imaged. Some are pure therapeutics, generally speaking, alphas and betas, although we think and hope that [ LJs ] are going to come in the future, much shorter range. The efficacy and toxicity profile is partly related to the radionuclide. The other part of the toxicity and efficacy portion of the overall construct is the vehicle. And generally speaking, there's large antibodies and small molecules. They both land in PSMA-positive tumors. But their connection by distributions, we'll talk about, are a little bit different, and those can affect outcome. I have interchanged here some lay audience slides and some kind of more scientific. So I describe PSMA as a very specific lock. Think of it like the Yale Club. There's 1 door, forgot the name of this room, but 1 door that has PSMA on that. And we can float in a key that's going to go around and only be able to enter this door. Okay. So a lot of retrospective studies, anecdotal reports with very pretty pictures. That's part of the nice thing about theranostics, we have very pretty pictures. And then we finally got a couple of prospective single-arm trials followed By 2019, the completion of 2 randomized prospect trials. 2021, I think you all know -- the final results led to approval. The dual primary end point envision, overall survival as well as radiographic progression fee survival. And then therapy with end points that are -- that were largely PSA-based, although those secondary endpoints, that are important too versus -- in selected patients versus Cabazitaxel chemotherapy. Okay. We have made a series of incremental steps. I think these incremental steps are very important because some of these incremental steps in the setting of metastatic castration-resistant disease have translated into much bigger differences earlier on. And frankly, I hope that's where we're going for PSMA and TRT. But it is incremental. So you can see the median difference, and this is not without the cost. I'm not talking about financial costs, about the adverse events that you can see listed here. This is the table of some of the adverse events. And I think that there are 3 main kind of categories that are there. So constitutional fatigue, common side effect of virtually all of our systemic therapies. Bone marrow suppression that is mostly indirect, but partly direct because there is direct targeting of PSMA positive tumors within the bone marrow. We worry about thrombocytopenia most, but you can see the single highest-grade AE happened to be anemia. Now that's also true, the single most common high-grade AE in the control arm is also anemia. So it happens with cancer. We'll talk about direct PSMA targeting that's off tumor, so dry mouth and nausea. We worry about the kidney. Luckily, we have not seen any major kidney signal, but we have a very short-term follow-up. And if that's going to happen, it's likely going to be years out. Despite the higher AE profile, there is a maintenance of quality of life. So these are the original ESMO slides. This was published 3, 4 weeks ago in Lancet Oncology. So despite the AE profile, a prolongation of time to deterioration of quality life and/or pain. Now I stand up on stage, present a study, I say there's lack of Grade 3 problems. You can see Grade 3 dry mouth and dry eyes, it's horrible. So Grade 3 dry mouth is -- mean you cannot eat this way. It has to go directly in the stomach or into the veins. Luckily, we almost never see that, but the problem with these Grade 1 and Grade 2 definitions is they're not very sensitive, and they may not reflect the patient experience. So it may be that for some of these that patient reported outcomes are more important, and there's now something that's called [ Fact R&T ], published in J&M, January, February this year that we hope is going to come out and really supplement what we have to really include the patient experience, including bother from all of these, which I think is the most important factor. Okay. So I think you spent most of the early morning talk about imaging. I heard -- I walked into the CA9. PSA imaging can be a biomarker in many respects. So I'm going to talk -- most of this is about theranostics, so I was going to talk a lot about the first kind of bullet point. And I would say that there is very good data that for the PSMA targeting beta small molecules, there's very good data that there is an improvement in those that are more likely to benefit in those with higher PSMA uptake. But the problem is that flat negative imaging can sometimes also have some efficacy results. And I think it's important in a patient population that has no other real treatment options. One advantage of imaging over a biopsy, a blood biomarker, CTCs or cell-free DNA, is that we are able to assess in vivo at that point in time all the different individual lesions to get some sense of both inter and intratumoral heterogeneity. We can't tell that from a blood biomarker, that's a summary of the entire spectrum. And then a needle is not just even that tumor. It's whatever was in that needle from that tumor. So there's advantage of imaging there. There's a disadvantage. It is only that one point in time. And there is also a size issue. So there's a significant increase in sensitivity from all of these molecular imaging modalities. So things that were too small to really be apparent on CT, MRI, bone scan and whatever else we're going to do, or older versions of PET, still is dependent upon size. So individual small sales that have a ton of PSMA expression are not going to light up. So there is -- that is a drawback. It's something that we just need to know. We've just shifted what micrometastatic disease is. And then response assessment. I think that utilizing serial scans is not something that is prime time today. We do it sometimes, but I think that's especially in the world of prostate cancer, we're stuck with bone scans so we can only really tell progression. Well, now we might be able to assess response and really push the bar, is this individual patient sitting in front of me benefiting, or even more broadly speaking, especially for this audience, speed up drug development. And the FDA has bought into this and we're working with them on what's called Prostate Cancer Working Group 4. Okay. So I have a set of slides from a year plus ago. So this is ASCO last year. Phil Kuo was the lead author and the [ Armstrong ] presented this. It's subtle. These data have been updated at ASCO this year in the Vision nomogram, but it's subtle and probably hard to see. So this is the -- only the investigational arm. So no ability to look at predictive characteristics. The brighter it is, the longer the rPFS and the longer the OS. As it turned out, just looking at quartiles, that number of approximately 10 that you'll see in the therapy data. What you may not have picked up in the Vision nomogram is that it doesn't matter what the [ sEV ] mean was, you still do better than control. So you get lutetium-PSMA, you do better than not getting it if you qualified for the study. So this is not a necessary a way to select out patients, but it is a way to select in probably the top responders to mostly single agent therapy, but it's also hidden in the background of the study, it's a combination therapy with 55% receiving [indiscernible]. This is a very -- we didn't like the way that slide was there, and we've changed the language, but -- this is very similar to what we've seen using CT as well as bone scan. So having liver is the worst, having bone is next, and lymph node only is after that in terms of prognosis. That also has been updated in terms of the nomogram. This is therapy. So this is looking at both the treatment arm and the experimental arm and the control arm. And this has now, because of that, a predictive characteristic. It actually does envision in the updated data set from 2023, which is not from 2022, that it is -- the brightness of the PSMA-PET is predictive for outcome with lutetium-PSMA, but not Cabazitaxel chemotherapy. And we validated what my colleagues at [indiscernible] published many, many years ago is that FDG is prognostic. So it doesn't really matter what we're treating the patient with, they do worse if there's a lot of right FDG uptake. Okay. So virtually everything so far has been discussing both therapy and -- not the study, but therapy and the diagnostics imaging utilizing small molecules. There are differences between antibodies and small molecules, and those of you that may or may not remember, 1996 was the first diagnostic PSMA imaging agents approved, didn't work that well. As you'll see in the supplement slide, their different characteristics, so their physical properties lead to differences within the body. So antibodies are large. They circulate for a long time, which is advantageous and disadvantageous, but advantageous in targeting PSMA with lower expression. And then they target via the vasculature, which limits the kind of off-tumor PSMA exposure. Some molecules rapidly diffused all PSMA-positive sites makes it very nice for imaging on the same day versus days later, which is inconvenient for patients, rapidly diffused all sets of expression, and I'll show you some comparative data. Unlike [indiscernible], Neil Banner, my colleague, 4 -- actually today is his retirement party, developed 4 antibodies that bind to the external domain of PSMA and the rapidly internalized J591 went forward in terms of [indiscernible]. So these different keys, these are targeting molecules. I talked about the different properties. So what would we predict based upon them? So antibodies are large proteins, they might have an infusion reaction. So that is just something that happens with all antibodies. Luckily, it's the minority, and it's not such a big deal. But we didn't know premedication for the first 15 years or so of study, and it generally does never be on Grade 1, except for single patient, in maybe 20%, 25%. Off-tumor effects are essentially non-PSMA driven. So the circulating tumor time, especially with the beta, might lead to some mild expression, very predictable. And then clearance through the parabiliary system, particularly the liver, which could lead to liver toxicity. Luckily, we have not really seen that. The small molecules, so the benefit is rapidly clearing. But because of their size, they are able to access the luminal surfaces of PSMA, so the off-tumor on-target effects, the salivary glands, lacrimal glands, intestine and kidney, although, really, it's the first 3 that we've seen so far in terms of toxicity. We -- what we did is we compiled several different prospective clinical trials and then retrospectively look at the data and what happened was as expected. We looked at the different toxicity profiles, we'd say, okay, mild expression is probably going to be more common with the antibody. Nausea as well as dry mouth, probably more common with small molecule, and that's exactly what we found. So those physical properties do translate. This is exact same radionuclide lutetium.177. Now some interesting data that came out of us wanting to see could we combine these 2 PSMA targeting agents is the binding uptake, in particular, the retention of the small molecules versus antibodies. So you can see here, these different shades of blue are 3 different cell lines, essentially low, medium and high PSMA expressing cell lines. and particularly in the -- those with lower PSMA expression, the cell lines -- there is a significant difference in injecting today, seeing how much is retained within the tumor at 3 days. And you can see significant differences comparing color against color. I'll show you why that is in a second. And this is the fourth model, fourth cell line, very similar effects, rapid uptake, tight binding and then retention within the tumor over days. So this is -- this goes back to the initial work with the antibody. And you can see that upon binding PSMA plus the antibody plus whatever is attached to it is internalized and it essentially goes into the lysosome is retained. What happens to this molecule binds? So PSMA-615 binds, is internalized. But in the endosome, the pH drops, it separates from PSMA and then the endosome is kicked back out and externalized. Probably not -- obviously, these drugs work, right? There's approval. But some -- but not optimal probably for those areas with lower PSMA expression as well as smaller volumes, such as bone and bone marrow, which appears to be -- retrospectively appears to be the weakness of these small molecules. So we -- I am going to go through some great detail. We performed a number of sequential Phase I and II studies with initially just Indian trace labeled antibody followed by the beta emitters, yttrium as well as Lutetium. We went forward with lutetium, including the combination study with docetaxel chemotherapy. And this is the summary. I think you've all seen this data before. But essentially, these are the Phase I and II data sets looking at either giving everything in 1 day or fractioning it, giving it on day 1 and day 15, i.e., 2 weeks apart. And based upon the retention time and the half-life of lutetium, in my mind, that is -- the idea behind this, it's a dose-intense regimen where there's continuous radiation over a month for a tumor and that's when we would want to cure the primary prostate cancer. Clear dose relationship, so the higher the amount of radiation that we inject, the better we have in terms of PSA declines and overall survival. Also more in terms of mild expression, not so surprising. And then when we fractionate the dose, we're able to administer higher doses. So very -- not exactly the same regimen, but the very similar regimen on the far right, these 90 millicuries per meter squared is more or less the regimen for ProstACT. We use solid radiation. So if someone has a prostatectomy, PSA goes up, whether we can see it or not -- we now can see it sometimes with PSMA -- PET. But whether we can see it or not, we know that some patients can be cured by radiating where the prostate used to be. However, not everyone is cured and that's likely because there's some cells that are elsewhere that we can't see. So we said, what about if we target all these cells with PSMA using the antibody. And I do think that the antibody -- this is one of the areas that would -- an antibody is advantageous versus small molecules in very low volume disease, and this was M0 without PSMA-PET. So we know that PSMA-PET would've been positive in a lot of these patients. Primary endpoint having no metastases visible at 18 months, and we hit that endpoint, you can kind of see in the middle there. Better durability as well as numbers in terms of PSA decline. Differences, as we'd expect in terms of toxicity in terms of the gamma [indiscernible] versus the beta gamma lutetium 177. So the first randomized data with lutetium J591 presented as positive 4 months ago. Sometimes we'll get around to publishing that. So the summary of lutetium As well as yttrium-J591 is accurate targeting. We didn't have PSMA-PET at the time, but we could image these SPECT, and 9 out of 10, we're positive, which we would more or less expect. So the dose response in addition to PSAs, with clear circulating tumor cells, in that randomized trial, we can delay metastatic disease and then dose fractionation, so giving half on day 1, half on day 15, has superior characteristics, I think, both in terms of efficacy as well as toxicity and may lead to some durable control, and that's what's in ProstACT. And then there's the myelosuppression. So there is Grade IV times. There's a fraction that may need transfusion or sometimes growth factor. It's very predictable. So we and oncologists are quite used to dealing with this with chemotherapy although chemotherapy is maybe 7 to 10 days later. This is, depending on the regimen, 4 to 6 weeks later. But we know when it's going to happen, so we know when to monitor the patient and to prepare for a transfusion just in case, even though it's a minority that needed transfusion. Okay. So this is now going beyond me. This is Telix's slides, but I know about this. So J591, now called TLX591, we showed data for nearly 20 years, both efficacy and toxicity utilizing different regimens. What I didn't actually mention that differentiates the ProstACT study versus other studies, it's a combination study with an AR targeting agent, which may do -- only one needs to work, increased PSMA and/or [indiscernible] that both work even better for that regimen. And then next generation 592, so altering the 591 antibody that may lead to improvements in terms of alpha targeting. And alphas and betas are just different. I don't know that one is better and the other just different. There are certain situations, I think, that one characteristic is probably better than the other. Landscape. So there's -- small molecule is already out there, right? So there are several -- depending on how you count, there's 3 or 5 small molecule diagnostics approved in the United States and many others available elsewhere in the world and one therapeutic with likely -- the move for that therapeutic earlier with additional agents coming out for metastatic CRPC and maybe even first diagnosis, metastatic non-castrate, what's typically called hormone sensitive, castration sensitive disease. So these small molecules, [indiscernible] beta are here and potentially moving forward. There are -- just like I said, there's differences between antibodies and -- alphas and betas, there are differences between antibodies and small molecules. I think there are certain situations where, in my mind, it's very clear that one is better than the other. So such as small volume disease. If we're looking in early disease, we're looking to cure patients, I think antibodies are going to be clearly superior than small molecules. Also certain areas, so areas with lower PSMA expression such as the liver. I think -- and that's -- if you look at the 4 spots for vision, that's a weakness of lutetium PSMA-617, not surprisingly, because even though they had to be bright enough to get in, in the liver with the vision image criteria overall, we know from my colleague and former mentee, Himisha Beltran, who published a couple of months ago, the liver is a site that overall, is the general rule, has lower PSMA expression. And then areas that are small volumes such as bone and bone marrow, which is a weakness of the small molecule that I think may be advantageous for the antibody. The retention time also lends itself to patient-friendly regimens such as the single cycle fractionated dose, that may work as well as 4 to 6 cycles of every 4 to 6 week -- I'm sorry, 6 to 8-week dosing. So certainly, more convenient, probably better for taxpayers in terms of Medicare and/or the insurers. So every drug is approved in the same setting, let's say, for chemo-naive mCRPC. Some patients are going to want to choose those regimens, some insurances are going to have a preference for that. There's -- every patient is a different individual. Patients starting off with low counts, maybe I want to go with small molecules. So I think there's going to be room for both. But I do think there is -- even if there's 3 different agents, which work kind of the same, but 3 different agents approved for mCRPC, an antibody is different. Talk about retention. So what you have side-by-side is a small molecule PET. And then the antibody SPECT. So 2 weeks out, what you can see. So it's being cleared to the liver, so that's not a big tumor. The top right is the phantom image, it's not extracranial tumor. But what you can see is that at 2 weeks, there is retention, both in lower tumor burden as well as higher tumor burden of the antibody that has lutetium on it, which is still active. It's 2 half lives past, but it's still active. And you can see -- here, we're not even measuring the beta component, which is the largest component of the lutetium. It's the 5 or so percent is gamma. I haven't changed the images on the left, but on the right, what you can see is 1 week out with a small molecule. So this particular patient doesn't have a lot of bone. But I would wonder if there's still retention in bone, and that's study that we want to look at retrospectively, but there's still continued exposure to the PSMA-positive off-tumor sites. So they're still -- at a week still continued exposure to salivary glands, lacrimal glands, small intestine and kidney. So those will also persist. So very clearly, there were some naysayers maybe in the audience because I know there were some investors that said, PSMA, like why would we invest in that? It's been around for so long, and there's no drugs. It can't be a good target. Well, now it's been validated. We know that there are several different diagnostics, the first therapeutic. I think there's many more therapeutic to come even outside of the radiolabeled space. So whether that's another conjugate or a bispecific or a CAR-T cell, I think that clear, the target has been validated and/or derisked depending on your viewpoints. We can target both with antibodies and small molecules. I think there are certain settings where one is advantageous over the other. But overall, what I'd say very clearly that they're different. They have different properties. And me in a clinic, I would like to be able to have multiple options to choose for the patients. We know that prostate cancer is a radio-sensitive disease, it almost always has PSMA on it, and we can tell when it doesn't by these noninvasive tests, and there's a dose response. Unlike some of the -- unlike the only current available drug, the dosing and regimen of 591 has been prospectively studied and optimized. So there's room to go with optimization of the approved agents and others that are out there, but I'm not sure that's ever going to happen. And then can we lead to cure? So can we give a high enough dose in rescue stem cell or a combination or something like that? I don't know because there still is some heterogeneity. So a single agent, maybe not, but in terms of combination therapy, absolutely. Combination therapy could be surgery. So why aren't some people cured with surgery alone? Well, there's micrometastatic disease that we may not even be able to see on PET. Well, antibody can get to single cells and radiate it. So I think there's advantages that are way down the line. And then beyond prostate cancer. So PSMA is expressed on the neovasculature of virtually all solid organ cancers, all these carcinomas, 90% or so. So targeting neovascular, I think, has some possibilities, that's underexplored. And then beyond PSMA, you heard about -- I don't know, the whole morning, part of the morning was on CA9 that's within the [indiscernible] but there's a lot of other self-service targets that are out there. Obviously, somatostatin has improved agent. But there's a number of other ones that can be exploited. And my bias -- and I'm not a nuclear medical physician, I'm not a physicist, but as an end user who has been involved in both imaging as well as therapy, I think it's a nice pair. So theranostics really is a term used for -- in the pure sense, the same agent for both imaging as well as therapy. But I think we can broaden that and use it as a diagnostic. So whether it's a drug, an antibody conjugate or radiolabeled therapeutic, we can assess patient eligibility via an image. And I think there's a major advantage for that down the line. And I did -- I don't know, 5% of the work. The rest is all done by these other people. So a lot of other people to thank. I think that's it.

Great. Thank you. Dr. Tagawa. I appreciate the informative presentation. So I have a few questions I wanted to get your thoughts on. Given the approval and availability of some of the -- [ I'm not sure if it's the ] approval, on the PSMA-targeted small molecule therapies, where do you see the advantage for PSMA-directed radio immunotherapies like TLX591?

So I think the obvious advantage is on the clinical side in terms of the regimen. So finishing treatment within 2 weeks, obviously, monitoring for the next month, I think, that has the major advantages, particularly because -- I think you talked about PSMA-PET, I'm going to extrapolate. Whatever the agent is, whatever the setting is, very clearly, we are underutilizing PSMA-PET in this country. And part of that is limited access because there's certain centers that may be just physically 100 miles distant or 50-miles different, and it's difficult. So that, I think, is the kind of the obvious example in the average patients with pretty high semi-homogeneous PSMA expression. The other [ subtleties ] having both -- patient lives across the street, so we don't have to worry about convenience, having both available, I would think about if there is liver mets or if there's mostly small volume bone metastases, that, to me, I would take advantage scientifically of the data I have without the [ headed ] trials and say, okay, this is a patient that I think may benefit from -- it's still lutetium, that is an antibody delivery versus a small molecule delivery. So those are the two kind of main differences, I would say.

Do you think about -- for the clinical trial, do you foresee any challenges with recruitment or excitement around these trials?

I don't think so. So certainly, we have been able to recruit -- so all of the trials that we have within our group, we see kidney cancer, urothelial cancer, et cetera, prostate cancer recruits the best. And amongst all of the different agents with therapeutics, we have PSMA recruits the best. And that hasn't changed since before and after [ lutetium-PSMA-617 ] approval regardless of shortages because patients will hear about these, and [indiscernible] present, "Okay, you can have standard VISION dosing or you can have this agent, which, for these reasons, we think this is going to be better, is experimental, so you have to understand that." And some will want this kind of standard of care, but the majority will actually enroll in the clinical trial. So even post approval and availability, pretend there's no such thing as shortage, I think that any center that has these is going to be able to accrue. And then there's the other problems in terms of shortages, et cetera, as well as potentially for reimbursement. So add a -- patients probably in the summer, so several months , actually maybe in the fall. So wide availability going to an academic center in the city couldn't have access because they can't get approval. We got approval because we argued. So I think there's a learning curve with that, too. And I think, unfortunately, one of the reasons that patients are not getting PET's or treatment is because they go with initial denial and they do something else. So I think that the more that we fight for individual patients, we can help them as well as hopefully change insurance.

Great. And in that trial you were talking about, that was a -- that's a small molecule trial.

We like to say we have it all for PSMA. And I think there's -- I think it is not just for some paper to get out there. I think that there are different advantages and/or disadvantage of different molecules, whether it's an alpha, beta, different betas, different targeting vehicles, I think that there can be different uses and then combinations.

And do you see the safety profile? I'd like to get your thoughts on the safety profile of the TLX591.

Yes. So 3 main ones. So there's an infusion reaction component. So like I said, we, for our first couple of hundred patients, did not pre-medicate. And then we started doing multicenter trials. And then we suggest, "Okay, go ahead and pre-medicate," so typically acetaminophen and H1 blocker such as diphenhydramine or Benadryl. And that will decrease it, I don't have the exact number, less than 5%. The major intervention if someone has an infusion reaction is put a blanket on them for 20, 30 minutes. So it's usually not such a big deal, but just in case that something is there. And the most common side effect that they walk out with is drowsiness from Benadryl. So anyway, that's one component that is real, but it's not such a big deal. Clearance to the liver. So in the prior studies, Grade 1, AST or ALT elevations above the baseline because sometimes they're elevated to begin with, and then coming back down over weeks, a lab abnormality without any major sequelae, but it's probably because of some of the clearance, although it is seen with the small [ molecules ] well. Clearly -- okay, and then lack of significantly -- so far, we've seen kind of the PSMA-related things such as dry mouth and nausea. The major dose-limited toxicity is myelosuppression, and it can be high grade enough to say, "I want to give this person a white blood cell growth factor. I want to give this person a prophylactic platelet transfusion because luckily, patients don't bleed, we just catch it. And if it's less than 10,000, then we give a prophylactic platelet transfusion." What's nice is it's predictable. So I know that depending on the regimen, it's going to be somewhere between 20 and 32 days or pushed out by a couple of weeks in the fraction of the dose. So we just prepare for it. We know and check, most of the time is checking, what is the blood count. If it's a little bit low, watch it closely, and we don't have to do anything other than monitoring. But sometimes, it drops and we give a prophylactic platelet transfusion, and we prevent any major sequelae. So -- and if the end user is an oncologist, we're kind of used to that in terms of chemotherapy.

And that's likely because it's targeting the bony mets and the low volume to these...

I think it is kind of on target as well as off target. So there is circulation of the antibody over days, and the beta emitters have a long enough path length that some nonspecific radiation is happening. The reason that we see myelosuppression with this small molecules is not so much that circulation, it's because it lands in bone or in bone marrow, and the path length of the beta emitter, Lutetium-177, is long enough to hit in, what's called bystander effect, stem cells.

We have some time to open up to the audience.

I'm going to ask a really long and complicated question, so I hope you're ready. It's around -- you're very clear about the differences between small molecule and antibody. Do they change as that sort of category moves earlier and earlier in the treatment phase, say, like from the VISION population through in the pre-chemo, through the hormone sensitive and possibly even as far as the neoadjuvant? Do the differences change?

So the differences in the characteristics of the antibody small molecules don't change, they're just -- they're static. They're in [indiscernible]. Yes. So I would say that in terms of PSMA expression, I'd say, the risk or hazard of PSMA-low tumors is higher with more lines of therapy, particularly AR-directed therapy. So I think that the VISION patient population was possibly the worst patient population in terms of PSMA, but we know that still 19 out of 20 had at least one tumor [ greater ] than liver. So PSMA is just a good target that's there. So that may change. Competition may change just in terms of the landscape, obviously, earlier disease, there's more competition that's there. And then when we're looking at micrometastatic disease, so we go way earlier to biochemical relapse or high-risk disease in combination with local therapy. That's why I think that the differences may be the most important, so retention within the primary to really get a high enough dose to the primary tumor, but even more important, why we give systemic therapy in combination with surgery for any cancer? It's to eliminate micrometastatic disease, so then the surgery is more likely to be curative. So that's where I think it may be magnified the biggest, not quite there yet. But we are not seeing cures right now, and that's what I think it would take is either some novel combination or earlier disease.

Dr. Tagawa. Can you put that -- you put up a data sort of some clinical records there, some outcomes here that showed the 41-month extension in survival. It was a 41-month median survival impact. Can you put that in context with what we saw from the VISION study? And what do we expect from prostate? And is the 41-month median overall survival a number that we can look at?

The data of the data. So I think...

I mean, the difference is [ partially ] stacked. I mean ....

So in one way -- so the clear limitation is 17 patients, right, 17 patients. The potential issues are beyond the 17 patients, they're -- during that era, new drugs came out. So some had fully been exposed to all drugs, but others hadn't had ever on enzalutamide, but they were a lot alive long enough to get that upon approval. So I don't think that is the major component, but there are -- new things will come out, the longer someone is able to stay alive, which is why we like some of these incremental benefits. So we go through -- we only had 2 lines of therapy, then we have 5 lines of therapy, you can live long enough to get line #6. So anyway, those are the kind of caveats with that, but these were sicker patients, as a general rule, compared to what we'd see now in prostatic [ P74 ], [ SPLASH ], et cetera, because these are typically only hormone-treated [ SPLASH ] chemotherapy. But I think that the patients we treated on that study that was published in cancer, I think, were sicker than these patients going on the studies now. So it is what it is. But it's fairly clear -- regardless of that exact number, was fairly clear to me is the dose response. So whether it's all at once or the fractionated dosing, the incremental increase in radioactivity leads to everything being better in terms of efficacy, whether we're looking at PSA drops or survival. And then we have to watch the toxicity as well.

Did you see responses in every patient in that group?

I do not remember -- so I don't think so because I just think that's unlikely, but I don't have the exact data. I'm sure there were patients that had stable [ disease ] is kind of the best result. They're in the -- I mean, you can look at the publication because the waterfall plot is -- at least one of the waterfall plot is color coded. So you can see the doses that they're on, and I bet there's at least one in that cohort that had a PSA that went up as their best response. But I don't remember exactly.

And just -- I can't recall a little bit with the upcoming prostate trial, is that going to be earlier- or later-stage patients in the VISION study?

Earlier.

Professor Tagawa. I noticed that in the final slide, you mentioned the bispecific antibodies. And I'm just interested in your view on the utility and the efficacies of bispecific antibodies, especially having seen clinical development of the PSMA CD28 and CD3 from Regeneron?

So I've been disappointed. So I think it's a work in progress. I think that I'm optimistic as an oncologist. So I'm optimistic that we're going to get there. I just don't think we're there right now. So where we're seeing the most response is, we're also seeing a lot of toxicity, including deaths, specifically with the CD28 one. So I think we have to figure that out. It's different -- clearly different, CAR-T cell is the same, clearly different in solid tumors than in [ heme malignancies ].

Thank you, everyone. I appreciate your questions, and that's all the time we have. And I think we are moving on to the next section. And thank you.

Tool that a medical oncologist can access and have influence over the utility. And I think that's the disruptive opportunity for nuclear medicine. So we're working really hard to achieve that objective. And I think you've seen from the presentation today that there's lots of evidence that we are achieving that. And what I'm most excited about is that where radiation oncology can be used as a layered-in tool at all stages in the disease progression in combination with these other drugs and modalities that we just didn't have 10 or 20 years ago. And immunotherapy is the obvious one. But some of the stuff that's coming down pathway where DNA damage repair inhibitors and PARP and stuff like that, this is really exciting. When Andreas and I started the company, we believed in the value of antibodies because the #1 objective, if you're really going to do those combinations, is to residualize and retain that radiation so that you have the best chance of getting a treatment combination effect. So I think we're going to see data over the coming 18 to 24 months, which is going to demonstrate, does that, in fact, work or does it not? I'm not going to -- I realize today in watching all of our presentations, we have a tendency to throw a lot of icon slides up. And so I'll think about that in the future. But I mean, I just wanted to -- just to really again reiterate what our growth strategy of the business is, we're clearly doing well with our current imaging agents. We're excited about the 2 more approvals that we have this year. But the whole purpose of this business model now is to really to be able to fund those therapeutic studies. And you can appreciate those studies are not inexpensive. So the amount of investment that we're making into the clinical program right now is really just beginning. We do have an appetite to continue to expand the pipeline. Clearly, we made an announcement today about a small bolt-on acquisition. I actually think some of our small bolt-on acquisitions turned out to be strategically really exciting for the company. I don't always have to be super material to be important. I think, sometimes, putting together the puzzle with all the little pieces of the puzzle is more elucidating of the bigger picture than just something massive that we tag on. But obviously, we also have a fairly large pipeline that we have to execute on. So I do want to assure you that our appetite to grow the pipeline is also a function of our ability to execute on the current work we have to do. And it's not an infinitely elastic equation, I would say. That said, we have our core programs in renal and PSMA and our glioblastoma program. Those are pretty well-baked programs. The investment that we are making in those clinical trials is well established and fairly predictable now because those trials are actualized. But this is our research pipeline, which I almost never get a chance to talk about. It's our alpha -- we actually have one of the largest alpha pipelines in the industry, which is now at the clinical translation stage. We have some really exciting combo trials, as Colin has talked about. We have been dabbling in radio-guided surgery for quite a while now. In fact, that was the impetus to turn a collaboration into an acquisition. We like to do that, by the way. We like to build a collaboration, get to know a partner over a period of time, get underneath the bonnet and then decide, "Okay, is that an area that we want to be more protective of?" So I think that's a really good execution strategy for the company. And I think it's important for you to understand that, that's how we kind of play. So there's just a lot of exciting stuff. And all of these programs now or almost all these programs are clinical-stage programs. So I'd like to think of this slide as what does Telix look like maybe five years from now, what are going to be the core pipeline we'll have? Hopefully, if we execute well, we'll have a pipeline of products that are out there being used, going into earlier lines of therapy, having indication expansion. But some of the -- not all, but some of the things that are on this slide will represent that future pipeline. And there are some really exciting targets and opportunities in this research pipeline. So it's Pride Month. So this is my Rainbow slide. But actually, although it's a little bit of a conceptual slide, I wanted to take our R&D activities and explain why sometimes investors and shareholders, they look at our company, they go, "Wow, you have a really complicated business." And actually, we just don't really see it that way. We see that there's a natural kind of continuum and overlap between the different areas that we are trying to service in our R&D initiatives. So clearly, with PSMA and CA9, and LAT-1, by the way, our glioblastoma program that has wide utility in CNS malignancies far beyond glioblastoma, that's a really cost-efficient place for us to continue to grow and expand our business. The clinical work that we have to do is super efficient, a combination of clinical -- of company-sponsored programs and investigator-led studies really gives us a big bang for buck there. And I really have to acknowledge, Mary and her team had played an incredibly valuable role in really exploring that expansion opportunity. We do believe that bringing molecular imaging into the OR is an important thing to do. I was grateful, and I promise you that it wasn't a prompted -- a transplant of information. But when Scott said, we can take a more expansive view of what a therapeutic intervention is when we talk about theranostics, that's something that we really believe in passionately. And for those of you who are not day-to-day in nuclear medicine, that is not a straightforward conversation right now. There are some people in the industry that believe that theranostics are -- see it treated radiopharmaceutical and don't necessarily subscribe to the idea that molecular imaging can have a wider role. I think that it's -- you've heard multiple examples today of where improving surgical outcomes can be a real-world achievement. And that's going to get traction for some of these technologies from a payer perspective early on. Clearly, we have our therapeutic pipelines. And then, not just to think about our pipeline through a monotherapeutic lens, but where does it fit into the wider spectrum of pharmaceutical interventions? And again, that comes back to my opening slide. For this whole field to be disruptive, it's got to be embraced by medical oncology, and it's got to integrate with all of these other standards of care. That is why when you look at our clinical trial programs, you will not see a single head-to-head study between a nuclear medicine agent and an existing standard of care because that's not our corporate objective. Our corporate objective is to integrate and to bring the benefits of nuclear medicine as a partnership specialty into medical oncology, that's just a fundamental part of our strategy. By the way, we think that that's the strategy that's going to make Telix that sort of cornerstone partner opportunity for somebody bigger that really wants to get into nuclear medicine. That's the fundamental ethos that we think is important to support that possibility for the company in the future. But what's really neat is that if you subscribe to the fact that there is interplay between these kind of 4 pillars of research, there's some profound outcomes that are going to take place over the next, let's say, 4 to 5 years. Image-guided interventions like with a gamma probe or with a fluorescent agent, that's going to become standard operating procedure, if you'll pardon the pun. We do believe that personalized dosimetry is going to matter. If we really want to use these therapeutic agents in different stages of disease burden, we've got to tailor the dose for the patient. We can't just give a one-size-fits-all dose. And as we understand how the current approved agents are being used out in the field, this is manifestly evident. If you want the best patient outcome, you need to tailor the dosing regimen for the patient. It's not going to be an easy journey to undertake, but it's going to be a clinically vital one to achieve. Patient response assessment, super important; prediction, even better. I think CA9 is going to turn out to be one of the most exciting areas because we know that if you're a high CA9 positive, don't say that 3x quickly, CA9-positive tumor, you're going to have a higher resistance to immunotherapy. So then the question is, what are you going to do to prime that patient first? That's a really -- I mean that's just a blue sky for us. And so I envisage Colin's STARBURST trial is a kind of LOXO style; one day, we'll treat CA9-positive cancers. We won't choose a particular cancer. We'll use an imaging biomarker to select first. And I think that's just a massive opportunity. So as you can see, there's some really exciting research areas that I think are clinically transformative. And they only come out if you're willing to tackle those what appear to be distinct and disparate research areas, but actually have a ton of overlap. So I feel compelled to share that because sometimes our R&D strategy does appear a little bit disjointed, but I can assure you, there's method in the madness. And hopefully, the clinical data will speak to that over time. And in fact, it's -- I'm not going to rehash one of Colin's slides, but if you take that very abstract vision and then you teleport it into what are the clinical trials that are happening today, we are collecting this data. So I think that I'm going to be able to stand in front of you, Colin is going to be able to stand in front of you in the next 12 to 18 months and say, this is how the clinical data is supporting that vision for the company. And I think it's an immensely exciting area. And I think we can all take, as a company, a lot of gratification from the fact that we may not be doing fundamental drug discovery, it's not really the thing that we do. But some of the clinical concepts that we are exploring are so new and so massive if we get even 1 or 2 of these things right. So I think there's just a ton of -- there's an abundance of opportunity in our pipeline. I do want to briefly address Lightpoint. I'm not going to talk too much about it today. It was that, frankly, with all acquisitions, it's touch and go, whether you get it done in time. For a certain point in time, and it was just coincidence that it landed this week. We've obviously got the Society of Nuclear Medicine Meeting coming up, so we were motivated to get it done, but you can never tell for sure. But this is a -- this is to address an elephant in the room of Illuccix, which is currently the indication for Illuccix, the main 2 indications, [ bookend ] prostatectomy. So we want to really have that special relationship with a key stakeholder of Illuccix, which is the urologist. We need to have things that can go into the operating theater. And we want to make it so that when a urologist goes in to do a prostatectomy or 1 day, maybe even pelvic lymph node dissection as a more routine pathway that, that person is going to say, "Hey, where is my Illuccix scan? And where is my PSMA-guided intervention?" and to have the confidence that those more complicated surgeries are going to get dealt with well. If you've ever tried to get a meeting with a urologist, it's hard because they're normally in the OR. I need to find ways to go into the OR to build that relationship. That's what Lightpoint is about. So I think it's a really exciting acquisition. It's not a distraction from a pharmaceutical strategy. If you really believe, as Scott mentioned, that these therapeutics are going to go into very early line settings as an adjunct modality to surgery, you've got to be able to quantify that PSMA effect in the operating theater. We might even one day deliver drugs in an adjuvant setting in the operating theater, that's happening in other parts of oncology, right? So surgery is not just taking out. surgery can also be delivering a localized adjunct therapy as well. So there's just, again, so much potential in this. So anyway, that concludes our session today, and we're going to bring the management team up now to be in front of you to take any questions that you may have. I hope that somebody else other than the 3 analysts that keep asking the same questions, will ask questions, but they're pretty good questions, too, so I don't really mind. But these are the major catalysts that we have for this year. We're making good progress on achieving those catalysts. Drug development is not a perfect science, but I think we're executing pretty well to plan. We are still planning to submit 2 more drug approvals this year. So there's a lot of people -- whilst we're here with you in New York, there's a lot of people that are working very hard to deliver on those corporate objectives, but the floor is open, and we're here to answer any questions you may have. So thank you in advance for your questions and for your time today.

Thanks for your time today, team, and appreciate the presentation so far. This is just a minor one to you, Tom. I think you made a comment, rewinding back to your presentation, that you don't even need to adjust minimally with the sales model to distribute 250-CDx. Can you give us a little bit of like clarity of what that means? Is that more feet on the ground? Is it different relationships? What does that actually entail?

Yes, it's a great question. It's a small increase. We predict about a 20% increase to our salesforce. And the great thing about our current salesforce is the call point is the same. So we're just going to expand in a couple of big metropolitan areas where we might need that headcount. But the great thing is we have the urology call point, they're already in. And then in the new [ bed ] call point, we're already there. So it's a minimal investment, we see about 20%.

Boris Peaker from Cowen. I guess two questions on TLX250. What should we be expecting in the label specifically in terms of patient -- the patients that will be targeting for this drug? And also, your thoughts on kind of first-year commercial adoption, is it going to be a slow ramp? Or how should we be kind of modeling that out?

Let me take the label discussion initially. We're relatively focused in our label because we have a breakthrough designation with 250-CDx. So that is about characterization of renal masses as clear cell or non-renal -- or non-clear cell renal cancer. And that goes along with all the advantages of having the breakthrough therapy. So I think there will also be potential to have discussions around active surveillance because that's characterization of the renal mass for sure. And then, as we know that a lot of imaging is used off-label anyway, and we've heard today how surgeons, oncologists are excited to use it beyond those areas as well, so potential staging metastatic setting and so on and so forth. So that's the label. I'll hand over to the commercial team for the commercial aspects.

Do you want to talk about ramp? I can do it. Well, I think that given Kevin's team has established the relationship with the customer that's going to use this, I mean I think from what we've seen on inbound interest on the back of the ZIRCON trial, people are waiting for this. So I think there's a natural sponge effect, I guess, it's a terrible descriptor, but I really do think that we're not going to have to push the door very hard to get people to start adopting. And we've had -- and actually, I think Scott said it really nicely when he stood up that we've gone through a lot with PSMA in terms of the payer dynamics, the insurance process. There's a whole mechanism of action there around the commercial dynamics of PSMA that serves us really well, going into CA9. Now we've learned some hard lessons. We know that we've got to set up the market access teams. We know that when we go into a -- maybe you want to talk about it, but when we go into a customer site, we've got to hold in the hands of the customer.

Yes. I think the question is -- just kind of pulling the two questions together, it's really about the density that we think we need in terms of these major markets as we call on the single urologist, right? It's still the same urologist group that's calling on that. So when we're in there, there's a synergy effect of being able to combine both products. And that actually makes us more valuable. We're solving more problems for the same urology group. And then we've talked a lot -- in my talk, I tried to go through the breadth-and-depth example of what we've got in the field from a cross-functional support. So that's very focused in the urology group right now. And we understand that market. We understand that scan. Our medical support team understands all the scanners that are in the market. And we are able to change isotopes easy to make sure the scans have the highest quality. So what you're -- what we're going to get is the synergistic effect that we've seen in many other companies that commercially we've been part of, is that you start selling the portfolio, the reason and the value. And as you do that and you think about this from an imaging standpoint, the [ see-it ] part and then the treated part, we just become more valuable to them as we go. So the ramp, to Tom's point, is incremental because we're looking for density in major markets, and then we still got great coverage out in the more rural. There was a comment earlier about how we're going to access those? But in our Illuccix platform, that's one of our value propositions, is that we can take the Illuccix to those markets and still treat those patients. And so we're going to have those relationships out there because we have 200 points of distribution where we have relationships, and that local knowledge would let us -- allow us to really execute on that. So it's synergistic in the [ ramp ].

Yes. And also, I mean, everyone thinks that, well, people have been talking about PSMA for a long time, so that's a pent-up. I mean there's a decade of evidence. Nuclear medicine is not a fast-moving field because it's typically been underinvested and so -- I mean by the time -- I mean, the first somatostatin therapies were done in the late 60s. I mean -- and now we have [indiscernible], right? So there's a long gestation period, but it's important to understand that CA9 is one of those targets that's been on radar in this community for a long time. In my personal opinion, Redectane, which was the I-124 variant of girentuximab, which many of you even remember, that should have been approved. I mean it wasn't, and there was a technical reason why it wasn't approved, and that's reasonable. But nonetheless, we took that [ aspect ], we improved it. We've made it significantly -- the chemistry and the radiochemistry significantly better. The commercial parameters around the product are significantly better. The clinical parameters, no thyroid blocking, lower-radiation dose. All of those good things that came from making a zirconium-based product, we've really addressed the target product profile of the asset. And we're going the door to a stakeholder that wanted that product approved, frankly, in 2015, 2016. When I started the company, I mean, I've had a long association with CA9 and with girentuximab. And actually, Memorial Sloan Kettering and Cornell were key development sites for those assets. When we decided that we would pursue a confirmatory study with a kind of revised product, I mean we've got dozens of letters and support from really senior figures in the renal cancer field. And I think that's one of the reasons why we have such a vibrant clinical program. People want it. They understand the importance of the target. Everyone understands there's a genotype-to-phenotype relationship with CA9 and clear cell renal cancer that's unique. That's why the positive predictive value is so high. If you have clear cell, VHL mutation, you will have overexpression of CA9, that's it. It's a one-to-one relationship. So I think we're pushing the door open on a target that people really understand well. And I think that's what will make the adoption rate very high.

Mike Sarcone from Jefferies. Just had a question or two on -- you talked about expanding the use of Illuccix to active surveillance and then planning for biopsy, radiation and surgery. Can you just talk about the pathway that you see to getting there? Does that entail showing more clinical evidence? What do you expect the reaction from payers to be as docs are ramping up the use of scans? Would just love to hear about your commercial plan for getting there and maybe even timing as to when you think that could play a more meaningful role for Illuccix.

Sure. Maybe I'll start off with the indication section, then talk about the health economics and the different commercialization aspects. So really, we see certainly in imaging, there's a number of routes to increasing the utilization. That's our own studies that then potentially can progress to formal indications, but we know a lot of imaging comes through guidelines and through practical data usage as well. So it's really a sort of a 3-pronged approach to develop all of those areas in terms of our own potential indications, but also guidelines and then established use cases, data cases, publication cases that show the utility. In terms of the health economic arguments, and again, it's about coming away from this being just a one-point-in-time diagnostic. My sense right now is given the prevalent population is biochemical recurrence and the smaller incident population is newly diagnosed patients, most of the people are getting it as their first time presenting for whichever reason in the biochemical recurrence population. As we see the market establish and continue to grow over time, we'll be able to demarcate precisely where these use cases are being used the most. I suspect it's going to evolve pretty rapidly. But maybe I can hand over to the commercial team to talk about that evolution.

Yes. I'll use the term medical necessity in the way that introducing the market is typically by indication. But anytime you get a technology like PSMA gallium, physicians start using it where they see medical necessity. So that takes care of the health economics question. And then they begin using it in the academic centers first as they expand the use of this medical necessity. And that's where you see guidelines like AUA came out with expert opinion. And there are really 2 big use cases that we're talking about, that we'll start working with both clinically and commercially to start expanding on that and letting the market understand where the experts kind of see the use of PSMA. I mean it's been a year, 1.5 years since it's been commercially available, and you're ardent to see smart people like you saw on stage today, thinking of other ways to use the product. And you'll continue to see that expand as they deem something medically necessary.

Can I add on to that? Actually, that's a wonderful point. I think when Dr. Tagawa mentioned the PSMA imaging expansion of that, and you can see it that it's going from beginning from patient journey all the way to the end with [ med onc ]. And so our PSMA is touching at not only the urologists in nuclear medicine and then all the way through to medical oncology, but also in between. And if you see the real-world evidence around the prescribing behaviors, you can see it being used as treatment planning for surgical margins. You can also see it in radiation oncologists that they want to direct the radiation for PSMA targeted, so that you don't have to [ irradiate ] the whole prostate. So we actually are seeing that. And in the guidelines, actually, the -- what Kevin is mentioning is that they just came out with SUO, mentioning that they recommend and acknowledge PSMA-PET for periodic scanning every 6 to 12 months for suspected disease and spread and then also for periodic scanning for those that don't advance on disease in the mCRPC space. So you can see that the guidelines are really seeing the significance of PSMA-PET, and you can see that physicians are using it in the clinical practice where that necessity is needed.

Yes. And then maybe we shouldn't underestimate the impact as well of, I mean, a big pharma and all of these really important Phase III trials that are coming out, and there are multiple where PSMA, for the first time, is actually being used as a proper volumetric tool. If you think about it through all the generations of tweaks and changes around RECIST criteria and how truthfully, how minimally quantitative that approach is or how under quantitative that is to see something like this come along and just rapidly make it into a significant measurement tool for looking at systemic disease progression, I think that's really tantalizing kind of indicator of what can happen. I just -- again, not to oversell it, but I really feel that our commitment to delivering these imaging modalities globally, it just puts us in a very strong position. We don't tend to put out a slide, right, with all of the pharma logos all tiled across it, like it doesn't serve us well to do that particularly. But I can tell you that if a partner wants a dose of Illuccix in a hospital in Shanghai or in Osaka or in Sao Paulo, I mean we can deliver that to you tomorrow, it's there. And I think that that's a really strong opportunity. It's a unique opportunity for Telix. We had the great privilege of supporting the VISION trial. We are a key source of imaging in the VISION trial. We had to deliver that in a lot of different countries, which we did, I think, very well. And so that's given us the credibility to be a partner and to deliver mission-critical imaging in those very large global multicenter trials. So that's going to absolutely impact the way that physicians think about the longitudinal use of these agents. And by the way, the same thing is going to happen with CA9. Once we get approval, once it's out there and it's readily available, now we have a -- I think a lot of literature that shows that this is a prognostic biomarker, you have a high CA9 expression, you're going to have -- you're going to be less disposed to immunotherapy. And so we're going to see that used as a tool more and more. And I think just the imaging alone will have an impact on trial design for better objective complete response. So that's -- I mean that alone is exciting, let alone the therapeutic pieces that are coming in behind.

This is David Oh with TimesSquare Capital. I'm just wondering whether you could talk a little bit about how you're thinking about pricing strategy in the U.S. and ex-U.S.? And kind of along with that, whether you've tried quantifying overall cost savings, if any, in both the U.S. and non-U.S. markets, maybe that's something that helps accelerate acceptance, adoption, commercialization?

I'll talk about global, and then I'll hand it over, maybe, to the U.S. team. I mean, we have a global pricing committee. We start with a pharmacoeconomic model, which is based on the consensus standard of care. For prostate and renal cancer, the U.S. is fairly similar to most of the major markets. Clearly, in Europe, we have some different reimbursement kind of landscape, which is -- does result in a more price-sensitive market. So there's like two issues, right? One is the pharmacoeconomic advantage or the benefit of the product. The second is what is the reimbursement kind of policy around it. And certainly, in Europe, we see a more diminished appetite to pay. Although I have to say, that's changing as well. There are quite a lot of reimbursement working groups now that really understand that if there isn't the ability to pay for innovation, innovation won't happen, right? So I think that generally, there's a trend in the right direction and an understanding that if we can properly diagnose and stage patients, that has a big downstream cost benefit to healthcare systems. So I think that's a positive global trend. I think for the U.S., I mean, we have a pretty clear understanding of what the cost savings are to the healthcare system when we bring these products in line. I mean you want to sort of elaborate?

Yes, we feel like the pricing in the U.S. is pretty stable. And we see that it's bringing way more benefit to the system as a whole than the cost of acquisition right now. And then, we really see that from a strategic account standpoint and integrated delivery network standpoint. And remember, those are like franchises. If you're not familiar, integrated delivery networks are like franchise hospitals. There's anywhere from 2 to 20 hospitals that work together in an integrated delivery network. And we'll work with them to manage that from a pricing perspective, some, but we don't see a lot of downward pressure on pricing right now.

Yes. And I think longer term, and everyone's aware of pass-through. That's a dynamic that's kind of front and center of the industry right now, but it's also -- it's a double-edged sword. If we really believe that, to your question before, PSMA imaging could go from 300,000, 350,000 scans a year to, let's say, 1.5 scans per patient, on an incidence basis, to 10 scans, just for hypothetical conversational purposes, that's not going to happen without a shift in price. So there's going to be a volume price trade-off there. And actually, we plan for that. That's in our business growth strategy.

And remember, not the whole market is under pass-through. There's still VAs, there's 340B pricing as well as commercial payers. And then the independent centers, because we're such a broad network and we provide out in the suburban and the rural areas, there's a lot of self-standing centers, too, that are reimbursed differently under Commercial and Medicare. So we feel pretty comfortable that the upward pressure on doses and on scans and the downward pressure on pricing because of that to get to that larger market that Chris is talking about, is manageable.

We don't really break down typically our R&D spend, but for discussion purposes, I mean it's public domain information, but about 25% to 30% of our R&D budget is actually in life cycle management of our commercial products. So Illuccix is generation 1, and it's evident in our pipeline. We've got other things coming down the pathway that will enable us to come to market with fresh product ideas. So we have a very long-term category commitment to being a leader in prostate imaging. So it's an exciting field to be in.

[ Sam Berdowski ] from Truist Securities. Thanks for that color on the market. That was really helpful. Christian, you sort of throw out a theoretical scans per patient through their lifetime. Is that -- where do we think realistically that could go over the next maybe 3 to 5 years and maybe over the long term? And where do guidelines sit today in terms of supporting that? And then, very early days here, but another competitive F-18 agent on the market or soon to be on the market. Any thoughts on that? Or anything early you're seeing from that?

Yes. I mean I don't mind it's maybe starting it, and if anyone wants to chime in. I mean I think that I don't have a forecast for you. I don't have a crystal ball on how many scans per patient we're going to get to. What I do know is that if we don't invest in the clinical studies to elucidate it, it's not just going to happen. So we invest in clinical trials. We support -- Mary's team supports a lot of investigator-led studies. By the way, that's, I think, a good industry-wide phenomenon. To some extent, all experience with PSMA imaging is a good thing. So we do kind of embrace that. I mean obviously, we want everyone to use Illuccix, but we're also kind of happy to see progress being made, overall, with PSMA. And then, I think those really large therapeutic studies that are using PSMA longitudinally, by the way, including our own, right? ProstACT GLOBAL uses -- makes extensive use of PSMA imaging. I think that those are all opportunities to get to that point of expansion. So I do believe -- I don't have the exact number for you, but I do believe -- I mean, we have an internal number, but not an external number. I do believe that in sort of the 4- to 5-year period, it will be typical that a patient will at least get 3 or 4 scans. And in some markets, like in Australia already, it's already established. You get 3 scans if you want it. So I think that there's -- I mean, do you want to add something to that, Mary?

No, I mean, you can clearly see from the excitement around PSMA utility at ASCO a couple of weeks ago, [ FNMI ] this week, all the abstracts that are being presented are a lot around PSMA with response to therapy, using it for outside of prostate in different tumors, you have it in serial scanning and in combination and -- so you can see the explosion of excitement. And speaking to the guidelines, you have the major guidelines just last year across the globe, [ FNMI, EA&M, EA&O ], a few of the SUO as well, all of them having a consensus around PSMA-PET and have recognized it and included in their guidelines. I think you can see the evolution now with even [ FNMI ] and NCCN, [ EA&M ] coming together, having a more consensus language around having it preferred over conventional imaging, recognizing it as superior in micrometastatic disease and detection as well as now SUO came out this year seeing periodic scanning, recommending that and also for patient selection, [ FNMI ] and NCCN. There's a lot of Ns and Ms. But clearly, you can see that you have a collection of a lot of guidelines, and societies that have come together across the world, recognizing PSMA-PET.

Yes. My only add is that, that was really quick from first commercial use, right? So to see the excitement in AUA to update with expert opinion, the next step would be to take it into the guidelines itself, and that's all happened in the first year or so of launch. So it goes back to what they're deeming as medical necessity. Many times, industry puts great products out there with an idea of how it's going to work and how it's going to fit. And then when you broadly get it adopted, then you get a lot more smart people thinking about, "Wow, this would be advantage in." And so you get that practice-of-medicine effect, where they start seeing medical necessity in other areas. And so that's what we've seen really quickly, and it's really encouraging to really kind of talk to Chris's number about what will be typical in 2 years from now, couldn't have been imagined a couple of years ago when we didn't really understand the broad commercial adoption of the products.

And also, just the good news is there's a ton of investment now in scanner capacity. We're seeing higher -- I mean, the waiting list for scanners is pretty long because there's so many under order. We're also seeing an interesting -- and I've been in the nuclear medicine industry since 1997 and started my life in the capital equipment side of things, where it was always a battle between GE, Siemens and, to a lesser extent, Philips and Toshiba. And it was always kind of the Germans versus the Americans, and you never got fired for buying GE. But the Siemens guys always did it slightly better. Now we're seeing really crazy market in versions, where the Chinese have developed the most incredibly innovative whole-body scanners because you got to have an imaging center that's doing 100 patients a day. And that technology is now coming here in the form of things like the [ microexplorer ]. Of course, Siemens has responded with their Quadra system. But now, you're seeing super high capacity scanners at an amazing price point per patient scan coming in the door, and that's just revolutionizing the capacity of the industry. By the way, it also really helps us because the amount of localized production of gallium-based pharmaceuticals that we can deliver in that kind of scanning environment is just super productive for the site. So it's a really interesting time. I do want to address your question about -- I think you were alluding to the Blue Earth, the entrant. Look, I think when this field started, everybody -- and it's sort of a natural evolution of clinical understanding, everybody treats a product class like it's kind of a homogenous class. And then over time, performance and understanding of things improves. So I think, at face value, and it was a really positive thing when the guidelines came out, pretty equivocal, it was all about PSMA. And I actually think it's great that patients have multiple options available. That's what's going to drive the field. That's what's going to make this a routine part of much more extensive patient care. So I actually think multiple vendors in the market is a good thing, broadly speaking. And by the way, there's no competition. It means there's nothing worth doing. So I mean, that, in and of itself, is a positive dynamic. But I do believe, and I want to be very clear about this and very careful, we don't talk about Illuccix versus our competitor, right? We talk about F-18 versus gallium? That's not a product, that's an isotope. Okay? So -- and what we're seeing now is the separation and clinical performance between PSMA-targeting agents based on F-18 and those based on gallium. And the fundamental issue is false positive rates. When you have a bulk of F-18-based radiopharmaceutical and you have radiolysis and you get free F-18, you get -- as a side effect, you get a bone scan. And that is no longer a targeted imaging agent. That's a targeting imaging agent, plus a bone scan. And readers need to be aware of that. And if they understand it and they know how to read it, it may not be a problem. But it can also lead to patient overtreatment because if you can't verify that a false positive is a false positive, the standard of care guidelines say you're going to get 3 years of hormone therapy and targeted radiation. So that needs to be understood. And that is being clearly elucidated in the guidelines. It's already come out for the radiohybrid for the Blue Earth product. And it's a significant clinical issue, and it can't be swept under the carpet. So my personal view is that not all PSMAs are created equal and that the customer base that we all have to interact with every day is super sophisticated. They understand sensitivity and specificity and false positive rates. And they will select what they will deem the best product for delivering a patient outcome.

And there's data to support that. I think now that we have more products in the market, you see a lot of publications culminating coming to light. You have guidelines calling out certain specific F-18 products for their benign uptake, bone-specific uptake. You have some recent publications that were presented at ASCO that showed higher benign, indetermined bone uptake as well as large prospective papers and retrospective papers now coming to light. So there's quite a bit of conversion evidence to support that.

Yes. I think it's also just going to add to the ZIRCON study, I think it makes the path forward for that at very nice -- because you've got a potential study in those other studies that haven't met their primary endpoints, have extremely high inter-reader variability and then contextualize that with the ZIRCON study that has a specificity and sensitivity above 85% and an over 90% inter-reader agreement. I think that contextualizes ZIRCON study very nicely as well.

Just one additional point, as it is F-18 based, we anticipate the same scheduling and challenges that you see with centrally produced isotope today. And our ability to deliver doses to customers throughout the country on time and allow them the ultimate scheduling flexibility will continue to be an advantage.

Yes, I think, that's a great point. Like a lot of our customers, to your point, have bought into the idea that a nuclear pharmacy-based solution is really is beneficial to them. And that doesn't go away with another entrant to the market. So -- and look, frankly speaking, we know that there's -- it's going to be product #5. We know who that's going to be. We know who product #6 is going to be. I think that good competitive business dynamic dictates. If you're the fifth or the sixth or the seventh person in the market, it's a diminishing return. And we're now getting into a penetrated market environment. So it's going to be established players with a track record of delivery and a good-quality product that's got clinical validation behind it, those are the players that are going to blossom. And I frankly think that's 2, 3. It's not more than that.

A question for Tom. There's lots of discussion there around product differentiation. How would you describe the markets, the urologists on the [ call piece ], their knowledge of that, you see it every day? And...

Yes. Good question. I think it's the education that our team's doing daily. And it's really the education of the urologists more about our products. We talked earlier about availability and differentiation clinically. And those really are two main parts daily that our team is out there. What's great about our team that we hired is that's the background they have. They know how to educate the different specialties, and they have that urology background. We also have a team of nuke med techs well. So one thing we haven't talked yet about, but we have all these different specialties that can do that education and cover all those physicians.

But I mean just to be clear, from a compliance perspective, we can't do competitive product positioning. But I think the first time we've ever seen something really phenomenologically strange is urologists turning up, urologic oncologist turning up to nuclear medicine in radiology meetings, right? Like standing room only at PSMA forms did not come from nuclear medicine. It came from the customer of nuclear medicine turning up to really understand. So those publications and those conference papers, they're high impact. We don't need to sit down and feed a lot of publications to our customers. They're at the conferences. They want to learn. They want to understand. It's out there. A new paper comes out, you go and have a meeting with a KOL on the urologic oncology side. They're like, "Did you see that paper?" We don't have to highlight nuclear medicine and radiology there. Like this is practice-changing for me. I'm going to go out, I'm going to seek the information. I'm going to be aware of what's happening in the field. So it is an education process. We have a great team's, but it's -- we also have to be honest with you, it's kind of a shallow education process. They kind of know where to look. And by the way, the practice guidelines, they really do reflect the moving art of the field extremely well, as Mary pointed out. So you know what, we don't have to do anything more as a company than just talk to the practice guidelines. And that's what we've typically -- well, that's what we're required to do, frankly.

Yes. They have been very interested in basically going from black and white to the color PET CT that they're seeing under -- they'd see versus in MRI or CT or something like that. So they are interested and more interested in the diagnosis piece than just ordering the dose and letting the read come back to them with what they needed to do. They actually are, to Chris' point, getting it more involved and interested in what that really looks like and then how they approach their surgical considerations the way Dr. Tagawa has talked about.

And urologists love technology. They love toys. I mean, look at what they do every single day. I would go so far as to say, they're not even just interested in going black and white to color. They're like they want to go from plasma to OLED. And so yes, they're highly engaged. It is an easy conversation.

It's the same [ Alice ] asking a different question.

You ask good questions, [ Maggie ], so fire away.

It's very encouraging to see from the recent Cardinal Health on Investor Day that they are committed into expanding capacity and have further investments into the center for theranostics advancements segment. I appreciate that today is not an Investor Day for Cardinal Health, but could you talk more generally as to the level of commitment and investment you have seen from the industry participants on the nuclear medicine infrastructure?

Do you want to take that?

Yes, sure. I mean there is a high level of interest as these radiopharmacy partners, and again, talking about 2 of the best, 2 or 3 that we really deal with, they have invested heavily in the infrastructure to support the growth in what we're calling theranostics from a radioisotope perspective. So we see a lot of investment. In fact, I think Cardinal actually re-upped their, really, commitment to our business, we think, in terms of their increased investment in R&D over the next couple of years in that investor presentation. So we see a high level of interest. They see it as a high-growth target and high margin for them as well in terms of what they're doing compared to their typical radioisotope business.

I mean, just strategically, we are highly committed to the nuclear pharmacy model. We think that -- I always make this joke, right? You're having your Friday gin and tonic, okay? We're here in New York. So do you, a, call your friend in Los Angeles and have them make a brick of ice and then fly it across in time for your 5:00 drink, so it's melted down to the correct size you drop in your glass? Or do you; b, go into the next room and pop an ice cube of your freezer, right? That is really the difference of the nuclear pharmacy model. And the way that the nuclear pharmacy standards are evolving with USP 823, there is the facility there for us to dispense a wide variety of products. And so we just see that localized delivery model is really powerful. We are committed to it. Cardinal and Pharmalogic and Jubilant and RLS and all of the great organizations that our team works with every day, they see the pipeline of products that we have coming down the pathway and our commitment to that nuclear pharmacy model. And I think it's got a real longevity in the relationship. And frankly, I mean we love working with these people. They're super talented. Their sales teams are highly motivated. We work together very closely. It's a very effective partnership. And I would say that if you really look at what we've built, what Kevin's built -- I had very little to do with it actually, but if you look at what Kevin has built in terms of the sales and marketing infrastructure and then you layer our partnerships around that, we have, by far, the largest team out there telling the story about the [ space ], like by far the largest team. So that bodes well for the growth of our business, I think.

Yes. I think Tom commented on that on how it really enhances our -- and extends our sales and marketing reach. When we really think about the metropolitan areas, the suburban areas and the more rural, I mean, patients want to be scanned and treated where they live. And so that really extends that. So the local knowledge from our -- and value in the motivation of our independent pharmacies that we use, to more regional, to the more national, all of that just kind of layers in as an extension of our information and our ability to really reach our customers where they are and the patients that they serve. So it's an incredible value when we specifically talk about PSMA, Illuccix in imaging.

Yes. Good point. Got one more.

Just to follow up on the infrastructure investment. You had already made a comment about investments in PET CT scanners and technological innovation. So it doesn't seem like you have any concerns about the capacity to support demand, but could you maybe just elaborate a little more on where the market stands today? And how much of that investment in scanning capacity is needed to support the rapid uptake of PSMA?

I'll start and then if anyone wants to chime in. But I think we're going through a kind of a 3-step evolution in the industry. So today, we're just seeing the flex of the current infrastructure. That means extended operating hours, Saturdays, evenings like people are packing it in. There's also, by the way, a lot more -- when the first F-18-based PSMA agent came out, it meant that you had to schedule a block of time or you had to do a certain workflow. Now that there's multiple opportunities to get access to product, you can weave it in and layer it in much more efficiently and depending on what your -- what the time of day is or what your patient load looks like. So today, it's about optimization of the existing infrastructure. Then 18 to 24 months out, you're really looking at the leading centers expanding their capabilities, adding additional scan capacity. And then the sort of third stage of all of that is the emergence of -- and it's a really interesting concept, is the emergence of the stand-alone theranostic center, which we've never seen before. So these are typically interdisciplinary practices that are only going to practice theranostic medicine. And they're popping up everywhere. There's one down the road from Kevin's house in Texas. There's one across the road from our headquarters office in Melbourne. They're just popping up, private nuclear medicine, private theranostic departments. And they tend to start off with infusion and using local imaging services. And then eventually, they go, you know what, we just want -- we want integrated control. We're going to bring in our own scanners. So I see that as like that's the short-, medium- and long-term capacity build. Do you have anything to add?

No. Short term, they do what everyone does. They try to flex workforce, right? So they pay a little bit more to have Saturdays. They hire a few more people to extend their hours. We're seeing that in different areas as maybe there is some constraint in time, but eventually, you'll see that kind of equalize or reach an equilibrium around. And then because they're seeing that, then they're already starting to talk to their scanner companies of choice that they are looking for, while we're doing the same thing to give a broader market view of "Hey, it's not just Illuccix, it's 250-CDx, it's 101-CDx. There's other things coming. So they get a broader view of what's going on. And that's why it's so important for us to be out there talking about that portfolio so that the infrastructure stays ahead of it. Now, it's also infrastructure and technology. So as Chris was describing, scan times are coming down when you buy new technology. So that even opens up more capacity. I mean, it is amazing to watch the explorer pictures that you saw, high quality, short time. So we're getting even better pictures in shorter time. So we'll see that market go that direction as we do a better job of getting out there now. Now that they know we're real and everything is happening in PSMA is going to happen with 250 or 101, then they see that expansion happen. And so infrastructure will start catching up and leading them.

I'm bound to note that when you're dealing with a super-busy imaging department, whether it's an IDTF or a hospital environment, okay, you're down to critical -- I mean you're cramming in every last patient you can get in a day. When you have an interruption to supply chain, it's devastating, right? It's not like you're just trying to fit 1 or 2 patients, and you may have like 8 PSMA patients lined up for that day and you have a failed delivery, it's devastating. And I can tell you that for a customer, it happens literally once, and they will reevaluate their supply. So with critical operating mode comes the critical necessity for reliability. And that's where Illuccix just has -- it's just in a league of its own. We do stack doses for competition all the time, every single day. Even in this city, we do stat doses for competition every week. So it's a really great opportunity for us to show our differentiation. And then the cool thing about from an operational perspective, we don't have Darren from the ops team here, who's really, honestly, is the [ god ] of the company, I would say. Yes. Yes. When we moved -- Illuccix was our training wheels product, as I said in the beginning, but wow, what a crazy bike to have a training wheel on. we had 200 points of distribution for a product with of 4-hour half-life. When we get to 250 and the zirconium-based products, we need about 8 dispensing pharmacies to cover the entire country. So we actually deescalate in terms of complexity. And so what does that mean? It means that the reputation for delivery that we built with our customer base is even going to be more reinforced. So I think it's a great opportunity to build our corporate brand.

And to put that into a patient's perspective, right, I mean we know what they're going there for. They're going there to see if they have metastatic disease. It's kind of an important decision. And many of your nuclear med radiologists call that scanxiety, right? So they've got scanxiety as they're sitting there waiting. And then, to think you're going to get that scan that day and then not to get it, just adds to that because then they just have to move you. They can't move you to the next day because there's already somebody scheduled that day. So it usually means they or the staff have to work a Saturday or fit it in even longer. So that scanxiety just last even longer. That's why it's more important for reliability, it is really from a patient human standpoint. Just do what you said you're going to do so they can time their life and manage it and get the results of their scan. Good or bad, people want to know, so they can get treated.

And if I can add just ASCO talking to a lot of the medical oncologists, they said that it was so important to get that scan, not only just for the scan anxiety, but for patient selection for therapy. And so if you didn't get it, they would miss out on therapy, and that's critical for them that they couldn't get on therapy right away.

Well, look, people have come from all over the place to be here, as far away as Connecticut and as far away as Sydney, and both take about the same amount of time, I think. But really appreciate everybody being here and for your questions and your engagement, and I think we're at the end of time. So I believe there's some food outside. So feel free to ask any informal questions. And again, thanks so much for your attendance. It's really appreciated.