Good morning, ladies and gentlemen. My name is Kynan Williamson, and I am 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 success of Illuccix, our 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? 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 CA IX 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. The order of presentations, we will start with presentations from the Telix team.
After this, our two KOLs will come to the stage. Their presentations will be 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. 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 email address to submit questions, which is also on the screen right now. For those in the room, we do have scheduled breaks. We please ask you to feel free to help yourself to refreshments throughout. 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 Christian Behrenbruch, our CEO, Kevin Richardson, CEO of Telix Americas, Ted Stevens, our VP of Marketing for Americas, and Tom Frahm, Vice President of Sales. I'm also really pleased to welcome our medical leaders, Dr. Colin Hayward, Group Chief Medical Officer, and Mary Jessel, Senior Vice President, Global Medical Affairs. Joining us today will also be two 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.
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 an 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, Kai, 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. 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 Kai illustrated by the invitation of our two key opinion leaders for renal imaging and for prostate cancer therapy, we're really deeply committed to discussing the evolving scientific data as part of this forum. 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 a viewpoint around parity of these products. 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.
Again, and, you know, we'll certainly be doing that with reference to the science, 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. I just wanted to outline that a little bit in advance. 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.
First of all, we take the view that we are one of the really leading companies in this space, and there's principally four 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 and revenue generation opportunity. 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. We have regulatory filings, as Kai mentioned, underway for two more imaging products, BLA and an NDA, that will be filed this year. 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 radio radiopharmaceuticals. We have over 20 clinical trials running around the globe, demonstrating the utility of that pipeline. That pipeline is gonna generate super exciting data over the next 12 to 18 months. We think there's some significant commercial catalysts. You know, 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. You know, as you will appreciate, we develop products that have an incredibly short lifespan, sometimes a few hours in the case of Illuccix, maybe out to a week for some of the longer products. Manufacturing and supply chain is critical to integrate into the commercial execution strategy for the business. We've invested a good deal of shareholder capital in making sure that that is something we have command over. 2 weeks ago, I was in... Seems longer than that, but 2 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 a fully vertically integrated developer and 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. 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. You know, we really feel that puts us in a very strong position, particularly in the current market conditions.
Now, I'm not gonna spend reels of time giving you a potted history lesson, although, you know, in the hallowed walls of the Yale Club, the wooden panels sort of tend to make you a bit nostalgic. 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. We can go back to amazing discoveries by Röntgen and Marie Curie, and that's historically interesting. It does start to fire up a little bit about a century ago, when we started to use brachytherapy 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. I think that trend has really continued in the sort of roughly a decade since then. I think, you know, 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.
You know, 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 well the team that's here today. We have kind of four pieces to our business globally. First of all, clearly, we're a drug developer, so we do develop our pipeline and 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 Eli Lilly last year. We just think that as this 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. We are bifurcated into three distinct operating regions: EMEA, Americas, and an APAC region.
It's great to have Kevin, who represent Americas, who's 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. There'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. We have a global services group led by our Group Chief Financial Officer, really covers all of our internal services, and we're becoming quite self-sufficient in that respect. Those teams are all distributed across the globe.
We have kind of three 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 a great clinical and commercial team in Geneva. We have a huge focus in Indianapolis, which is really our kind of biggest hub for the company now. I think it is fair to say that we are a US 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. Again, that, I think, just brings the relevancy of this meeting together.
You know, you are 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, it's, you know, 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.
There are, you know, 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. It's also strategically important. I think from an oncology stakeholder engagement perspective, these are the marketing tools of our science, right? You know, 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. 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 a, you know, a bastardization of the English language in some respects. I think the fact is that combining any kind of therapeutic intervention with a diagnostic imaging agent is a good outcome for patients. 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 theater. Clearly, if we're targeting a specialty like urology, we are working with a surgeon, right? That's an extremely relevant customer touch point for us to have. The diagnostics business is important, but clearly, the biggest growth over the next few years is gonna 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. There's no doubt that these products are going to change the practice of medicine for the better. You know, that's where that growth is really gonna come from over the next few years. 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 three or four years, even more than it has been in the past. 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.
To be able to get product regulatory approvals, not just in the U.S., but in other countries, I think that that shows, you know, again, an execution maturity that's a little bit unusual in this industry. 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 gonna really see that today. 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. I think, just to kind of wrap it up, what we feel is that with Illuccix 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. 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, I think this is a kind of an engine that we're gonna be able to use for really a lot of long-term growth in the company. I think that when bigger companies look at a company like Telix, they really recognize that we've built three 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. You know, the fact that we are able to do things like partner with Bayer on their recent phase III trial, and we're delivering Illuccix in, you know, 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 gonna make a big difference. Being a domestic market actor? is not enough to demonstrate the value and the potential of this, of this field. The commercial team, you know, it's not probably gonna be surprising to you, but it's hard to sell radiopharmaceuticals to oncologists. It's a really high bar of commercial execution.
We're positioning a new asset class to people that haven't traditionally used radioactivity, 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 is an asset. I'm really excited about that. You know, just to wrap up, you know, our near-term strategic opportunities and priorities really focus around that leadership position in urologic oncology, and we're really gonna be clearly showcasing that today. We haven't probably talked that much about our neuro-oncology program. You're gonna 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 is starting to get some really nice data.
Of course, more broadly, to unlock the value of that therapy pipeline, now that we've started to get those revenue streams moving, and we've got some wins under the board, it can really focus on delivering that. Just to summarize, you know, we really feel that we're 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. As Kai said in her opening comments, this is really about: How do we look at the end-to-end utility of radiopharmaceuticals?
That's a really exciting commercial and clinical question to ask. 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 gonna 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, this doesn't happen by physician eyeballing. There's a ton of data science that has to go behind that, if we don't build those clinical applications to link the diagnostic and therapeutic pieces together, we actually don't have a clinical solution. What we're gonna do is we're just gonna give doses to patients. That's not gonna be the best outcome at the end of the day.
Anyway, I'll come back around to some of those sort of 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 gonna now move on to my esteemed colleague, Kevin Richardson, to talk about building our U.S. commercial team. Thanks.
Hey, Chris. Thank you, Chris. Good day, everyone, and thank you for being with us. I'm excited to talk to you about the impressive commercial organization that we've 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 Stevens, our VP of Marketing, and Tom Frahm, 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. 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 and Puerto Rico. 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. I'm pleased with the team's accomplishments to date. I'm excited to share with you how we built the team that delivered these results, how they are preparing for the next assets in our portfolio. 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 set a great foundation for our urology business. 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. With our commercial team driving broad adoption of Illuccix into urology offices around the U.S., we continue to move closer to this vision. One of our best differentiators is our leadership team. If you're gonna 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 integrated business plan objectives.... Our VP of Medical Affairs, Dr. Mary Jessel, has years of experience in medical science and oncology and rare disease. Every day, her team works closely with the KOLs around the U.S. to develop medical strategies for Telix products. She's 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 Pateman, is a nuclear pharmacist by education and has over a decade of experience in pharmacy and nuclear pharmacy operations. Darren Pateman 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 Frahm, 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 records in nuclear medicine, medical device, interventional and therapeutic oncology, as well as medical imaging.
Our VP of Strategic Accounts, Tony Zeno, 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 Stevens, 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. 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? Well, we operate in a multidisciplinary market where we need to understand urology, oncology, and radiology across several disease states. 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.
Each customer-facing function must understand the nuances of our customers and the segments, so they can be effective in their role. Third, is bringing in the right people and the previous experience and subject matter expertise, and then leveraging that experience to raise the knowledge and understanding among everybody on the team. 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. 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. Finally, we must foster high-performing teams through operational excellence or operational discipline.
This means planning, executing, debriefing, and then repeating this process again and again. High-performing teams do this together, 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. Once you've built this world-class organization, you need to deploy them. While Tom's gonna cover this in a little more detail, this slide is gonna 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, are also able to leverage our vast network of distributor partners to support our customers and grow Illuccix. The Telix team makes everything run smoothly for them.
This is why our customers tell us that they love the support they get from Telix. Telix makes this us the easy-to-use PSMA. I'll now turn over the podium to Ted Stevens, our Vice President of Marketing, who will tell you more about our go-to-market strategy.
Thank you, Kevin. Good morning, everyone. We believe PSMA PET/CT continues 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 three 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. 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've 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 as best-in-class and industry-leading levels of clinical support to our customers. 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.
I've mentioned the emerging clinical data, suggesting that clinical differences between gallium and F-18-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 six times less. Gallium and Illuccix PSMA has great detection of pelvic lymph nodes, greater reliability in identifying PSMA-positive lesions across a broad range of patient populations. Because of what the experts are seeing in their practice and what is being published in literature, key societies are updating their guidelines to call out these differences and educate their members. Illuccix is physically positioned closer to the end user than any other PSMA imaging agent, allowing us to meet the demands of high patient volume while enabling flexibility in scheduling.
As discussed earlier, our goal is to make Illuccix easy for our customers to access and use. Customer service and end-to-end support is a large part of that ease-of-use story. With that, I'd like to take a minute just to discuss the true value created by our partnerships or by the partnership that we've 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. Nuclear medicine departments can use all 8-10 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, where large distances between manufacturing and the end user create challenges with reliable, on-time dose delivery. 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. 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. 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 customer 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 but simultaneous processes. Our product development teams are focused on delivering what we call a, quote, 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. 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 Frahm, 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, effectiveness training 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 . You can see, we have great coverage in the US. 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 the 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.
How do we build a world-class commercial team? It's about the people and the process. We begin 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 a 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 trade. 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 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 in the Telix commercial playbook has delivered great results, moving customers efficiently from initial contact to revenue generation and ensuring customers' stickiness along the way. The territory account manager is responsible for making initial contact with the customer. The AVP quarterbacks the cross-functional care team, which supports our customers at any given time and makes sure they're set up for ongoing success. The cross-functional support team positions us as the easy-to-use PSMA with the clinical advantage. A central element to our support team that is involved with all our customers is our local pharmacy model.
They have been selling nuclear medicine products to the PET imaging centers for years. 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 the 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. 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, and the Telix and the commercial playbook is how we execute our plan. Following 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 arrive prior to the first dose. We want to make sure that the account is ready to go from reimbursement in a medical perspective. Of course, our field-based team is at the first doses to make sure everything runs smoothly.
This is a big reason customers view us as the easy-to-use PSMA, and will be a huge advantage as we introduce some 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 Lu-177 imaging centers. I'd like to now turn it over to Kevin for a few closing comments.
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 gonna get there. You know, 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 a leadership team in the planning process and decision-making process.
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 TLX250- CDx and TLX101, 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. Thank you for being with us today. I'll now turn it over to Colin Hayward, our CMO, to talk about the future of PSMA imaging.
Thanks, Kevin. I'm Colin Hayward, I'm the Group Chief Medical Officer. I'm responsible for the medical affairs and the clinical development of Telix. As you've just heard from the U.S. commercial team, the clinical momentum, 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, 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 irradiation, anti-androgen therapy would be recommended, both of which have potentially severe side effects. For pelvic irradiation, for example, urinary incontinence, bowel problems, fatigue, sexual dysfunction. Some of the side effects for anti-androgen therapy are the same. Loss of muscle mass as well, increased body fat, erectile dysfunction, hot flashes. I could go on. There's an extensive list of side effects.
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 irradiation and anti-androgen therapy. This immediately shows the use for increased imaging for any one patient from that 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 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.
With fast imaging, more patients can be scanned in 1 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 is demonstrated by 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? 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 study correlated well with that histology. Clearly, the interpretation of that imaging can be quite subjective, so could be enhanced with new AI tools such as our recent acquisition.
Subsequent to finding clinically significant disease, often 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 thought unlikely because of the shorter 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 a drop in beta, was used on the specimens approximately two and a half hours post-injection, showing it can detect positron emissions. In patients where cancer recurs, reirradiation 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 radiation on that PSMA-positive lesion. Of course, using Illuccix helps 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.
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. 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 their disease evolves. This slide features three 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. It can help guide in terms of management and understand what outcomes you might expect. Not just for radioligand therapy, but other treatments as well. Thirdly, in a large meta-analysis with over 4,000 patients, we see how PSMA imaging has potentially changed management in over 50% of patients. Again, throughout that continuum. As we discuss managing patients, I'd like to briefly just remind you of our collaboration with Bayer and their large study, the ARASTEP 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 standards of care, with Illuccix being used not only for patient 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 timeline chart, with the blue areas calling out the current indications for Illuccix and where they lie on the prostate cancer continuum.
As you've seen today, in just a very small snapshot of that publications 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. Although the PS in PSMA stands for prostate-specific, it's a little bit of a misnomer. It's a marker of neoangiogenesis. It's in a number of other tumors, and in the literature, describe 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.
As a diagnostic, 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 their very exciting SENSEI probe that can be used in combination with our technetium agent. Of course, our commitment to therapeutics with ProstACT GLOBAL and TLX591 in startup 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 CA IX as well. We're now gonna take a break.
I'm happy to speak to anybody during the break, as are my colleagues, apart from any Australians about cricket, of course. We'll start again at 9:45 A.M. Thanks very much. Thanks for living up to my expectations and not discussing sport and rubbing my nose on it. Thank you very much for that. Welcome back. When I joined Telix, the CA IX or carbonic anhydrase IX program, was the target I was most excited by. Why? Because of its potential to affect the tumor microenvironment and its potential pan-tumor applicability. CA IX 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 CA IX in a very sensitive and very specific way, particularly in the recent ZIRCON Phase III study.
Whilst CA IX 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. CA IX has the potential to show pan-cancer applicability, both diagnostically and therapeutically. This is what we're exploring in the STARBURST study, which I'll come to at the end of this presentation. I want to briefly go over the science and the background of CA IX expression. In normal oxygenated conditions, HIF-1α, Hypoxia-inducible factor 1-alpha, is degraded. Under hypoxic conditions, as seen in many tumors, that HIF-1α is overexpressed, and this leads to upregulations in other genes, such as CA IX. What does that mean to the patient?
The CA IX expression may lead to treatment resistance of the cancer and poor prognosis, that tumor microenvironment, that ecosystem, creates hypoxic conditions that can help a tumor survive and develop resistance to therapy. The CA IX 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. We know we can effectively target CA IX with TLX250-CDx or zirconium girentuximab, the antibody imaging target for CA IX. Girentuximab is a monoclonal antibody and thus cleared by the hepatic biliary 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.
In previous studies, we've shown that girentuximab has the ability to effectively target CA IX expression. Dr. Brian Shuch will be going in to further detail about the ZIRCON study, but I just want to touch on it because really, the results are exceptional. ZIRCON was a phase 3 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. 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 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 of 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 a worse overall survival. We have an extensive development program, both in imaging and, of course, therapeutics. 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, cabo and nivo, cabozantinib and nivolumab. STARLITE-2, here in New York, is in second line with nivolumab only in those patients who've 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, in these patients, a progression-free survival of eight to 11 months was 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-89 girentuximab scan, 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 spec scan, the 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, in this case, with the DNA damage response inhibitor, peposertib, in this preclinical model. I promised to talk about the STARBURST study, 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 imaged later this week. We know that girentuximab is an excellent targeting antibody with unprecedented sensitivity and specificity. We've seen that the lutetium antibody has demonstrated antitumor activity. We're taking this to the next level with different therapeutic combinations and looking at the potential to target multiple tumor types. I'd now like to turn it over to Dr. Brian Shuch, who joins us from UCLA today.
Thanks, Brian. As promised, he'll be going into greater detail about the ZIRCON study and the potential clinical utility of TLX250-CDx. Okay, thank you.
It is my honor to introduce Dr. Brian Shuch, expert surgical urologist in renal cancers. Dr. Brian Shuch is the director of the UCLA Kidney Cancer Program and the Alvin & Carrie Meinrath Endowed Chair in Kidney Cancer Research. He completed his urology training at UCLA, followed by a urologic oncology fellowship at the National Cancer Institute. He serves in leadership positions with various kidney cancer research organizations such as SWOG, NCI, and SUO . Dr. Shuch is a leader in translational research with over 160 peer-reviewed papers in prestigious journals including Nature, PNAS, and JCO. He was our lead investigator on 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 left for warmer weather, so I'm surprised they let me in the building, but good to be here. I'm excited. This is a seismic shift. You know, I'm 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. I'm really gonna just talk about some treatment perspectives coming from, you know, a surgical-minded person, and also talk about the imaging quality here. This is really gonna really be a paradigm shift over the next few years.
... just some disclosures. Just to briefly go over the ZIRCON study, the ZIRCON study was really designed to have three independent radiologists review imaging before patients went to the OR. These are three 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%.
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, you know, other cancers. I had a patient with a renal sarcoma, very rare, and it was very positive on that, on the imaging agent. That patient, unfortunately, had brain mets and died 6 months later. Okay, so am I upset that it was a false positive? No, I want to know about that. I think the data is actually better than what will be published. 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. Everyone said, "What about the very small lesions?" These are the ones which pretty much are enriched for more benign lesions. 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. Really, this pivotal Phase III study really exceeded its primary endpoints, which were both sensitivity and specificity set by the FDA. There's really good interobserver 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 is, as surgeons, we sometimes harm patients. This is an agent which hopefully will kind of decrease the unnecessary burden of surgery in some patients. Just going over our patient journey, you know, we do see more and more patients. You know, this is not, you know, 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 three or four times more kidney cancer today than really ever before when you look at the rate per 100,000 people. That's because, you know, you sneeze and you're in the ER, and they'll scan you. You have chest pain, and they'll scan you, and it catches your kidney. Actually, the increased use of imaging is directly correlated to a nephrectomy. In people in the Medicare population, about 43% of patients in a 5-year period will get imaged in their chest or abdomen. If you go to the ER, you know, you probably want to not be imaged unnecessarily. It's hard. We are in an era of defensive medicine.
We call it CYA medicine. A lot of patients get scanned, and lo and behold, we're found with something which maybe we wanted to know about, and a lot of times, maybe we didn't want to know about it. 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. 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, and they got a chest CT, it catches part of the kidney. Maybe a patient had lower back pain, and they got an MRI of their back, and lo and behold, something's seen in the kidney.
We always have an opportunity to say, "Hey, should we order more imaging to get more workup?" That's really a point where the scan, if available, will be, you know, the urologist will say, "Hey, I have an image showing a kidney lesion. Let me get more information." Then there's really high variability of management, really depending on who you see. Some people will just cut everything out, other people will be more thoughtful. 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. You know, why girentuximab, why the 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, you know, a common phone on 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. 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. A lot of these non-clear cell subtypes are usually 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. Most of those are indolent. Just looking at not looking at anything like size or stage, just histology, you see that clear cell is going to have worse prognosis. A lot of these other less common subtypes, we're talking about maybe less than 1%, they're going to be rare, and usually when they present, they're usually much worse and not localized. 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. In kidney cancer, we have not done that often.
Some of the reasons why our radiologists, despite being very good, a lot of times they're swing and miss, okay? About 10%-15% of patients will have a biopsy, will have a large needle put probably 10 centimeters deep into their back, and there'll be an insignificant amount of tissue, so it'll be a non-diagnostic biopsy. There are a lot of errors. There's some sampling errors, sometimes part of the tumor might be necrotic, or there might be, you know, a part of the tumor, which they say is, you know, poorly differentiated, we can't tell, or the immunohistochemical profile will be unclear. Sometimes the pathologists, you know, are not willing to make a call. 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 kinda resembles their third most common type of kidney cancer, called chromophobe, which is pink. A lot of times, urologists say, "Well, why am I gonna do this if it's gonna be non-diagnostic, and it's not maybe gonna change management?" For many years, we've just not done biopsies, and we've led to this wives' tale that it's really super harmful. In reality, there are some complications, but when we need to do it is safe. The complications we have to discuss, hematomas, transfusions. Transfusion's 1%, it's rare, but most patients do get a small hematoma. Pneumothorax, you know, patients are breathing. They're breathing, the needle's going in, well, their lungs could move, and they could get a collapsed lung. Then there is seeding. A needle can come in and pull some tumor out into the fat.
You know, 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 track, and there have been some rare horror stories. About 10% to 15% of people in the United States do biopsy. In other countries like Canada, there's some centers which biopsy everyone. What about our guidelines? Our clinical guidelines right now are just based on, you know, there's a suspicious mass, maybe do a biopsy, get some imaging, a CT or MRI. There's no mention of PET scan here, yet.
We have all our management, which is based on really, you know, location and size, okay? You know, I'm looking for a house, you know, it's location and size, but I wanna see the inside. I wanna know what is inside that house before I make a purchase. What about tumor biology? I would tell you that biology often is destiny. It's gonna determine, you know, who's gonna go and be in the NBA draft in 20 years when they're born, okay? If I'm 7 foot 4, you know, I have a good chance of being in the NBA. I'm unfortunately 5 foot 10. And the draft's tomorrow, if you guys wanna watch in New York.
In terms of our, kinda 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 mass, there's an algorithm to move forward. If I do the girentuximab, a zirconium-89 PET/CT, it will clearly either be positive or negative. There were really no equivocal kind of cases here. You'll see later on, the imaging is very strikingly bright or strikingly, you know, absent. If you do have a positive scan and you're a candidate for treatment, you know, why would I wanna watch that tumor? If I'm young and I'm healthy, I potentially would wanna just have it removed. If I'm older and maybe not as healthy, maybe I'd wanna have some less invasive modalities.
We have other treatment modalities, ablation or stereotactic radiation, new treatment modalities, ultrasonic treatment called histotripsy. A lot of these newer other technologies are effective, and we know that clear cells grow on surveillance. Patients always ask me, "Why would I wanna watch it when I'm just gonna get older and sicker when I need treatment? Why wouldn't I wanna treat it now?" 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. It does enrich now for more benign, more indolent histologies, and maybe those are the patients I would wanna get additional information on. Maybe I'd wanna consider biopsying those patients because I wanna try to find an excuse not to operate on them.
We do have a large number of patients who have cystic renal masses, these are patients that are, we call Bosniak, you know, two Fs, threes and fours. 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 wanna get more information. 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. In those patients, if it's positive, I'm going to probably consider treating that patient with a treatment modality.
If it's negative, those patients who have, you know, a higher risk of benign disease, I'm probably gonna follow them. Clearly, having this imaging agent available upfront on most of these patients is gonna be quite useful. Now, just to summarize, well, 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 toolkit. We do believe this improves the identification of clear cell kidney cancer. Compared to, you know, the current sensitivity and specificity of CT and MRI, this is clearly better, and it's very safe. More information is going to lead to more appropriate treatment. We remove about 5,000-7,000 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 two in the hospital, other than that, they really may not have benefited from surgery. 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 gonna try to do it rather than offer patients a biopsy. I think it'll help us risk stratify patients and decide who really is most appropriate for management. 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, you know, give you quality information?" I just want to kind of put it out there, what our current imaging does and doesn't do.
What do we want to know as surgeons? Well, we want to know about stage and size, okay? 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. 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? Our current standard imagings, you know, besides the MRI and CTs, there are things out there like FDG or other nuclear medicine study, one called the SPECT/CT, not really that great. 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.
The ability to give patients information on benign and malignant is not that reliable. About, you know, looking at the sensitivity and specificity, about a third or quarter of our cases are clearly going to be mischaracterized. The sensitivity at best, you know, 65 to, you know, one study 85, it really doesn't compare to the data in the ZIRCON study. These are 2 of my patients that I treated. Imaging does not tell you it's malignant. These are 2 patients, one is a 2-centimeter mass, one 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, you know, both of these actually are malignant. Again, the imaging anatomically just gives you a level of suspicion.
It doesn't give you the information about what's inside that house, okay? Here's just three patients that were on the ZIRCON study, and basically, this shows you three different examples, looking at the coronal PET/CT with a very bright uptake of the agent. The CA IX , again, is upregulated in clear cell kidney cancer, which 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. girentuximab binds CA IX . There is very minimal uptake in biliary epithelium. It's not enough that even on a therapeutic study, there was any, you know, concern of any GI toxicity. On this study, there was no toxicity other than really surgical toxicity.
This is really a really high-quality imaging agent, and our nuclear medicine said, they, you know, docs say this is among the cleanest target that they've worked with, and they're very impressed by the image quality. What about the high performance? 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. On your imaging, you know, it really confirms that it is going to be a non-clear cell kidney tumor. If you do immunohistochemical, there's no CA IX 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. Clearly, it's either going to be very, very bright with uptakes, the SUV uptakes on the trial, you know, anywhere from, like, 30 to 80. The negative, they were just, you know, there was not even a question. This leads to very, very high interreader reproducibility. Again, on the trial, you had three independent readers, and the outcomes were outstanding. What about FDG? You might say, "Can we use FDG? Is that something that's available?" Yeah, FDG is widely available, but if you see here, you know, the whole kidney becomes bright. 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.
You see on the patient on the study, they got the TLX250, and clearly, there's a clear cell kidney cancer there, and, you know, patient went for a partial nephrectomy on study. Maybe if the patient in, you know, in the future would go on active surveillance, that lesion would grow, and maybe they would not be a candidate for a partial nephrectomy. I think it's getting the patients the information they need and the surgeon the ability to make more informed treatment decisions. Now, from, you know, 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.
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, you know, 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 at diagnosing cancer. You know, I think the performance in the very small kidney tumors, the 1 to centimeter masses, are going to be, you know. We showed that before, it's outstanding. It's just as good as the large lesions. I think this is a game changer in the field, and I'm really excited to get my hands on it clinically, outside of the trial.
We just need our folks to get this approved in the next few months. Okay? Great. Thank you.
Okay, we'll stay here and... Wonderful. Thank you so much, Dr. Shuch, for your insightful presentation. I'd like to get your thoughts on the potential impact of the ZIRCON trial results. What is the scale of the renal size, potential patient population that could potentially benefit from this scan?
That's a moving target because, unfortunately, people are not getting any smaller, okay? If you go on the airline, you know, it's a more crowded space because people are getting bigger and bigger, and the obesity epidemic and the aging population is actually making our rates rise. It's gonna be about 80,000 new diagnoses a year, kidney cancer. 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. If you put them all together, it's gonna be at least 110,000 patients a year are gonna be diagnosed with a renal tumor. Again, you have an opportunity, you know, to impact them once. These patients, you know, there's a large number of them.
The prevalence of kidney cancer is much, much higher than just the incidence.
That's great thoughts on that. You know, you mentioned a little bit on the patient journey. How are patients being referred to you for the clinic?
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. Another doctor is doing a workup and say, "Hey, I just did a workup for, you know, chest pain." I did a, you know, imaging of their 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, could be a direct referral from their primary care, or it could be another specialist who's doing a workup and finds a lump on the kidney and knows they usually need to send them to a urologist for further characterization.
The referrals can come in from all sorts of different directions.
Yeah.
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?
It's very variable. I mean, there's some doctors who just take everyone to the OR, right now with the absence of very reliable tools like the TLX250 imaging agent. You know, in my office, I always, you know, try to give them the information. A biopsy is available. We don't wanna do a biopsy in a lot of patients, these are the reasons why. We offer patients, you know, 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. 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 gonna be something that our guidelines, you know, as a member of the NCCN guidelines will tell you that people are hungry to give patients more information to make more informed treatment decisions. I think this fits in nicely on our diagnostic workup, before treatment decision, algorithms.
You mentioned that some folks will undergo biopsies or even surgeries. 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?
Biopsies, you know, again, I said it, they're not 100% accurate. There's a lot of limitations in the U.S. It might be 9-15% of people biopsy. My good friend, Tony Finelli, in Toronto, he biopsies everyone, and he says the era of biopsy in his hands now is over, okay? He is no longer gonna 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. I'm going to offer this to everyone where I feel that a biopsy could have been undertaken. For treatment, again, I think this is going to give us more informed. Not every patient needs surgery. Other patients could be followed by active surveillance.
Other patients may be followed by ablation. 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 gonna be very aggressive, and a patient wants treatment.
You mentioned the treatment stratification. From your perspective, from a surgeon, what is it, the information that you're looking for that's gonna help you better inform?
Yeah, I mean, again, we get size and location, but the idea we get some biology and biological information before treatment is gonna help. There are some tumors that are gonna be deep and central. I can't take a margin, and if I know a tumor has more aggressive biology, I may not wanna 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? It's gonna help me decide maybe who should have a partial nephrectomy, who's gonna have a radical nephrectomy. 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 decision.
Even for you might say, "Hey, this patient's going to be a surgical candidate," I still want to use it, and I also have the added potential that I can maybe stage patients a little bit better. You know, that wasn't part of the trial, but there's massive potential to stage patients. 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. 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 practice of medicine currently?
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%. That comes out about 5,000-6,000 cases a year in the United States that patients have a partial nephrectomy for a or radical nephrectomy, God forbid, for a benign tumor. 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, you know, treatment modalities, but that's a lot of patients.
We actually estimated there's about 20 patients or 30 patients who are actually dying from surgical complications, you know, from unnecessary treatment, and that's pretty outrageous when you come to think of it. The cost to U.S. society, we estimated about over $150 million in U.S. charges for removing benign tumors. You know, I think we have probably more, you know, we can invest that money with, rather than on unnecessary surgery.
Following up on that, what do you think about the ZIRCON results and how that can impact this over treatment with unnecessary surgeries?
I mean, again, the data speaks for itself. I mean, the positive proof to value, I think 94% is awesome. Again, if you consider that it also, those false positives were actually really cancer, some of them very aggressive, I mean, I'm gonna use that on everyone. The ones that are negative, I'm gonna 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 wanna know, and they're anxious watching it. I have other scans that we could use that are occasionally reimbursed, 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, knowing 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?
Biopsies, yeah, we're not the ones who do the biopsies, so we, you know, we'll probably do less referrals for biopsies. At the end of the day, you know, urologic surgeons like to operate, but we also don't like to do unnecessary surgery. You know, again, sometimes we take a lesion out, and it's depends on, you know, how you spin things. Like, you can say, "We got it all, and it's benign." I think of it as, you know, I did unnecessary surgery, and I, you know, may not have helped you. I do think that, you know, when our guidelines change, and we say this should be incorporated, you know, I consider in our field, we may start considering these things never events. You know, it's clearly a never event to remove the wrong kidney, okay? I'll get fired for that.
I think in the future, when you take a whole kidney out, and it's ultimately benign, I think it's gonna 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. Well, how can you justify that when you have a tool like this?
Where do you see the other potential for this imaging agent?
I think staging is going to be, you know, 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, you know, going through our 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. You know, it's just, you know, it's good in prostate cancer. We have other... You know, 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 radiate them.
We cut 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 phenomenon. You know, we're gonna be reclassifying patients into different buckets and giving them more appropriate management. 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, you know, alpha emitter, beta emitters, you know, to kind of treat patients.
You know, I'm excited 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, then I only operate on the ones who are not doing well or progressing. I can go to the beach. I don't go to the beach enough. Yeah.
What do you think about the guidelines currently? Where do you think it'll fit in, and do you think that this will change rapidly once this agent gets approved?
I mean, our clinical guidelines don't have much about PET. It's actually nowhere. I do see, you know, for NCCN, I can only speak 'cause I'm on those guideline panels, also AUA, they're very rigorous. 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, T, you know, renal mass. I see that first panel being the workup of the renal mass, it's probably gonna be a no-brainer. This is an agent which has very high sensitivity and specificity for the workup of a indeterminate renal mass, and that will be something I think will be looked at very, you know, 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 gonna be different things added, hopefully, different parts of the guidelines. Right now, in that workup of the indeterminate 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, from the webcast.
Brian, hi.
Hi.
Can you hear me?
Yep.
Just... You mentioned just a minute ago that with a negative scan, you know, 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?
In terms of... A lot of it depends on the patient. If I saw Mary here, who's healthy and fit, you know, I would probably wanna get more information because I wouldn't wanna miss it. If you look at it in a patient who's like, you know, like my mother, my mother has a small renal mass, I'm following her, okay? I do love my mother, okay. If she had a negative scan, I know that she's 75, and she, you know, has had a stent in her heart. I'm gonna feel more confident, probably just doing active surveillance and not getting more information.
If someone like Mary, who probably ran eight miles this morning and, you know, you know, is fit, I don't wanna kind of just sit tight on something that has a chance of being malignant. I'd like to use the scan in her, and if it's negative, I probably wanna get a little bit more information, whether it's a multiphase MRI, multiphase CT. I can pull out the papillary lesions. I may wanna biopsy it, and then I can assure Mary she has another 60 years of life ahead of her, that, you know, I know what I'm dealing with.
Thank you. I feel very.
Yeah.
about that.
Yeah.
Are there any others?
Good morning, Brian. 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 we get an approval on this product?
I mean, I you know, there are companies that submit very often, try to say, "Hey, you know, we'd like you to reconsider this." Every year, there's submissions to the NCCN to look at the data. Really, the data is what leads to people saying, is this something which they approve? The level of approval, Category One, you know, Two A, Two B, there's different levels. I mean, again, if, you know, once this becomes, you know, available, you know, I think a submission to the NCCN and, you know, the AUA, the data is there. It's a positive study. I don't know how that, you know, you couldn't consider this, whether it's Level One uniform consensus versus Level Two, you know, majority consensus.
I see this being, you know, something which will be, people will be hungry for adding to the guidelines because it helps us improve care with, you know, and maybe spare people unnecessary treatment.
We have time for one more.
Yep. Yeah.
Hi, Dr. Shuch. Thank you for taking your time away from seeing patients to see us. I think, from the emerging data from ZIRCON, the key message is that histology is probably more important than size alone. The data really addresses the current clinical concerns around the overutilization of nephrectomy. My question is that, by looking beyond the initial staging and diagnosis, would you see the role of the PET on some of the use cases, such as post-systemic therapy monitoring?
Yeah, you know, there are 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, you know, we have actually really effective systemic therapies. About 10%-15% of patients now get a really good, either a complete response or a very deep partial response. They go on their, you know, CABONIVO, their AXIPEMBRO, their LENPEMBRO, or IpiNivo. Now triplet therapy, you know, 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 you know, a lot of patients have a really deep response, and there are a couple of spots here and there, do you start biopsying lesions to see if they're actually alive or active? If this tool was available, it would be an agent where you would image patients. You'd be able to probably say, you know, what is their actually disease burden. If you see very little left on your scan, then you potentially could consider and maybe, you know, whether it's making the treating oncologist feel more confident about stopping therapy, or 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, you know, the willingness or to make treatment decisions, but the cost to keep a patient on therapy for a month, you know, a month of, like, pembro is, like, $20,000. 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 an honor to introduce Dr. Tagawa, a leader in prostate cancer theranostics. Scott Tagawa is Professor of Weill Cornell Medicine and led the early phase clinical trials of the anti-PSMA radioimmunotherapy J591. Dr. Tagawa's research 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 radioimmunotherapy 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, Doctor.
Thanks, Mary. Thanks for the presentation. I'm gonna make one final comment in terms of CA IX targeting. The end users, the doctors that order these tests are the same for PSMA. we're used to already ordering the nuclear medicine test. I think that's going to be one extra advantage, as well as getting prior approval from from insurance, which is painful, but we're used to it now. Switching targets, PSMA. Disclosures, leave that up for a second. Does include Telix and everyone else, kind of. I think that it's highly unlikely that most of you have not heard of this, but just kind of as an introduction 'cause there are different terminologies.
PSMA, I think you know what that is, a cell surface protein, or 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, brushed border of the small intestine, and proximal renal tubules. TRT is one of the terms that we use for targeted radionuclide therapy. We're targeting PSMA, give a systemic infusion intravenously. There's two 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 alphas are gonna 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. Generally speaking, there's large antibodies and small molecules. They both land in PSMA-positive tumors, but their kinetics and biodistributions, 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. I describe PSMA as a very specific lock. Think of it like the Yale Club. There's one door, I forget the name of this room, but one door that has PSMA on that. We can float in a key that's gonna go around and only be able to enter this door. Okay. 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 prospective trials, 2021. I think you all know the final results that led to approval, the dual primary endpoint in VISION overall survival, as well as radiographic progression-free survival, and then therapy with endpoints that were largely PSA-based, although the secondary endpoints are important, too. 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 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 cost, about the adverse event that you can see listed here. This is a table of some of the adverse events. I think that there are three 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 the most, but you can see the single highest grade AE happen to be anemia. 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, and its off-tumor, so dry mouth and nausea. We worry about the kidney. Luckily, we have not seen any major kidney signal, but we have very short-term follow-up, and if that's gonna happen, it's likely gonna be years out. Despite the higher AE profile, there is a maintenance of quality of life. These are the original ESMO slides. This was published three to four weeks ago in The Lancet Oncology. Despite the AE profile, a prolongation of time to deterioration of quality of 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 what Grade 3 dry mouth and dry eye is. It's horrible. 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, the problem with these Grade 1 and Grade 2 definitions is they're not very sensitive, and they may not reflect the patient experience. It may be that for some of these, that patient-reported outcomes are more important, and there's now something that's called FACT-RNT, published in JNM, 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. I think you spent most of the earlier morning talking about imaging. I heard, you know, I walked into the CA9. PSMA imaging can be a biomarker in many respects, I'm gonna talk.
Most of this is about theranostics. I'm gonna talk a lot about the first kind of bullet point. 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. The problem is that flat negative imaging can sometimes also have some efficacy result. I think that'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 intra-tumoral heterogeneity.
We can't tell that from a blood biomarker. That's a summary of the entire spectrum. A needle is not just even that tumor, it's whatever was in that needle from that tumor. There's advantage of imaging there. There's disadvantage. It is only that one point in time, and there is also a size issue, there's a significant increase in sensitivity from all these molecular imaging modalities. Things that were too small to really be apparent on CT, MRI, bone scan, or whatever else we're gonna do, or older versions of PET, still is dependent upon size. Individual small cells that have a ton of PSMA expression are not going to light up. That is a drawback, but something that we just need to know. We've just shifted what micrometastatic disease is.
Then response assessment. I think that's utilizing serial scans is not something that is prime time today. We do it sometimes, but I think that's, you know, especially in the world of prostate cancer, we're stuck with bone scans, we can only really tell progression. Well, now we might be able to assess response and really push the bar, is this interval patient sitting in front of me, benefiting? Even more broadly speaking, especially for this audience, speed up drug development. FDA has bought into this, and we're working with them on what's called Prostate Cancer Working Group 4. I have a set of slides from a year-plus ago. This is ASCO last year. Philip Kuo was the lead author, Andrew 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. 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. It turned out, just looking at quartiles, that number are 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 SUV mean was, you still do better than control. You get lutetium PSMA, you do better than not getting it, if you qualified for the study.
This is not necessarily 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 is also hidden in the background of the study. It is a combination therapy with 55% receiving abiraterone. 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 scans. 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. This is looking at both the treatment arm and the experimental arm and the control arm.
This has now, because of that, a predictive characteristic. It actually does envision in the updated data set from 2023, but it's not from 2022, that it is the brightness of the PSMA PET is predictive for outcome with lutetium PSMA, but not cabazitaxel chemotherapy. We validated what my colleagues at Memorial Sloan Kettering published many, many years ago, that FDG is prognostic. It doesn't really matter what we're treating the patient with, they do worse if there's a lot of bright FDG uptake. 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, those of you that may or may not remember, 1996 was the first diagnostic PSMA imaging agent approved.
Didn't work that well, as you'll see in the subsequent slide. There are different characteristics. Their physical properties lead to differences within the body. Antibodies are large, they circulate for a long time, which is advantageous and disadvantageous, but advantageous in targeting PSMA with lower expression. They target via the vasculature, which limits the kind of off-tumor PSMA exposure. Small molecules rapidly diffuse to 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 sites of expression, and I'll show you some comparative data. Unlike Capromab or In-111, Neil H. Bander, my colleague, actually, today is his retirement party. Developed 4 antibodies that bind to the external domain of PSMA, and they're rapidly internalized.
TLX591 went forward in terms of development. These different keys, these different targeting molecules, I talked about their different properties. What would we predict based upon them? Antibodies are large proteins, they might have an infusion reaction. That would just something that happens with all antibodies. Luckily, it's the minority, and it's not such a big deal, we did no premedication for the first 15 years or so of study, and it generally does never be on grade one, except for single patients, and 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 hepatobiliary system, particularly the liver, which could lead to liver toxicity. Luckily, we have not really seen that.
The small molecules. The benefit is rapidly clearing. They, because of the size, they are able to access the luminal surfaces of PSMA. The off-tumor on-target effects, the salivary glands, lacrimal glands, intestine, and kidney, although really it's the first three that we've seen so far in terms of toxicity. What we did is we compiled several different prospective clinical trials and then retrospectively looked at the data. 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." That's exactly what we found. Those physical properties do translate into the exact same radionuclide, lutetium-177.
Some interesting data that came out of us wanting to see could we combine these two PSMA targeting agents, is the binding uptake, and particularly the retention of the small molecules versus antibodies. You can see here, these different shades of blue are 3 different cell lines, essentially low, medium, and high PSMA expressing cell lines. Particularly in those with lower PSMA expression, the cell lines, there is significant difference in injecting today, seeing how much is retained within the tumor at 3 days. You can see significant differences comparing color against color. I'll show you why that is in a second. This is the fourth model, fourth cell line, very similar effects. Rapid uptake, tight binding, and then retention within the tumor over days.
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 is essentially goes into the lysosome, is retained. What happens is the small molecule binds, so let's say PSMA-617 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. Not optimal, probably for those areas with lower PSMA expression, as well as smaller volumes such as bone and bone marrow, which, you know, retrospectively appears to be the weakness of these small molecules. I'm not gonna go through this in great detail.
We performed a number of sequential phase I and II studies with, initially, just indium trace labeled antibody, followed by the beta emitters, yttrium as well as lutetium. We went forward with lutetium, including a combination study with docetaxel chemotherapy. This is a summary. I think you've all seen this data before, essentially, these are the phase I and II data sets, looking at either giving everything in 1 day or fractionated, giving it on day 1 and day 15, i.e., 2 weeks apart. Based upon the retention time and the half-life of lutetium, in my mind, the idea behind this is a dose-intense regimen, where there's continuous radiation over 1 month for a tumor, and that's what we do when we wanna cure the primary prostate cancer.
Clear dose relationship, the higher the amount of radiation that we inject, the better we have in terms of PSA declines and overall survival. More in terms of mild suppression, not so surprising. When we fractionate the dose, we're able to administer higher doses. Very similar, 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 salvage radiation. If someone has a prostatectomy, PSA goes up, whether we can see or not, we now can see it sometimes with the PSMA PET. Whether we can see or not, we know that some patients can be cured by radiating where the prostate used to be.
Not everyone is cured, and that's likely because there's some cells that are elsewhere that we can't see. We say, "Well, what about if we target all these cells with PSMA, using the antibody?" I do think that the antibody, this is one of the areas that with an antibody, is advantageous versus small molecules in very low volume disease, and this was M0 without PSMA PET. We know that PSMA PET would have been positive in a lot of these patients. Primary endpoint, having no metastasis visible at 18 months, and we hit that endpoint, you can kind of see in the, in the middle there. Better durability and, as well as numbers in terms of PSA decline.
Differences, as we'd expect in terms of toxicity, in terms of the gamma indium-111 versus the beta gamma lutetium-177. The first randomized data with lutetium, J591, presented as positive 4 months ago. Sometime we'll get around to publishing that. 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 with SPECT, and 9 out of 10 were positive, which we would, you know, more or less expect. The dose response, in addition to PSAs, we clear circulating tumor cells.
In that randomized trial, we can delay metastatic disease, 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. There's the myelosuppression. There's grade 4 sometimes. There's a fraction that may need transfusion or sometimes growth factor. It's very predictable. We as 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, 4-6 weeks later, but we know when it's gonna happen, so we know when to monitor the patient and to prepare for transfusion just in case, even though it's a minority that need a transfusion. Okay, this is now going beyond me. This is Telix's slides, but I know about this. J591, now called TLX591, you know, 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 is a combination study with an AR targeting agent, only one needs to work. Increase PSMA... and or radiosensitized, they both work even better for that regimen.
Next generation TLX592, so altering the TLX591 antibody, that may lead to improvements in terms of alpha targeting. You know, alphas and betas are just different. You know, I don't know that one is better than the other, just different. There are certain situations, I think that, one characteristic is probably better than another. Landscape. There's small molecules already out there, right? There's 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. One therapeutic, with likely, the move for that therapeutic earlier, with additional agents, coming out for metastatic CRPC, and maybe even, first diagnosis, metastatic noncastrate, what some people call hormone-sensitive, castration-sensitive disease.
These small molecules, radiolabeled beta are here and potentially moving forward. Just like I said, there's differences between antibodies and small... I'm sorry, alphas and betas. There are differences between antibodies and small molecules. I think there's certain situations where, in my mind, it's fairly clear that one is better than the other. Such as small volume disease, if we're looking in early disease, we're looking to cure patients, I think antibodies are gonna be clearly superior than small molecules. Certain areas, so areas with lower PSMA expression, such as the liver.
I think, and that's, you know, if you look at the four 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 the liver, you know, with the VISION imaging criteria. Overall, we know from my, from my colleague and former mentee, Himanshu Beltran, who published a couple of months ago, the liver is a site that overall, as a general rule, has lower PSMA expression. Areas that are small volume, such as bone and bone marrow, which is a weakness of the small molecule that I think are may be advantageous for the antibody.
The retention time also lend itself to patient-friendly regimens, such as the one single cycle, fractionated dose, that may work as well as four to six cycles of every two to four, I'm sorry, six to eight week dosing. Certainly more convenient, probably better for taxpayers in terms of Medicare and, or the insurers. I, you know, every drug is approved in the same setting, let's say, for chemo-naive mCRPC. Some patients are gonna want the two-dose regimen, some insurances are gonna have a preference for that. You know, there's every patient's a different individual. Patients starting off with low counts, maybe I wanna go with a small molecule.
I think there's gonna be room for both, but I do think there is, even if there's 3 different agents, 2 of them look the same, but 3 different agents approved for mCRPC, an antibody is different. Talk about retention. What you have side by side is a small molecule PET, and then the antibody SPECT. 2 weeks out, what you can see, it's being cleared through the liver, that's not a big tumor. The top right is the phantom image. That's not a extracranial tumor. What we 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 passed, but it's still active.
You can see. Here, we're not even measuring the beta component, which is the largest component of the lutetium. It's the 5% gamma. I haven't changed the images on the left. On the right, what you can see is 1 week out with a small molecule. This particular patient doesn't have a lot of bone. I would wonder if there's still retention in bone, and that's a study that we wanna look at retrospectively. There's still continued exposure to the PSMA-positive off-tumor sites. There's still, at a week, still continued exposure to salivary glands, lacrimal glands, small intestine, and kidney. Those will also persist.
Very clearly, there were some naysayers, maybe in the audience, because I know there were some investors that said, "PSMA, that's like, why would we invest in that? It's been around for so long, and there's no drugs. Can't be a good target." Now it's been validated. We know that there's several diagnostics, the first therapeutic, I think there's many more therapeutics to come, even outside of the radiolabeled space. Whether that's an antibody conjugate or a bispecific or a CAR T cell, I think that clearly, the target has been validated and/or de-risked, depending on your viewpoint. We can target both at antibodies and small molecules. I think there are certain settings where one is advantageous over the other. Overall, what I'd say very clearly is that they're different.
They have different properties, and me, in the clinic, I would like to be able to have multiple options to choose for the patients. We know that prostate cancer is a radiosensitive disease. It almost always has PSMA on it, and we can tell when it doesn't by these non-invasive tests, and there's a dose response. Well, unlike the only current available drug, the dosing and regimen of five nine one, it has been prospectively studied and optimized. There's room to go with optimization of the approved agent and others that are out there, but not sure that's ever gonna happen. Can we lead to cure? Can we give a high enough dose and rescue a stem cell or a combination or something like that?
I don't know, 'cause there still is some heterogeneity, the single agent, maybe not, but in terms of combination therapy, absolutely. Combination therapy could be surgery. 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. You know, I think there's advantages that are way down the line. Beyond prostate cancer, PSMA is expressed on the neovasculature of virtually all solid organ cancers, all these carcinomas, 90% or so. Targeting the neovasculature, I think, has some possibilities that's underexplored. Beyond PSMA, you heard about, I don't know, the whole morning.
Part of the morning was on CA9, you know, that's within the girentuximab realm, but there's a lot of other cell surface targets that are out there. Obviously, somatostatin has an improved agent, but there's a number of other ones that can be exploited. You know, my bias, and I'm not a nuclear medicine 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, it's a nice pair. Theranostics really is a term used for, in the purest sense, the same agent for both imaging as well as therapy. I think we can broaden that and use it as a diagnostic.
Whether it's a drug, an antibody project, or relabeled therapeutic, we can assess patient eligibility via an image, and I think there's major advantage for that down the line. I did, I don't know, 5% of the work, the rest was all done by these other people, so a lot of other people thank. I think that's it.
Great, thank you, Dr. Tagawa. I appreciate the informative presentation.
A lot of us sit down.
Oh, yeah! Sure, we can stay out here. Have a seat.
Good enough.
I have a few questions I wanted to get your thoughts on. Given the approval and availability of actually, more of approval on the PSMA-targeted small molecule therapies, where do you see the advantage for PSMA-directed radio immunotherapies like TLX591?
I think the obvious advantage is on the clinical side in terms of regimen. Finishing treatments within 2 weeks, obviously monitoring for the next month, I think that has some major advantages, particularly because, you know, I think you talked about PSMA PET, I'm gonna extrapolate. Whatever the agent is, whatever the setting is, very clearly, we are underutilizing PSMA PET in this country. 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. That, I think, is the kind of the obvious example, in the average patients with pretty high semi-homogeneous PSMA expression. The other subtlety, having both, you know, patient lives across the street, so we don't have to worry about the convenience, having both available.
I would think about if there is liver mets or if there's, mostly small volume bone metastasis, that to me, I would take advantage scientifically of the data I have without the head-to-head trials and say, "Okay, this is the patient that I think may benefit from... it's still lutetium, but it's an antibody delivery versus a small molecule delivery." 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. Certain, you know, we have been able to recruit. Out of all of the trials that we have, which 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 generally, I'll present, "Okay, you can have standard VISION, you know, dosing, or you can have this agent, which for these reasons, we think this is going to be better. It's experimental, so you have to understand that." Some will want this kind of standard of care, but the majority will actually enroll in a clinical trial.
Even post-approval and availability, you know, pretend there's no such thing as shortage, I think that any center that has these is going to be able to accrue. Then there's the other problems with in terms of shortages, et cetera, and as well as potentially for reimbursement. I had a patient, probably in the summer, several months after, actually, maybe in the fall. Wide availability, going to an academic center in the city, couldn't have access 'cause they couldn't get approval. We got approval 'cause we argued. I think there's a learning curve with that, too. I think, unfortunately, one of the reasons that patients are not getting PETs or treatment is because they go with initial denial, and they do something else.
I think that the more that we fight for individual patients, we can help them as well as hopefully change insurance.
Great. In that trial you were talking about, that's a small molecule trial?
Ve-
No, no.
We
Okay.
We like to say we have it all for PSMA.
Mm-hmm.
I think there's, you know, it's not just for some paper to get out there. I think that there are different advantages and/or disadvantages of different molecules.
Mm-hmm.
Whether it's an alpha or beta, different betas, different targeting vehicles, I think that there can be different uses and then combinations.
Mm-hmm. Yeah. Do you see the safety profile? I'd like to get your thoughts on the safety profile of the TLX591.
Three main ones. There's an infusion reaction component. Like I said, we, for our first couple hundred patients, did not pre-medicate, and then we started doing multicenter trials, and then we suggest, "Okay, go ahead and pre-medicate." Typically, acetaminophen and a H1 blocker, such as diphenhydramine or Benadryl. That will decrease it. I don't have the exact number, less than 5%. The major intervention, if someone has a infusion reaction, is put them on a blanket on them for 20, 30 minutes. It's usually not such a big deal, but just in case, that's something that's there. And the most common side effect that they walk out with is drowsiness from Benadryl. That's one component that is real, but is not such a big deal.
Clearance to the liver. In the prior studies, grade one AST or ALT elevations above the baseline, 'cause 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 as well. Clearly, mild expression... lack of significant so far, we've seen kind of the PSMA-related things, such as dry mouth and nausea. The major dose limit toxicity is mild suppression, and it can be high grade, you know, enough to say, "I wanna give this person a white blood cell growth factor. I wanna give this person a prophylactic platelet transfusion." 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. I know that depending on the regimen, it's gonna be at somewhere between 28 and 32 days or pushed out by a couple of weeks in the fractionated dose. We just prepare for it. We know to check. Most of the time, it's checking what is the blood count? Oh, it's a little bit low. Watch it closely, and we don't have to do anything other than monitoring. Sometimes it drops, and we give a prophylactic platelet transfusion, and we prevent any major sequelae. And, you know, if the end user is an oncologist, we're kind of used to that in terms of chemotherapy.
That's likely 'cause it's targeting the bony mets and the low-volume disease.
I think it's kind of on target as well as off target. 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 the small molecules is not so much the 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, you know, in what's called bystander effect, stem cells.
We have some time to open up to the audience.
Thank you. I'm gonna ask a really long and complicated question, so I hope you're ready. 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, let's say, like from the VISION population through into pre-chemo, through into hormone sensitive, and possibly even as far as neoadjuvant? Do the differences change?
The differences in the characteristics of the antibody and small molecules don't change. They're static. They're in the shelf somewhere.
The advantages or disadvantages of each?
Yeah. I would say that in terms of PSMA expression, I'd say that the risk or hazard of PSMA low tumors is higher with more lines of therapy, particularly AR-directed therapy. 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. PSMA is just a good target that's there. 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, we go way earlier to biochemical relapse or high-risk disease in combination with local therapy, that's where I think that the differences may be the most important.
Retention within the primary, to really get a high enough dose to the primary tumor. 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. That's where I think it may be magnified the biggest. Not quite there yet, but, you know, we're not seeing cures right now, and that's what I think it would take, is either some novel combination or earlier disease.
Dr. Scott Tagawa, can you put that you put up a data shot of some clinical records there, some outcomes there that showed the 41-month extension in survival. It was a 41-month median survival, in fact. Can you put that in context with what we saw from the VISION study and what to expect from ProstACT? Is the 41-month median overall survival a number that we can look at?
I mean, the data are the data.
Yeah.
I didn't-
I mean, I just.
I promise I didn't make it up.
The differences are so stark. I mean,
In one way, the clear limitation is 17 patients, right? 17 patients. The potential issues are beyond the 17 patients. During that era, new drugs came out. You know, some had fully been exposed to all drugs, but others hadn't had abiraterone and enzalutamide because they were alive long enough to get that upon approval. I don't think that is the major component, but there are. You know, new things will come out the longer someone is able to stay alive, which is why we like some of these incremental benefits. We go through, we only have 2 lines of therapy, then we have 5 lines of therapy. You can be live long enough to get line number 6.
Anyway, those are the kind of caveats with that. These were, you know, sicker patients, as a general rule, compared to what we'd see now in PSMAfore, SPLASH, et cetera, because these are typically only hormone-treated, SPLASH allowed chemotherapy. 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. It is what it is. I, you know, it's fairly clear. Regardless of that exact number, what's fairly clear to me is the dose response, whether it's all at once or the fractionated dosing, that incremental increase in radioactivity leads to everything being better in terms of efficacy, whether we're looking at PSA drops or survival.
We have to watch the toxicity as well.
Did you see responses in every patient in that group?
I do not remember. I don't think so, because I just think that's unlikely. I don't remember the exact data. I'm sure there were patients that had stable disease as kind of the best result. They're in the I mean, you can look at the publication because the waterfall plot is, well, at least one of the waterfall plots is color-coded. You can see the doses that they're on. I bet there's at least one in that cohort that had a PSA that went up as their best response. I don't remember exactly.
Just, I can't recall either, but with the upcoming ProstACT trial, is that gonna be earlier or later-stage patients than in the VISION study?
Earlier.
Earlier. Okay. Thank you.
Hi, Tagawa. I noticed that in the final slide, you mentioned the bispecific antibodies. I'm just interested in your view on the utility and the efficacies of bispecific antibodies, especially as seen clinical development of the PSMA CD28 and CD3 from Regeneron.
I've been disappointed, it's a work in progress. I think that, you know, I'm optimistic as an oncologist, I'm optimistic that we're gonna get there. I just don't think we're there right now. Where we're seeing the most responses, we're also seeing a lot of toxicity, including deaths, specifically with the CD28 one. I think we have to figure that out. It's different, clearly different. CAR T is the same, clearly different in solid tumors than in hematologic diseases.
Thank you, everyone. I appreciate your questions, and that's all the time we have, and I think we're moving on to the next section. Thank you. Thank you, Dr. Tagawa.
Tool that a medical oncologist can access and have influence over the utility. I think that's the disruptive opportunity for nuclear medicine. You know, we're working really hard to achieve that objective. I think you've seen from the presentation today that there's lots of evidence that we are achieving that. 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. Immunotherapy is the obvious one, but some of the stuff that's coming down the pathway with DNA damage repair inhibitors and PARPs and stuff like that, this is really exciting.
You know, when Andreas Kluge and I started the company, we believed in the value of antibodies because the number one objective, if you're really gonna do those combinations, is to residualize and retain that radiation so that you have the best chance of getting a treatment combination effect. I think we're gonna see data over the coming 18 to 24 months, which is gonna demonstrate, does that in fact work or does it not? 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. I mean, I just wanted to, you know, 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 two 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. 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 turn out to be strategically really exciting for the company. They 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.
elucidating of the bigger picture than just something massive that we tag on. Obviously, we also have a fairly large pipeline that we have to execute on. I do want to assure you that, you know, 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, you know, 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. 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. That was the impetus to turn a collaboration into an acquisition. We like to do that, by the way. You know, 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 wanna be more protective of? 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.
There's just a lot of exciting stuff, and all these programs now, or almost all these programs, are clinical stage programs. I like to think of this slide as what does Telix look like maybe five years from now? What are gonna 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. Some of the, not all, but some of the things that are on the slide will represent that future pipeline. There are some really exciting targets and opportunities in this research pipeline. It's Pride Month, so this is my rainbow slide.
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 and go, "Wow, you have a really complicated business." 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 initiative. Clearly, with PSMA and CA9 and LAT1, 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. I really have to acknowledge Mary and her team, who play 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, you know, a transplant of information. 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. 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, you know, see it, treat it, 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 gonna 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? 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, 'cause 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 gonna make Telix that sort of co- 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.
What's really neat is that if you subscribe to the fact that there's interplay between these kind of 4 pillars of research, there's some profound outcomes that are gonna 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 gonna become standard operating procedure, if you'll pardon the pun. We do believe that personalized dosimetry is going to matter. If we really wanna use these therapeutic agents at 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. You know, 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 gonna be an easy journey to undertake, but it's gonna be a clinically vital one to achieve. Patient response assessment, super important. Prediction, even better. I think CA9 is gonna 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 three times quickly, CA9 positive tumor, you're going to have a higher resistance to immunotherapy. The question is, what are you gonna do to prime that patient first? That's a really, I mean, that's just a blue sky for us. I envisage Colin's STARBURST trial as a kind of Loxo s tyle. You know, one day, we'll treat CA9 positive cancers. We won't choose a particular cancer. We'll use an imaging biomarker to select first.
I think that's just a massive opportunity. As you can see, you know, 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. 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.
In fact, it's, you know, I'm not gonna rehash one of Colin's slides, but if you know, 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. I think that I'm gonna be able to stand in front of you, Colin's gonna be able to stand in front of you in the next 12-18 months and say, "This is how the clinical data is supporting that vision for the company." I think it's an immensely exciting area. 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 one or two of these things right. I think there's just a ton of opportunity in our pipeline. I do wanna briefly address Lightpoint. I'm not gonna 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 know, you can never tell for sure.
You know, this is to address an elephant in the room of Illuccix, which is currently the indication for Illuccix, the main 2 indications, bookend a prostatectomy. If we want to really have that special relationship with the key stakeholder of Illuccix, which is the urologist, we need to have things that can go into the operating theater. 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's going to say, "Hey, where's my Illuccix scan? Where's my PSMA-guided intervention?" 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's about. 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 gonna 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? Surgery is not just taking out. Surgery can also be delivering a localized adjunct therapy as well. There's just, again, so much potential in this.
That concludes our session today, and we're gonna 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 three analysts that keep asking the same questions will ask questions, but they're pretty good questions, too, so I don't really mind. You know, these are the major catalysts that we have for this year. We're making good progress on achieving those catalysts. You know, drug development is not a perfect science, but I think we're executing pretty well to plan. We are still planning to submit two more drug approvals this year.
There's, you know, 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. The floor is open, and, you know, we're here to answer any questions you may have. Thank you in advance for your questions and for your time today. You know, they're very, very bright. Do you want some sunglasses?
Yeah, that'll be good.
Lower the lights.
Thanks for your time today, team, 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'd only 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?
It's a great question. It's a small increase. We predict about a 20% increase to our sales force. The great thing about our current sales force is the call point's the same. We're just gonna expand in a couple big metropolitan areas where we might need that headcount. The great thing is we have the urology call point that we're already in.
In the nuc med call point, we're already there. It's a minimal investment. We see about 20%.
Hi, Boris Peaker from TD 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? Also your thoughts and kind of first-year commercial adoption. Is it gonna 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. 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. I think there will also be potential to have discussions around active surveillance because that's characterization of a renal mass for sure. 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. That's the label. I'll hand over to the commercial team for the commercial aspects.
You want to talk about ramp? I can do it, whatever.
Well, I think that, given Kevin's team's 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, you know, people are waiting for this. I think there's a natural, a sponge effect, I guess. That'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. I actually, I think Scott said it really nicely when he, you know, 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.
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 customer site, we've got to hold in the hand of a customer.
Yeah, I think the question is, to kind of pull the two questions together, is 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. When we're in 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. We've talked a lot in my talk, I tried to go through a, the breadth and depth example of what we've got in the field from a cross-functional support. 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. What we're gonna get is this synergistic effect that we've seen in many other companies that commercially we've been a part of, is that you start selling the portfolio, the reason and the value. As you do that, and you think about this from an imaging standpoint, you know, the see it part and then the treat it part, we just become more valuable to them as we go. 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. In our Illuccix platform, that's one of our value propositions, is that we can take Illuccix to those markets and still treat those patients. We're gonna have those relationships out there because we have 200 points of distribution where we have relationships, and that local knowledge will let us allow us to really execute on that. It's synergistic in the round.
Also, I mean, everyone thinks that, well, people have been talking about PSMA for a long time, so that's a pent-up, you know. I mean, there's a decade of evidence. You know, nuclear medicine is not a fast-moving field because it's typically been underinvested. It, I mean, by the time, I mean, the first somatostatin therapies were done in the late sixties. I mean, and now we have Lutathera, right. 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. It wasn't, and there was a technical reason why it wasn't approved, and that's reasonable.
Nonetheless, you know, we took that asset, 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, you know, no thyroid blocking, lower radiation dose, you know, all of those good things that came from making a zirconium-based product. You know, we've really addressed the target product profile of the asset, and we're going in the door to a stakeholder that wanted that product approved, frankly, in 2015, 2016. When I started the company, I mean, I'd 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 got dozens of letters and support from, you know, 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. 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. Yeah.
Hi, Michael Sarcone from Jefferies. Thanks for hosting the event today. Just had a question or two on, you know, you talked about expanding the use of Illuccix to, you know, active surveillance and then planning for biopsy, radiation, and surgery. Can you just talk about, you know, 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, you know, docs are ramping up the use of scans? Would just love to hear about your commercial plan for getting there, and, you know, 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. Really, we see certainly in imaging, you know, 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. It's really a sort of three-pronged approach to develop all of those areas in terms of our own potential indications, but also guidelines and then establish use cases, data cases, publication cases that show the utility. In terms of the health economic arguments, I, you know, again, it's about coming away from this being just a one point in time diagnostic.
My sense right now is, you know, 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 that 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 gonna evolve pretty rapidly, but maybe I can hand over to the commercial team to talk about that evolution.
Yeah, I'll use the term medical necessity, and the way that's introduced into the market is typically by indication. Anytime you get a technology like PSMA gallium, physicians start using it where they see medical necessity. 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. That's where you see guidelines like AUA came out with expert opinion, and really two 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 and a half since it's been commercially available, and you're already 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 oncs. Our PSMA is touching at not only the urologists in nuclear medicine.
Yes
all the way through to medical oncology, but also in between. You can 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. We actually are seeing that. In the guidelines, actually, 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.
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.
That's a great point. Maybe we shouldn't underestimate the impact as well of, I mean, of 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. You know, how... If you think back 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 a really, it's a really tantalizing kind of indicator of what can happen.
I just, you know, 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. You know, we don't tend to put out a slide, right, with all the pharma logos all tiled across it. Like, doesn't serve us well to do that, particularly. I can tell you that if a partner wants a dose of Illuccix in a hospital in Shanghai or in Osaka or in São Paulo, I mean, we can deliver that to you tomorrow. It's there. I think that that's a really strong, that's a really strong opportunity. It's a unique opportunity for Telix. We had the great privilege of supporting the VISION trial.
We were, you know, 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. That's given us the credibility to be a partner and to deliver mission-critical imaging in those very, you know, very large global multi-center trials. That's gonna absolutely impact the way that physicians think about the longitudinal use of these agents. By the way, the same thing is gonna happen with CA9. Once we get approval, and once it's out there and it's readily available, now we have a, you know, I think a lot of literature that shows that this is a prognostic biomarker. If you have a high CA9 expression, you're going to have a, you're going to be less disposed to immunotherapy.
We're gonna 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. I mean, that alone is exciting, let alone the therapeutic pieces that are coming in behind.
Hi, this is David Oh, with Times Square Capital. I'm just wondering whether you could talk a little bit about how you're thinking about pricing strategy in the US and ex-US, and kind of along with that, whether you've tried quantifying an overall cost savings, if any, in both the US and non-US markets to maybe that's something that helps accelerate acceptance, adoption, commercialization.
Well, 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 a 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, you know, does result in a more price-sensitive market. There's, like, 2 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? Certainly, in Europe, we see a more diminished appetite to pay. Although I have to say, that's changing as well.
There's quite a lot of, there are quite a lot of reimbursement working groups now that you know, really understand that if there isn't the ability to pay for innovation, you know, won't happen, right? 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. 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 wanna sort of elaborate?
Yeah, we feel like the pricing in the US 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. We really see that, you know, from a, from a strategic account standpoint and integrated delivery network standpoint. 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 a integrated delivery network. 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.
I think longer term, I mean, 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, you know, it's a double-edged sword. If we really believe that, to your question before, that, you know, PSMA imaging could go from, you know, 3 to 150,000 scans a year to, you know, let's say 1.5 scans per patient on an incidence basis to 10 scans, just for hypothetical conversational purposes, that's not gonna happen without a shift in price. So there's gonna be a volume price trade-off there, and actually, you know, we plan for that. That's in our business growth strategy.
Remember, not the whole market is under pass-through. There's still VAs, there's 340B pricing, as well as commercial payers. The independent centers, because we're such a broad network and we provide, you know, out in the, in the suburban and the rural areas, there's a lot of self-standing centers, too, that are reimbursed differently under commercial and Medicare. 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.
Yeah. We don't really break down typically our R&D spend, but, for discussion purposes, I mean, it's public domain information, but, you know, about 25%-30% of our R&D budget is actually in lifecycle management of our commercial products. Illuccix is generation one, and it's evident in our pipeline. We've got other things coming down the pathway that'll, you know, enable us to come to market with fresh product ideas. we, you know, we have a very long-term category commitment to being a leader in prostate imaging. it's, you know, it's an exciting field to be in.
Hi, Sam Brodovsky from Truist Securities. Thanks for that color on the, on the market. That was really helpful. I know, Christian, you sort of threw out a theoretical scans per patient through their lifetime. Is that, you know, where do we think realistically that could go over the next maybe 3-5 years and maybe over the long term? Where do guidelines sit today in terms of supporting that? 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? Thank you.
I mean, I don't mind it's maybe starting it, and then 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, you know, how many scans per patient we're gonna get to. What I do know is that if we don't invest in the clinical studies to elucidate it's not just gonna happen, right? We invest in clinical trials, Mary's team supports a lot of investigator-led studies. By the way, that's, I think, a good industry-wide phenomenon, you know. To some extent, all experience with PSMA imaging is a good thing. You know, 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. 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. 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. In some markets, like in Australia already, it's already established.
You get, you get three scans if you want it. I think that there's... I mean, you wanna add something to that, Mary?
No, I mean, you can clearly see from the excitement around PSMA utility at ASCO, a couple weeks ago, SNMMI this week. All the abstracts that are being presented are a lot around PSMA with response to therapy, using it for outside of prostate and different tumors. You have it in serial scanning and in combination. You can see the explosion of excitement. Speaking to the guidelines, you have the major guidelines just last year, across the globe, SNMMI, EANM, EANO, a few of the SUO as well, all of them having a consensus around PSMA PET and have recognized it and include it in their guidelines.
I think you can see the evolution now with even SNMMI and NCCN, EANM coming together, having a more consensus language around having it as preferred over conventional imaging, recognizing it as superior in micrometastatic disease and detection, as well as now, SUO came out this year saying periodic scanning, recommending that, and also for patient selection, SNMMI and NCCN. There's a lot of Ns and Ms. 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.
My only add is that that was really quick from first commercial use, right? 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, you know, year or so of launch. It goes back to what they're deeming as medical necessity. You know, many times, industry puts great products out there with an idea of how it's gonna work and how it's gonna 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." You get that practice of medicine effect, where they start seeing medical necessity in other areas.
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.
Also, just the good news is there's a ton of investment now in scanner capacity. We're seeing higher. You know, I mean, the waiting list for scanners is pretty long because there's so many under order. We're also seeing an interesting. 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. It was always kind of the Germans versus the Americans, and you never got fired for buying GE, but, you know, the Siemens guys always did it slightly better. We're seeing really crazy market inversions where the Chinese have developed the most incredibly innovative whole-body scanners, 'cause you got to have an imaging center that's doing 100 patients a day.
That technology is now coming here in the form of things like the MicroExplorer. Of course, Siemens has responded with their Quadra system. 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, you know, 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. 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 a kind of a homogenous class. Then over time, performance and understanding of things improves. I think at face value, and it was a really positive thing when the guidelines came out, they're pretty equivocal. It was all about PSMA, and I actually think it's great that patients have multiple options available. That's what's gonna drive the field, that's what's gonna make this a routine part of much more extensive patient care. I actually think multiple vendors in the market is a good thing, broadly speaking. By the way, if there's no competition, it means there's nothing worth doing. I mean, that's, that in of itself is a positive dynamic.
I do believe, and I wanna 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, okay? That's not a product, that's an isotope, okay? What we're seeing now is a separation in clinical performance between PSMA-targeting agents based on F-18 and those based on gallium. 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. That is no longer a targeted imaging agent. That's a targeting imaging agent plus a bone scan. Readers need to be aware of that.
If they understand it, and they know how to read it may not be a problem. 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 gonna get three years of hormone therapy and targeted radiation, okay? 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. 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.
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, indeterminate, bone uptake, as well as large prospective papers and retrospective papers now coming to light. There is quite a bit of conversion evidence to support that.
Yeah.
I think it also, Just gonna add to the ZIRCON study, I think it makes the path forward for that, very nice because, you know, you've got a potential study those other studies that haven't met their primary endpoint, have extremely high inter-reader variability, and then contextualize that with the ZIRCON study that has a specificity and a sensitivity above 85% and an over 90% inter-reader agreement. I think that contextualizes ZIRCON study very nicely as well.
Chris, just one additional point, as it is F-18 based, we anticipate the same scheduling and challenges that you see with this centrally produced, you know, isotope today. Our ability to deliver doses to customers all throughout the country on time and allow them the ultimate scheduling flexibility will continue to be an advantage.
Yeah, 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, you know, is beneficial to them, and that doesn't go away with another entrant to the market, so. Look, you know, frankly speaking, we know that there's gonna be product number 5. We know who that's gonna be. We know who product number 6 is gonna 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.
It's gonna be established players with a track record of delivery, and good quality product that's got clinical validation behind it, that those are the players that are gonna blossom. I frankly think that's 2, 3. It's not more than that.
Yeah.
Hi. Question for Tom. There's lots of discussion here around product differentiation. How would you describe the market's urologists on the call pace, their knowledge of that? You see it every day, and.
Good question. I think it's the education that our team's doing daily. It's really the education of the urologist more about our product. We talked earlier about availability and differentiation clinically. 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. They have that urology background. We also have a team of nuc med techs as well. 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.
I mean, just to be clear, from a compliance perspective, we can't do comparative product positioning. I think the first time we've ever seen something really phenomenologically strange is urologists turning up and urologic oncologists turning up to nuclear medicine and radiology meetings.
Mm-hmm.
Right? Like, standing room only at PSMA forums did not come from nuclear medicine. It came from the customer of nuclear medicine turning up to really understand. 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 there 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. They're 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. It is an education process.
We have a great team, but we also have to be honest with you, it's kind of a shallow education process. You know, they kind of know where to look. By the way, the practice guidelines, they really do reflect the moving art of this field extremely well, as Mary pointed out. You know what? We don't have to do anything more as a company than just talk to the practice guidelines. That's what we typically... Well, that's what we're required to do, frankly.
Yeah, they have been very interested in basically going from black and white to the color PET/CT that they're seeing under, you know, they'd see versus a MRI or CT, something like that. They are interested in, 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's point, getting 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.
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 from black and white to color. They're like, they want to go from plasma to OLED.
Yeah.
You know? Yeah, they're highly engaged. It's, it's an easy, it's an easy conversation.
Right.
One question here, and I'll just go forward. Hi, it's the same analyst asking a different question.
You ask good questions, Maggie. Fire away.
It's very encouraging to see from the recent Cardinal Health Investor Day that they are committed into expanding capacity and have further investments into the Center for Theranostic Advancement segment. Appreciate that today is not a investor day for Cardinal Health, 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?
You want to take that?
Yeah, sure. I mean, there is a high level of interest as these radiopharmacy partners, and again, talking about two of the best two or three 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. We see a lot of investment. In fact, I think, I think Cardinal actually re-up 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. 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, so.
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 o'clock 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 out of your freezer, right? That is really the difference of the nuclear pharmacy model. 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.
We just see that localized delivery model as really powerful. We are committed to it, Cardinal Health and PharmaLogic and Jubilant Radiopharma and, you know, RLS Radiopharmacies 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 long, a real longevity in the relationship. Frankly, I mean, we love working with these people. You know, they're super talented, their sales teams are highly motivated. You know, we work together very closely. It's a very effective partnership.
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 you look at what Kevin's 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 this, by far the largest team. You know, that bodes well for the growth of our business, I think.
Yeah, 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, that really extends that. The local knowledge from our and value and the motivation of our independent pharmacies that we use to our 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. It's an incredible value when we specifically talk about PSMA and Illuccix imaging.
Yeah, good point. Got one more?
Hi. Just to follow up on the infrastructure investment, you had already made a comment about investments in PET/CT scanners and technological innovation. It doesn't seem like, you know, 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, you know, 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 three-step evolution in the industry. Today, we're just seeing the flex of the current infrastructure. That means extended operating hours, Saturdays, evenings, like, you know, people are packing it in. There's also, by the way, a lot more. You know, 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 the time of day is or what your patient load looks like. Today it's about optimization of the existing infrastructure.
Eighteen to 24 months out, you're really looking at, you know, the leading centers expanding their capabilities, you know, adding additional scan capacity. 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 standalone theranostic center, which we've never seen before. These are typically interdisciplinary practices that are only gonna 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, they're just popping up. Private, private nuclear medicine, private theranostic departments. They tend to start off with infusion and using local imaging services, and then eventually they go, "You know what? We want integrated control.
We're gonna bring in our own scanners. 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? 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. Because they're seeing that, they're already starting to talk to, you know, 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, you know, TLX250-CDx, it's TLX101-CDx. There's other things coming.
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. It's also infrastructure and technology. 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. We're getting even better pictures in shorter time. 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 gonna happen with 250 or 101, then they see that expansion happening, so infrastructure will start catching up and leading then.
I'm bounded to note that, you know, when you're dealing with a super busy imaging department, whether it's an IDTF or a hospital environment, okay, 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.
Mm-hmm.
Right? It's not like you're just trying to fit 1 or 2 patients in. You may have, like, 8 PSMA patients lined up for that day, and you have a failed delivery. It's devastating. I can tell you that for a customer, it happens literally once, and they will reevaluate their supply. With critical operating mode comes the critical necessity for reliability.
Mm-hmm.
That's where Illuccix just has. It's just in a league of its own. We do stat doses for competition all the time, every single day. In this city, we do stat doses for competition every week. You know, it's a, it's a really, great opportunity for us to show our differentiation. Then, you know, the cool thing about, from an operational perspective, we don't have Darren from the ops team here. honestly, he's the god of the company, I would say.
He makes the trains run on time.
Yeah. Yeah. You know, when we moved, you know, Illuccix was our training wheels product, as I said in the beginning, but wow, what a crazy bike to have a training wheel on. You know, 200 points of distribution for a product with a 4-hour half-life.
Mm-hmm.
When we get to 250 and the zirconium-based products, you know, we need about 8 dispensing pharmacies to cover the entire country. We actually deescalate in terms of complexity. What does that mean? It means that the reputation for delivery that we've built with our customer base is even gonna be more, reinforced. I think that's a, that's a great opportunity to build our corporate brand.
Yeah, 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? They've got scanxiety as they're sitting there waiting. Then to think you're gonna 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. It usually means they or the staff have to work a Saturday or fit it in even longer. That scanxiety just lasts even longer. That's why it's more important for reliability, is really from a patient-human standpoint.
Just do what you said you're gonna do, so they can time their life and manage it and, you know, get the results of their scan. Good or bad, people wanna know, so they can get treated.
If I can add just to, at 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. 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.
Yeah. That's a great point. Well, look, people have come from all over the place to be here as far away as Connecticut and as far away as Sydney. Both take about the same amount of time, I think. Really appreciated everybody being here and for your questions and your engagement. I think we're at the end of time. I believe there's some food outside. Feel free to ask any informal questions. Again, thanks so much for your attendance. It's really appreciated.
Thank you.
Thank you.