Good morning, everyone, and welcome to our R&D Day. For those of you I haven't met, my name is Annie Kasparian, and I lead investor relations and corporate communications across U.S. and Europe. It's a pleasure to welcome you today. Our presentation today includes forward-looking statements that are subject to substantial risks. Actual results may differ materially. You are cautioned not to rely on the forward-looking statements, which are made only as of today's dates, and we recommend you refer to these statements along with the risk factors across our ASX and SEC filings. Today, you will hear from Telix management, Dr. Christian Behrenbruch, Managing Director and Group CEO, Mr. Kevin Richardson, CEO for Precision Medicine Business, Mr. Richard Valeix, CEO for Therapeutics Business, Dr. David Cade, Group Chief Medical Officer, and Dr. Michael Wheatcroft, Vice President for Discovery Sciences.
I also wanted to point out or acknowledge that we have our recently appointed Chairman of the Board, Mr. David Gill, joining us in the audience today. In addition to hearing from our management, you will also hear from prominent key opinion leaders, including Dr. Alicia Morgans, Associate Professor of Medicine at Harvard Medical School and Director of Adult Survivorship Program at Dana-Farber Cancer Institute, Dr. Varun Sundaram, a surgical urologist and advanced prostate cancer specialist at Urology Austin, Dr. Sumanta Pal, also known as Dr. Monty, Professor and Research Co-Director of Kidney Cancer Program, City of Hope, and Dr. Arthur Braat, Associate Professor at University Medical Center Utrecht. Our agenda today will begin with a strategic overview by Dr. Behrenbruch, followed by an update of our R&D capabilities and pipeline. We will then move into prostate cancer portfolio, where we will hear from both management and our clinical experts.
Dr. Morgans will provide an update on the TLX591 program, while Dr. Sundaram will discuss the BiPASS study. We will take questions specific to TLX591 program immediately following Dr. Morgans' presentation since she will join us virtually. All other questions will be reserved for the dedicated Q&A sessions. On renal cancer portfolio, you'll get an opportunity to hear from Dr. Monty, and on brain cancer portfolio, you'll get an opportunity to hear from Dr. Braat. Dr. Behrenbruch will share some closing remarks, after which lunch will be served. We encourage you to stay around for lunch. Today's event is being webcast live and available for replay. With that, I'd like to introduce you to Dr. Behrenbruch.
Thanks, Annie.
Of course.
Good morning, everybody.
Good morning.
I really appreciate you coming here today to join us for this R&D Day. We are trying to get into the habit of doing this on an annual basis. I think it is a great opportunity to get you up to speed on what is going on in the company. Very grateful to our KOLs who are here today, managed to carve time out of their really valuable clinical time to be here, s o extremely grateful for that. Thank you. I was going to say next slide, and then I realized I had to drive it myself. First of all, this slide is Telix in a nutshell in terms of our corporate strategy. As we have built the business over the last 10 years, these different pillars of the business have come into real focus. Today, we will talk about the precision medicine business. It is an incredibly important part of what we do.
It's the way that we finance our R&D and infrastructure growth, but there's going to be a strong emphasis today on the presentations around our therapeutics pipeline, which given the historical investor focus on the revenue-generating part of the business has perhaps received less attention. Part of our goal today is to get you up to speed with what the latest activities are across some of the really exciting data that these programs are generating and to help you to understand disease focus areas that are important to the company. One of the things that's also evolved over the last, I guess, two, three years is really a purchase price premium on early-stage assets in the radiopharma space. When I started the company over a decade ago, didn't really have the appetite to do really early-stage stuff.
It felt like there were enough assets and opportunities out there without having to go into the lab. But we now feel that there are opportunities and reasons for looking at novel targets, looking at novel targeting methods, and so we'll touch a little bit on that today. In the last couple of years, we've made some transactions that are around building that in-house capability. I'm grateful to be joined today by Richard Valeix and Kevin Richardson, who really represent the commercial drivers of the business. Kevin in particular leads our precision medicine portfolio. But we see the commercial organization that we've built as an asset to our organization, just as definitively as our infrastructure or our pipeline. Nuclear medicine products are not typical pharma products. All right?
The way that we sell them, deliver them, educate, it's really about delivering a clinical workflow all the way from a dose being delivered to the loading dock of a hospital through how do you calibrate a scanner, do dosimetry, manage a patient, radiation safety, and even waste recovery. This is a really unusual business, and that's why the emphasis on supply chain and manufacturing is so important. If you can't reliably deliver a dose, whether it's a diagnostic or a therapeutic product every single day and manage the whole delivery process of getting that into clinical practice, you actually don't have a business. It's astonishing how few people in radiopharma really understand that. Today, we have three approved products. Really excited, and I realize it was a little time coming, but really excited to have gotten Pixclara approved last week.
This is an important product for neuro-oncology patients in the United States. We do intend to expand the availability of this product globally. Pixclara builds on the very vibrant franchise that we built in prostate cancer imaging. We were second to market, but we really believe that we are delivering as the market leader in this space. You're going to see some fantastic discussion today around what we're doing with BiPASS, which is a step change in prostate cancer. Our two-track or two-product strategy has proven to be very successful in terms of managing the reimbursement dynamics in the United States . This is really how the growth of the business has evolved over the last couple of years. As you can see that we've really built a vibrant business, but the growth drivers for our precision medicine business will continue.
I think in particular, I think a particular note, aside from getting the resubmissions and commercialization launch of Pixclara and Zircaix going, the step change in our business that you are going to see come out of BiPASS and the operational and margin benefit of running our own nuclear pharmacy network is something that is really starting to take shape for us. You would have seen in our half-year results, RLS went from being the fifth-largest distribution partner that we had at the time that we acquired them to the second largest. When we put product volume through our own nuclear pharmacy network, we not only have greater control over customer delivery, but it has a beneficial margin impact as well.
You are going to see as the company matures and evolves, that we are going to be a lot more selective about how we manage our distribution strategies in key markets. This is the company today. We are commercially active in 22 countries. We do supply product beyond that, but as a regulatory approved product, it is 22 countries today. We are expanding in 2027 into China. We have an NDA that is in review right now. We have agreed with the Japanese regulators on an accelerated approval pathway in Japan for Lu-6, and we are commercially active in terms of preparation for commercialization in Korea as well, s o really, if you look at the supply chain infrastructure, clinical capabilities that we built inside the company, it really is about servicing all of this.
Today, I am not going to talk very much about the ITM transaction, of course, in the breaks and whatnot, I am happy to take your questions. Just to note that this transaction really expands this footprint. ITM is commercially active in 65 countries, and we see the opportunity to push our product pipeline and slipstream that isotope availability and reach a whole lot more patients, as well as deliver to the next level of standard in the key commercially critical markets that we already serve. Our tagline is creating a global radiopharma powerhouse, and I could not be more excited about what the combination of the two companies will deliver, of course, subject to closing conditions.
We are a company that has grown through execution on our development pipeline, building a commercial team, but we also have been a company that has grown inorganically through strategic investment and partnerships. These are some of the key ones. I can tell you that all of the transactions that we have undertaken as a company have really led to the growth in our revenue and global reach. I am particularly, as I said, excited about the ITM transaction, but you will obviously be aware that we have a partnership with Regeneron, which will get a little bit of airplay today in the R&D day, as well as some of the enabling technologies that we have invested in, like ARTMS and IsoTherapeutics Group. These are acquisitions that are actually enabling these next generation of assets that you are going to hear about today to come into fruition.
When I think about the future, we believe that we are creating a radiopharma company that has really no peer. I think that there is a growing appreciation in the investor community that radiopharmaceuticals are melting ice cubes. The supply chain and distribution is incredibly complicated, and that customer delivery excellence matters, and you only achieve that if you have that vertical integration. Supply chains are, t here is no magic radiopharmaceutical or radioisotope store in the sky. If you are committed to delivering a pipeline, you have to have that infrastructure coming in behind it. I am not going to go into all the details, but between isotope supply chain, pipeline augmentation, and really the talent that comes through in this merger, I think that there is a really bright future for what the combined organization looks like.
Just to kind of wrap it all up and bring it back to my opening strategy slide, as we think about what does a business that has global supply chain reach, the best therapeutics pipeline in the industry, a cash generative business now on the precision medicine and the manufacturing piece. I think if you think about what the combined businesses look like, essentially it is a book ending of a therapeutics pipeline with precision medicine and manufacturing. Their isotope business is very profitable. It is cash generative. It is highly differentiated. There is not another radiopharma company that has scaled to deliver terbecquerel level of production output. When you see those two commercial businesses supporting the pipeline, you can see that the combined company has a very bright future indeed.
Exciting future and a lot to talk about and to understand over the next few months as we close that transaction out. That is it from me today, I just want to again reiterate, thank you for coming, and now I get to hand over to a very special guy in the Telix organization. Mike actually was employee number one of the company, so he has been here from the very beginning, and we have all aged appropriately, commensurately. I am really appreciative for Mike to come out today and give you a little bit of an overview on what is happening on the early stage and innovation side of the business. Mike, over to you.
I am never quite sure when Chris says a special guy. I think it is a positive thing, right? So I think it is positive. You will see the VP discovery sciences, some of the, been running the R&D efforts in Telix for a number of years. I hope to give you a little overview of, or a bit of insights into how we think about drug development and drug discovery, what goes into the design of a radiopharmaceutical, and hopefully not too much of a science lesson, but more of a guideline to what we think about, which is kind of slightly differentiated in the industry we see. I am going to spare you the slide where you have got a targeting agent and a radioisotope attached to a chelator and all those things.
But this audience knows that we have a targeting agent, which is the cancer-specific part, and the radioisotope, which is the payload. I think one thing that really doesn't get enough air time, if you like, is around target selection. The actual cancer target you deliver to is probably the principal feature of the actual drug. In terms of the therapeutic window of that particular drug is defined by that target, both in efficacy in terms of making sure you deliver enough radiation to that cancer cell, but also making sure it's selective enough that you're not hitting off-target tissues and creating a safety issue. All the good things we like in targets, so we want to have high expression, we want it to be very specific, we want it to have a high prevalence in the disease you're going after.
But one key thing as well we really look for in a target is the ability to internalize, to flip inside and drag the radiation inside the cell. That's how we get really great efficacy, by retaining that radiation inside the cancer cell. So Telix has got in its late phase portfolio, we have a number of really well-validated targets with PSMA, CA9, and LAT1, and FAP I'll add to that list as well. We're also starting to explore those novel targets in our early-stage research as well. So there are many different targeting agents you can use for delivering radiation. I think the key thing we believe is that each one has their different properties. They have a different set of properties, and it's somewhat of a trade-off of things like pharmacokinetics. How quickly does your delivery vehicle get into the tumor? How quickly does it penetrate?
How quickly does it clear from the blood? Also, how well does it internalize? I think this kind of approach, we value all these different approaches. It is a trade-off of these sort of parameters. So that's why Telix has this kind of unusual targeting agent-agnostic approach. We think that antibodies and small molecules all have their place, and it's about how you use them and for what purpose that really matters. For example, small molecules and peptides on the left-hand side of the screen, very small. They actually penetrate tumors really rapidly, and that's great, but they also wash out really quickly as well. They may not be as specific as, for instance, antibodies, which have a great specificity to cancer. They may be, because they use slow kinetics, they do take some time to get into and saturate that tumor with radiation.
Once they're in, that sort of sustained circulation alongside this ability to internalize and get into the cancer cell means that the cancer cell's exposed to radiation for a long period of time. So we get kind of length of time, length of exposure to irradiate that tumor is really a beneficial thing. In Telix, we're starting to also look at, we're always looking to optimize, and we're now looking at sort of what we think might be a sweet spot in the middle somewhere in this diagram with engineered antibody fragments called minibodies. So essentially, these are sort of cut-down versions of full IgGs. They're slightly smaller, and they clear quickly, et cetera. So we're starting to look at these as a new delivery format in the research and early clinical studies.
We have two minibody programs in early development, one targeting αvβ6 integrin and another targeting DLL3, both in different forms of lung cancer. This smaller format we think is really exciting because it can, not only has it kind of clear quickly, but that actually is shown in clinical studies that were done just down the road in Memorial Sloan Kettering Cancer Center. They have already validated this early-stage minibody. This has already been clinically validated in studies where you have shown really quite a faster, much faster uptake into tumors in this red line here on the tumor, compared to IgGs. When you think about the targeting agent, then think about which payload are you going to choose. Obviously, diagnostic versus therapeutic is a key one, the mission profile.
Really, the secret sauce here is matching a radioisotope with the properties of your targeting agent. Often you would choose your pharmacokinetics of your drug to match that of the decay properties of the radioisotope. This freedom to choose different targeting agents means we have much more freedom to choose a complete array of radioisotopes. I think, again, matching the targeting agent with the disease, with the isotope, that agnostic approach to not just sticking with one thing being best, but actually thinking what is best for the situation you are using it in. It really underpins that strength of that approach. While clinical studies have really shown the benefits of alphas in terms of potency, it does also have a very short path length. It does not penetrate very deep into tissue.
We think the optimal use of those alpha emitters will be around that early disease or small volume disease, micrometastatic disease. That can, we hope, will have a real great benefit in those sort of diseases. We still see value in beta emitters in those bulkier diseases or diseases where you may have heterogeneity, so patches of cancer and healthy tissue. The ability to crossfire radiation across those bulky tumors is actually a real benefit. The answer really here is that no one isotope is going to be best. It is really about what is the best application for the actual disease. When you have designed your molecule, and you may have the best radioisotope, the best radiopharmaceutical therapy in the world, but it is no use unless you can make it and deliver it.
It is no secret, as Christian Behrenbruch showed before, that we have been developing a Telix Manufacturing Solutions network, a TMS network, which is a global network of sites both serving radioisotope production, so acquisitions such as ARTMS help us do that. That is a technology that adds to any cyclotron to produce radioisotopes that are consistent and reproducible and reliable. No matter where you are in the world, you are getting reproducibility of that radioisotope raw material, which is something that often gets overlooked if you are using multiple different providers. We also have our own in-house production of certain isotopes, such as Lead-212, a generator initiative, so that we can fully support the full range of radioisotopes. Within TMS, we also have dose production and radiopharmacy, dose production and delivery.
Our RLS network across the U.S. is an extensive network to actually make our products and deliver them to sites reproducibly and reliably. That reliability and reproducibility of delivery is really important for both clinical and commercial success. I am very pleased to also announce that we have added a new facility in Melbourne, Australia, where we run a lot of our clinical studies, where we actually have a clinical manufacturing and imaging site. So actually now straying into the clinical utility, clinical dosing. Just to wrap up, one thing we wanted to talk about is that Telix's core strategy is about theranostics. It is about the interplay of the diagnostics and the therapeutics.
While imaging is powerful on its own, it really has a synergy with the therapeutics, both in terms of showing clinical proof of concept, the ability to look at dosimetry, to estimate dosing for the therapeutic. Also looking at are you dosing the right patient population, but as this slide shows, showing disease response to a therapeutic is supremely valuable. They work in synergy together as a theranostic. While we have a lot of emphasis on our commercial pipeline being diagnostics, what we are very pleased to be able to show is the progress we are making in our therapeutic pipeline. With that, I will hand over to Richard Valeix, our CEO of the therapeutics business.
Hi, everyone. It is my pleasure to be on stage with you today, and my role today will be to present to you an overview of the therapeutics late-stage portfolio that we are currently developing. Probably you are familiar with these slides, but what I wanted to bring to you today is really that Telix has probably the largest and the deepest portfolio under development currently in the radiopharma world. We can say that, as mentioned by Mike, we are a theranostic company because you will see that in front of each therapeutic compound, you can find a diagnostic one or a precision medicine one, as we are used to call that, because it helps to diagnose some disease, but it helps also to select the patients as patient selections, eligibility for therapy, and also monitoring the efficacy of our therapeutic compounds.
That is really a good synergy that you can see there, and it is illustrated with the pairing of a therapeutic and diagnostic compound. If we look at the disease areas that we are working on, you can see that we have a huge tropism and huge focus on the urology oncology, and namely, we have the prostate cancer treatment that we are developing heavily, but we have also some compounds in the kidney disease area. We will come back on these compounds during the presentations today. Really what I wanted to highlight there, it is the urology is really one of our core disease area and focus. We are also working in neuro-oncology, where, as you know, recently we obtained the marketing authorization for Pixclara, our precision medicine compound, and we are developing two assets in the treatment of neuro-oncology disease.
The first one is in recurrent glioblastoma, and as you know, it is a really debilitating disease where no recent approved drugs have demonstrated a huge value for the patients. Third, we have the pan-tumor, pan-indication compounds and targets. I will just focus on the 400. It is in fact a FAP compound that we acquired a year ago. FAP is currently under the sunlight, as you saw in the press recently. I really wanted to focus on the fact that we have here two compounds that we named the FAPs. We have a diagnostic compound and also a therapeutic compound. These two compounds have probably the most data published on the field. If you are interested, we can provide you the latest publication on these two compounds, which de-risk the development of that because we have already proof of evidence with expanded access programs in value centers.
The attention I wanted to bring to you, it is not illustrated there or perhaps yes, we have three phase III trial ongoing. Two in urology with ProstACT Global, in prostate, with LUTEON trial in kidney, and with IPAX BrIGHT in recurrent glioblastoma. That is amazing to have three phase III trial running in parallel with this portfolio. What I wanted also to highlight is something that Mike said, that with the recent acquisition of ITM and all the vertical integration that we have done recently, we have a platform that authorizes us to deal with antibody, peptide, and also more recently with mini bodies and nanobodies. That is for the targets. With ITM, we have also now secured the access for all the isotopes that we are dealing with in this portfolio.
You can see that it confers us probably a unique capability that even some competitors and big competitors that do not have yet. I wanted also to highlight some partners that we are dealing with. You are aware about the Regeneron deal that we made earlier this year. It is very interesting to develop antibodies with Regeneron, which is probably one of the most well-known company developing ADC drugs, and they have a pipeline of antibodies that it is difficult to imagine. We are currently dealing with four initial programs under development in a co-development, co-promotion deal that we have signed earlier this year. Currently we are extremely proud of that.
Very quickly, ITM, you understood that the deal has different dimensions, but if I look mainly on the therapeutic compounds, we acquired ITM-11, which is a phase III data which has demonstrated efficacy in neuroendocrine tumor, which is the first indication for radiopharmaceutical drug. That is very exciting to be capable to launch this new assets in neuroendocrine tumor. It will authorize us to start to work in therapy with these new compounds for the treatment of the neuroendocrine tumor. That is very exciting, and I can tell you that the team internally are extremely attached to that. Now, I will hand over to David Cade, our Chief Medical Officer, to introduce the topics related to our therapeutic compound in prostate.
Very nice, Richard. It is now my great pleasure to introduce the first of our four key opinion leader presenters, Dr. Alicia Morgans, who is dialing in virtually. Annie tells me that we might be just a couple of minutes early. Tell me if you would like me to flip the order, Annie. Dr. Morgans is an Associate Professor of Medicine at the Harvard Medical School. She is a genitourinary medical oncologist and the Director of the Adult Survivorship Program at the Dana-Farber Cancer Institute. As a clinician and investigator, Dr. Morgans has very extensive expertise in trials in prostate cancer, as well as patient-reported outcome measures, which we sometimes forget as a field.
This is an emerging area that is critically important to the way we design our phase III trials these days, the way patients flow through a trial, and what is important in terms of other measures that we do not think of. As well as that, Dr. Morgans is very focused on incorporating patient preferences and the beliefs into clinical decision-making outside of the trial context when she is seeing patients in the clinic at the Dana-Farber. Have we got Dr. Morgans online?
Yeah.
Yeah, go on? Okay. All right. Let us change the order slightly. Dr. Morgans is going to cover our TLX591 program. I will cover our 597 program. Before we go into discussing our small molecule candidate, TLX597, I think it is really important to understand and appreciate why we have both a small molecule and an antibody in our pipeline. To do that, it is critically important to understand the main prostate cancer disease states. Of course, it is a spectrum, but I think it is reasonable that we can categorize early and late prostate cancer and the implications for how we best manage our patients. Let me just go forward to. Okay, p erfect. While the pictograms here are highly simplified, they do illustrate the baseline characteristics of the two main populations of patients that we see in clinic.
On the left-hand side, we have patients with early metastatic disease. That is typically, not always, but typically of smaller volume, typically responsive to androgen pathway suppression with ADT and ARPI drugs. These patients are usually newly diagnosed, so they are otherwise fit, apart from early prostate cancer. Really the objectives of treatment are to maximize quality of life, to delay progression into the androgen pathway modulation resistant state, and to prolong overall survival as far beyond 5 years or 6 years as we can. They are really the objectives in this early population. On the right-hand side, we have patients with later metastatic disease. Their tumor burden is now increased. They have got bulkier disease. Their disease has now become resistant to androgen pathway suppression.
Our objectives of treatment evolve in this group of patients, really to now optimizing the combinations of therapy that are remaining for us to use, controlling bulky disease, and ultimately really prolonging the remaining usually two or three years of life that these patients have with acceptable quality of life. This slide summarizes our portfolio approach to metastatic prostate cancer, utilizing two distinct mechanisms of action that are really adapted to each of those two categories of disease state within the continuum of care. As the first-in-class radio antibody drug conjugate, TLX591 is administered in two doses two weeks apart, which really enables it to be layered on top of a backbone of conventional ARPI or taxane chemotherapy that a patient with metastatic APMR disease would typically receive.
So far, we have confirmed the safety of this approach from part 1 of our ProstACT Global study, as well as having confirmed the encouraging early efficacy of 8.8 months of radiographic progression-free survival in the earlier ProstACT SELECT study. TLX597, which is our next generation small molecule, on the other hand, is really designed to enable dose intensification and adaptive dosing. These are two very important points that I will go into in a bit more detail in a moment. Dose intensification and dose adaptation is really suitable for patients with earlier metastatic androgen pathway modulation sensitive or naive disease. These are the new terms for metastatic hormone sensitive and metastatic castrate-resistant prostate cancer. We use the new terms now. The aim with dose intensification and dose adaptation is to delay progression into the APMR state, while at the same time maximizing quality of life.
Now delving into TLX597 in a little bit more detail, you will see here on the right-hand side what is a very highly favorable biodistribution and pharmacokinetics of the small molecule. What you can see is that there is a very, very low uptake in the salivary glands. That is the the top smaller football there, and also very low uptake in the kidneys, which is the lower football. Give you a minute. Thank you, low uptake at five hours in the salivary glands and kidneys. A little green but very daisy chained prolonged residence time when active is in both the soft tissue and the bony compartments of the tumor, 597 presentation of the tumor volume. This pattern is quite remarkable, and it is really not what we have come to expect from the earlier small molecule radioligand therapies.
This is unsurprisingly reflected in the resulting dosimetry, with TLX597 imparting about a half the dose to the kidneys and about a third of the dose to the salivary glands while delivering about twice the dose to the tumor target compared to the current first generation small molecule RLTs. These are very attractive properties of this small molecule. Now some very interesting work. Go forward. Some very interesting work of the past, I would say, two or three years has highlighted two very important factors that may enable us to improve on what we have already achieved with the small molecule RLTs to date. Firstly, PSMA receptor density. The density of PSMA expression is an important factor in treatment response with lutetium PSMA therapy. Secondly, Johann De Bono's group at The Royal Marsden in the U.K. has shown that this PSMA receptor density can be manipulated.
We can markedly up-regulate that density in response to ionizing radiation like that from lutetium. You can see this, I think very clearly on the right-hand side. I think the pictures are crystal clear. This is a patient who has received two doses of TLX597 on day 1 and day 3. You can see that in the post-treatment imaging after the day 3 fraction, there is much higher total tumor volume on SPECT imaging. This is due to the upregulation of the PSMA target. The first dose has caused upregulation of the target, and when we dose again with the second dose on day 3, there is much more target to hit. This is a very attractive property that we aim to exploit with dose intensification.
This is the overall concept of dose intensification, using both a higher injected activity of lutetium, so 8.5 gigabecquerels, is substantially more than we would typically give. It is given in what I would describe as a compressed schedule on days 1, day 3, and day 15 instead of the usual schedule of every six weeks. This is to exploit that upregulated PSMA expression and the incomplete tumor DNA repair in the first early period after the first dose. To evaluate the potential of dose-intensified TLX597, we undertook the OPTIMAL-PSMA phase II randomized trial in men with metastatic mAPMR disease. This has been led by Professor Louise Emmett in Sydney. This is a multicenter study that enrolled a VISION-like population of patients who had received prior ARPI and chemotherapy.
We completed the enrollment in the study back in June, and anticipated the initial top-line readout around the time of ASCO GU in early 2027. That data is very eagerly anticipated. Let us now look at a couple of case studies which really illustrate why the OPTIMAL-PSMA data will be so interesting. This is a 71-year-old patient with very diffuse skeletal metastases who previously was treated with ARPI and two separate lines of taxane chemotherapy. There are two important points that you can see here. Firstly, the question is, can a dose-intensified regimen be undertaken safely? With TLX591 and a highly favorable dosimetry profile, it appears that the answer to that question about, can it be done safely, is yes. Specifically, we can see that this patient's kidney function remains normal and his bone marrow function remains normal.
They are two very sensitive indicators of the tolerability of an intensified regimen. Secondly, does a dose-intensified regimen seem to deliver clinical benefit? Here we can see a 97% PSA response at week 10, and serial SPECT imaging performed after each of those first four doses demonstrates very clear disease shrinkage. In this patient, this is a very nice example of the apparent viability of dose intensification. This is a second case, with even more pronounced skeletal metastases as well as infiltration of the bone marrow. In this patient, the bone marrow has been infiltrated to the extent that this patient has become both anemic and thrombocytopenic, low platelets. He was anemic and thrombocytopenic at baseline. This is a very delicate and fragile patient to treat. Encouragingly, he tolerated the dose-intensified regimen very well.
Not only did he tolerate it, through the reduction of the disease burden infiltrating his marrow, his anemia and his thrombocytopenia improved in the absence of blood transfusion. His overall health state improved from a dose-intensified regimen. From an efficacy perspective, this patient had a 99% PSA response, out to week 20, a very durable reduction in his PSA expression. Again, I think this patient's a really nice example of the viability of that dose-intensified approach. Just going to go forward. Thank you. In summary, we believe the unique profile of TLX597 fundamentally enables three important development pathways. The first of those is dose intensification, which is being evaluated in OPTIMAL-PSMA, as I've described. Secondly, the use in earlier metastatic hormone-sensitive prostate cancer, where safety and quality of life are critically important given the patient's relatively longer life expectancy.
Thirdly, I think it's quite evident that this favorable small molecule could be an ideal candidate or an ideal delivery vector for alpha isotopes. To close out, this is OPTIMAL-e, E for early, and this is a phase II study with TLX597 in earlier metastatic mAPMS disease that commenced enrollment back in July and which we anticipate will generate some very important clinical data about the earlier use of this small molecule in the coming 12 months. Annie, would you like to switch to Dr. Morgans?
Actually.
Keep going. Okay, good. Let's go beyond Lutetium, and we'll have a quick tour of our assets further in the disease journey. Let's move really briefly to our targeted alpha therapies for prostate cancer. I think the clinical experience we've gained as a field with the first generation small molecules has probably taught us two basic principles. The first of those is that alpha isotopes like Actinium-225 and Lead-212 must be kept away from the salivary glands, as xerostomia dry mouth, is the main dose-limiting toxicity, which really markedly impacts and degrades a patient's quality of life. We've got to avoid the salivary glands. Secondly, alpha isotopes must be kept away from the kidneys, as renal injury is a significant safety concern.
While they're early stage, we're evaluating a re-engineered radioantibody drug conjugate approach with TLX592, which, like TLX591, is a highly specific antibody to the tumor-expressed PSMA, as my colleague Dr. Wheatcroft pointed out very nicely. It keeps away from PSMA expressed on endogenous tissues like the salivary gland. As well as TLX597, due to its biodistribution profile, which I've gone into a bit of detail, it really makes it an ideal candidate, we believe probably the most attractive small molecule for targeted alpha therapy development because it keeps away from the salivary glands and the kidneys. I think this slide summarizes our approach very nicely. I wanted to provide some brief insights on our TLX090 asset, which, beyond alpha, aligns to our approach of really serving the patient across their disease journey.
TLX090, it's a novel candidate that we're developing for actually quite late-stage patients where the palliation of metastatic bone pain, which is a very common hallmark of late-stage disease, needs to be addressed. TLX090 employs Samarium-153, DOTATATE, which is a bone-seeking small molecule that uses that novel chelator that we're developing as an alternative to the mainstays, which are opioids and targeted external beam radiation therapy for very specific foci of bone pain. Each of these, opioids and EBRT, do remain suboptimal for different reasons. On the right side, we can see here from an earlier phase I study that both dosing levels of TLX090, there are significant reductions in the pain scores achieved quite early at six weeks, but these are durable reductions in pain out to four months following treatment. These are patients with a relatively brief prognosis in terms of survival.
This is a meaningful improvement in pain scores and improvement in quality of life. To conclude, while I won't spend too much time here, this, I think, really nicely summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are really tailored to both the disease state itself, early and late disease, as well as the condition of the patient. The way I would summarize it is that TLX591, which Dr. Morgans, I think, will talk about in a moment. Yes, good. It utilizes an antibody targeting vector to deliver the therapeutic payload, which really enables ultra-specific and prolonged tumor retention with very limited radiation to the healthy organs.
Furthermore, that short two-dose regimen is intended to be combined with the other standards of care that the patient would otherwise be receiving in the metastatic mAPMR setting. This is really the intent of ProstACT Global, the phase III trial that's ongoing in seven countries. Whereas there's a very significant opportunity in early metastatic mAPMS disease for TLX597, due to its potentially best-in-class dosimetry profile that really makes it uniquely suitable for earlier use, as well as the dose intensification to achieve those further efficacy gains that we're looking for. With that, can I invite Dr. Morgans to-
Yes
go. Okay, thanks, Annie. All right. Dr. Morgans, can you hear us?
Yes, I can.
Oh, good. I have introduced you, and I have just done 597. We have changed the order for you, so I will hand the floor over to you, Dr. Morgans.
Thank you so much, David.
Okay.
Wonderful presentation. I really appreciate being here with everybody. Apologies that I am virtually here because I am also in clinic today, as you may see from my coat and background. I am an Associate Professor of Medicine at Harvard Medical School and the Director of the Survivorship Program for Dana-Farber Cancer Institute, where I am also a GU medical oncologist. I take care of patients with prostate cancer. Let us go on to the next slide, please. I think I am very grateful that everyone is here to think and learn a little bit about prostate cancer and the way that Telix is trying to address it. I am not sure that the slide is advanced, but hopefully we can see the slide that shows the prostate cancer disease overview, which is the next slide. Thank you. Apologies if there is a delay on my end.
Prostate cancer is the most common cancer in men, and it's the second leading cause of cancer death in the United States . This is actually something that's true in many countries around the world, where we see the incidence of prostate cancer actually increasing in many countries. Importantly, one in eight men will be diagnosed with prostate cancer during their lifetime, and one in 44 die from it. But actually many become long-term survivors after a diagnosis with prostate cancer, many actually living with metastatic disease. And metastatic disease remains associated with certainly poorer outcomes than cured disease. The five-year survival rate is 30% versus 90% for earlier disease that's curable, a nd despite all of our therapeutic advances, prostate cancer remains a substantial unmet need.
As we can see on that incidence chart for the United States . on the right-hand side, there's actually been an increase in diagnosis of prostate cancer, particularly in the advanced and metastatic settings over the last number of years. This is something we are actively trying to combat. If we go to the next slide, we can see the prostate cancer patient journey through various phases of advanced disease. Just to orient everyone, I think we've heard from David about the newer nomenclature that we are now using to be, I think, more sensitive to avoiding the use of certain things like the word castration. But let's talk about this broader landscape because the standard of care in prostate cancer absolutely has been evolving in the last number of years and importantly, incorporating radiopharmaceuticals into that landscape and into having quite an important role within this algorithm.
For patients with metastatic disease, they typically would start in what we used to call the hormone-sensitive setting or metastatic hormone-sensitive prostate cancer that we're now calling mAPMn or s, androgen pathway modulation naive or sensitive. This is where we are commonly using androgen receptor pathway inhibitors or ARPIs as the backbone of our treatment in combination with ADT and docetaxel sometimes added in there as well for patients with high volume and very aggressive metastatic disease. In July of 2026, lutetium-177 PSMA-617 also received approval in the United States in this earlier setting.
But I think it's important for everyone to recognize that although we do have that approval and I think in clinic we're certainly grateful to have options, there's definitely been some caution around that and whether we should really jump on board and absolutely integrate that immediately into our algorithms because there's not yet a demonstrated overall survival benefit and there is moderate acute toxicity. Importantly, just to level set for today's discussion, we don't know the late and long-term toxicity that might be associated with this regimen as we use it in this early disease state. Just moving along to the next settings. As patients do have progression of disease and that occurs in the setting of usually medical castration or pharmacologic castration, they move into first, second, and then third-line plus metastatic APMR, or androgen pathway modulation resistance settings.
In the first and second-line treatment settings we do have options including AR pathway inhibitor or ARPI switch, taxane chemotherapy, lutetium-177 PSMA-617 that we can use before or after taxane chemotherapy, and PARP inhibitors for certain patients who have HRR alterations. By third line and further than that, our options tend to narrow down to things like cabazitaxel chemotherapy or perhaps lutetium-177 PSMA-617 in a post-taxane setting if patients have not already received it. I think also importantly, just calling attention to the bottom of the slide, is that throughout all of this, particularly in the earlier settings, renal toxicity and quality of life considerations are something that are increasingly important to us in clinical decision making, and important as we move radioligand therapy into these early disease settings.
This is really critical because we think about these earlier stage patients as typically being healthier, being more active, and certainly having a longer life expectancy. Things like renal toxicity or salivary gland toxicity are things that we need to address with our newer generation of radiopharmaceutical agents as we're hoping to incorporate them into the earlier settings. We really need to balance that with cautious optimism that really considers those adverse events and the potential there. It looks like the slide that we're seeing now is the slide that's looking at advancing past first generation PSMA RLTs. This slide is really thinking about our toxicities here. Lutetium-177 PSMA-617 has transformed outcomes for patients with metastatic prostate cancer. The clinical trial data from things like VISION, PSMAfore, and PSMAaddition, the registration trials, have been practice-changing, as we've mentioned.
As we're moving into these earlier settings, patients are thinking about being really conservative or at least thoughtful about those toxicities that I mentioned, xerostomia and renal impairment. If we look at this slide, this is the U.S. package insert. The adverse event data across those clinical trials is presented, and xerostomia occurred in somewhere between 39%-61% of patients in the studies, and most cases were categorized as low grade, but they can still have an impact, a severe impact in some cases, on patient quality of life. As we think about xerostomia, I think many of us who grade these toxicities don't necessarily realize that Grade 2 xerostomia means that patients are already altering what they eat.
Even though the number seems low, there is a real impact on patients, and they are relying on things like mouth lubricants and saliva substitutes, and they're often having to alter their diet to be more focused on pureed food or soft food, moist foods, in order to be able to safely swallow and get enough nutrition. Grade 3, again, the number seems low, or at least in the middle of the range when we think of all the CTCAE adverse event grades here. Grade 3 is quite serious, and this is the highest grade for xerostomia. This means some patients are unable to adequately nourish themselves, and they do need tube feeding or IV nutrition. Even if the numbers look relatively low in terms of the grade, we have to be aware that they can affect patients.
On the renal side, we are definitely thinking about and concerned about long-term nephrotoxicity, especially as I said, as those agents move into earlier lines of therapy, when patients are going to be on treatment and exposed to that cumulative risk of renal toxicity for much longer, and they do need good kidneys because they're going to need further therapies for their disease over time. If we go on to the next slide, this is really going to be an opportunity to focus on TLX591, which I think is an exciting novel therapy for patients with prostate cancer. If we can go on to the next slide. This is a radioantibody drug conjugate, and it's meant to really address some of these key unmet needs.
Just to lay those out as a recap here, TLX591 is a differentiated PSMA-targeted radiopharmaceutical that's using a monoclonal antibody to target prostate cancer that's expressed PSMA on its surface, and it targets that with high specificity, enabling a really precise delivery to the cancer tissue of the radioactive payload. It addresses a number of these clinical needs that have been unmet, especially having a nice two-dose, 15-day cycle that helps us in clinic by facilitating a more feasible integration with our standard of care AR pathway inhibitors or our chemotherapeutic agents, as we often need to deliver those as well. It has a very low radiation dose that's imparted to the salivary glands and to the kidneys. These are, as I just mentioned, the two main organs that can be injured when we're using small molecule agents to target PSMA.
It's really a transient and mainly self-limiting hematologic profile, which is also something we're thinking about in clinic, especially as we think about bone marrow suppression being something that could limit later lines of therapy for our patients. There's also a specific internalization and prolonged retention of the agent within the prostate cancer cell, which is going to be visible clearly on post-treatment imaging, which helps us in clinic make sure that we're really getting the drug to where it needs to go. There's also the potential for real-world advantages from lower administration activity and lower radiation doses to normal tissues, especially to the kidneys. As we can see on the slide, we can see this mechanism of action where drug is binding to PSMA, and then it undergoes receptor-mediated endocytosis, coming into the prostate cancer cell, where it is then taken into the endosome.
It undergoes lysosomal metabolism and ultimately is broken down and excreted primarily through the liver. If we go on to the next slide, we can see the schema for the ProstACT Global, the phase III study of TLX591. Part 1 has been completed. The FDA is aligned to advance it to part 2 in the U.S., which is also important. This is the overall design. ProstACT Global is a phase III study, as I mentioned, and as you can see, the part 2 is the randomized treatment expansion that's going to enroll 490 patients, and this is currently enrolling patients in seven countries. They include Australia, New Zealand, Canada, Singapore, South Korea, the U.K., and Turkey. The study also has regulatory approvals for part 2 in China and part 1 in Japan.
On the left-hand side of the slide, you can see part 1, which was performed for safety and dosimetry, and this part has been completed. This was a prerequisite of the FDA that was required before commencing part 2 in the United States . Just to show, we can see that part 2, which is a randomized treatment expansion, it is a 2: 1 randomization to TLX591 plus abiraterone and enzalutamide or docetaxel versus abiraterone and enzalutamide or docetaxel. As I said, 490 patients currently enrolling. Patients can get into this study if they have metastatic mAPMR, and they have had exposure and progression of disease to one prior AR pathway inhibitor or ARPI. Let us go on to the next slide. Here we can see the primary objective of part 1's outcome here.
The primary objective of part 1 ProstACT Global was to assess the safety of TLX591 when it was given concomitantly with standard of care abiraterone or enzalutamide, or followed by standard of care docetaxel chemotherapy. Overall, the three cohorts showed an acceptable safety profile. There were no new safety signals when compared to prior studies, including the most recent ProstACT SELECT study. The most common treatment emergent adverse events were things that we might expect or would expect: fatigue, nausea, and dry mouth. Almost all of the non-hematologic adverse events were grade 1 or 2, which as I mentioned before, is really on the mild side, with the exception of one grade 3 dizziness event. Hematologic adverse events comprised grade 3 and 4 thrombocytopenia, which is a low platelet count number.
This occurred in 14% and 31% of patients respectively, grade 3 and grade 4, as well as grade 3 and grade 4 neutropenia, which is a lowering of the neutrophil count, a type of white blood cell, which occurred in 22% and 25% of patients respectively. These hematologic events were actually in line with a profile expected for one of these radioantibody drug conjugates and are transient, manageable, and we are going to go into that in a little bit more detail on the next slide. Let us go to the next slide. This slide shows the platelet kinetics across all three cohorts. You can see the blue is the patients receiving abiraterone, orangey red is enzalutamide, and green is those patients who had docetaxel.
What we can see is that the platelet level nadirs around 43 days after dose 1, and there is recovery to grade 1 adverse event or better roughly 15 days later. Again, short-lived and quite predictable. The recovery patterns were generally consistent across the cohorts. I think this is important too, because docetaxel obviously being a cytotoxic, it is reassuring to see that we still see that nice recovery. As I mentioned in that prior slide, the hematologic events are the main adverse events of interest for this class of therapy. In terms of thrombocytopenia or that low platelet count, we can see that they were consistent, the nadir occurring 43 days after, six weeks after that first dose of TLX591. No patients experienced any febrile neutropenia, which is a relatively common adverse event that can occur when patients get treatments like chemotherapy that cause low neutrophil counts.
No patients experienced any spontaneous bleeding, which is something that can occur when patients have low platelet counts. In summary, these hematologic adverse events are quite well-characterized. They are well understood from prior clinical studies with the agent. They were self-limited, and they resolve spontaneously without intervention in the majority of patients for part 1. If we can go on to the next slide. We can see that the safety was the primary objective of part 1 of ProstACT Global. The main secondary endpoint was to look at the PK, the biodistribution, and the radiation dosimetry of TLX591 when it was given concurrently with standard of care. Overall, these three cohorts receiving different agents, abiraterone in green, docetaxel in pink here, and enzalutamide in sort of a teal color. We can see three cohorts demonstrated a predictable PK profile.
If you think about where you want the radioactivity to be, you do want that to either be circulating in the blood pool so that it is available to bind to and be taken up by the tumors, in the tumors themselves, or in the liver, where the drug is going to be cleared from the body, as we saw and talked about earlier. For these two graphs, the importance is that the graph on the left shows the blood radioactivity concentration, and that is sustained but declining over time. In the right-hand graph, we can see that it is basically the reciprocal of that, demonstrating that the tumor radioactivity or the lesion activity is increasing early and then sustained over time because the antibody has been internalized and it has a prolonged retention within the tumor.
The exposure and washout kinetics were quite consistent across the three cohorts, indicating no evidence of TLX591 interacting with any of the ARPI agents that it was co-administered with, which is very important. If we go onto the next slide, this is, I think, really importantly demonstrating normal organ dosimetry. This is making sure that our normal tissues are not being exposed to large levels of radiation that will exceed a threshold of harm. These are the organs that we certainly want to keep the radiation away from. We can see quite clearly that part 1 confirmed that the radiation exposure, which you can see in the dark blue, to these normal organs is quite low and well below the safety limits that have been determined for external beam radiation therapy and the radioligand therapy literature.
Those are outlined in the gray and the orange-colored hashed marked bars that we can see overlaid on the same graph here. Particular note you can see that with TLX591, there is very low radiation dose imparted to the kidneys and to the salivary glands. We have talked about these being two normal tissues that the small molecule radioligand therapies tend to hit actually quite hard. This reduces the risk of developing kidney impairment and dry mouth when you have that low exposure to those organs, as we can see here. Each of these that we already talked about can really affect the patient's quality of life during treatment and certainly their lives over years to come. On the right-hand side of the chart, you can see the liver, which is relatively radiotolerant in terms of organ tolerance.
This is the primary clearance organ, so it has clearly received the highest dose. From there, the activity is going to be cleared from the body via the right and left colon, rectum, and via stool, ultimately. If we can go on to the next slide. I am happy to share three cases of patients who have enrolled in the study so far, just to illustrate the biodistribution and tumor retention characteristics. I also think to illustrate some cases where we might consider use in the future. What we can see here is the case of an 83-year-old gentleman who has known metastatic mAPMR disease with metastatic disease in the chest. He was actually diagnosed with prostate cancer in 2012 and had a prostate removal or radical prostatectomy at that time.
He was treated with enzalutamide therapy starting in November of 2023 in combination with ADT. He unfortunately had progression of disease in June 2025. He had a baseline gallium PSMA PET that identified metastatic disease in the thoracic vertebra, bodies and ribs, as we can see here, illustrated in that baseline or post-treatment SPECT is showing some of this. TLX591 treatment was started on August 5th, 2025, h e had a second dose on August 19th, 2025 and h e experienced a transient grade 4 thrombocytopenia or low platelet count and did recover. He received his first dose of docetaxel chemotherapy about 10 weeks later on October 28th, and he completed six cycles. His current patient status is bilateral peripheral neuropathy. This is something, nerve damage or irritation that can happen with docetaxel chemotherapy.
He has had no progression of disease reported during his last patient visit, and that was the time of data cutoff, 341 days after his treatment. If we can go on to the next slide. This is a second patient, and he has also known metastatic mAPMR, previously exposed to ADT enzalutamide. He received abiraterone in combination with TLX591. So you can see the sustained tumor-associated imaging signals over 15 days after the first administration, really demonstrating, I think so clearly to me as a clinician, at least, at that 15-day mark, we can see those areas of uptake, in addition, of course, to the liver. This is something that I think just shows the way the drug hangs in those tumor cells and hopefully is able to provide a long and prolonged radiation to them. So this patient was diagnosed with prostate cancer in 2019.
He was treated with ADT and received his first ARPI enzalutamide in the first-line metastatic mAPMR setting, and he progressed on that treatment. The treating physician or investigator in this case determined that he should get abiraterone standard of care in combination with TLX591. He had a baseline gallium PSMA PET that identified metastatic disease in the chest, abdomen, and pelvic lymph nodes. He was treated, as we can see, and he ultimately had stable disease for 339 days, but did have progression of disease on March 13th, 2026. That is very, actually impressive and quite reassuring for him. Not something we would expect with second-line ARPI treatment, abiraterone being something that we've used after enzalutamide and has minimal expected value there. If we go onto the next slide, this is a patient case of a final patient.
He is a 62-year-old gentleman with known metastatic mAPMR, previously treated with triplet therapy in the metastatic mAPMR setting with ADT darolutamide and docetaxel. Diagnosed with metastatic disease in 2017. High-grade disease, Gleason 9. Started docetaxel in October 2017 through February 2018. Darolutamide started in February 2022 and had progression of disease in May of 2025. His baseline PSMA PET on gallium Ga 68 PSMA-11 was demonstrated to show uptake. The investigator initiated concurrent standard of care enzalutamide on June 30, 2025, 14 days before TLX591. Had the first dose on July 9 and the second dose of TLX591 on July 23.
As you can see, starting on the left in the darker green, early vascular hepatic distribution, then to the right in lighter green, persistent uptake in the metastatic sites out to 15 days representing that signature of TLX591 rather than a small molecule ligand, which we would not expect to see there. The patient was on study in extended follow-up as a data cutoff imaging out to day 337 with no treatment discontinuation recorded and no progression of disease through day 337. That was the time of data cutoff. The message here is really that TLX591 plus enzalutamide was well-tolerated after previous docetaxel therapy and achieved a durable response in a post-darolutamide setting, again, post-ARPI. That second ARPI is expected to have minimal benefit. That concludes my presentation. I appreciate your time. I will wrap up here, David, and hand back to you.
Hello. Can we just get this mic on, please? Since Dr. Morgans is joining us virtually, this is Annie. We can take a couple of questions. If you do have any questions, please raise your hand. These would be specific to Dr. Morgans. There will be a broader Q&A session a little bit later after the conclusion of all the presentations. Please raise your hand if you have any questions.
Of course, Laura. Laura here. Hi, Laura. Nice to see you here in New York.
Hi, Dr. Morgans. Thank you very much for your time. I was wondering if you could talk a little about your experience with using Lu-PSMA-617 and, in particular, your view on some of the real-world evidence that was presented at ASCO on whether or not, or rather how much the renal toxicity is a problem, and what considerations you think we're really trying to solve for in this population that's post at least one ARPI.
Sure. I have used quite a lot of lutetium PSMA-617. This is something I've used in clinical trials as well as in standard of care in various settings. I think that from a treatment opportunity standpoint, patients are very keen to get radioligand therapy or these targeted radioactive drugs. I would say we are still defining the potential renal toxicity. I think that there's likely an under-representation of the renal toxicity that is likely occurring. It is not something that is as big of a concern when you're only using these drugs in the very late lines of therapy, because patients don't have an extended time to live and to need additional therapies over time. But especially as we move things into earlier settings, I would say that despite the real-world evidence that may be coming out, I think we have an incomplete characterization.
Often this renal toxicity is thought to be somewhat delayed and maybe incompletely captured. I think we, as a field, are continuing to try to work to put some of that forward. Can you just repeat the last part of your question was really around, I think, ARPIs?
[Audio distortion] The last part of the question was, what do you think the main toxicity considerations we're trying to solve for are in that population?
Okay. Thank you. Yeah. I think that these are the main toxicities that we're trying to solve for. As we just discussed, this xerostomia, as well as the renal toxicity. Just as an example, I had a patient who was on PSMAfore. Or apologies, he was on PSMAaddition. This is the metastatic mAPMN/S or formerly metastatic hormone-sensitive prostate cancer setting. He has had excellent disease control, has been followed in follow-up, actually at this point, probably four years. The challenge that he has faced, he's an older Italian gentleman, loves gardening, getting fresh tomatoes. He and his wife make a beautiful fragrant sauce. They've even brought some in to us. He's not able to taste sauce in the same way after having his treatment.
This is something that he notices and brings up and talks to me about in clinic, and it's been upsetting to him. It is not to the point that he is unable to eat and needs a feeding tube. That's really not the issue for him. But his life has been altered in ways that we think are meaningful to him and hopefully are contributing to his disease control, but is something that I think he would have liked to avoid if this was going to be possible. Kidney toxicity, also something as I said, difficult to pin down, but if you don't have highly functioning kidneys, you're not able to necessarily treat your other medical problems or potentially get other therapies for prostate cancer, which can limit you over time and absolutely affect the longevity and certainly the quality of your life.
I think any time we can reduce toxicity and ensure that the trade-off that patients are making in terms of having activity against the cancer and maintenance of themselves and their opportunity and ability to take care of the rest of them, it's going to be a win for patients and something that's going to be helpful in terms of therapeutic development.
If there are no Okay, looks like we may have one more.
Hi, thank you for your time. Just wanted to hear about your perspective, what kind of patient baseline characteristics would make a patient not very ideal or ideal for TLX597. Thank you.
Sure. I think the biggest barrier to getting treatment, if I were to say a patient who could not get treatment, is a patient who has preexisting bone marrow suppression. This might be a patient with a myelodysplastic syndrome, or who has low platelet counts for some reason, or some suppression of blood counts. This is relatively rare. These are going to be the same patients who are not going to be able to take things like chemotherapy or other radiopharmaceuticals, things that cause low blood counts. Again, it is relatively rare, but that would be the main patient population, I would think.
Luckily, these agents are well-tolerated and things that even patients who have functional limitations and mobility troubles or other medical problems are generally able to take, and this agent, TLX591, importantly, plays well with other medicines that we use commonly, these AR pathway inhibitors, and can precede chemotherapy. It really opens the door for most patients to be able to get this kind of a treatment, do it safely and well.
Thank you so much, Dr. Morgans. I think with that, I will transition to David Cade, who will introduce us to Dr. Sundaram. Thank you.
Thanks, Annie.
Thank you.
Yeah. On behalf of the 40 odd folks, I think, in the room, I would just like to acknowledge and thank Dr. Morgans for dialing in. She actually has a very busy clinic this morning at the Dana-Farber. She had a patient prior and a patient after, s o obviously, the next patient will be very fortunate to be being cared for by a clinician of that capability. Now we are going to switch from, I think, a very comprehensive review of prostate therapeutics to prostate precision medicine. This is a very important session. We have obviously got a majority of men in the room. While I am very fortunate with my colleagues to be the developers of this next approach, many of us, unfortunately, are likely to be customers of the next approach.
So it is my real pleasure to introduce our next key opinion leader presenter, Dr. Varun Sundaram, who moved to Central Texas as a surgical urologist after originally practicing as a urologist in Gresham, Oregon, I think is your original hometown. He completed his undergraduate studies, and his medical degree at Washington University in St. Louis, and subsequently went on to finish his general surgery, internship and urology residency at UT Southwestern in Texas, where my Texan colleague is also educated. Dr. Sundaram is now a very busy urologist at Urology Austin, the largest private urology practice in Texas. The last thing I would say is it is always entertaining to invite a surgeon to the stage. For obvious reasons. So Varun, welcome up.
All right. Thanks for the intro. I brought a little prop, and we'll get to that in a second, but thank you guys for having me today. My focus is primarily on the BiPASS trial, the use of PET scans to help minimize the biopsies and the risks of biopsies. Currently, as urologists, when we're evaluating patients with prostate cancer or with elevated PSA, we rely heavily on a biopsy. This is typically done with a probe transrectally. The biopsy can be either transperineal or through the rectum itself, and it'll sometimes require 15, even 24 samples to obtain all the tissue that we need. It really depends on where the lesions are seen on the MRI, and even if a lesion is seen, we typically sample the rest of the prostate because there's a chance that there's clinically significant cancer elsewhere.
A lot of our technique and our prior thoughts were kind of a blind shotgun approach. Let's hit this with a bunch of needles. Hopefully, one of them will land and we'll detect something. There are risks to that. Infection, urinary retention, bleeding. People can develop clots in their bladder afterwards, and then they can't urinate. Hematospermia is a relatively benign thing, but it is very, very shocking to the patient and their partner. People recover over the next couple of days. If they end up getting admitted for sepsis, it can be even longer. Here's just a quick video of this. What you see here is the ultrasound probe. This would go in a patient's rectum.
I'm about to show you the needle as well, but the entire time we're doing this biopsy, which is somewhere between 10 and 20 minutes, depending on how you do it, there is this probe in the rectum, which is probably the worst thing for the patients. That's the biopsy gun that we use, and Kevin was nice enough to get one delivered here. This is not a small needle. The patients will hear this 15 to 25 times as we're biopsying them, and it's hard not to jump every time you hear this click. Once they've had it and they come back for another one, they're sort of primed for it, but that can actually make things worse, and they're expecting this click and worrying about the pain. If we can avoid these things, we should avoid them.
That's where the BiPASS study, I think, has shown a lot of light. Typically, when we get an elevated PSA, we'll order an MRI of the prostate, and that's a multiparametric MRI, 3T MRI. That's a very complicated study, and we'll get to that in a bit, too. Then if that shows a lesion or if the PSA is too high for the size of the prostate, so the PSA density is elevated, we'll do a random biopsy as well. This says 800,000 biopsies every year. Some sources say a million, and a lot of them are negative. We do this biopsy because the PSA is elevated, the PSA density elevated, or the MRI showed something, and a lot of them could have been avoided because they're negative, patient had a spurious elevation. They don't have a true lesion or tumor.
There is a large percentage of patients who refuse a biopsy. There have been a lot of tools that have been developed in a post-PSA setting saying, "Hey, you got an elevated PSA. Let us do some tumor marker. Let us do a biomarker. Let us see if we need to go onto a biopsy." Unfortunately, those were not developed in a post-PSA, post-MRI model. The second you get an MRI, a lot of those are fairly useless clinically. Using TLX BiPASS, that would be a post-MRI model, and that would allow us a certain level of diagnostic accuracy we do not have right now, and we can avoid these things. We talked a little bit about the risks of biopsy, but again, hematuria, rectal bleeding, sepsis is the biggest risk.
There is about a 3% risk of sepsis with a transrectal biopsy, about a 1% or less with the transperineal biopsy. The other issue is false negatives. You can do a biopsy, see no cancer, and then subsequently a year or two later, you detect the patient with cancer. It is probably not because they did not have it at that time, but that you missed it because you are doing a partially blind approach. The PRIMARY 1 and 2 studies helped to develop a sensitivity and a specificity and a scoring system for the PSMA. What you see here is that the sensitivity of a PET scan plus the MRI is much more than the MRI alone. The idea is that this will allow us to reduce a lot of these unnecessary biopsies. Ideally, about 50% of them are unnecessary.
If we can reduce those, patients benefit significantly from that. Before each study or before each biopsy, a PET scan can help us say, "Okay, this lesion is a little bit more aggressive. This lesion is a little bit less aggressive." PRIMARY established the proof of concept, and PRIMARY 2 showed that it can safely reduce biopsies while still maintaining a clinically significant detection of prostate cancer. Then comes the BiPASS trial. This was a phase III trial, which I got to give a little shout-out for Urology Austin. We were the leading enrollers in this study. It took a look at patients who had an MRI of the prostate, had an elevated PSA, and were going to go on to biopsy already. The patients then got a PSMA scan before their biopsy, and then the biopsy was then random or guided towards PSMA or MRI targets.
There is a 6-month follow-up, so we are still in the process of that follow-up. The primary objective was to detect clinically significant cancer and to help identify which patients we can avoid a biopsy in. We talked about that. I think, again, the most important thing is this will likely be utilized between MRI and biopsy for almost all patients. Even if not everyone is spared a biopsy, everyone can have the diagnostic benefit of getting a PSMA scan, and the target population for that is somewhere between 800,000 and 1 million patients every year. The idea after the publication of the study is that patients with either symptoms or elevated PSA, they get a PSMA scan, they get a multiparametric MRI, and then we stratify their risk.
If they have a PI-RADS 5 lesion or a very high risk on PSMA, we go straight to biopsy. If it's a little bit less than PI-RADS 5, 1 or 4, but the PET's still positive, you still go to a biopsy because of the really high specificity. Then finally, if you have PI-RADS 1 or 2, or even a PI-RADS 3, but the PET's negative, you can really talk about avoiding biopsy in those patients, which there's a significant population in the U.S. that wants to hear you say anything but, "You need a biopsy," or, "You need another biopsy." You'd be surprised at how many urologists are out there in the community, mostly in rural settings, where they don't have access to an MRI, they don't have access to a PET scan.
You'll get patients from there who've had three, four, maybe even five biopsies, and we still can't find out why they have an elevated PSA. Those patients love it when you say, "Hey, we don't need to do this." We can reduce the amount of biopsies, we can eliminate the need for biopsy, and we really affect patient care by reducing anxiety and worry over a procedure that can be invasive and can cause significant harm. Ending up with sepsis in the hospital is a huge issue, and it drives up healthcare costs to the tune of millions every year. The other benefit of the gallium PSMA scan is it is less likely to show an indeterminate bone lesion than F-18. This is really important because when we do these scans pre-biopsy, pre-radiation, if we detect a bone lesion, that drastically changes our treatment course.
We now go from talking to somebody about curing their cancer to talking to someone about keeping them alive as long as possible. Even if we don't suspect or have a high likelihood of belief in a bone lesion, finding this creates a lot of anxiety and stress for the patient, creates a lot of unnecessary workload, and frankly, it'll delay treatment by quite a bit in the time it takes to get another MRI of the area, get a CT scan specifically at the spine or the chest. Having a tracer that is more sensitive and specific to bony lesions, and so is less likely to give us false positives, is huge. Here's an example of an anterior rib lesion. You see on the CT scan on the FDG, you see a little light up or activity. But on the gallium scan, there's nothing there.
The reason for the false positives can be numerous things. They can be small, benign bone lesions. They can be prior trauma, fractures. There are numerous causes in somebody's 70 years of life why they can have a little bit of imaging findings at a bone. Having a tracer like gallium is extremely important for minimizing the concern. Currently, we use a multiparametric MRI, and what you see are three different phases. You see the T2 weighted imaging, the DWI, and the ADC. These are very complex, t hey don't look very similar. One of them looks like a radar scan from the '50s. The quality of the MRI is not the most important thing. It's the quality of the radiologist or the urologist reading those MRIs. I'll be honest, most urologists don't know how to read these.
We rely heavily on our radiologists, and the vast majority of literature for MRIs and prostate cancer was developed using a single site and a single radiologist, so a person who read thousands upon thousands of scans. That is not the truth in everyday practice. These are not the people we have access to to read MRIs. They have to read less than 5% of all the MRIs done in the U.S. So that means 95% of the MRIs done in the U.S., you can't use the pivotal studies and the excellent diagnostic accuracy of MRIs based on papers because that was one person reading every single study for all of those papers. I'm lucky I have a guy that is very good, and I have patients drive just to see him for their MRI, but not everybody has that.
I only have one of those in the town of Austin, Texas. I think that says a lot. All right. I think.
Yeah.
Thank you.
Yeah. I will toss this for you.
Yeah, take that with you. Yeah. It is dangerous up here. Well, thank you for that highly effective and visceral presentation. We appreciate it. We've just heard a lot of great science up here today, and now I want to talk a little bit about translating that science into really highly effective patient experiences for the technologies that we're bringing to market. This is the way we see on the diagnostic side. This is the way we currently see the PSMA PET market. You can see the biopsy. Right now, everything that we look at is from the biopsy behind that. If you look at our current indications, it is initial staging, it is biochemical recurrence, and then radioligand selection, treatment selection.
You can see that we have also targeted and have ambition to go after response to treatment on APM resistance as we think about what that looks like in non-metastatic disease, and then of course, progression for that, and then monitoring progression. We are ambitiously chasing a lot of indications further down the line. All of them are after the biopsy. What I would like to think about is that there is really nothing more frustrating than an idea whose idea, whose time has not come yet, right? You have this idea. You are trying to bring it to market, but really the confidence in the scan was not there. We have been working through how to do this with PRIMARY-1, PRIMARY2, and now BiPASS, but r eally what we had to do is get some experience with it, and we have done that.
Now that we have done that, imagine if you will, a world where we have the confidence in PSMA PET scan, and then you can see nothing is really more powerful than an idea whose time has come. When you think about that shift, if you look at what happens before the biopsy, this 800,000 scans that he was speaking of and the 200,000 men that say no to biopsy each year. Really, if you just look at it before and you look at it after BiPASS, imagine if you will, this world where every patient that needs a biopsy, that is indicated for a biopsy, gets a BiPASS first. What you see is this capturing of over 800,000 scans or 800,000 patients that are indicated for biopsy get a scan first.
Now, we believe there is another 200,000, if you look at that little gray area above that actually say no to the biopsy. From his demonstration, you can see why you might say no to that. We think that just that market is approaching $ 1 billion. Just getting the people who said no to biopsy is about $ 1 billion. When you look at the 800,000 scans that we can capture because of the increased sensitivity and specificity, then imagine, if you will, a world where BiPASS gets approved by the FDA. As we have said, we have aligned with the FDA on a new NDA for BiPASS, and we intend to address that indication. What happens after? The question that we pose to our strategic advisory boards is, what happens if we get a BiPASS indication for the pre-biopsy setting?
Well, then you get an initial staging even with BiPASS. So you have this baseline and initial staging immediately pre-biopsy. That will most likely decrease. Then because of the imaging that you are getting and your surgical selection that you see now with the BiPASS image that you saw a few minutes ago, you will see that even biochemical recurrence may decrease as well. Then as you look at response to non-metastatic, we start thinking about how to really assess that response using the PRIMARY scores. We really think about what that may do in terms of why wait? Why wait for your PSA to increase? We go after that indication as well. You can see the redistribution, if you will, of what we see in PSMA scans today with what may be tomorrow if BiPASS is approved.
So some really exciting things that will happen for men around the world and a big part of what we are trying to do as we look at what we can do for men in this area. You got to hear from a urologist about his experience and the way he views it. One of the things that as we talked to the Urology Austin Group in this trial is that when they get a biopsy and it is negative, you cannot necessarily tell a patient they do not have prostate cancer. You just tell them that we did not find any prostate cancer. That patient, while he was indicated once, they will still track his PSA every 6 months, and they will bring him back in again on a watch and wait to get another biopsy. So that could be another BiPASS.
But as we start thinking about the patient side of this, then we surveyed over 1,000 patients that got a biopsy, and it comes out just like you would think. When poised the question, would you rather have a PSMA scan first and possibly avoid a biopsy, then, of course, 95% of the men said overwhelmingly that they would rather do that. Now, kind of makes you wonder about the other 5%, but I think that as we are really kind of understanding and educating this, we have not started any education at all on the patient side of this. So this is just a patient advocacy group that we worked through and did the study with and just positioned this or proposed this idea to them, and you can see that it is overwhelming.
And so much so that as we know now that when patients get educated about other alternative methods, especially for something that they are trying to avoid in general, then they are more than willing to either discuss it with their doctor or ask to discuss it with their doctor. You can read some of the comments as well about the experience they have had. What does that really do for our TAM, we call it, or our opportunity? We see that overall, we are approaching a $20 billion opportunity in the. This is U.S. only. We have the initial 670,000 scans that we are working with in the current state. We believe there is another 800,000 in BiPASS, another 200,000 that we can activate that are saying no.
When you net that out, we see that the TAM in that first three indications really just about doubles or a little bit more. Then as we progress in our indication expansion strategy, you will see we have got another 250,000 or a quarter million that we are going to chase down. Because of what we are doing in the theranostic area, and you got to hear some great presentations on our therapies, we look at that TAM in general. Remember, our idea is to really de-risk the targets by having the initial tracer in the diagnostic area and really understanding. The theranostics strategy does a couple of things for us. It de-risks the tracer, but also over the past three to four years, as we prepare for therapy, we have built relationships with regulators, with customers, with payers, not just here in the U.S., but globally.
That is a really important part of the theranostics strategy, is we have that both commercial, regulatory, and payer experience. As you combine those two TAMs and you look at metastatic APM, both naive and sensitive, and about 16,000 patients, we believe when you look at first line and second line in resistant, then we think it is about 22,000. Then of course, in second line plus, we see it over 12,000 patients. When you look at the entire portfolio on a theranostics perspective, then you can see that we are approaching $20 billion. We think that the portfolio and pipeline that the team put together for you enables us to achieve that. Thank you very much.
Thank you, Kevin. We are going to open it up for Q&A. If I can please ask all the speakers to go to the stage. If you have any questions, please raise your hand. Let us just give a minute for them to get situated. All right, please go ahead, Andy.
Thanks for taking a question. This is Andy Hsieh at William Blair. Kevin, you mentioned about the NDA submission based on the BiPASS study. I am curious if you can elaborate a little bit just about how you can achieve that. Obviously, we are in this game every three years. You got to have something new, but it would be helpful for the investment community to know what is the detailed strategy there. Thank you.
Yeah, I would say that we have aligned with the FDA that we want to pursue a new NDA. In pursuing a new NDA, that would allow us to get an NDC and HCPCS code, and then ultimately work for a transitional passthrough code. While it is not necessarily part of our lifecycle management overall, broadly for the portfolio, it is. But we believe this as more of a disruptive technology in the way that we are going to redistribute and move pre-biopsy versus post-biopsy. So it ultimately fits into that. The FDA agreed that it was a big enough change in the product and the indication that they believe we could pursue an NDA. So that is what we are doing.
Any other questions?
Hi. So there is new PET MRI systems from GE HealthCare in 2022, got FDA approved. The Siemens Healthineers got approved in January 2026. So is the rollout of these new, better, more sensitive PET MRIs going to help the diagnostic pathway?
Well, I think I would manage that from where the market is today and where it may go. If you think about how that combination between a PET-MR and BiPASS and how those could work together, I think we see a lot of synergy in that. We believe that the sensitivity and specificity of BiPASS will achieve our endpoints. We see that as a good thing for the direction we want to go. Just based on their rollout and how we manage that, we would be happy to help support and drive that. Yeah.
Thanks, Annie. Can you speak to the cost impact in the physician office in regards to current biopsies in practice versus a PET approach?
Sure. The health economics, we believe, is somewhat neutral in terms of how we approach that from either a PET-CT, PSMA, versus a biopsy. Each and every one of the clinics, of course, have a different RVU system on the facilities, on the technical side for what the physician does. As you know, including Dr. Sundaram's practice, there's many of the private practice urologists that have scanners now, and that's really a part of the emerging part of what we're doing. We believe it's at worse a net neutral. Because of what we think that is going to happen downstream and the overall complication rates, is going to be net positive for BiPASS. If you wanted to comment on your experience.
Yeah. I can say for the urologist, those who own their own PET scanners, it's net positive. The revenue from a PET scan far outweighs that of a biopsy. The other thing you have to think of is we're all at capacity right now. I don't think I can add another 10% of biopsies on to my schedule or any of my partners. If anything, we need avenues and ways of evaluating things that don't directly tie up our clinic, our time, and our biopsy machine. I would say that I think it can only be net positive. In those settings where they don't have their own PET scanner, again, they're also at capacity. We're not making more urologists in a timely fashion.
Any other questions? All right. If there are no other questions, I will hand it over to David Cade to go to the next session.
Okay. Thank you. No break then? Let's keep going?
Let's keep going.
Let's keep going. Okay. I think we have had a very comprehensive tour through both our therapeutic and prostate cancer pipeline. Let's switch now to kidney cancer. Prostate and kidney are obviously the main parts of our urology franchise. Our next speaker, I am delighted to say, is Dr. Monty Pal. Dr. Pal is a very much globally recognized leader in the research and management of kidney cancer. He is the co-director of the kidney cancer program at City of Hope. So thank you for coming all this way. And he serves as the clinical trials medical director at its comprehensive cancer center, which is a very busy comprehensive cancer center.
Over the course of his career, he has led and contributed to many, I would say, practice-changing clinical studies that have advanced the standard of care in kidney cancer, publishing more than, I think it is 500 papers over your career, and really leading a significant portfolio of clinical trials. So please join me in welcoming Dr. Pal up. Thank you. That is for you.
Oh, perfect. Well, really delighted to be here. Thank you for the very kind introduction. Really excited to share with you some of the latest developments in this space. But before we jump into that, just a quick disease overview. With respect to kidney cancer, it is really a disease that has been rising in prominence, the estimates suggest by about 3% per annum for several decades now. It represents the 14th most common diagnosed cancer worldwide. If you look at the age standard incidence and mortality, it tends to be highest in North America as well as in Europe. This is a male-predominant disease with about a 3:1 to 2:1 ratio.
When we think about kidney cancer in that vernacular, about 90% of cases are going to be renal cell carcinoma, and within that, about 85% are going to represent clear cell renal cell carcinoma. So that is by far the most common histology, and it makes up the lion's share of what I tend to see in the clinics. Now, I will point out, and we highlighted a bit of the disease burden, that incidence rates are rising, as I had mentioned, 3% per annum for several decades. A lot of that hinges on better imaging techniques. A lot of that also hinges on the fact that we have exposure to more carcinogens in the natural environment.
What is really quite strange is that despite the increase in the available imaging that we have to diagnose the disease, unfortunately, still about 30% of patients are diagnosed with metastatic disease from the get-go. Despite the many advancements that we will highlight momentarily, five-year survival remains rather dismal for this disease. There are about 180,000 deaths that occur worldwide. As we shift to the treatment challenges, I think the one thing that I would really emphasize is that at this point in time, kidney cancer therapy is really maybe a one or two-trick pony. When we think about the different therapeutic modalities that we have, we have checkpoint inhibitors, we have VEGF-targeted therapies, and typically those are tyrosine kinase inhibitors.
Although there are a certain subset of patients, I would estimate at around 10%, that can have durable, complete responses to these therapies, the vast majority of these individuals inevitably progress. Primary and acquired resistance occurs across the vast majority of these therapies. Truthfully, when we get beyond frontline management of this disease, we have very little in the third line and fourth line to offer patients. In fact, many would argue that second-line therapies as they stand currently can actually be very redundant. I will make that point in some of my subsequent slides. There is certainly a need for better-tolerated therapies. It is estimated that about 4,700 patients per year in the U.S. are going to need third-line options. At this point in time, the management strategy tends to be use of another targeted therapy.
I will put the patient in front of you who has received a regimen like nivo/ipi up front, maybe cabazitaxel in the second setting. What we have are just more targeted therapies to offer after that: lenvatinib, tivozanib, et cetera, and we will discuss this in subsequent slides. Intellectually and frankly, logistically, the clinic is not very satisfying to re-challenge the patient with a very similar class of options. I will say that adverse effects tend to really plague the third and fourth-line settings. Patients have already been exposed to treatments and have significant incurred toxicities like diarrhea, fatigue, et cetera. This only gets magnified as you get into later line of therapy. So it would be ideal to have therapies that can provide durable disease control with manageable toxicity.
I am really of the mindset that we are only going to get there if we really introduce novel mechanisms of action in this later setting. So what targets can we exploit that we have not to date? Ironically, it is actually one of the entities that we use to diagnose renal cell carcinoma, and that is CA9 or carbonic anhydrase IX. So this is a transmembrane glycoprotein. If we think of its physiologic function, it works in oxygen sensing. It is a pH regulator as well. As we will highlight in the next slide, it is really induced by von Hippel-Lindau tumor gene in many cases, but also by hypoxia as well. We see this in about 95% of cases of clear cell renal cell carcinoma. Our pathologists routinely use this. They use PAX8 and a handful of other stains to really classify clear cell renal cell carcinoma.
When we think about the mechanism here, I will start with the mutations that really sort of underlie clear cell RCC. As I had mentioned in the previous slide, that is this VHL alteration. When we think about VHL and its native function, its ubiquitin ligase, it tends to sort of target certain elements for destruction. When VHL is altered, and this happens in a somatic fashion in about 55%-60% of patients, in germline setting as well, in a small fraction of patients, what we see is that there tends to be accumulation of one of the products that really sort of drives kidney cancer growth, and that is hypoxia-inducible factor, HIF. Now, HIF is actually, CA9, as I had mentioned before, is a transcriptional target of HIF. When we have this accumulation of HIF in the context of VHL alterations, you tend to see increased transcription of CA9.
And again, we have described the function of CA9. One important element to really bear in mind is that CA9 expression is really seen minimally on normal tissues, and that is, I think, one of the key elements that lends itself to being a therapeutic target. Let us talk a little bit about the different targeting approaches to CA9. An agent that is maybe well known to some of the audience is girentuximab. This is an IgG1 kappa light chain chimeric monoclonal antibody, and it actually is very highly specific for CA9. It leads to internalization. One of the elements that I will point out is that girentuximab has been very heavily studied. Many may remember a presentation from ASCO several years ago, the ARISER study, in which there was an extensive look at girentuximab in patients with renal cell carcinoma, so there is extensive safety data around this.
We know that this entity is hepatically cleared. Moving on to the developments based on girentuximab, we have the zirconium-89 payload, which is useful in the context of imaging. This is a positron emitter with a half-life of 3.3 days, and again, this is suitable for PET imaging. What I am going to be focusing on, though, is listed on the right, and that is the lutetium-177 payload, and this is a medium-energy beta emitter, half-life of 6.7 days, and this is really suitable for antibody-based therapy. I am going to get into the development plan that we have for this in just a moment here. But before I do that, let me just sort of articulate the standard pathway for management of advanced renal cell carcinoma.
After the time of diagnosis and surgery, we have more than a modest fraction of patients who develop disease recurrence, usually with metastatic sites including lung, bone, liver, lymph node, et cetera. There is a small fraction of patients, I would estimate about 5%-10%, who really fit in the top of that first-line graphic. Those are patients with oligometastatic disease who have maybe limited sites of spread. In those situations, we can target patients with site-directed radiation or site-directed surgery. That is not the lion's share of what I tend to see in clinic. About 20% of frontline patients have what is deemed to be favorable risk disease. These are based on prognostic factors including time from diagnosis to treatment, serum hemoglobin levels, calcium levels, et cetera. But those patients are generally approached with a combination of VEGF TKI in association with checkpoint inhibitor.
About 70%-80% of patients are going to have what is termed intermediate or poor-risk disease, and these are patients with certainly a briefer prognosis and poor outcomes, even in the context of therapy. Most of these patients are approached with either a combination of TKI with IO or with a dual IO2 regimen such as nivolumab and ipilimumab. There is a very rare subset of patients in this day and age who would get TKI monotherapy. Those are patients who have absolute contraindications to checkpoint inhibitors, and that is a fleeting population. As we move to the second-line setting, this is really where the challenge arises. There is so much redundancy in what we do. Even for the patient who has been frontline treated with a TKI and IO-based regimen, you are oftentimes just going to re-challenge with another TKI-based strategy.
I'm happy to chat about some of the more recent developments in the landscape, but if you think to really what has been introduced perhaps over the course of the past year or two, we have therapies that target a hypoxia-inducible factor, HIF, like belzutifan. We most recently have under consideration for approval a combination of lenvatinib with belzutifan. I find that these options are maybe a little bit less palatable because, again, many of these therapies fall along the same signaling axis as VEGF and therapies that we'd use in the frontline setting. Again, patients are already facing substantial toxicities that they've incurred in the frontline setting from those therapies. In the third-line setting, the problem gets magnified where, again, there's a lot of redundancy. We're, again, re-challenging with VEGF inhibitors, mTOR inhibitors, largely a pool of drugs that can maybe be envisioned as almost cytostatic.
I wanted to outline some of the rationale that belies the LUTEON studies that I'll be highlighting in just a moment, and this hinges on, again, the use of lutetium-177 bound girentuximab. And what I'll point out here is that there is data from previous studies. These were investigator-initiated trials in a phase I study that included 23 patients and a phase II study that included 14 patients. There's a couple of really important lessons learned. The first is that patients who received the maximum number of cycles were actually those who'd received lower doses of therapy. So you can see that it was those individuals who received less than 3,145 megabecquerels of treatment that were really able to sustain a greater extent of dosing. There were none, in fact, if you'd received in excess of 4,000 megabecquerels. More treatment, frankly, correlates with better outcomes.
If you've looked at patients who received three cycles of therapy, median overall survival was 49.3 months. That falls down to 22.2 months amongst those that received two cycles. You're down to 18.7 months if you just received one cycle of therapy. So there really seems to be some diminution of benefit if you're not receiving three cycles of treatment in the course of these early studies. There also seemed to be, and this is perhaps expected, an increase in hematologic toxicity with higher doses. We didn't really see any grade 3/4 leukocyte or platelet toxicities in patients that received the dose of 1,887 megabecquerels, and we'll talk about that dose in just a moment. This dose was well-tolerated and allowed for multiple cycles of therapy.
Beyond these observations from initial studies, there's also a bit of pharmacologic rationale that belies our approach in the studies I'll highlight in just a moment, and that's the fact that if you look at TLX250 tumor residence time, there seems to be little or no relevant therapeutic activity that's maintained after about three weeks or so. With that in mind, if we fractionate therapy, we feel that we may potentially really maximize efficacy and reduce those intervals at which the patient is really receiving no therapeutic benefit. If you're spacing out at three-month intervals, four-month intervals, et cetera, you have a long period of time in which tumors aren't exposed to sufficient dose of therapy. Using the strategy that we've suggested here, each fraction stays low enough to avoid dose limiting toxicities as well. And moving forward, there's 2 strategies that we'd like to assess.
The first uses, again, that dose of 1,887 megabecquerels every two months for a total of three cycles, and this is really based on activities seen in previous studies. We are taking the further step of assessing 1,258 megabecquerels every month for a total of six cycles. How is this incorporated in our forthcoming study? There are 2 studies I would like to highlight here, but very similar in premise, LUTEON and LUTEON-ATLAS. I am the principal investigator for LUTEON-ATLAS. Some similarities. This involves the same patient population, patients with advanced or metastatic renal cell carcinoma. These patients should have had disease progression on or after 2 to 3 prior lines of therapy. Again, this is an area of unmet need, as I think I have painted a picture of in my previous slides. These patients have to be CA9 positive by zirconium-89 TLX250-Px PET.
Now, lending itself to some of the differences between these designs, in the U.S. there is a safety lead-in that is mandated. There are three patients in each of the two dosing cohorts. These patients can be sort of melded into the dose optimization schema that you see that is running both in the LUTEON study in Australia and the LUTEON-ATLAS study in the U.S./E.U. You can see the two schedules that we are evaluating. I have already highlighted that dosing strategy on the previous slide, but you can see this comparison of monthly dosing as well as look at every two-month dosing. Again, one of the differences is that in the design of LUTEON in Australia, we have the flexibility to actually migrate directly into a phase III design, and I think that is quite unique.
You can see here that the randomization proposed is either to our drug versus investigator's choice of therapy. Sample size is still to be determined, but I think it is a very pragmatic design in this setting. With that, I will pass it on to, I believe, Dr. Cade. Thank you.
Thank you, Pal.
You got it.
Thanks, Pal. Look, I would like to thank Dr. Pal. You are a very modest collaborator, Dr. Pal. You have been fundamental in the original and finessing of the design of the LUTEON family of studies, and I think that is ultimately going to generate some extraordinary data that we believe will move the field. What I would like to do is, I think Dr. Sundaram and my colleague Kevin Richardson articulated how we believe BiPASS is fundamentally going to change the diagnostic practices for prostate cancer. One of the very fortunate parts of my role as a physician in industry is to be able to work with collaborators like Dr. Sundaram and Dr. Pal and Alicia Morgans to design trials that ultimately generate data that will change practice.
I think we feel very strongly that Zircaix and the data from the completed ZIRCON Phase III trial will fundamentally change how we manage kidney cancer. Let us move on to Zircaix, for which we will be refiling our biologics license application very shortly. The clinical use for Zircaix, I think is very clear. Let us just recap what that clinical use case is. Given the increasing number of what we call incidental renal masses, and there is a slightly more memorable term for those in clinic, we sometimes refer to them as incidentalomas. These are incidental masses identified in the kidney through really the proliferation of conventional imaging with CT or MRI or even ultrasound that is widely used to examine other abdominal pathologies that might be from completely unrelated conditions.
When a clinician, whether they are a urologist or a surgeon who takes care of abdominal pathologies or whether they are a radiologist, when they are confronted with a newly identified renal mass, it is clear that this needs to be characterized very accurately without doubt as either a clear cell renal cell carcinoma, ccRCC, which is the most common and aggressive form of kidney cancer, or non-ccRCC, either a more indolent malignancy or a benign lesion. While conventional imaging can provide detailed information about structure and vascularity, these modalities still lack the ability to distinguish between benign and malignant lesions in the kidney. Consequently, similar to what we have just seen, I think very clearly in prostate cancer, for kidney cancer, today's standard remains renal biopsy, which has very significant drawbacks. Primarily, it is highly invasive.
It's a very large bore needle through the loin or through the back, and that carries significant complications such as pain and bleeding through pranging an arterial vessel that might require surgery or an interventional radiologist to stop that bleeding, and, of course, cancer seeding. If it is a cancer that we've put the needle into, when we withdraw the needle, we can actually seed malignant cells along the tract of the needle when we pull it out. This slide really nicely summarizes the results of our ZIRCON phase III trial, which I think demonstrated two key takeaways. The first of those is that ZIRCON fundamentally validated carbonic anhydrase IX or CA9 as a new target for therapeutic radiopharma development for renal cell carcinoma.
This really forms the rationale for Telix's decision to take shareholder capital and invest that into the LUTEON studies, which Dr. Pal has described so nicely. Secondly, I think what, for me, what ZIRCON has clearly demonstrated is the accuracy of Zircaix to non-invasively delineate clear cell renal cell carcinoma from non-ccRCC lesions. It's this latter use as a non-invasive tool using a new modality of PET, CA9 PET, to characterize ccRCC from indeterminate renal masses. We're really excited about bringing this to clinicians and their patients following eventual FDA approval. Let's look at a couple of case studies. I think the case studies are very illustrative of why Zircaix is so eagerly anticipated for the clinic. This is a patient for whom a small renal mass was initially detected on conventional imaging. Again, what we call an incidentaloma.
To work that up, to really investigate that further, this patient had more formalized contrast CT and MRI, which elucidated bilateral masses. No evidence of extended or metastatic disease. The initial plan was to do partial nephrectomy, so nephron-sparing partial nephrectomy of the larger lesions on the right kidney, and a procedure known as radiofrequency ablation to the smaller lesion on the left kidney. Fortunately for this patient, he went on to have a Zircaix PET scan, which turned out to be negative. Following his negative Zircaix PET scan, the decision was then made to change from surgery and radiofrequency ablation to active surveillance, much to the relief of this patient. For this patient, partial nephrectomy, which is a very significant operation, and radiofrequency ablation were safely avoided. The use case in this setting, I think, is crystal clear.
This is a second case, which is almost diametrically the opposite to that first patient. This is a 78-year-old patient, so they're getting elderly, and we have to be very careful about what surgical procedures we want to do in an older patient. This patient had already been diagnosed with advanced kidney cancer based on histopathology obtained from a biopsy. His diagnosis is known. What this demonstrates is that Zircaix is able to detect the extent of metastatic disease. This guy had advanced renal cell carcinoma identified in several organ systems. Obviously, the primary in the kidney remains there. He's not a surgical candidate, but it's also in his spine and in his lungs, and the scan can also distinguish tumor thrombus because renal cell carcinoma has a propensity to invade the renal vein that drains the blood from the kidney.
It is a property of renal cell carcinoma that enables it to gain access up the renal vein to the heart and can cause significant cardiovascular problems with advanced disease. What this Zircaix information was able to confirm was that this patient definitely is not a surgical candidate. He has multi-site metastatic disease, and clearly, he is going to require systemic therapy, as Dr. Pal has described. I will pause there, and I will hand back to you, Kevin.
Thanks, David. I am just going to take a few minutes to pull this together and what we see as the opportunity. You will have seen from Chris's opening slide really the next 3-4 years and how that evolves into our overall growth strategy. To put that into a couple of simple terms, our growth strategy over the next couple of years, as you can see from this second product, is to expand our products into multiple disease states, expand those products with new indications, as you have seen for BiPASS. I will mention another one here for Zircaix. As you saw from his presentation, we are in 22 countries. We are going to expand the geographies in which we sell those products, giving us a multi-product, multinational revenue stream to kind of diversify what we are doing.
That really evolves over the next 3 or 4 years into our overall theranostic strategy, which simply put, gives us the diagnostic platform, gives us a platform of target understanding and de-risk that, revenue diversification to de-risk that, and then ultimately building these relationships that we need to be an effective therapeutic company with payers and regulators, as well as our customer base, because they are very similar and synergistic. To describe that, and specifically as it relates now to our second product that we are talking about with TLX250-Tx-Px or Zircaix as a brand name, you will have to remember that many of these patients come in really by accident.
Usually you go in for a scan for something else and the doctor says, "Yes, you have got a broken rib," or "No, you do not have what you came in here for, but we found something in your kidney and you need to go see a urologist. It is most likely benign, but we need to make sure." He sends you to a urologist or into radiology scanning to make sure for the appropriate type test. What that does for us is that we already have, now back to that synergistic that we are talking about, we already have these relationships with urologists, especially as we start thinking about refer to imaging. But now urologists are much more involved in both the order to get the referral as well as the prescription to refer to a radiologist.
Now, it will ultimately be read by a board-certified radiologist, preferably, as you heard Dr. Sundaram describe, preferably a nuclear med physician that really has the expertise in reading that. But once we get that diagnosis, to David's point, the ZIRCON change of management is really what the most important part of this is as we think through now we're going to be alongside of people we've already been working with in this growth strategy of a surgical urologist, a med onc, a radiation oncologist, and/or an interventional radiologist along with for the ablative treatments that are possible. What does that do for the opportunity? We described the prostate opportunity as approaching $20 billion and 130 or quite a few patients. As we think about what that looks like for renal cell carcinoma, again, expand the product, our first indication, diagnosing indeterminate renal masses.
We believe that's over $ 0.5 billion or 100,000 patients. As we think about expanding the indication back to our growth strategy, that is metastatic disease in clear cell. Then as you saw from the therapeutic study, we believe there's 5,000 patients in that third line, third line plus in clear cell renal cell carcinoma. Then in that second line plus, as we continue to look at how effective this product is and move it upstream a bit into second line, we believe that's twice as many patients in that second line and approaching 11,000 patients or $ 2.5 billion. Describing our renal portfolio, theranostic portfolio, we see that approaching about $ 4 billion-$5 billion in opportunity.
Again, you can see now how that fits into our overall strategy of growing the platform both from a diagnostic standpoint over the next couple of years with the imminent launch of Zircaix and then as we roll that into theranostics. Anyway, thank you for your time.
All right. We'll open it up to Q&A again. If I can please have the speakers up and then please raise your hand if you have a question.
Is that a good thing from your perspective?
Hi. Good to see you. Thank you.
Anyone? Any questions?
As I understand it, CA9 is a general marker for hypoxia, which is almost definitively what a cancer is. Is there a path forward for all advanced cancers for CA9, either a diagnostic agent or a therapeutic agent or both?
You want to comment on the
Yeah
target now, rather?
Sure. Yeah. So indeed, I think there is specific reason to think that CA9 may be overabundant in renal cell carcinoma based on VHL alterations in the disease. That lends itself to increased transcription of CA9 ultimately through the pathways that I cited. There certainly is abundant expression of CA9 in a handful of other diseases. We see it across a spectrum of some gynecologic cancers, for instance. So I certainly see outlets for CA9-directed therapies in other settings too, beyond renal cell carcinoma.
Yeah, I would just add to that it often gets put to us that, "Oh, why do not you do a basket trial?" A basket trial being a term for not the species of cancer that might be included in a trial, but including patients that express the target, and that target might be expressed across numerous different species of cancer. For example, it might be kidney cancer that is included in the basket and ovarian cancer, for example, that is included in the basket. And while on the surface that is an attractive approach, FDA does make it a little bit more complex than that. And so our philosophy is, as Dr. Pal has described, is to obtain a first beachhead with kidney cancer, both because there is a major unmet need in kidney cancer.
Patients do progress through the available therapies often quite quickly, and kidney cancer has a very high prevalence and specificity of expression of that target. That is where we plan to go first, and I think that is a very responsible way to go about it.
Thank you. Dr. Pal, in terms of efficacy of some of the TKIs that you see in the second and third line, could you speak to where you see the hurdle for Zircaix in terms of efficacy, what you would like to see to be excited about the product? Then David, maybe in terms of CA9, what the next interesting indications could be beyond renal cell?
Mm-hmm. Maybe I can comment on your first question there. The benchmarks for third line therapy are not particularly impressive. If you look, for instance, at data for belzutifan, which is perhaps most abundantly used in that setting, median progression-free survival is 5.6 months. Median PFS was also 5.6 months for its comparator in that study, everolimus. The hazard ratio between the two just happened to be 0.75 favoring belzutifan. I would say that benchmark is one that is easily surpassed by a lot of novel therapies. If you think to other potential strategies in the third line setting, tivozanib comes to mind, and there, the TIVO-3 study, which actually looked at tivozanib in the third, fourth line setting, produced an almost identical benchmark with a PFS of around 5.5 months.
I actually think that the strategy here provides a potential comparator that is easily surpassed.
Jeff, I think you asked about where else could it go. I think if renal cell carcinoma, in the first instance, was able to have its overall survival prospects improved upon, that would lead us to investigate other species of cancer that express the target. We would look at things like bladder cancer. We would look at female genitourinary cancers. We would probably start there. Say, for example, specifically ovarian cancer is characteristically diagnosed late and often in younger women. We certainly need better options for such malignancies. I think that is where we would probably go looking.
Maybe a question for Dr. Pal, if you do not mind. I guess in the adjuvant setting from a clinical trial perspective, I hear a lot of investigators talk about patient selection, maybe patients who do not really need pembro or belzutifan are getting it, vice versa. I am just curious about your view on having a diagnostic agent, CA9 for example, as a potential selection biomarker down the road. Is that something that could be very interesting? Maybe from Telix perspective, could Zircaix be something positioned there? Or you might need something that is in ITM's pipeline with a small molecule gallium-68? Thank you.
Yeah, so just to paint a really brief picture of the landscape for adjuvant treatment of renal cell carcinoma was pretty barren until about five or six years ago. There was an approval for adjuvant sunitinib. Frankly speaking, that is very rarely utilized. Pembrolizumab entered the marketplace several years back and now is supported through the KEYNOTE-564 study with positive, not just disease-free survival data, but also overall survival data. I think that there is a penchant for most patients who are candidates to actually receive pembrolizumab, where I think a lot of the debate lies in the more recently presented LITESPARK-022 clinical trial, which looked at pembrolizumab plus belzutifan versus pembrolizumab alone as an adjuvant strategy. There we saw a significant improvement of disease-free survival, no benefit in OS.
Paradoxically, it was actually the patients who were at lower risk that seemed to benefit to a greater extent from belzutifan. It really begs for an appropriate biomarker. If you are going to give a drug with toxicities like hypoxia and anemia, which belzutifan carries in the adjuvant setting, it would be ideal to have a biomarker for benefit. To your point, I actually think that given the relationship of CA9 to HIF and VHL and so forth, I think that there is a lot of rationale in exploring perhaps Zircaix as a potential biomarker for benefit there. That is speculation, but I think that it is definitely worth study. It is a great point.
All right. Any other questions? If not, then we'll move on to the brain cancer portfolio. I'll ask David to introduce our next speaker, Dr. Braat.
Okay. Thank you, Annie, and thank you, Dr. Pal, for the Q&A session. I'm absolutely delighted to invite our next key opinion leader speaker who's come all the way from Europe. I think it just really is a reflection of the collaboration in the field, particularly in glioblastoma, which is a devastating diagnosis. We've got so much more work to do. I think you'd concur, Dr. Braat, it's been a drug development, not graveyard, but certainly a drug development desert over the last 20 years. The last major advance really was Stupp regimen back in the mid-2000s. Dr. Braat is a nuclear medicine physician, a Dutch nuclear medicine physician, at the University Medical Center Utrecht in the Netherlands, specializing in a whole range of different radionuclide treatments.
He completed his PhD thesis, which was in a different area, an earlier area that was very close to my heart, hepatic radioembolization in neuroendocrine neoplasms back in 2019, I think. In 2023, Dr. Braat was appointed as Associate Professor of Translational Nuclear Oncology at the University Medical Center Utrecht. He also serves as an advisory board on the European Neuroendocrine Tumor Society, ENETS. So liver neuroendocrine tumors, and also a leading researcher in brain cancer as well. I think, obviously, you can tell from my accent, I'm Australian, come from Sydney, but if I was a Western European, I would come to your center for treatment of my glioblastoma without a doubt. Dr. Braat, over to you.
Thanks, David, for the kind introduction. Thanks for the opportunity to speak about glioblastoma because, as David already mentioned, it's a big clinical unmet need. I came into touch with glioblastoma patients when I finished my PhD, and speaking from the heart, these are people from my age, young people in the middle of society, having small kids, but are confronted with brain cancer. As mentioned by David, I think this is striking. We see these brain cancer incidences rising over the past 20 to 30 years, and as mentioned, the only real breakthrough we had was in the 1990s, beginning of the 2000s, is Stupp regimen. Stupp regimen is nothing more than having external beam radiation therapy combined with classic temozolomide, and afterwards get temozolomide maintenance therapy. If your patient is lucky, before they go into Stupp regimen, they get a surgical resection.
But of course, if the tumor is in a very unfortunate location, patients do not get a resection because they will get neurological problems. As you look at these curves, you can see there is still a very big plateau in survival benefit over the past 20 years. We really have to make some changes there. Overall, survival is poor. Patients have a mean overall survival of about two years, and a fter two years, more than 90% of patients has already progressed. After initial therapy, within the first half year, most of our patients already show progressive disease. This is just a feature of how aggressive glioblastomas really are. As pointed out, we do not have really any other therapies. There is lomustine. It was back from the 1980s.
It showed a progression-free survival benefit of 1.5 months, but we really do not have anything better. That is the reason why the NCCN guidelines, but also EANO guidelines, actually state that in case your patient has a recurrence, you should go for clinical trial participation, because that is maybe a better alternative than getting just standard lomustine for therapy. Another thing is imaging. Imaging with MRI, it is our gold standard, but having changes within the brain is very difficult, especially after radiation therapy, where you can see these post-treatment changes, pseudoprogression, radiation necrosis, and it is very difficult to distinct radiation necrosis versus tumor progression. With FET-PET, it is starting to generate a lot of evidence nowadays. It is already in the guidelines because we see it really has advantages over only MR. Going straight for FET and LAT-1. LAT-1, large amino acid transporter, LAT-2, also a large amino acid transporter.
They are two subtypes, but LAT-1 is the most interesting at the moment. It is highly expressed in gliomas, and it is also expressed in your normal blood-brain barrier. The blood-brain barrier is actually our biggest challenge. Besides having a glioblastoma, which has very infiltrative growth, so you do not see it as well on imaging, the blood-brain barrier also blocks drugs from passing into the tumor. More than 96% of drugs we develop in clinical practice do not pass this blood-brain barrier. This physical barrier really makes it very difficult to treat. This is why looking at LAT, just amino acid transporter, radiolabeling amino acids, just tricking the normal physiological pathways into getting a drug in your tumor is actually quite elegant.
With TLX101, which is iodine phenylalanine, and TLX102, which is astatine phenylalanine being just a normal amino acid, allows to pass the blood-brain barrier through these LAT transporters. Predominantly, the data that is out there now are IV therapies, so intravenous administrations. It is simple. Patients come into department, we administer the drug, and because at this time it is with iodine-131, patients need to go into isolation, as we are used to with thyroid cancer patients and patients that get MIBG therapy. Patients need to be in isolation in a short period of time. Once they are in isolation, they actually have no adverse events. After a week or so, patients are discharged, and then some fatigue starts to play in. Actually, that is the only clinical adverse event we really see in our patients. Like 10% of patients get some nausea, but otherwise, these patients do fine.
We have clinical data. We started off with the IPAX-1, IPAX-2. Now we have the pivotal IPAX-3, so IPAX BrIGHT study coming up. We have safety data, and now we are really looking forward to getting this real clinical efficacy data. There is also the IPAX-Linz, which was an extension of the IPAX-1, where we combined TLX101 with external beam radiation therapy. It was run by Josef Pichler, who is a PI in Austria. Those just demonstrated that there were no DLTs. It is a safe therapy for patients to get, and they had very encouraging results with overall survival numbers passing the three months. For a dismal disease with a median overall survival of just two years, getting an overall survival of up to three years is very encouraging. Let us just briefly touch upon the ongoing studies.
As mentioned, IPAX BrIGHT, or used to be called IPAX-3, is a study where we combine TLX101 with lomustine being the backbone therapy for patients that have a first recurrence of their GBM. Within this first part, we do a dose optimization just as a safety run-in before we go into the randomized phase III part of the study, where we do TLX101 plus lomustine versus lomustine alone. The biggest thing we are concerned about is lomustine, because we know lomustine actually gives a lot of thrombocytopenia. Of course, with an RLT, we see a lot of bone marrow depression, so thrombocytopenia is the thing we are looking for the most. For the first part, of course, will be what is the tolerated dose, and for the second part will be overall survival.
Because as mentioned, once these patients get a second or the third recurrence, there are no regular treatment options left. This big study is running internationally, and they already recruited patients in the first cohort of part 1, so that readout is pending. Before getting to IPAX BrIGHT, in our institution, we did a named patient program or a compassionate use program where we offered this therapy to patients in our clinic. Just a brief recap, we had 14 patients in the compassionate use program. 10 of them were glioblastoma. As you can see, these were heavily pretreated patients. Only ive fwere treated as a first recurrence, and nine of them had second, third, or even fourth recurrences. These were heavily pretreated patients. Just to show you some efficacy data, and this is maybe a bit confusing, but look at MR.
If you look at the MRI scans of the 12 patients we had MRI data, you can see three out of 12 have stable disease, two had progressive disease, and the majority had unconfirmed progressive disease. Why unconfirmed? Because here, this problem of radiation-induced necrosis comes into play. It is very difficult on an MRI to state whether or not a patient is progressive, yes or no. After the initial experiences, we also started doing FET-PET response assessments in these patients, and that is what you can see in the seven patients below. Seven out of seven had stable disease on FET-PET, so both visually as quantitatively. We see a lot of radiation-induced changes, but that does not mean the patient is actually progressive. Looking at safety, there was one grade 3 toxicity with cerebral edema. We see that a lot in patients with GBM.
It was very good to be managed with dexamethasone, which is standard, but probably because of its tumor progression. There were no other adverse events. Just some examples. This is a patient with a third recurrence of a GBM. Actually, this man was in a very good clinical condition, still was running marathons. But as you can see here, he has a very big occipital lobe tumor and has high expression of LAT-1 on his FET-PET. We treated him twice, and this was, I think, our fourth patient. As you can see, after his two cycles of TLX101, we saw this very big, aggressive growing tumor. The radiologist said, "Well, it's probably progressive disease." This is where we needed this distinction with FET-PET.
We started doing FET-PETs, unfortunately, after this case, which was striking because if it's a third recurrence, you would expect that his survival would probably be somewhere between three and five months. But a year later, he passed away. This is a very difficult image on MRI alone, so we need something more. Another case, I think this was my fifth or sixth patient. Again, glioblastoma. This was a first recurrence patient, already four months after his Stupp regimen, so it was a very aggressive tumor. You can see the FET-PET and MR images here. The arrows are a little bit below. They should be, of course, a little bit more upwards. It was just in the vicinity of his central gyrus, so where he has motoric and sensoric functions, so it could not be operated upon.
As you can see here, the lesion was very fat avid. The discussion was, can we enroll him in our compassionate use program, or should we opt for lomustine? But the chances of lomustine giving you an objective response is less than 1%. This was one of the reasons why this patient came to my office and asked, "Can I participate in our compassionate use program?" This is the result. You can see 31 months later, there's very nice tumor regression. You don't see any enhancement anymore on MR, which is striking. We never saw that before. The FET-PET just shows this very vague accumulation in the same area, which, as we see in nuclear medicine, could still be some inflammatory reaction after therapy, some radiation-induced changes. Just for this meeting, I got his MRI from last month, 33 months later.
What's nice to see here is that you see this tissue decay in the region where his initial tumor was. He's still disease-free at the moment. This is very promising data. We also treated other tumor types. Oligodendroglioma is also another tumor that doesn't have a lot of therapeutic options nowadays. Here's a young man with a very big frontal oligodendroglioma. He was heavily pretreated, so external beam radiation therapy, temozolomide, PCV courses, and lomustine. We treated him three times with TLX101 with four weeks in between, and this is the result 10 months after three cycles. You can see the FET-PET accumulation is decreasing. The tumor itself on MR is still the same. On MR, it's stable disease, but with molecular imaging, you can see the accumulation is decreasing.
Unfortunately, we are pausing his treatment at the moment because he is getting more epileptic seizures, so in isolation, that is of course quite tricky. But at this time, he is still doing quite well. He has no neurological complaints. So for now, this only gives us a signal that maybe this is also something for oligodendroglioma patients and not for GBM patients alone. So advancing from recurrence setting to first-line setting, because also in first-line setting, as mentioned, 90% gets a recurrence within the first two years after initial therapy. There is the IPAX-2 study. It is completed, combining Stupp, so external beam radiation therapy with temozolomide, with TLX101. So from my own experience, it was well-tolerated. Nothing in particular happened. So the safety readout and the official efficacy readout will follow because it has been completed now. So eagerly awaiting those results.
In line with the rest of the presentations we had earlier this morning, of course, also for phenylalanine, we are going from beta emission towards alpha emission. As mentioned, beta emission with iodine-131 is a bit tricky because we have these high energetic gammas which patients need to be in isolation in. That is not a particular setting as a patient you would like to be in if it is your last treatment option. You want to be at home with your family. So going for alphas makes clear sense from an emotional societal perspective. Together with Telix, we are doing this first in man astatine-211 phenylalanine study in Utrecht, in which astatine-211, which is an alpha emitter. It is less known than actinium-225, but it is more promising in my perspective. It has a shorter half-life, just seven hours, so it has a very high dose rate.
The other nice thing is, of few things, the only alpha emitter you can decently image. So this is a phantom scan on a SPECT scanner, and you can see lesions as large as 1 cc. So if you have dedicated SPECT time and reconstruction methods, you can actually image this alpha emitter. That is something we cannot do with actinium-225, and with lead, it is also a bit tricky. In this phase I study, we are going to do a classical dose escalation study, in which we are going to administer this intra-arterially because in my belief, we should treat localized disease locally. By giving it intra-arterial, we will get a very high drug concentration in the tumor and hopefully get better responses. This is also supported by KWF, the Dutch Cancer Society, and together with Telix, we are going to initiate the study in 2027.
Looking a little bit further, I think another unmet clinical need in neuro-oncology is leptomeningeal disease. It is a metastatic disease, so primarily breast cancer, lung cancer, and melanoma. Once patients are diagnosed with leptomeningeal disease, their survival is approximately somewhere between the three and the five months. Of course, their blood-brain barrier is leaking. But what we know is if patients get systemic therapy, their metastases tend to respond initially, but then the BBB recovers. Once the BBB is recovered, their systemic therapy does not work anymore, and their leptomeningeal disease takes over, s o also for these patients, we have a big problem because depending on the location of the leptomeningeal disease, patients can get neurological problems. Just as an example, I think that one is also very interesting here. This is one of my pediatric patients with a PXA.
You can see there's a very small enhancing intracranial lesion, but next to it, you can see a little bit extension of fat signal outwards. And under another level, you can also see fat uptake outwards into the old resection cavity. It also showed some foci in the spinal cord, which we did not acknowledge on MRI. A couple of months later, of course, on MRI, we did start to see contrast enhancements on those locations, and it was confirmed to be leptomeningeal disease. I guess also for molecular imaging with FET-PET, that's an interesting thing to figure out for leptomeningeal disease, but also in the future for therapy. With that, thanks for the attention. I'll give it to, I guess, Kevin, right?
[Audio distortion]
[Audio distortion] Thank you very much. As you can see now as we're rolling through the different indications, both from a therapy standpoint and then a diagnostic standpoint on Pixclara, I think you'll continue to see what I talked about in the last session is this platform growth strategy that we're building out. It's really nice to see this in succession, where we started with prostate, and Chris showed a slide, some of the excellent results we've been able to achieve over the last four years building this base of business that is generating the revenue we need to continue to build the future part of the business, which is part of the diagnostic therapeutic, theranostic strategy that we have de-risking revenue.
We start really adding to this platform we're talking about over the next couple of years, where we have launched Illuccix, Gozellix, and then we expand into neuro-oncology next, and w e have an imminent launch in urology with Zircaix. You can start to see that expand the product part of the growth strategy work. We've talked about BiPASS for prostate. We talked about ZIRCON or metastatic disease in kidney, and now we're talking about our fourth product or third product in the portfolio, Pixclara, where we have just received PDUFA and approval. Really excited. The first dose announcement is imminent as well, as we plan through that process of getting the manufacturing set up, and it is, and we're going to the first dose just this month. Really exciting news we'll have to announce soon.
As he spoke of, we also have an MAA in Europe that we have applied for and submitted. We will take Pixclara or Pixlumi under its brand outside of the U.S. as a part of the overall expand the geography strategy as well. This product has been called FET-PET for many years and used in Europe, so it is already in guidelines around the world. When you are launching a product, specifically in the U.S., you want good clinical data, you want it in the guidelines, you want the approval, and you want reimbursement. You see all that lining up for us here in the U.S. The second piece of that and part of the overall growth strategy is to, and we have submitted an IND here in the U.S. for brain Mets, and we will talk through the opportunity there.
It was also granted orphan drug designation because of the high unmet need that we were just speaking of, really being able to understand immediately whether it is pseudoprogression, and/or it is true progression, and being able to change quickly the treatment that you want to offer the patient. This is the first drug approved, and it is really a first-in-class imaging agent approved for glioma. As you may know, we did an expanded access program of over 100 patients. We have good experience with this. We have been educating the market on the disease state and the unmet need.
One of the most interesting things, I think that of the data, besides the good clinical data as we think about the commercial data for this is that out of over 100 patients, we did not have one patient cancel, which I thought was a really interesting statistic because this is a pretty sick patient. Over 100 patients, the caregiver or the patient was so inclined to get this because they wanted to know exactly what happened after the last treatment and quickly get another treatment if they needed, that somehow, the caregiver or the patient got themselves to get the scan and did not cancel at any time. A really important statistic.
We have done a little bit of research just to prep the market, and over 70% of our physicians say they are ready to refer because this is a referrer down to the nuclear med physician who is going to read it. We have reader training set up to make sure that we get the best results. If there is one thing I have learned in this business over the past four years is that you want to make sure your first dose is as good as the 1,000th dose in a hospital. We do that through our modular approach. I have talked about that in our commercial team. We have MSLs and clinical theranostic specialists that are technical specialists in the nuclear medicine lab, and it is really important to make sure that that first dose is just like the 1,000th dose.
80% of these physicians are going to rely on the NCCN guidelines here in the U.S., of which, of course, we're a part of. The great thing is, this isn't an outside-of-the-hospital refer or order. It's going to be in-house in most of these places. As you know, this really isn't an outpatient scan in terms of IDTF or a freestanding facility. There's about 150 centers in the U.S. that are really active in this. 100 of them or so are really busy as we think about this as more specialized. That doesn't really curtail the opportunity that we see. We still see this as a large opportunity for two reasons.
Number one is we think it's a significant part of the market that we have both a theranostic point of view, so we want to be able to really expand that, as well as the therapy side of the opportunity that's out there. So that's what this looks like. If you remember, we had a $20 billion opportunity or approaching that in prostate, approaching a $5 billion in urology, kidney, or renal cell, and then now a $3.5 billion opportunity. Now you can really start to see the growth strategy stack up, if you will, as we're thinking about two products going to three products going to four or five, multiple indication, and of course, over 22 countries that we already have a footprint in that we can take this.
We have filed the IND for brain mets, and we see that as about a $500 million opportunity that we plan to progress as well as we commercialize what we think is the right thing to do, even though it's a smaller opportunity for us because of this high unmet need and the desire to get to a better therapy, we're going to bring Pixclara to market and build that footprint or that platform for us to launch from. Then as we think about the therapeutic side and the theranostic platform in that second line, we see about 8,000 patients and then about 25%-50% more than that in the first line in wild type. So really an exciting platform for patients as we bring this to market and really part of our mission as a company as we think about radiation oncology as our core platform.
When you add those three together, we're approaching about a $30 billion opportunity over the next three to five years. Of which that first platform, if you just added up the diagnostic opportunities, you would see that along with BiPASS, somewhere approaching $4 billion-$5 billion of opportunity realizable. Really, if you look at our past experience and history, we've grown 16 quarters in a row in an area where we were second to market. Now imagine, if you will, a world where we're first to market in Pixclara and we're first to market in Zircaix or in clear cell renal cell carcinoma. I think that ends my presentation as we change out of the first three products and move into TLX400.
Thank you, sir. Look, just listening to you, Kevin, one thing I can say unequivocally is it's very gratifying to be part of a clinical and a medical and an R&D and a regulatory team that does all of the work as a team to get Pixclara finally through the FDA and to be able to now hand it to what is clearly the best commercial team in the business. I know that you and your team will get not just a drug, but a clinical workflow to patients and the clinicians who look after those patients, and that'll be to the benefit of those patients and hopefully their longevity through the improved imaging. Kevin, it's always a pleasure to know that it's going to land in the right hands.
We are now on the home stretch, and you can tell that we're on the home stretch because we're getting into the earlier stage assets. Richard, you and I are going to close it out before we hand back to Chris. We're going to cover the early-stage assets. I'm going to start with the first of those, which is TLX400. Let's turn briefly to our pan-cancer asset, TLX400, which while being earlier stage, as Richard, you articulated right at the opening, this is a phase I asset. Our TLX400 FAP asset, FAP being fibroblast activation protein, has been engineered to improve upon the existing multiple. There's many of these existing FAP candidates. None of them, we believe, are particularly encouraging.
But the TLX400 one we really like, and we like it because it's able to exhibit very prolonged tumor retention that's critically important to achieving a high dose, minimized off-target organ uptake, and enhanced systemic clearance. It goes where we want, it doesn't go where we don't want, and it clears out the excess very efficiently. We believe FAP is an important target for both molecularly imaging patients diagnostically, but also, I think more importantly, for therapy due to the FAP target's prevalence on over. It's about 90% of epithelial cancers that it's expressed on. And it's primarily expressed in the stroma or the scaffolding of a solid cancer, the fibrous tissue that holds the cancer together, b ut in some of those cancers, it's also expressed on the tumor cell membrane itself, b ut it's relatively absent, FAP's relatively absent in most normal adult tissues.
Now you can see here on the right that TLX400 FAP has to date achieved some very encouraging disease control and progression-free and overall survival rates in early studies across thyroid and breast and some soft tissue sarcoma cancers in patients where we're using it in these studies that have really exhausted all of their conventional therapy options, s o really this is a last gasp shot in patients that are refractory to conventional therapy and they're clearly deriving significant disease control benefit. I think, besides the encouraging, these are early signals of potential efficacy. Really the key takeaway is the favorable biodistribution of TLX400, which has been designed to overcome the limitations of the first generation or alternative FAP-targeted radiotherapies. Again, very low normal organ uptake, which enables higher administered radioactivities, and longer tumor residence times. This is a candidate we believe holds a lot of promise.
Now again, I love the case studies because they really articulate the potential of an asset. Let's look at a couple of case studies now. This is a case study from our TLX400 FAP program, which really illustrates why FAP is a pan-cancer target. I think the question earlier was about CA9 as a pan-cancer target. FAP is also a pan-cancer target and why it is such a high-interest one. This is a female patient in her mid-50s, with advanced breast cancer, which you can see on the left-hand side in the baseline, FDG, the conventional PET, but also the FAP-based imaging has very disseminated involvement in her axillary or armpit, thoracic, and abdominal lymph nodes, s o very broad lymph node involvement as well as her liver and some skeletal involvement as well. This is very advanced disease.
Now this patient who had received multiple prior lines of both systemic hormone and chemotherapy went on to receive a total of, I think it was five cycles of lutetium TLX400 and was able to achieve and enjoy very significant and durable reduction in her disease burden, as well as very significant improvement of her clinical symptoms as well. This is a very late-stage patient, who has had a positive impact with quality of life, but also disease burden reduction. This is a recent study in 19 patients with a type of thyroid cancer known as medullary thyroid cancer. I think this really demonstrates the potential versatility of FAP as a target for therapeutic radiopharmaceutical development across a broad range of cancers.
In this study, 19 patients with progressive medullary thyroid carcinoma were treated with either lutetium or actinium-225 labeled TLX400, receiving, in this series, a median of five cycles. Of the 19 patients enrolled, 17 patients were evaluable, and radiological response was assessed in 15 of these patients, resulting in a disease control rate, so partial and complete response, of 80%, PFS of 26 months, and overall survival of 42 months. So very prolonged disease control durations extending survival. Only two of these patients experienced grade 3 adverse events. The other hematological and biochemical adverse events were all mild. They were all grade 1 or grade 2.
I think the key takeaway here is that the early TLX400 FAP data demonstrates really encouraging disease control rates, with acceptable safety, which has been a challenge to date, and preliminary, and I emphasize because it is early, preliminary evidence of increased survival duration in patients with really advanced medullary thyroid carcinoma. I promise we are on the home stretch. Richard, I would like to invite you up to close it out. 309.
Yeah. Thank you, David. Perhaps one comment on the 400, that you can imagine that FAP is targeting the microenvironment, so we probably will have to develop this compound in combination with other classical treatments. That is really where the potential of this drug is. Because there are few cancers where we have the expression of the FAP directly on the tumor cells, but the vast majority of the cancers are with the microenvironment that we need to destabilize in order to authorize the classical treatment to treat the tumor cells, s o I am very passionate about this one. Let us move to the last two compounds that we have in our portfolio, at early stage, the TLX66 and 300.
Our 66 compound, it is an antibody that we are developing, and we want to use to develop in the bone marrow conditioning for authorizing the hematologist to do the transplantation that they are doing on a regular basis, s o this compound is extremely interesting because we can also extrapolate potential use in all the diseases which need a bone marrow transplantation, a nd we recently obtained some very interesting long-term data that I will present in a minute, s o you will see that we had some initial IITs in Europe, and these IITs have been followed up with some striking data that I can share with you here. So we have 90 patients across multiple malignancies, mainly hematological malignancies, as you can see there. And what is really interesting is the safety profile of these patients after treatment.
Because you can look on the right part of the slides that the patients with AML or multiple myeloma represent a probability of survival, which is quite striking because we have here a long-term follow-up of more than 200 months, s o that is really amazing because usually the issue with that is when you have a bone marrow conditioning preparation, the patients have no immunity anymore, and then you treat the patients with the classical treatment. But the safety is really the concern for these patients, s o we expect a lot from this compound. It is still early stage, so we have to continue the development, the manufacturing of the antibody. But that is something that we expect to develop, especially for the hematology malignancies. We also have the second compound, the TLX300, which is this one targeting the PDGFR-alpha receptors.
This antibody is well-known because it is a license that we have and a partnership with Eli Lilly and Company. So that is something we are currently also developing currently with a zirconium radioisotope that we are attaching to this antibody in order to define the dosimetry and pharmacodynamic and pharmacokinetic profile of the compound. Currently, we are running this clinical trial named ZOLAR, as you can see here, s o we evaluate the safety and the specific characteristics of this antibody in order to see where we can use. Usually, we are used to say that these receptors, the PDGFR-alpha, are very well known to be expressed in the soft tissue sarcoma, s o that is something which we are interested because if you make the correlation with the FAP, you understand that we can here create a kind of portfolio around the soft tissue sarcoma disease, which are extremely heterogeneous.
With two compounds targeting two different targets, that could be some game changer for the future. That is also something that we are developing in parallel of the rest of the portfolio on the early stage steps, I would say. I think we touch at the end of the presentation.
Yes. This is our very last opportunity to ask questions, and I promise there is lunch after this. If you have any questions, please raise your hand, and if I can please have the speakers up there.
Guys.
Okay, great. Just a couple of questions on the TLX101 therapeutics for brain cancer. Just maybe a question for Dr. Arthur Braat. If you look at the sort of competitive landscape for treatment for brain cancer, what are you looking for in terms of overall survival bar for the IPAX BrIGHT study as clinically meaningful to you, your opinion? Then if the study becomes successful, ultimately, where do you see it fits into current treatment landscape for brain cancer?
We know from data from lomustine that their progression-free survival benefit is 1.5 months, which is very poor for any treatment we have within the oncology field. My hope is that we at least reach three months, which is already, for this very aggressive tumor, a big win because this means patients get time to settle their administration before they pass away, s o having a progression-free survival benefit of three months is already a major impact in this field.
What about overall survival? That is the primary endpoint.
Yeah. Overall survival will probably be also around a year. With lomustine, we know it is somewhere around seven months. Getting a year is, again, big benefit.
Where do you see it fits into the current landscape for treatment?
I think if we establish efficacy in IPAX BrIGHT, it will definitely get a place in first recurrence. I already noticed my neuro-oncologists referring patients to me before even discussing lomustine nowadays. They do not like lomustine. If we confirm efficacy in IPAX BrIGHT, this will definitely have a place in first recurrence. Depending on IPAX-2, the question will be whether or not it also goes towards first line. I think if it is safe there, then we need an additional study to look at additional survival benefit. If we can show efficacy there as well, then that will have major impact in the field. Compared to other drugs that are currently being discovered, there are not a lot of very promising targets at the moment. I have known there has been a big fuss about peptide vaccines from Germany. I saw a couple of those patients myself as well.
I'm not that interested in those vaccines. I think the field is going the opposite direction because they're more looking towards having high-intensity focused ultrasound, a method to open the blood-brain barrier to get other drugs in. I think the neuro-oncology field is nowadays going more towards having sonation devices to get drug penetration. All those technical developments, the HIFU is also still in phase I, so that will take a long time.
Got it. Maybe just one last question for Kevin here for Pixclara commercial launch. Thanks for outlining all the successful launch. Curious in terms of where do you see as the biggest barrier for adoption? Do you think this is physician awareness, reimbursement issues, PET capacity, or any other issues around changing MRI-based workflow?
I don't really see any of those as a barrier. I would just say that any time you incorporate a new test or a new scan into workflows, it just takes time to make sure they understand the ordering process to timing of the scan, which is appropriate for the patient, and the timing of that patient in their treatment workflow or algorithm. So I don't really see any of those as a barrier. Again, when I talked about what it takes for good adoption, good clinical data, we have it. Reimbursement, we plan on processing through that. So up front, we'll see a little bit of a scale-up around waiting for using a NOT code up front, which as you know, we saw with PSMA, when there is no alternative, they'll use a NOT code, which helps them with reimbursement.
If we're successful with TPT, then you'll see that pick up again once we do that, because it's just easier in their workflow. Just understanding how it fits in and when it fits into what they're doing, and we're using that as a part of that. Now, part of that education process is what the medical team that works with us, the MSLs and the CTS we talk about with their reader training. All that is part of that education process to be able to help them integrate that into their workflow. The data is pretty well known from FET-PET overseas, as you know. So it's in the guidelines. A lot of those things that would consider to be barriers are already knocked down.
It really is just the adoption process and then availability as we scale up nationally over the next two to three months.
Any other questions? This is your very last chance. All right.
Thanks for taking my question. I guess we got some data really comparing iodine-131 and astatine-211 in the thyroid cancer space. That is pretty comparable. I am just wondering, one, can you extrapolate that to your neuro-oncology strategy there as you go from beta to alpha?
Yeah, me first?
Yes.
So yeah, of course, we have the Alpha T-1 study from the Japanese colleagues nowadays that has been published on thyroid cancer. The only difficulty about that study is that patients already had a lot of iodine therapies in metastatic setting before they went on for astatine, s o they were considered iodine refractory before getting astatine, which in my opinion, does not really make sense because you are using the same transporter. Even though they were considered iodine refractory, they had very nice results. And what I understood from the PI from that study is even in patients with bulky disease, they saw quite nice tumor reduction. So as I showed in my slide, the case with the oligodendroglioma, which are often very big tumors, I feel switching from iodine to astatine, even for bulky tumors, makes sense in this particular patient population.
Yeah, the other benefit is just getting it as a complete outpatient clinic therapy will be a major benefit because now they are in isolation for a week. So I think also from a societal and emotional perspective for the patient, it will be better.
All right. Any other questions? Okay, we have one more.
Maybe just a question on the payload selection. I-131, you were just talking about the high-energy gammas there when there is lutetium available as a beta emitter with a lot of history in astatine, maybe a less robust supply chain when you have Lead-212 and actinium, s o maybe can you just comment on the selection of the isotope payloads here?
You want?
Yeah.
If I'm not mistaken, I think that we also selected iodine and astatine because there's also a question of penetration of the BBB. We tested and we had some issues with lutetium. Mainly, I would say that it's because we can cross the blood-brain barrier when we attach mainly iodine and astatine. You're right, astatine is currently not yet fully available for clinical practices, but there's massive investments that we saw from different companies in order to develop that. We have experience in Europe and also recently in the U.S. from big companies. That's where the demand will drive the manufacturing capabilities, if I would say like that.
Can I make a comment?
Please.
Also, I think that anything that's chelated and radiometal does not cross the blood-brain barrier just by innate charge. The other thing is that don't discount I-131. It's a fantastic radionuclide that has the potential to have a really robust supply chain. It's very cost-effective. Unlike the historical experience with the thyroid, we ultimately don't believe this has to be a long hospitalization period. It's a relatively small amount of the injected dose gets into the tumor and the rest clears out very fast. There's no peripheral irradiation in the patient. When we get the dosimetry protocol right, you're going to be able to release patients from hospital pretty quickly. That's just an evolution that people need to get comfortable with compared to the historical use of I-131.
All right. If there are no other questions, I will ask Christian to make a few final remarks before we close the day.
Yeah. So, realize that was a marathon session, but hopefully it was interesting and useful. It is good to see that everyone in the room has outstanding bladder control, so congratulations. It is also very gratifying for me to watch my team in action, so thank you. We have got a really talented group of people at Telix and very grateful again for all the KOLs that contributed to the session. Hopefully, you can see some of you were at the R&D day last year. You can see the huge progress that we have made as a company, a lot of new data, a lot of new clinical activity moving ahead, and that really reflects the whole cross-functional progress of the company. So very pleased with the progress that has been made. We do have a well-funded R&D program. We continue to feel that investment in R&D is important.
As you can start to see these products dropping out that have huge clinical utility, I think that that R&D investment becomes increasingly justified. Just as a kind of a final wrap-up, we really have evolved enormously as a company in the last few years in terms of our commercial trajectory, a multi-product, multi-jurisdictional commercial business. The fact that we have now this very late-stage therapeutics pipeline, which we believe is having real clinical impact and has a sort of a tangibly proximal commercial potential as well. Then as we start to think about the next phase of Telix's life, which is that pivot more from a precision medicine funded business to that manufacturing supply chain integration with the ITM acquisition, of course, subject to closing that and that combined therapeutic pipeline.
I really feel that we are building a radiopharma company that has no peer in this space. We look forward to keeping you informed of our progress in the coming months. A lot of catalysts between now and the end of the year or between now and the end of Q1 of next year. So, watch this space and thank you for your support and interest in the company. Lunch is going to be shortly available next door, so please do join us. It is an informal Q&A opportunity as well. Thanks a lot.