Robotic surgery fellowship program at the Royal Melbourne Hospital, Professor Louise Emmett, Director of Theranostics and Nuclear Medicine at St Vincent's Hospital in Sydney, and Professor Andrew Scott, Professor of Medicine at the University of Melbourne and La Trobe University, and Head of Tumour Targeting Lab at the Olivia Newton-John Cancer Research Institute. We're really, really grateful to these KOLs for giving up their time to speak with you today. We have the agenda up here. As a follow-on to the R&D day that we hosted a few months ago in New York, today's session is really focused on the near-term growth opportunities across our commercial and late-stage portfolio. Chris will start with sharing some words on strategy, David will share some details of our key programs and introduce our key opinion leaders, and Darren will give a financial overview.
We have included dedicated Q&A sessions throughout the morning, so please hold your questions for those discussions. For those joining online, there is an option to submit your questions in writing. We'll endeavour to answer them in the room if there's time, or if not, we will respond to you separately. Today's event is being webcast and will be available for replay. The slides have been lodged with the ASX and the SEC. With that, please let me hand over to Chris to kick things off.
Thanks, guys. Thanks very much, everyone. Great to see you all, and great to see such a robust turnout. It's also nice to have visitors at our headquarters. Melbourne still remains an important part of the company's platform, and so thanks for coming in. As Ky said, I'm going to start off a little bit with some fairly high-level perspectives on the company. I'll apologize in advance, I'm just coming off a cold, so if I come across as a bit croaky online, that's the reason why today. But essentially, nutshell level, the business that we've built over the last decade obviously has been a very rapid trajectory. We currently have three approved products in various jurisdictions, but notably a focus on the U.S. market. We've built, I think quite unusually for a biopharma company of our size, our own commercial organization.
This is because, as you'll hear from some of the KOLs in the room later on, radiopharmaceuticals are not the same as regular drugs. They're really different, and they require a commitment to clinical workflow and clinical practice that is just, it's very unique compared to traditional pharma. So we view a commercial team as a distinct advantage and a strategic pillar of the company. We are commercially active in 22 countries. That means we sell an approved product in 22 countries. Of course, informally, we support many other parts of the world, but that's where we have licensed product, and we expect that multi-product, multi-jurisdictional approach to continue. We have 45 manufacturing sites globally. What does that mean? That's 45 sites where we handle radioactivity and where we produce products for human use.
So it is a huge investment in infrastructure, which I think is going to be a part of the recurring theme of my presentation, because I think that there is a lack of understanding why that is important, why it is a differentiation. If I could ask you to take away one thing from this session today, it is to understand that radiopharma is just going into a boom. I do not really want to describe it as a gold rush, because I think that is very transactional, and it is actually not the reason why we get out of bed every day. We get out of bed every day because we think we can have a big impact on patient outcomes. From a commercial perspective, this space is going gangbusters. The strategy for how to win and compete in this space has changed really dramatically in the last five years.
I think that we have done a good job of staying apace of those changes and being out in front of the market, but it does require making some commercial decisions that will take time for the markets to internalize. Of course, I am also talking specifically about things like the ITM transaction, which I will go into later today. This year, we will do roughly $1 billion in revenue, and we expect to come in per our maintained guidance, at the top end of that guidance this year. We do not forecast to a quarter. We forecast on an annual basis. That means that we consider the totality of headwinds and tailwinds in a given operating year. We have had a very good year. Our precision medicine business will exceed 25% growth year-on-year.
We expect to be able to continue that kind of growth in the future through our multi-product strategy and through indication label expansions. We also operate now in some more mature market arenas where we do see the impact of things like seasonality, which we saw last quarter. We can go into that in a bit more detail if you want. This is the sort of the big picture of the business that we have built over the past decade. The field itself is undergoing a huge pivot away from traditional nuclear medicine, which is really about diagnostics. If you look at the diagnostic growth in this graph of sort of 5% CAGR, that is across all diagnostic imaging. That includes PET, SPECT, more traditional areas of clinical activity. Obviously, the PET segment is growing much faster than that.
The key message here is that the transformation that will take place over the next, call it a decade, is really the therapeutics business. It would be a mistake to kind of oil and water these graphs and think that the two sets of product categories are not entwined with each other. They absolutely are, because regulators want to see patient selection. Clinicians want to know that they are giving a dose and they are engaging with a patient that is going to respond well. You cannot disintermediate these as classes of products, but the point of it is that the growth in the market is going to come from the therapeutics business. We really only have two approved therapies today that are of commercial consequence. What we have is 100 other drugs that are coming in behind. You have to contextualize that.
That's 100 drugs, and without exaggeration, 50 companies, many of which are fairly well-financed to do their drug development work, are going to be relying on a very limited amount of infrastructure that's available to deliver patients globally. There's a parallel race that's happening in our industry. One is a race to build pipeline, and to build capabilities on the development team side of things. The other race is about commercialization. Who has the share of the market voice when it comes to commercial activity, and who owns the supply chain and distribution infrastructure? You can't, again, separate the two from each other, right? If you want to be the commercial leader in this space, you have to be able to guarantee performance and delivery to a patient.
Takes one missed dose, as we find out when we have startup challenges getting a clinical trial running or we're launching a new product, it really does take one missed dose, and you've changed the relationship with a clinical partner or a customer. That's why the infrastructure is not a manufacturing business. It's an integral part of delivering a clinical outcome. That's why, on a very strategic and selective basis, we care a lot about this vertical integration process. As you're well aware, we've invested heavily to achieve that goal. So the three things that are going to generate really long-term value for the company, and for shareholders, and hopefully, of course, with outcomes for patients, because that's what we care about at the end of the day, above everything else, is that we have a commercial business that's going to continue to grow.
I'm going to show you, I'm going to help you imagine in a year from now what the business is going to look like in terms of its commercial offerings. We will continue to grow that pipeline. We have a greater focus these days on innovation. I think what we've done quite well is commercialized some of the low-hanging fruit in nuclear medicine. We still got a few things that are really exciting that are in late-stage development that will crystallize over the next year or two. But now we've got this new wave of very innovative stuff that's coming in behind where we're thinking expansively about new targets and new opportunities. For example, our collaboration with Regeneron is an example of that.
Last of all, as I've said repeatedly, this manufacturing and supply chain piece is really about controlling that path to market and guaranteeing that delivery to a patient. As I said on my first slide, we have three FDA-approved products today. I'm probably not going to go into too much detail on this, except to note that we continue to expand the jurisdictions in which these products are available. We have a commitment to being a globally active commercial organization. That's an unusual commitment for, again, a pharma of our size. We actually don't have a peer that does that.
I think that when we think about developing a product, we increasingly think from the outset, what are the regulatory and the quality and the manufacturing and the distribution and then the compliance and commercial considerations that come in behind that to operate in more than just one or two key markets? I think it's by being globally active that we create the best opportunities for the company in the future in terms of partnerships and potential long-term relationships with big pharma. In terms of the opportunity that we're prosecuting right now, on the left are our commercial products. I think the market understanding around the prostate space is well understood in the market. PIXCLARA in the U.S. market starts off as a very modest opportunity, but grows very rapidly with some near-term label expansion opportunities that we believe are imminently achievable.
We see really a lot of potential growth in that platform as well. Again, I just want to reiterate, this is for the U.S. market. This time next year, we expect to have doubled. You can see on the bottom here, we really have six products. We consider the BiPASS opportunity, which you'll hear about today, as a distinct product. Indeed, we've agreed with the FDA that it will be a de novo NDA submission. We're doing that for a whole variety of regulatory and commercial reasons, to be able to segment that as a commercial opportunity. These are really significant opportunities that will multiply our revenue over the next three to five years. This is not far off. All the clinical work has been done. We're waiting on a readout for BiPASS. We're obviously waiting on the resubmission, which is very shortly for Zircaix.
The ITM acquisition includes the ITM-11, which will accelerate our pathway to therapeutics over the next six months. Really, 2027 is a multiplier effect on where we are, and just a hugely exciting year ahead. I know that it's going to take some time to digest, so the reason why we do these days is to get out in front of you and to help you to see what's going to be coming down the path. We still want to have the catalyst of the business well understood. But we're also starting to focus more on what is the big picture game plan of the organization, and hopefully the revenues, and in due course, the earnings.
Because we've talked about 2026, 2027, and Darren's going to go into more detail on it, but really about building the business, integrating ITM-11 with that view to 2028 starting to be an earnings growth story for the business. I think that with a multi-product, multi-jurisdictional demonstrated commercial performance, and then shifting to that earnings-based model, I think that's when we're going to really start to see the next level of performance of the company from a capital markets perspective. We have four programs that are in late-stage development. You're going to hear snapshots from both Telix staff and KOLs today around most of this activity. I think just to point out, though, that these are not really early speculative programs. We have a lot of data behind these programs to support their clinical development.
You're going to see a lot of data readouts over the next 6- 12 months that I think will further elucidate the quality of the pipeline. We think we have the best pipeline in the industry and some very competitive product offerings. We think that our products can move earlier into treatment journey for the patient with the right sort of clinical trials. I think that's when, from a commercial tension perspective, it starts to become a lot more interesting for Telix. TLX591-Tx, our flagship program in phase III trials, will very shortly be recruiting U.S. patients, but is currently recruiting in eight or nine countries globally. You're going to hear from Professor Emmett today on our next-generation prostate agent, which has got a lot of potential in earlier lines of therapy, where perhaps other solutions may not be as effective.
We've got really exciting data that's been starting to come out in our glioblastoma program, which is one of my personal passion projects of the company, because I think we really have a huge unmet medical need there. David is going to talk a little bit about the kidney cancer opportunity. But when you think about in the initial indication that we can go after with these assets, there is a really substantial commercial opportunity here that is genuinely attainable for the company. I want to quickly drop back to manufacturing for a second, just because I think that if I could summarize a tagline that's been given to me for the last couple of weeks, particularly in the context of the ITM transaction, it's, "So you bought a manufacturing business," right? We didn't buy a manufacturing business. We're a pharmaceutical company.
We're not a CDMO. But I can't impress upon you enough that there are very few other areas of the pharmaceutical domain where supply chain distribution, commercialization, and development are so densely entwined with each other. The only other area that I can think about is maybe some of the personalized cell therapy, personalized vaccine opportunities that are being developed now, which are really N equals one drugs. They're almost a bespoke drug, right? You're going to harvest some tissue from a patient. You're going to develop a cell therapy that's maybe trained to recognize a particular patient's tumor antigen, and then you're going to inject that back into a patient. That's kind of a vanguard of part of oncology at the moment. Aside from that sort of needle-to-needle application, there isn't much else that has the inherent supply chain complexity.
If you're going to think about it from a basic level, you can think about it as security of supply. There are a limited number of reactors in the world. There are a limited number of cyclotrons in the world. The infrastructure is hugely expensive to operate and run. Unless you have a critical mass of commercial opportunity, you really can't do it. If you're a single asset or a two-asset pharma company and you're planning on running a phase III trial, you aren't going to be building your own production infrastructure, right? I want you to keep that thought in the back of your head. One of the things that we also want to do is move faster from development through to commercialization, that transition from end of phase II into phase III, and then launch.
Some of you will recall when we did the ILLUCCIX launch, we had an almost four-month delay from the time that we got our FDA approval to the time that we sold the first dose. When we did GOZELLIX, it was six weeks. When we did PIXCLARA, it was two weeks. Why does that happen? Because we have integrated supply chain, because we can control our launch much more effectively. It also means that when we go into phase III studies, we are using infrastructure that is more validated and closer to the company's regulatory footprint, and gives us a huge advantage in dealing with regulators.
Because when we do get feedback, like we did with Zircaix in the middle of the year, "Can you please consider extra things when you resubmit the package?" we can internalize that much more within the company than going to outside parties and having to change practices out in the field. It also won't surprise you to know that every time we use a contract manufacturer in an ad hoc way, we are also educating the manufacturing landscape for third parties, and we want to keep more of that domain knowledge in-house. How we formulate things, how we improve yields, how we maximize isotope production, all of these things have an impact on our product margins at the end of the day. We also want to set the bar from a regulatory perspective, not follow other people's standards. Again, it's really important, that speed and efficacy of execution.
I've mentioned cost of goods, and when we did the RLS transaction, it was about having a tighter control over U.S. product distribution and being more selective about who we work with, but it's also about distribution margin. When we acquired RLS, they were our fifth-largest distributor. In that time, we've more than doubled the dose volume that goes through RLS. They're now our second-largest distributor after our partner, Cardinal Health, who's a long-term partner for the organization. That has a really big impact on gross margins for the business, and ultimately, the cash generation that funds our pipeline. So, there's an immediate financial accretive effect when you add that supply chain into a commercial business. I think scaling is fairly self-explanatory, but it's, believe it or not, the hardest thing in radiopharma.
It's dead easy, well, not dead easy, but it's fairly easy in a research clinical environment to make a dose for a clinical trial. The standards vary globally, but it's not an intractable thing because nuclear medicine has always been a physician-led practice of medicine. But when you want to then scale something to produce hundreds or thousands of doses, we delivered 3 million doses to patients last year, that scaling problem is an execution and delivery problem, but it's also a technical problem. It's formulation and radiation handling, and by the way, lots of safety and operational considerations as well. So, that scale-up is super tough. I think that then lends itself naturally to risk mitigation, and if we can control the whole thing more effectively, you'd hope that the innovation cycle goes quicker.
I think you can all, Jen, most of you have followed the company for a long time. I think what you can see is that we do hit our inflection points faster and faster. We are getting better at tracking to stated timetables on clinical trials, and a large part of that is because we do not rely on other people's timelines anymore or competing for resources. We want to do a first-in-human study, we do it in-house. We want to do scale-up manufacturing for a multi-center phase II trial, we do it in-house. It just means that we can go a lot faster. Without going into all the nitty-gritty of this, because I think I have talked to most of it, what you can see is that through a mixture of organic investment and M&A, we have really built out that parallel infrastructure.
I would say that the organic investment has mostly been into pipeline and building out the catalog of molecules that we are developing, both for imaging and for therapy, and the M&A has really focused on building that infrastructure and curating what we see as a very strategic end-to-end capability. Of course, ITM now kind of really represents the vanguard of that capability from an isotope production perspective. It is really about basic discovery all the way to last-mile delivery. A person wearing a Telix polo shirt or an RLS polo shirt, depending on the context, carries that dose into hospital. That is a vitally important relationship in the way in which we conduct ourself in this field. Just to cap the isotope conversation a little bit, we have always had a commitment to building that isotope supply chain robustness.
When we acquired ARTMS enabled both ILLUCCIX and Zircaix. We would not have ILLUCCIX and Zircaix without ARTMS. We have now exceeded 50 installations globally of the ARTMS platform, so we are really augmenting the gallium supply chain from generators with cyclotron-produced gallium, which is very cost-effective, particularly in larger jurisdictions, and of course, reliable zirconium supply, critical for launch of Zircaix. With the addition of the ITM business, ITM delivers about 80% of the world's lutetium every day. Hundreds of hospitals in 65 countries make therapeutic doses for patients every single day. It is a supply chain that we will slipstream with pharmaceutical product, so we really see ITM as not just about building that supply chain robustness, but also about that continued global expansion of our business. Then together, ITM brings some pieces. We have also been developing some pieces.
We have the next generation isotopes well in hand. We have actinium, we have lead, we have terbium. There is really no area that is a vanguard of the field that we can not participate in. We have scaled up lead-212 production, which will roll out next year through our RLS pharmacy network and be available to third parties. We are just pouring concrete right now in Philadelphia for the first commercially available astatine supply in the U.S., which is a very exciting molecule. We have two locations where we are making actinium today, in Europe and in the U.S., and we expect to expand that as well. So, really have a ton of capability, both for clinical and commercial scale-up. This is kind of where we started. These are the pieces of the puzzle that were sort of pre-ITM.
Now, with the ITM addition, we really add this kind of reinforcement to the Telix strategy through the isotope leadership, really underpinning the supply chain of the next set of products, accelerating our entry point into therapeutics. 2028 was our planned commercial year for Telix. We bring that forward now to 2027 with the ITM-11 product. That enables us to build the commercial and the compliance and the pharmacovigilance infrastructure for a therapeutic drug, which is quite a bit different than a diagnostic drug. The competitive landscape to be a therapeutics company dictates different commercial practices, so we have a step change in that sort of performance as a commercial organization to really look forward to over the next 12 months. Then, of course, there is pipeline and lifecycle management opportunities that also come with the ITM acquisition.
Once the deal is closed, we will obviously go into a lot more detail around how the pipeline synergies evolve. Just to make it really clear, as I said before, ITM isotope business underpins our pipeline and the entire market's pipeline, but this is a growth opportunity in its own right. The supply chain demands for lutetium and actinium are only going to grow exponentially over the coming years. Again, to repeat, we only have two products that are approved today, but we have 100 products coming in behind. You should take that as a signal that our mission as a company is not just to be an internal sourcer of pipeline or a select in-licensor of pipeline, but to really be a go-to commercial partner in key markets.
We will continue to make that isotope supply chain available to strategic partners, to big pharma, to other pharmaceutical companies that are developing agents. We want to be the shop front for all those companies that will be ultimately looking for isotopes, manufacturing infrastructure, and above all, a capable and proven commercial team to get that product to market. That is not the behavior of a small pharma company, I realize that, but this field is growing so fast, and it is just an opportunity to take if we have the right pieces of the puzzle, and we really do. You can see that just how we compare and contrast ourselves, there are aspects of the industry that you would recognize as sort of inherent to a big pharma model. Then there is the sort of niche pipeline, niche isotope development capability of what you would call specialty radiopharma.
Really together with ITM, we bring all of those pieces into one platform, and I think it is hugely powerful to have that integrated R&D manufacturing and commercialization. This is my last slide. This is what it looks like as a combined business. I am trying to resist the urge to put my pinky finger in my mouth and talk about global domination. But really, the goal is to leverage the isotope supply chain that ITM has built. They sell every single week isotopes into 65 countries globally. The consolidated commercial footprint is really huge. We want to use their supply chain to push out our APIs broadly into the market, and to be influential in the practice of nuclear medicine globally. I personally believe that patient access globally is something that good companies do. We do not just focus on one or two markets where it is wildly profitable.
We should be defining a new medical practice and a new medical standard globally. I actually don't think we would have the quality of investigators and partners and collaborators that we do if we didn't have that mission firmly in mind. But I also think it's a really good business, because if we can develop pharmaceuticals from the outset with the view that they're going to be made available globally, then I think that we can make them commercially effective as well as serve a lot of patients at the same time. But that has to be the upfront goal of the business. That's a huge footprint, and I couldn't be more excited about the future. This is not 10 years from now. This is six months from now. It's a very exciting opportunity.
Well, with that introduction and being one minute over time, which I think, given my sort of slow pace this morning, is tolerable, I'd like to hand over to David Cade, our Chief Medical Officer, to lead the festivities further. Thanks again for coming in today. Over to you.
Thank you, Chris. Yeah, one minute, you've done actually pretty well. That's not really normally the case, but kudos, Chris. Welcome everyone. There's a lot of familiar faces in the room. It's nice to see so many people turn up down here in Melbourne at this very salubrious office that we have. We've had this office, I think, from day one, and we've been here for quite some time. Look, David Cade's my name. I think I know pretty much everyone in the room. I have the privilege, the absolute privilege of serving as the Group Chief Medical Officer. I'm based in Sydney. I travel the world, meet with key opinion leaders all of the time, and I learn a lot every time I meet with a key opinion leader.
We thought it was critically important not just to hear from Chris and Ky and Darren and myself, but we are very fortunate to have four global key opinion leaders with us today. It's the case that Australia is one of the leading contributors to radiopharmaceutical development, so three of our four key opinion leaders are local, from Sydney and Melbourne. Chris has, I think, used the term over the last sort of couple of months, as we did the ITM transaction of radiopharmaceutical powerhouse to characterize our aspirations. I think that is an entirely appropriate term, as this is really one of the deepest theranostic or therapeutic and diagnostic pipelines in development in the radiopharma universe globally. It's really our fundamental belief that you need to have both. You need to have both therapeutics and diagnostics.
You will hear us describe therapeutics and diagnostics using the portmanteau of theranostics. We have a very deep theranostics pipeline, and you will see that beside each of the therapeutic candidates on the left, that is very rich in urologic oncology, in prostate and kidney, but also in neurologic cancers and other cancers. You will see that beside each of those therapeutic assets, over on the right-hand side, there is a diagnostic compound. We do not just call them diagnostics. These are precision medicine assets, and it is not really just a fancy term. We call them precision medicine assets because they both diagnose and stage cancers. Make the diagnosis and establish that the patient has a cancer, and stage it, work out where it is and how much the patient has. It is much more than that.
These assets can also help us select patients for therapy, and when a patient has been treated, they can help us to gauge the response of the patient's cancer to that therapy. It is diagnosis, it is staging, it is selecting patients for therapy, and then it is gauging whether the patient is benefiting from that therapy or whether we need to do something else. I really think the take-home message here is that we are focused on three key areas. Obviously, urologic cancers, prostate and kidney. This is one of the largest areas in oncology at the moment. Also neurologic cancers, which is obviously much smaller, but it is a very high-impact area in oncology.
The reason for that is that Professor Scott is going to talk about both the imaging and treatment of glioblastoma a bit later on in the morning, but we really have not had any significant advances in the way we would treat a patient with glioblastoma for the best part of 20 years now. The last couple of decades, it is a drug development desert. Against that context, we are delighted that we have been able to, I guess, be rewarded by the FDA, that we have stuck with it and gotten PIXCLARA over the line and approved. Just as of six weeks ago, have changed the practice of medicine in the U.S., and we will see PIXCLARA start to get used as an imaging agent for brain cancer over the coming months.
Finally, we have a number of assets for other cancers. I think, I will not go into all of them in detail, we do not have time today, but one of the most exciting is the pan-cancer compound, FAP, which is fibroblast activation protein that cancers express, that we are developing for a number of FAP-expressing cancers. These are high-value cancers that are underserved currently, for example, ovarian cancer. Now I think that previous slide beds down what we have today, and we have clearly a very extensive late-stage therapeutics pipeline with three assets. It is three assets. It is quite remarkable for a smaller biotech company in phase III development. Late-stage phase III in prostate, kidney, and brain cancers. I think by any measure, you could say as a biotech, as a board and a CEO and a leadership team, that is enough for the time being.
We are not happy with that. We see that there is a lot of, let us call it white space out there in a whole range of oncology applications, where patients clearly need better options than what we have got. There are some catastrophic cancers, pancreatic cancer, ovarian cancer, brain cancer, and so forth. That is why really we have decided to pursue these partnerships and acquisitions or mergers with both Regeneron and ITM to expand our pipeline of the future, much further than what we have today on that previous slide. To put it very simply, we consider Regeneron globally as the best-in-class antibody or antibody fragment, mini-bodies and other components of antibodies. Really the best-in-class globally for those constructs that we choose to use as targeting vectors to take radioactive isotopes to cancers for treatment.
Likewise on the right, we would consider ITM, as I think Chris has described, globally as the best-in-class for both the beta and the alpha isotopes, the therapeutic component. So we have got Regeneron with targeting, ITM with the isotopes, both beta and alpha, and these are clearly going to be the isotopes of the future. With ITM, there is a bit of icing on the cake as well. It brings in a highly complementary therapeutics portfolio that dovetails very nicely with Telix's existing portfolio, and that is going to drop through in the very near term into Telix's commercial machinery that has generated the revenues, the cash flywheel that we generate from imaging today. Let us move on to our Have we got Professor Ghesani on the line? We do, Annie? Yep. He can hear us okay?
Can you hear me?
Yeah, we certainly can. Okay, so I would like to introduce our first key opinion leader speaker, Professor Munir Ghesani, who I, correct me if I am wrong, I think you are dialing in from Princeton, New Jersey, or thereabouts?
That's correct.
Yeah, I got it right. Wild guess. Professor Ghesani is a nuclear medicine doctor and professor of radiology at Mount Sinai in New York, where he's previously served as the Chief of Nuclear Medicine. He's also a recent past president of the Society of Nuclear Medicine and Molecular Imaging. With, I think I'm allowed to say this, with close to 30 years of experience in the field, and with the evolving clinical practice guidelines, Professor Ghesani, you've had a major influence on the practice guidelines over those decades. I think you're uniquely placed to describe some of the critical lessons that we've learnt since PSMA-PET was first approved by FDA in 2021, and also how Telix's BiPASS study builds on Dr. Emmett's PRIMARY and PRIMARY2 studies that she led with Australian colleagues, and how BiPASS might influence the diagnostic pathway for prostate cancer in the future.
That's enough from me, and I'll hand over to you now, Professor Ghesani. Floor's yours.
Thank you very much for the kind introduction. Good morning, everyone in Australia, and happy to be able to share my experience and my couple of investigator-initiated trials that I have performed with my team. We have an academic arm of our practice, which is United Theranostics, and academic arm is called Institute of Nuclear Medicine. I serve as the endowed chair of that group, and they're really dynamic and very forward-thinking colleagues that I have, both in the physician side, but also in the physics side. I always tell my residents that having a knowledge of physics in practicing nuclear medicine is not optional, it's inevitable. I would even argue that you need to first learn physics before you can fully practice the medicine of nuclear oncology.
I will show you how powerful that involvement in physics is by sharing my three investigator-initiated trials that we have performed at the Institute of Nuclear Medicine. Let me start by first showing how gallium PSMA has set a high bar in staging and biochemical recurrence. As David mentioned, I served as the president of SNMMI, and I remember convening this guideline group that really is a powerful group, who is who of nuclear medicine all over the world. Many of the guidelines have clearly demonstrated how powerful gallium PSMA has been. Excuse me. This slide on the left column shows the ability of high-risk pretreatment staging, and there are multiple trials, but this one particularly mentions the proPSMA randomized trial with 295 patients who were followed up. The middle column shows the CT plus bone scan.
The matrix are on the left side, and then the right side with the color-coded values that are provided for gallium PSMA-11. You can see the difference night and day in terms of the ability to have a 92% accuracy versus only 65% with CT and bone. Even more so is the sensitivity of 85% with only 38%. In the current day and age, when every single finding that we provide to our clinical colleagues, whether it's a urology or radiation oncology, they are what we call actionable finding, meaning anything that we find is directly addressed by targeted treatment, and that makes a big difference in the outcome of these patients.
You can imagine, if you jump from 38% to 85% sensitivity, then you have considerably higher number of populations with the actionable findings that can be treated, and not only it can improve the quality of life, but I would argue that there are already trials that are showing that even a survival advantage exists. This is all done without compromising the overall accuracy, right? Even specificity is 98% versus 91%. You can see the management change, exactly what I was mentioning, that it's almost twice as many patients, there's a management impact on it. It all comes with equivocal findings, only one-fourth of what you find in CT and bone scan.
I clearly remember, as the item number one at the bottom says, supported by guidelines, that the NCCN guideline, which is the reference number three at the bottom, clearly spelled out that you do not need a CT scan or a bone scan for applications that are appropriate for only using PSMA-PET/CT, and in this particular case, the gallium PSMA-11 PET/CT. Those guidelines were most powerful advocate of those guidelines were, in fact, urology colleagues, along with the nuclear medicine support. But they understood why this is so powerful. If you look at the right side of the slide, it talks about the study in China using 140 patients with biochemical recurrence, and patient level positive predictive value of 95%. As I'll show you on my subsequent slides, not all PSMA molecules are made equal.
So, if you have 95% positive predictive value, you have a much higher degree of confidence that if I see something, I can treat something. As opposed to, as I'll show you, there are other molecules that are using the fluorine-18, you cannot get that high degree of positive predictive value. While we are, you can see at the bottom, as you go down the individual rows, that as you go lower and lower into PSA, this is really a paradigm shift. 10 years ago, we were not able to detect any disease in those patients with a PSA of 0.5 ng/mL- 2 ng/mL. Here, you have 93% positive predictive value, the very last row. That really makes a big difference in the outcome of these patients. Now you have supported by guidelines, imaging is done on the same day.
The other thing is, Chris alluded to it a little bit in his presentation as well, is the dosing flexibility and reliability. What we have found is that there are a number of times where I get a call from a urologist who tells me, "I need this patient scanned today because I have to urgently operate. I have a slot available in the OR tomorrow, and you need to provide me the capability to do the scan today." Sometimes the VIP patients who are seen by our Chief of Urology at Mount Sinai in New York, they take an Uber and come down because they do not get a time to wait a little bit. They are out of town, they are going for surgery next day.
When we call RLS, we get an hour or two timeframe, and then we get a delivery of the dose. It is, I have to say, for a clinician who are the end users, that same-day dosing flexibility is tremendous for us, which makes a big difference in our ability to meet the demands of our patients. Here's what I was referring to for gallium versus fluorine-18. If we have a 95% labeling efficiency, we are allowed to proceed with that injection. 99% is better, but it's not always feasible. That's why the bar is set at 95%. But you always have to think about what happens to that small 5% that is not bound to PSMA. Obviously, gallium can have that capability too, and that could be a susceptibility of fluorine-18 as well.
But what happens is that free gallium ends up in the liver. I'll show you one of my slides later on that really shows that if anything, gallium uptake of PSMA-11 uptake in liver is less intense than fluorine-18. If you shunt a little bit of gallium to the liver, it does not make a difference. Whereas if you shunt that small amount of fluorine, it is big enough to cause false positives in the bone. That goes back to my previous slide where it compromises the actionable finding addressing capability. Because if you are not confident that what you're seeing in the bone is something that can be treated with EBRT, then you have this question of, then you have to go for a biopsy or sometimes additional imaging and deprive that patient of timely targeted treatment.
So, that is a big difference why even the guidelines are, the SNMMI guideline that I was alluding that occurred during my year of presidency in the society, clearly spelled out that there is a higher propensity for fluorine-18 labeled agents to result in false positives. In today's day and age, that is unforgivable because we need to provide every single image finding that should be actionable, that can be addressed with a radiation oncology or surgeon going for targeted treatment. The next item I would like to talk about is the actual example of that. This is one of my own patients, and I mentioned I have performed three investigator-initiated trials. This is one of them, and it shows that the uptake was there on fluorine-18 scan, and it is not present on gallium-68 PSMA-11.
The reason why we were able to do this investigator-initiated trial is that we have a very unique outpatient setting where we do scanning to treat the patients with lutetium PSMA-617. Our insurance companies require that we need to have a documentation of finding. That allowed us to do that very unique investigator-initiated trial where we have intra-patient comparison. This is not an anecdotal separate patient. These are the same patients who had sequential scans, sometimes in a very short time. You can see six months later, the uptake is not there. If this was metastatic disease, two things would have happened. The uptake would have become more intense, or at least it would have remained the same. Secondly, the PSA would have gone up. In this patient's PSA was 3.4 ng/mL when the fluorine-18 scan showed the uptake and actually dropped down to 3.1 ng/mL.
So, this is one perfect example of what that free fluorine-18 does to the bones. The next slide I would like to share is exactly what I was referring to earlier. The left, we call this maximum intensity projection. So, the human image that you have on the left is with fluorine-18, and one on the right is with gallium PSMA-11. You can see, first of all, the image quality is considerably crisper of gallium PSMA-11. Secondly, as marked by the arrows, that there are two lesions that are only seen with gallium PSMA-11, not seen with fluorine-18. These patients had their scans done only three weeks apart from each other. So, it is not a prostate cancer's capability to spread that fast. It is more likely that small lesions were appropriately picked up by the gallium PSMA-11.
You can see that gallium PSMA-11 on the right side, the liver uptake is less intense. So, if a little bit of gallium shunts there, it is not going to create much of a dilemma. Plus, whenever we read the liver, when we go through the axial slices, we dynamically adjust the intensity display so that any subtle lesion in the liver is readily appreciable. So, there is absolutely no compromise, in my opinion, of having a little bit of gallium going to the liver, as opposed to even a small amount of fluorine-18 going to the bone can have devastating effect of false positives. The second investigator-initiated trial that we performed, thank you to our entire dynamic team who allowed me to do this in a very short time, so that I was able to present it at the EANM meeting, just about two weeks ago.
And what we were looking at was the ability of gallium PSMA-11 to do delayed time point imaging. What we did was the same patients who signed a consent form, IRB approved, and we did two time point imaging. The first time point was 50 - 100 minutes within that timing window. In our case, it was at 60 minutes. The second time point was at 120 minutes plus time window. In our case, it was 150 minutes. I will explain to you the reason why we picked those particular time points. The reason why we did that was we wanted to do this intra-patient comparison, but also wanted to emphasize that if you do a delayed time point, the conventional wisdom would say that you have to image for a longer time.
What we did was we acquired it, as it says here, list mode acquisition, and then we fractionally reconstructed so that it is the same amount of time that a 60-minute image acquisition did. Then we compared in same patients, and I will show you the results in the subsequent slides. Here is the first patient who had a lesion in the retroperitoneal lymph node, and you can see, marked by the arrow, that that lesion is still very discretely delineated in the 150 minute time point. These are fractionated acquisitions, so we only took the same amount of time that was taken for the first time point imaging, and you can still see it clearly. I would argue that they are almost identical, if not a little better delineated on 150-minute image. Here is another example. These are tiny paratracheal lymph nodes.
If you look at the arrow on the rightmost side, which is a CT scan, the two arrows that are marking the lymph nodes that are only 2 mm- 3 mm in size. This is a powerful paradigm shift that we are able to see even a millimeter or two lymph nodes where the reader of the CT scan will never call them suspicious. The left column has a 60-minute image, and the middle column has a 150-minute image. You can see that the images are still picking up those two tiny lymph nodes, whether you look at them at 60 minutes or 150 minutes.
Then we did the more detailed analysis of each and every lesion, including their SUV peaks, and you can see that 10 out of 13 lesions delineated by the orange bar showed a higher SUV value at delayed time point compared to 50%, the one-hour time point, and then delayed time point was 50% reconstruction. Even with half of the data used, we still were getting higher SUV values into the lesions at delayed time point. The next item I would like to share, this is my third investigator-initiated trial, and there is a misconception, or at least prevailing assumption, that delayed imaging is clearer because background tracer washes out.
What I would like to emphasize, as I mentioned earlier, I am a big physics advocate, and if you dig deeper into the copper-64 molecule and its physics characteristics, only 19% of disintegrations of copper-64 result in a positron emission. You have to discard four out of five disintegrations because they have no value in generating an image. I would like to just set that up here so that I, in fact, I can put the appropriate context in the subsequent slides why we found what we found, and there is an explanation of physics of why that was our observation. With that, this is the design, a paired within patient, again, same patients, blinded to alternative forced choice. We were three of us who were provided these images, were blinded.
We were not told whether these are one-hour or 24-hour images, and we had to force ourself to say which one is better, or in terms of lesion detection and image quality. These are matched anatomy, matched window display, and liver-normalized images. There were 20 patients. These are somatostatin receptor positive NET. The reason we chose that was that's something that is approved and available in the U.S. So this is the first patient. You can see a MIP mentioned at the bottom left on the very first column, and you can see at 24 hours, the image quality is considerably poor. The reason for that is that only one out of five disintegration is picked up.
Not only you have that disadvantage, but now you have two half-lives lost, and you can do the math and you can find out how poor your image quality is going to be. That's clearly, I don't even have to emphasize it, you can just look at your own two eyes with those two MIP images on the left columns, and you can see which one would you like to see. Clearly, it's the one-hour image. On the right side, you can see that that lesion in the retroperitoneum has started to become fainter, and that's the reason why the compromised count density results in poor lesion detection. This is even scarier. You can see that the liver lesion that was there in the one-hour image has completely washed out at 24-hour image.
If you only did 24-hour image, you would not be able to call that a positive lesion. Then the CT scan that is on the right that shows the arrow, many times we see the lesions in the liver that are either cyst or hemangioma. So a reader would look at that and say, "Well, I don't have a copper-64 uptake there, so this must be a benign lesion." They would miss the fact that this is a highly active metastatic lesion. Another example where a one-hour image has no focal uptake in a retroperitoneal lymph node, and then that's the left column. The middle window shows that that lesion showed up on a 24-hour image, and then the right side, the CT scan shows again a very small aortocaval lymph node. So what we found was that early imaging alone picked up 104 lesions.
Delayed imaging alone picked up 82 lesions, and our conclusion was that if you really want to get the best out of the overall image quality and lesion detection, you need to do a two-time point imaging. In our cases, when our patients are asked to come back for additional imaging the next day, oftentimes they are busy, many of them are still working, and having to come for two separate time point imaging is not very practical in their day-to-day life. I'll spend a couple of minutes on describing where the paradigm shift can occur with the earlier moving of gallium PSMA-11 scanning. You will hear more about the BiPASS study, but I just wanted to show you that there are 1 million biopsies performed, and initial staging is 451. You find PSMA-11 application. Biochemical recurrence, there's about 460,000 patients. Response to treatment, 143,000.
Monitoring for progression is 71,000, and then you can see the rest. That leads to about 58,000 patients for RLT selection. What if you move the entire process early? Particularly since the many years that MRI is in use, this has not really changed. While MRI has been pivotal in the management of prostate cancer, this patient journey has not changed significantly. If you apply the BiPASS study applications and look at how significant that curve changes, where you would perform 821,000 scans in a year in the very appropriate application at upfront. That reduces all the subsequent downstream numbers, including the biochemical recurrence, response to treatment, monitoring for progression. RLT selection, I don't think will change much because inevitably there are subset of patients who are being progressed and monitored will need the RLT.
Again, the response to RLT will also remain similar because there will be some patients who would escaped and will have disease progression. With that, I would like to thank you again for your time and attention, and I'll stay on the call to see if anybody has any questions later.
Yeah. All right, everyone. Thank you, Dr. Ghesani. We're going to open it up for questions to the room here. If anybody has any questions specific to Dr. Ghesani, please raise your hand, and we'll walk over there with the mic. All right.
Yeah, it's David from Morgan Stanley. My question's on the PPVs at the lower PSA levels. There was a study in 2019 sort of showing that the PPVs at PSA levels 0.5 ng/mL, et cetera, were relatively low, but the China study is showing sort of 90% +. I suppose what might be different between those two studies? How are you thinking about gallium at those lower PSA levels, and what could maybe explain difference between those studies?
Yeah, that's a great question, and I would say that there are a number of factors that result in that change. Number one, the ability to detect the disease early on is a combination of several factors. It is the appropriate radiopharmaceutical, but it is also the imaging equipment. If you look at the imaging equipment, and again, as I mentioned, I'm a big physics advocate, and I follow what's called the full width half maximum paradigm shift. So, five, seven, eight years ago, the full width half maximum of the scanners was about 6 mm-7 mm. There are now a number of scanners in the market, and each vendor is competing with other to get ahead in their ability to decrease that full width half maximum. Current market, there are about 2 mm full width half maximum scanners available.
Increasingly, because of the growth and the change in the patient management, the centers all over the world are upgrading their systems, and that has transformed quite significantly. The second factor I can think about is that the comfort level of the readers in calling something. We used to have this concept that you have to use a certain SUV threshold, and nobody really talked more about that SUV threshold is a moving target. You cannot apply the SUV value for one centimeter lesion and say, "If that lesion is 2 mm, you should expect the same SUV values." So, there's something called partial volume effect or recovery coefficient. All of those concepts have resulted in our mindset change in dynamically reading the scans relative to the size of the lesions.
These are the two main factors, I think, that are very powerful in really improving our positive predictive value.
Hi, it's Craig Wong-Pan from RBC. I've got two questions. First one is, you outlined a lot of benefits of gallium product over an F-18 product. Why, in your opinion, do you think there hasn't been a greater shift towards gallium products? Then second question, you gave the example of a urologist asking for a same-day scan. I just wanted to understand how often that occurs.
Sure. Yeah, so I'll answer the second question first. The same-day scan, typically not very common, because in U.S., we have to have a pre-authorization. We have our team that does the pre-authorization, so if a call like that comes in, we mobilize our machines and make sure that we get that pre-authorization right away and make a case to the insurance companies that we need to get this patient in. Otherwise, the patient may not get appropriate surgical approach without the knowledge of PSMA-PET. If the patients have Medicare, then we don't have to worry about the pre-authorization. I would say, on an average, about 2% or 3% of our total volume of cases are same-day or next-day requests. Usually, they are more elective.
These happen when somebody is traveling and looking for an expert, and the expert advises that they should have surgery as soon as possible, then they don't want to travel back without getting surgery done. Those are usually the instances where we do the same-day surgery, scan on the same day. The second question was about how the shift has occurred to using the gallium. I think that there is increasing awareness of the false positives. The SNMMI guidelines have called it out, the EANM guidelines have called it out. If you attend the medical tumor boards in any given setting, whenever the fluorine-18 is used, there's an enormous amount of time that is spent on trying to figure out if there is a prior scan, two prior scans, three prior scans that can help in delineating whether that fluorine-18 uptake in the bone is real or indeterminate.
The other thing is, many of us during our day-to-day activity get injury, even minor impact to the ribs, to some of the bones, and even minor bruises can take a long time to heal. It is not uncommon for all fluorine-18 labeled scans to see that people have learned to ignore it, but sometimes if the PSA value is going high and you say, "Well, yes, I'm ignoring it as a potential false positive, but what if that's my earliest indicator of oligometastatic disease? Am I really missing the opportunity to get this lesion treated with an appropriate targeted treatment?
Okay. Well, Professor Ghesani, thank you very much for your time. You're welcome to stay on.
Thank you.
I think it's critically important to get the impressions of Dr. Ghesani of, again, as I said at the opening, what have we learnt in the five years since FDA approval of the gallium and the fluorine tracers in 2021? We've learnt a lot. What might it look like in the future as the data from the BiPASS study potentially change the dynamic of how we diagnose prostate cancer in the early setting, and what benefits it might have for patients and lowering the rate of recurrence down the track. Professor Ghesani, thank you very much, and you're welcome to stay, but we appreciate your insights very much.
Thank you for the opportunity.
Okay. Let's go from physics to surgery. I would now like to introduce our second key opinion leader speaker, Dr. Philip Dundee, or Phil Dundee, who is a urologic surgeon and the Director of Robotic Surgery, the Robotic Surgery Fellowship. He trains the fellows coming through at the Royal Melbourne across the road. Dr. Dundee has published very widely in the field of prostate cancer research and was one of the highest recruiting investigators to Telix's BiPASS study of gallium PSMA-PET in the pre-biopsy diagnosis of prostate cancer. Dr. Dundee is really at the forefront of how the diagnostic pathway has evolved over the past 10 or so years, but also, I think, is uniquely equipped to discuss how the diagnostic pathway might evolve in the coming 6- 12 months. Dr. Dundee, Phil, welcome up to the podium. There you are. Thank you.
Good morning. That was a great presentation about the science behind the PSMA-PET imaging that we are using. I will just talk a little bit about the clinical application of PSMA-PET and where it fits into the diagnostic and treatment algorithm. I think it is worth just discussing a little bit about the history of the diagnosis of prostate cancer. Even as recently ago as 10 years, so around about 2015, which was when MRI was introduced almost universally into the diagnostic algorithm. Prior to that period, we would see patients who were referred to us with an abnormal PSA, which is a blood marker, sometimes with an abnormal rectal examination. Then those patients would undergo what was essentially a blind and systematic biopsy of the prostate.
The prostate sits deep within the pelvis, just in front of the rectum and underneath the bladder. It wraps around the urethra, and it varies in size. We had a systematic biopsy where we would take 12 samples. Again, this was essentially blind. We would use an ultrasound to guide where we would take those samples from, but it is rare that you would see prostate cancer on an ultrasound. You were hoping that one of the 12 samples that you took from the prostate would hit a prostate cancer and that it would be a genuine reflection of what the true disease state in that patient's prostate was. There were many problems with that diagnostic algorithm. Many men underwent biopsies completely unnecessarily.
So one of the most common reasons for an elevated PSA is that a patient just has a big prostate and they do not in fact have a prostate cancer, and that would be at least 50% of the patients that we see with an abnormal PSA. In 2015, MRI was introduced almost universally just on the back of many of the diagnostic studies that were done showing the utility of MRI, and almost instantaneously, that dropped the number of biopsies by about a half. This was an extra test that was introduced into the diagnostic algorithm that had an expense associated with it, but because it reduced the number of biopsies that we were doing, and biopsies are very expensive. They are done in the operating theater. They are now done under general anesthetic, so they need pathology review of the slides. It is a very expensive procedure.
About half of those procedures were abandoned because they were unnecessary on the back of having a negative MRI. So we got better at diagnosing prostate cancer in patients who had prostate cancer because we were able to target the lesions at the time of doing the biopsy, and we were able to do fewer biopsies and then less harm to men who did not ultimately have prostate cancer. So MRI is a good test, but it is not perfect, and there are patients who will have an abnormality on their MRI that in fact is not prostate cancer, and there are men, up to 30%, depending on the definition of what we classify as clinically significant prostate cancer, who have a negative MRI but who have cancer nonetheless.
There are still some gaps in the diagnostic algorithm in terms of making sure that we diagnose the right men with prostate cancer and that we do not do biopsies on men who do not require biopsies. So that is where PSMA-PET imaging has started to be shifted forward. So you have seen where it is used in the clinical staging of patients where they are known to have a cancer, and then they have a whole body PSMA-PET to determine whether they have a localized prostate or clinically disseminated prostate cancer. Then patients who have had treatment who then have a biochemical recurrence where we are looking to find where the cancer is so that we can treat men appropriately when they have a recurrence. This is a completely different part of the diagnostic algorithm.
It is bringing it right forward to even before the men have had a diagnosis of prostate cancer. So this is basically the way we used to do a biopsy. You can see that on the left-hand side, where we would do a systematic sampling of the prostate, and you can imagine if someone has a small but significant prostate cancer, that can easily be missed. Again, up to 30% of patients with a negative MRI now have clinically significant prostate cancer, and that leads to a conundrum for us is that of the men who have a negative MRI, which ones still need a biopsy and which ones can safely avoid a biopsy? So the PRIMARY and the PRIMARY2 studies, and Professor Louise Emmett was the key investigator on those studies. I recruited patients for those studies as well.
Primary one showed that PSMA-PET in the diagnostic setting for the prostate, and again, these were not whole body PSMA-PET scans, these were pelvis-only PSMA-PETs, looking just at the prostate. PSMA-PET has a higher sensitivity and a higher specificity than MRI, but we would not look to replace MRI with PSMA-PET because the two studies are complementary. Some cancers are found on an MRI that we don't see on a PSMA-PET, some are seen on a PSMA-PET that are not seen on an MRI, and some are seen on both of them. But if you have a double negative, then you've got a very low risk of having a clinically significant prostate cancer. Almost all of the men with a double negative, so a negative MRI and a negative PSMA-PET, can safely avoid having a biopsy.
MRI also provides us with anatomical information that we don't get from a PET. Rod Hicks, who's across the road at MTIC, he was marrying the PET imaging over an MRI scan, and for a clinician who's doing the biopsy, that is sometimes of the most useful information that we can have. Furthermore, if you've got a PSMA-PET on top of the MRI, the PSMA-PET and the MRI combination can tell you which patients almost certainly have clinically significant prostate cancer. I think moving forward, that will allow us to avoid a biopsy in some men, even when we know they've got a cancer, because we know they're going to need treatment.
With some of the scans that were referred to in the last presentation, the pelvis-only PSMA-PET, I think, will become a thing of the past, and that certainly at MTIC, all patients have a whole body PET. There's no advantage in limiting that just to the pelvis, and so they get a whole body PET. You've got the staging as well as that diagnostic information about what's happening in the primary, even before the patient has had their biopsy. They can go to treatment much more rapidly compared to if they go through these processes sequentially.
This was the BiPASS study, and we are yet to see the results of this, but essentially men who are referred in with a suspicion of prostate cancer, so elevated PSA, they have an MRI, and then they're getting a PSMA-PET in addition to the MRI prior to having their biopsy. The questions that we have from this study are, who are the patients who can avoid having a biopsy altogether? That might be because we know they don't have prostate cancer, but it also might be because we know they do have prostate cancer. I think we'll wait to see the results, but I think this will back up what we've found already in the PRIMARY2 study. Again, a more precise diagnostic pathway. What I'll introduce as well is the concept of active surveillance for men with non-clinically significant prostate cancer.
We diagnose now many men who have either low risk or some intermediate risk prostate cancers that we think are unlikely to be a clinically significant problem for that patient, either in the medium to long term or in their lifetime. PSMA-PET imaging is helping us to better identify the patients who might have a clinically significant cancer that maybe we've missed on the biopsy, where we've caught the edge of a cancer, and in fact, they've got a more significant cancer than what we had appreciated. This is an MRI, and then down the bottom you've got a PSMA-PET. As I say, Rod Hicks over at MTIC was marrying these two images together so we would get the information from the PSMA-PET overlaid on the MRI.
But what you can see of the MRI is that it's giving you quite different information about the prostate itself. They're also very difficult to read. We run MDTs where we review cases that are maybe not as straightforward. You get some MRIs where the diagnosis is very clear, they've got a very obvious abnormality. But not infrequently, I will read MRIs that have come through a radiology service where a prostate cancer has been missed, because they're very difficult to read. I do a lot of prostate cancer, I look at a lot of MRIs. At the time I biopsy a patient, I review the MRI, I review them at surgery, I review them again after they've had their prostates removed, and I get a map of the actual prostate.
I see probably more clinically significant MRIs than what even the radiologists might do, and I pick up lesions that are not obvious to the radiologist reading the report. That's one of the shortfalls of MRI, but you can see in the image down below, it can be much more clinically apparent when you've got a very clear PSMA-PET finding that even my 12-year-old could read that PSMA-PET and tell you there's an abnormality there. Any questions?
Thank you, Dr. Dundee. I'll invite David, Dr. Emmett, and Dr. Dundee just to the seats here for Q&A, and we'll bring Dr. Ghesani back online as well. Dr. Emmett will present more on TLX597-Tx shortly, but we're very pleased to have her join us for this session, given her expertise with the PRIMARY studies. Do we have any questions?
Thanks. Hi, it's Dave from Morgan Stanley again. Just that 12% versus 16% clinically significant in the PRIMARY2, can you just talk a little about the margin of safety there, or non-inferiority margin, then how we should interpret that, then what you're looking for in the BiPASS study as well, please?
So what's important when you look at diagnosis of prostate cancer is look at the percent. What the definition of clinically significant malignancy is quite difficult, as Phil will agree, on pathology. So we chose 10% pattern four for significant, not significant. It's still a low percentage, and a lot of patients with 10% pattern four wouldn't be considered to have clinically significant malignancy. So you can look at it two ways. That 12% versus 16% was anything above or 10% pattern four or more, but we also looked at Gleason 4+3 , which a lot of MRI studies did, and we missed 0.86%. So, really went down. So it's higher proportion of patients with low volume significant malignancy is the difference between 12% to 16%. Very few patients with high-grade malignancy, very, very few patients were missed.
It's a shifting target as well. Even using a percent pattern four, when we use grading, the first number, the three in the Gleason 3+4 is the most common pattern that is seen under the microscope. The four is the second most common pattern. Four could be anywhere from 5% up to 50% before it becomes a Gleason 4+3 . So it's a shifting target, and if you've got a very small sample, say 2 mm of Gleason 3+4 or even Gleason 4+3 , you're talking about a tiny amount of pattern four disease. We use a little bit of art to work out, has this patient got a clinically significant prostate cancer?
Actually, when we look at the original MRI studies where the false negative rate was, or the negative predictive value was about 71%-72%, a lot of those patients actually had what we would now classify as clinically insignificant prostate cancer. I think what's interesting from the PRIMARY2 study is that the only case that was a higher -grade cancer, and it was a Gleason 4+3=7 , that was missed on the central read, but it was picked up on the local read. That was, in fact, picked up on a biopsy, a targeted biopsy. You could say that might have been a false negative read from the central read.
Just doubling down on that a little bit, that is actually 16%, so 12%-16% of a total incidence of 15% in this group, but these men were still going for biopsy. So 16% of 15%, so very small overall percentage. In order, what we gained was halving the number of patients who actually got biopsy. We halved the number of clinically insignificant malignancies that we found, and halved the number of patients who did not have cancer at all on their biopsy. So a small increase for a dramatic change in, I would say, quality of life outcomes for patients.
Yeah, I would agree with that, particularly the non-clinically significant cancer. So we know we still diagnose too much low-grade prostate cancer, and that is a significant burden on individuals, so they need much closer follow-up. They need repeat biopsies, repeat MRIs. It is psychologically a burden on patients, and so it is both a cost burden to the cost funders, and it is a psychological and it is a medical burden on patients who are diagnosed with disease ultimately that will not cause them any problem. I think our expectation of how we are diagnosing patients and the accuracy with which we diagnose them is changing as well. So again, if we go back to the original algorithm 10 years ago, where patients were referred in with an abnormal PSA and then they just had a blind systematic biopsy, we were missing far more cancers than what we do with the more sophisticated algorithms now.
Actually, I am probably talking too much, but I just wanted to give an anecdote as to why we even did the PRIMARY. So I have a family member who had a rising PSA, was 42, and went and had an MRI, which was equivocal, had a biopsy, which showed a very small percentage of pattern four. Could not cope with the idea of active surveillance because he was worried he had cancer. Had small children, had a radical prostatectomy, and he is incontinent and impotent as a result of that radical prostatectomy. If he had been on PRIMARY2, he would never have known he had cancer, he would never have had that biopsy, and he would be well.
Thanks. Andrew Paine at CLSA. Just coming to the current TAM for PSMA imaging and the views that will shift into pre-biopsy, where do you think that 670,000 current TAM will, like what proportion of that will shift into biopsy?
If it were up to me, all of them. My ideal diagnostic pathway would be abnormal PSA followed by an MRI and probably a PSMA-PET in just about all patients before they get the biopsy.
Yeah. Thanks.
With the number of PET scans that we are doing, I think the postoperative biochemical recurrence, and you saw the sensitivities of how accurate these scans are, that only tells part of the picture, that this is an iterative test. We are seeing things that we could not see on conventional imaging, even macroscopic disease that was visible with hindsight, and you saw the 2 mm and 3 mm nodes that were visible on CT, but you did not know that they were positive because we do not get any functional information about them just on a CT. It is just anatomical information. But it is an iterative test over time, and if a patient has a PSMA or biochemical recurrence and they have a PSMA-PET, number one is it is changing how we are managing those patients.
Historically, we used to give everybody with metastatic disease hormone suppression, and that is a terribly disabling treatment for patients. It is really only in the PSMA-PET era that we have had much more accurate diagnosis in the biochemical recurrent setting that we can now treat those patients without having to use these systemic agents like ADT. So they are having what we call stereotactic radiation, where we are basically pinpointing the areas of recurrence with radiation. We are avoiding these systemic treatments, and then we are getting the PSA back down, sometimes to zero, sometimes for many years. Then in the future, it might rise again, and we repeat the PSMA-PET again, and then we can go round again and treat them with stereotactic radiation. For many men now, we are able to hold off treating them with systemic treatment.
We are able to ensure that they have got much better quality of life compared to had they had that systemic treatment, and that it ends up being treatment that they become resistant to. We are pushing that down the track as well. We are keeping all of these very heavy-hitting treatments in our armory without having to use them earlier in patients and then running out of options down the track.
Hi. Andrew Hamilton from Antares Equities. Two questions. Firstly, we have talked about the risks of biopsy. What are the rates of adverse events? Secondly, in a success case for BiPASS, I presume that for ongoing surveillance, or indeed if a patient progresses, you would use the same imaging agent throughout their journey. Is that correct?
I will let Louise answer the second question, but I can answer the first question. It depends on how you define adverse event, and it depends on how you do the biopsy. In Australia, we have now almost universally moved to what is called a transperineal biopsy. Historically, we used a transrectal biopsy, and in the U.S., it is still the most commonly performed biopsy is the transrectal. The difference is that with the transrectal, the needle passes through the rectal wall and into the prostate, and there is about a 2%-3% incidence of urinary sepsis or prostatitis. You are introducing rectal organisms into the prostate, and that can make a patient very unwell. They need antibiotic cover before they have the biopsy and during the biopsy.
Despite that, 2% or 3% end up back in hospital, some of them in intensive care, and some of those men do not even have cancer. They have ended up with a procedure that has left them in ICU. A very, very small but non-zero risk of death from that type of complication. Now we have moved to transperineal prostate biopsy, where the needle goes through the skin just in front of the anus rather than through the rectal wall itself. The risk of sepsis now is virtually zero. The risk of urinary infection is about one in 1,000, so very rare. Most patients will have some discomfort, and they will have blood in their urine for a couple of days after the procedure, and they will have blood in the ejaculate. There are no medical consequences of that, but for obvious reasons, some men find that alarming.
Depending on how the biopsy is performed, there are some patients who will end up in urinary retention because you get swelling of the prostate at the time of having the biopsy. With a targeted biopsy, where you are sampling only the abnormality, that is significantly lower and close to zero risk of acute retention. If we have a better imaging pathway that we do not have to do these systematic samples, then we can avoid those sort of complications. There is a real incidence of erectile dysfunction, again, with the systematic sampling rather than just a targeted biopsy. Someone who ends up with a systematic biopsy, erectile dysfunction, they do not have cancer, that is a terrible outcome for that patient.
None of those symptoms from PSMA-PET. In terms of your question about active surveillance, serial PSMA-PET imaging is not something that has actually been evaluated in a great deal of detail. If you were going to be doing serial PSMA-PET, and I think that in the long term, I can hopefully persuade Telix that it is a good idea to do that, then you would want to use the same agent.
Dr. Ghesani, I think you could probably hear the nature of the discussion, if not the specific questions from the floor, but did you want to add any commentary?
Yeah. I just heard the comment from Louise about using the same agent, and I completely agree with that because, one of the things I do is, again, going back to my interest in physics, I show our residents, our faculty, and also our urology colleagues that there are misconceptions about the particular agents. For example, there is one misconception is that fluorine-18 has better imaging characteristics. That is because the reconstructions that are done are done with the same algorithm, and Louise can correct me if I am wrong, that if you apply the appropriate subsets and orders in the OSEM reconstruction, it needs to be optimized for each individual isotope. You cannot apply the same algorithm to all available isotopes of PSMA.
Hi, it's Laura from Citi. My question is actually mainly for Dr. Ghesani, but I'd appreciate input from all of our speakers. Can you hear me?
Yes, I can hear you very well.
Okay, great. Okay. Let's say the BiPASS trial goes as Telix hopes and the labeling is as people anticipate, so you have the option to use a gallium-labeled scan in patients who do not yet have a prostate cancer diagnosis. At this point, let's say you do that and the world kind of goes that way. Absent the situation that Andrew and Dr. Emmett have just described, where you're trying to build up a longitudinal series in a patient with fluorine. Absent that situation, what would be the reason for anyone to keep using fluorine, given the issues with IBLs?
Yeah. You just heard Dr. Dundee also mention that the last thing you want is to create the morbidity to the patient who does not have a cancer. Imagine now, if you have a patient who has negative finding in the prostate, but then you found a lesion that is in the rib or in the spine, and if you are not sure, there are two potential concerns that can occur, right? One is that, of course, it is an indeterminate bone lesion, but what if that is not a metastatic disease from prostate cancer or something else? There are now number of case reports and some of the series demonstrating that other cancers, such as lung cancer, can express PSMA.
That patient who does not have a prostate cancer has a very suspicious finding in the bone, and now you end up doing a biopsy of that only to find out that it is false positive. My concern would be that if you are applying anything in that earlier stage of the disease, you need to have both higher sensitivity, but also higher specificity as well.
Hi, Shane from Canaccord. Louise, could you provide a little bit more background and just information on what you meant by serial PSMA imaging, just the frequency and how much and for how long? As a follow-up perhaps for David, how straightforward is the health economic argument for, I guess, dragging this such a big sort of diagnostic workload forward?
We were talking about active surveillance, which would require a baseline around the time of biopsy, and then active surveillance actually have serial MRI. You would need to do, and that is a separate indication to diagnosis. I guess when I talk about serial PSMA-PET imaging, as someone who treats patients with metastatic prostate cancer, I am super interested in PSMA-PET replacing bone scan. I think that PSMA-PET has got a high sensitivity and specificity compared to bone scan. We use bone scan at the moment to guide treatment for early metastatic and late metastatic disease patients, and I think it would be great.
Well, Shane, I think the clinical use case is crystal clear, and again, Louise had a patient, I think you presented at EANM just a couple of weeks ago, who was a patient on Dr. Emmett's OPTIMAL-e study, which is in the early, what we now call metastatic androgen pathway modulation naive or sensitive. Very, very long terminology for what used to be called hormone-sensitive disease. Did this gentleman come from Dubbo, or is he somewhere way out in rural New South Wales, and we funded him to come into your trial?
Yes.
Could you talk about maybe just the, he had ARPI, three fractions of TLX597-Tx, then you paused him because you didn't want to overtreat, and that's why serial scanning's so critically-
Critical.
Important, right?
Critical to identify progress in responders. We're moving from just dump treatment onto patients to try and personalize treatment, right? In order to do that, we need biomarkers, companion biomarkers to guide which treatment we should use, when we should use it, and how, and what combination of treatments we should use. PSMA-PET is going to be a big companion biomarker. It's prognostic, and it's predictive for response with a lot of agents. This particular case, we're taking men with newly diagnosed metastatic disease, and we're doing a scan at baseline. We're doing one at three months, and we're doing it at six months. If they've got nothing left on their PSMA-PET scan at three months, we're pausing one of the treatments, which is the lutetium PSMA-597, but then we're imaging them again at six months.
That is one way you can use it. The other way you can use it is to identify when a patient has progressed and needs to change treatment. Using a more sensitive and specific agent to do that from what we have actually currently got, I think is extremely appealing, and Telix is probably the only company in the world that I can think of that can actually do that.
Yeah, I would just add to that, Shane. You might have heard a colleague of yours, Rod Hicks, across the road, used to be the head of nukes at Peter Mac. He describes MRI and CT as lumpology. Is there a lump there, or is there not a lump there? That tells us really nothing, whereas a PSMA-PET scan is not lumpology, it is biology. Is there something there that needs treatment, or should we stop? Isn't that right?
He sounds a bit biased. He is a nuclear medicine physician, isn't he?
Yeah.
No, but MRI is good. But PSMA-PET has the capability of not only looking at volume of disease, it can actually coalesce all volume of disease, so it looks at every single deposit in the body, and it also gives you phenotype, so it gives you characteristics of the aggressivity of that tumor. I think we haven't even started to tap that potential yet.
Okay, I think we will pause there. Thank you for the very thoughtful questions. They are great questions, and I would like to acknowledge the responders here, the two professors beside me. Thank you very much.
Thank you to Dr. Ghesani, Dr. Dundee, and Dr. Emmett. David will move on to our next session now.
Okay, Dr. Ghesani, it is getting late for you probably in Princeton. You are welcome to stay on. If you like, we are going to switch to neuro-oncology with an N now, and we have Professor Scott coming up shortly. I would now like to introduce our third key opinion leader speaker, Professor Andrew Scott, who is also a nuclear medicine doctor, so we have had three nuke med physicians today. He is a Professor of Medicine at the University of Melbourne and Head of the Tumour Targeting Laboratory at the esteemed Olivia Newton-John Cancer Research Institute across town in Heidelberg. Professor Scott has only published 480 peer-reviewed papers. He has only published 27 book chapters. Maybe it is 30 now, Andrew. He is the former president of the World Federation of Nuclear Medicine and Biology. Professor Scott clearly brings extensive experience across the entire field.
Today, he is going to take us into the highly focused area of unmet need, which is brain cancer. Professor Scott, welcome to you, and thanks for joining us.
Thank you. It's actually 540.
[That was right. It was 480.]
That was 12 months ago. That's okay. That's okay. Thank you. I'm pleased to be here. I would also mention that I've had an interest not just in nuclear medicine cancer biology, but I'm a Co-Director of a Centre for Research Excellence in Brain Cancer for the last few years. From my lab, actually have developed a molecule which has gone into phase III studies in GBM patients, which was negative. I know exactly what it's like to be able to develop something in the brain cancer space. I hope to share with you which I think is some really interesting and exciting work that Telix is doing that we're helping support as well. First, in terms of imaging.
Hopefully all of you are aware of the fact that fluoroethyltyrosine amino acid imaging PET, FET PET, has been around for many years, but has not been approved in the use of the identification of residual disease or transformation of disease in brain cancer. In September, the FDA did approve PIXCLARA, which is fluoroethyltyrosine PET in the U.S., which I think is a major step forward. This is in the context of assessment of patients that have got suspected recurrent disease after initial treatment. In Europe, this has been used for some time.
In Australia, we do not yet have approval, although we do have a trial called the FIG study, which is also generating substantial data, not just in the relapse refractory setting, but also in the pre-chemoradiation setting, which is still not approved by FDA, but which is going to, I think, be the next area where this will gain approval. We know that FET PET plays a hugely significant role in the evaluation and management of patients with glioma. It is included in clinical practice guidelines in the U.S. and in Europe, as indicated, and there is also potential use in brain metastatic disease.
This is important because we know that if you are treating patients with glioma, one of the principal problems is assessing whether or not there has been transformation of disease in low-grade glioma, or where you have higher-grade glioma, particularly after treatment with chemoradiation, the MRI and the anatomical changes can be very nonspecific and can last for a long time, and can even appear up to 12 months after completion of chemoradiation when there may not even be disease still present.
This is just some data which shows that in the U.S. in particular, where obviously there is now, with the FDA approval, a huge increase in the use of FET PET, that there are substantial numbers of clinicians who agree with the clinical practice guidelines, have capability to perform the test, and I think we will see PIXCLARA following the PSMA imaging in the U.S. as being an area of huge utility for patient management. Now, how does PIXCLARA work and how is it relevant to also therapeutics? There is a receptor, or two receptors, LAT1, LAT2, which occur within the brain, particularly on the blood-brain barrier component, which are responsible for the transfer of specific molecules. Amino acid imaging is reliant on both LAT1 and LAT2.
But in addition to imaging, you can also exploit this particular receptor for the transport of molecules which could take a therapeutic isotope into these brain tumors. That is the basis for the TLX101-Tx and also the TLX102 -Tx approaches. We are using I-131 or the alpha particle emitter astatine-211 could potentially be used. So when you see brain MRIs in patients with glioma, typically you look at a range of different MRI sequences, T1 plus contrast, T2, FLAIR as well. It demonstrates edema as well as the sites of where there is disruption in the blood-brain barrier, which may or may not correspond to sites of disease. What we have on the left is just a typical MRI, a T1 plus contrast, and on the right is the fluoroethyltyrosine PET, or PIXCLARA, as is referred to as well. You can clearly see the focal site of disease.
Seeing as you have just had a bit of a dive into prostate cancer, it is similar principles here. You look for where the focal area of uptake is, and that is highly sensitive and specific for true tumor that is present within often very complex and extensive MRI changes. This is an example here. This is a patient that you can see in the middle and the right-hand MRI. You can see the white. It is quite dispersed and quite large. In this context, that could be post-treatment changes or it could be actually disease. It is very difficult to tell. But if you look on the left-hand side, it is just that one small focus, which is in fact the site of residual disease. If it is just treatment-related changes, you may see nothing at all.
Again, this is an example of where imaging, molecular imaging, in this case with fluoroethyltyrosine or PIXCLARA, can very, very specifically identify where the site of disease is after treatment or transformation of disease in lower-grade gliomas at initial diagnosis. Another example of where you see a patient who ended up having, in the first instance, a grade 2 lower-grade glioma diagnosed, and you can see on the left-hand and the middle MRI the disparate changes which are present. The patient had some symptoms. The question was whether there was transformation to a higher grade of malignancy. On the right-hand side, you can see where the FET-PET abnormality was. That site was biopsied and shown to be grade 3, and therefore treatment initiated. Now, you can appreciate that, particularly in the brain, you do not want to just biopsy without good reason.
Normal brain can be incredibly impacted by both the edema which is present, but also by the procedures that you do. It is even more important. Have to be careful here because Louise is in the audience. More important than in prostate cancer to be very careful about where you biopsy, just as important. But the normal tissue side effects from not directing your biopsy properly is obviously even more pronounced, particularly when you have a lesion near the eloquent centers and so on, where you could make someone unable to speak or cause them to have weakness in specific areas based on where you biopsy. Now, one of the key things about the treatment of brain cancer is that essentially since 2005, so 20 years, there has really been no advances in treatment, particularly for high-grade disease.
In 2005, the Stupp protocol, which is chemoradiation, was implemented for patient with high-grade glioma, glioblastoma. Despite many, many, many trials, even the implementation of bevacizumab, which got approval by the FDA, but really is only used as a last resort and is not consistent in its therapeutic effects, there is very little change which has occurred subsequently. We do know that in low-grade glioma, which are IDH mutant, vorasidenib was recently approved, so that is an example in a lower-grade glioma where a new treatment for a specific mutation has been shown to improve survival. But otherwise, it is probably the tumor type where new treatments are most required. That is important because even though it is not as high a number of patients as you see with lung cancer, colon cancer, prostate cancer, in the U.S. it is over 25,000 patients a year.
In Australia, it is about 1,200 patients a year are diagnosed with gliomas. The other important statistic is that the survival is actually very short. You can see that over 20 or more years, the average survival really has not changed. 12-month survival is only 40%, and the overall survival, again, has not changed within that 20-year period, again, illustrating the need for new treatments to be obtained. What is TLX101-Tx? It is an iodinated iodine-131 labeled molecule which is transported into tumors in the brain through the LAT1 receptor. It has been evaluated in a series of phase I trials, including IPAX-1, IPAX-Linz, and the IPAX-2 study, which has completed recruitment, and we are just waiting for the readout. It has been shown to have encouraging results in terms of overall survival and also progression-free survival from patients being entered into studies in which it has been given.
I have been involved with a lot of neuro-oncology GBM-based trials, and invariably, you see patients relapsing within typically three to four months after treatment, which is very discouraging, but we continue to be optimistic that we can find new treatments that will be effective. What are the ongoing trials that Telix is involved with? Well, there is the IPAX BrIGHT study, which is a phase III study in patients who have relapsed after first initial treatment with chemoradiation. Then the upfront IPAX-2 study, which is combining TLX101-Tx with the Stupp protocol chemoradiation in patients with newly diagnosed high-grade glioma. IPAX BrIGHT is a study which is being conducted in the U.S., Europe, Singapore, and Australia. It involves two components to the study.
One is a establishment of the appropriate dose of combining TLX101-Tx with lomustine being the chemotherapy which is typically used at first relapse after initial chemoradiation and the original surgery. After the establishment of the appropriate combination dose of the two, it is planned to go into 1:1 randomized study combining TLX101-Tx with lomustine versus lomustine alone. The primary endpoint for the part two of the study will be overall survival. It will be a pivotal study to see whether the addition of TLX101-Tx with lomustine compared to lomustine alone improves overall survival of these patients. That is the IPAX BrIGHT study, which I think is a very exciting study for those of us who see and treat patients with high-grade glioma.
This is just some information from data which has already been obtained in the patient population who have got brain tumors, have been treated with TLX101-Tx, where there has been stable disease and partial responses in just over 50% of the cohort of patients that has been analyzed. Still small numbers, but encouraging enough for this series of studies to be pursued because it is very hard to find any treatment in this patient population which shows responses or reasonable stable disease for long periods of time. Over 26 patients have been treated on a compassionate use protocol that Telix has established across a range of institutions in Australia, Europe, New Zealand, and U.S.A. The IPEX-2 is combining the TLX101-Tx with chemoradiation, where the TLX101-Tx is given on day one and 49 of the approximately six-week period when the radiation is combined with temozolomide after initial diagnosis and surgery.
And so this study, which has completed recruitment, was able to establish the safety of combining the TLX101-Tx with chemoradiation. There was no dose-limiting toxicities observed, and we're just awaiting full data set, but encouraging enough to proceed into a phase II trial. Okay, any questions? I think they need morning tea.
Yes. Thank you.
Have to have at least one question.
Hi, it's Laura at Citi again.
Yeah.
Can you just talk to what you think an OS improvement that would be considered substantial in each of the target populations?
Three months. I mean, literally because of the very short progression-free survival we typically see in this patient population. I think that would be even enough to get a positive response from a regulatory perspective. Yeah.
Oh, hi. Thanks for your time. Just wondering why there has been so much underinvestment in brain cancer specifically, or lack of progress, I suppose.
Small numbers and it is hard. That is a bit of a simplification, but there have been quite a lot of trials and a lot of therapeutics that have been evaluated. Nowhere near as much as in most of the other large solid tumors, for example, or in the hematologic malignancies. It has been such a desert that it has been very difficult for, I think, a lot of companies to focus compared to some of the other cancer types. But it is a very hard disease to treat, and it is one of the very few, for example, where immune therapy does not work at all. That is also because the immunosuppressive microenvironment within the brain is very different to the rest of the body. So, it is just one of these outliers.
Just a follow-on from that question.
Yeah.
Just the blood-brain barrier.
Yeah.
Just how difficult is it to sort of get through that, and how has LAT1, two been able to give you some progress on that front?
The blood-brain barrier is mainly an issue with large molecular weight proteins. If you have an appropriate transporter and you have a small molecule or ligand, and the advantage of TLX101-Tx is that you can actually image how much is actually getting in there. It has not been shown to be a major issue. I think this is a class of molecule where the blood-brain barrier in this particular receptor for uptake is quite well-suited to getting appropriate concentrations deliverable. I mean, the blood-brain barrier remains an area of intense research for many reasons. But this particular molecule has not got an issue in that regard. Yeah.
Hi.
I have one question here.
Okay, it is just a follow-up to my previous question.
Yeah.
Could you talk a bit about a hypothetical trade-off between route of administration and, say, modest improvements in OS? Let us say you got something that was systemically viable with three months of OS, and something else that gave you four months of OS but required intracranial administration.
Well, I think that is fairly self-evident, that you are always going to be able to have an advantage if you have got a systemic administration if there is only a very small improvement with local administration. It does go to the point about blood-brain barrier and drug delivery, because there are a number of therapeutic approaches with direct injection with Ommaya reservoirs and so on to try and get around that problem of delivery. But there is quite a bit of morbidity that can be associated with that. I think that if it is only a very tiny or modest increment in overall survival with a local delivery, then systemic delivery is likely to get the preference. Certainly from a clinician and patient perspective, it is going to be much easier to give, and more patients are likely to be able to get it, and it is probably going to be cheaper too.
Thank you.
Hi.
Yeah.
Andrew from Antares Equities. TLX101-Tx is targeting LAT1, not LAT2. Is that correct?
Correct.
What proportion of GBMs express that target?
The vast majority of them, because the screening for these patients is also with FET PET as well, so you can actually determine what the likelihood is that they are going to be able to be going on to study. But it is, in a practical sense, and we can use our data from PIXCLARA, it is more than 90%. Yeah.
All right, we will transition to the next question.
Okay.
Thank you so much.
Thank you, Dr. Scott.
Okay, look, thank you, Professor Scott. Always a very enlightening discussion. I have the benefit of being the CMO at Telix, of being part of a company that is, I think, a very ethical company, highly ethical company. We have a very open, compassionate use program, so where if there is a patient that a clinician has that might not be suitable, might not be strictly eligible for one of our prostate cancer or kidney cancer or brain cancer trials, that we will provide compassionate use access to our therapeutic candidates. And we see quite a lot of requests for brain cancer, glioma, access to TLX101-Tx, and that is because of the drug development desert, as Professor Scott and I termed it, nothing new for about 20 years. Clinicians are clearly looking for other things. Let us move on to kidney or renal cancer.
We have, again, a whole This is not a technical term, but as I said in the opening, we have a beast of a pipeline. We do not have time today to go through all of our kidney cancer trials. Hence, we will look at some of the key programs. While prostate and brain cancer do receive a lot of attention, prostate cancer is the most common cancer in men, brain cancer is a devastating diagnosis, and there is a lot of attention brought on it because of that. I thought for kidney cancer, it is a long way down the list. It does not sort of attract the same attention that those other two cancers get. So I thought it would be useful to start with a quick disease overview on kidney cancer. So, with respect to kidney cancer, really it is a disease that we have seen rising in prominence with the estimates.
If you look at the literature, suggesting that there has been about a 3% per annum increase in the incidence of kidney cancer for a number of decades now. And that has got a lot to do with the improved imaging techniques that we have had over the last couple of decades, contrast CT, fine slice CT, MRI, and ultrasound, but also perhaps increased exposure to carcinogens in the natural environment. So now, it is the 14th most commonly diagnosed cancer worldwide. And if you look at the age-standardized incidence of kidney cancer, it seems to be highest in both North America and Europe. Unfortunately, it is a male predominant disease with about a 2:1 or 3:1 favoring, or actually it is not a favoring, it is a higher incidence in men.
When you think about kidney cancer in that vernacular, about 90% of kidney cancer is going to be what we call renal cell carcinoma. It is that species of kidney cancer, about 90% of it is RCC. And within that group, about 85% or 90% of that is going to represent what we call clear cell renal cell carcinoma. So I will not say clear cell renal cell carcinoma every time I mention it. We abbreviate that to ccRCC for obvious reasons. So that is by far the most common histology or species pattern that makes up the lion's share of the patients that we would tend to see in the clinics. What targets could we exploit that we have not to date to treat kidney cancer? Well, ironically, it is one of the targets that we currently use to diagnose renal cell carcinoma, and that is CA9 or carbonic anhydrase nine.
This is a transmembrane glycoprotein. If you think of its normal physiologic function, it works in oxygen sensing, it works in pH or acidity regulation in a normal cell. This target is induced, meaning that it is upregulated when a tumor becomes hypoxic, so low in oxygen, or by mutation of the von Hippel-Lindau tumor suppressor gene. If you think about that is all complex stuff, but a tumor suppressor gene, when it is operating normally, suppresses the propensity for tumors to grow, and if you knock it out, that control mechanism has gone. This target really exhibits the three characteristics that are needed for radiopharmotherapy development. I always keep these in the back of my head, SP&E. SP&E. What are they?
S is for specific, meaning that the target is expressed on the renal cell carcinoma, but there is very little target expression on normal tissues and organs. So it is specific for the cancer. The P is prevalent. If you have 100 patients with renal cell carcinoma, about 95 of them, maybe 96 of them, so it is over about 95% of them will express the target. So it is a highly prevalent target, which is a big check. The E is for expression. Finally, the expression of CA9 is very high, meaning that there is a lot of the target available to go and hit with radiopharmaceutical drugs. So it is specific, prevalent, and it has got high expression. That checks all of the boxes to be a beautiful target. Let us talk a little bit about the different targeting approaches. The target is a beautiful target.
How are we going to hit that target? An agent that perhaps is well-known to some in the audience, and that is because it has been very highly studied in prior phase I to III trials, is girentuximab. This is an IgG1 kappa light chain monoclonal antibody that is really specific itself for hitting the CA9 target. Once it binds to CA9, it leads to internalization into the cancer cell where it stays put. Moving to our theranostic compounds that are thus based on girentuximab. In the middle there, we have got the zirconium-89 payload, which we have shown in our phase III ZIRCON study to be exquisitely useful for PET imaging and diagnosis of ccRCC, and that has become the basis for our Zircaix asset that we anticipate FDA is going to approve sometime in 2027. I think that is the beauty of theranostic.
It is the target engagement validation that the ZIRCON study confirmed that really inspires us and inspires us to allocate shareholders' capital to substitute in lutetium for the zirconium, turn it into a therapeutic agent, and take it forward into our phase III LUTEON therapy trial. That is the beauty of imaging. You can see how well it engages the target, and it gives you confidence about taking it forward to develop it as a therapeutic. This slide really nicely summarizes, just very briefly, the results of our phase III ZIRCON trial, which I think demonstrated two key takeaways. The first of those is that ZIRCON fundamentally validated CA9 as a new target for therapeutic radiopharmaceutical development for kidney cancer.
And this forms really, as I said, the rationale for Telix's decision to pursue LUTEON, which is our phase III trial of lutetium girentuximab for the treatment of kidney cancer. The second thing, I think, is that ZIRCON clearly and unequivocally demonstrated the accuracy of Zircaix to non-invasively delineate clear cell renal cell carcinoma from non-ccRCC or benign lesions in the kidney. That is a major clinical need, because what we call indeterminate renal masses show up on imaging for other reasons. We do a CT, an MRI, an ultrasound for suspected gallbladder disease or appendicitis, or pancreatitis, and we see a lesion in the kidney that we did not know existed, and we have got to work out what that is.
So, it is this latter use as a non-invasive tool using CA9 PET to characterize ccRCC for an indeterminate renal masses that we are really excited to bring to clinicians and their patients following FDA approval, which we anticipate in 2027. This is my view, and Professor Emmett and Professor Scott will have a view as nuclear medicine doctors, but it is my view, and I think this is well-founded, is that CA9 PET will transform the diagnosis and staging of kidney cancer in a very similar manner to what we have seen with PSMA-PET, and what it has done over the last five years for prostate cancer. I think it will be the same type of transformational pattern in the way we manage these patients. This brings me to our phase III LUTEON trial. I will try to make this is quite a complex slide.
There is a lot going on here, but it is actually very simple. Let us just look at LUTEON. We will ignore for a moment LUTEON-ATLAS, and I will explain what that is. LUTEON, which is our phase III study of lutetium girentuximab in patients with advanced metastatic ccRCC. These patients have progressed after two or three lines of prior therapy. This is a population that we would call treatment refractory. When I talk to investigators that are participating in this trial, they say to me, "David, I really need this trial," because patients classically progress through those first and second lines of treatment in almost all instances, and they do so pretty quickly. Today, our first-line options comprise, unsurprisingly, immune checkpoint inhibitors and a class of drugs known as VEGF tyrosine kinase inhibitors.
But most patients develop primary resistance to those agents, and it is probably only about 10% of patients who are treated with these current agents who get a durable, complete response. The other 90%, progress straight through them and develop primary resistance pretty quickly. Looking at the study schema there, what we have learnt from prior studies is really pretty simple, and that is that more treatment cycles with lutetium girentuximab correlates to longer survival durations, and in turn, lower administered activities are better tolerated, and they allow us to give more cycles. So, lower activity allows you to give more cycles. More cycles correlates really well with extended disease control and survival. What we have done in LUTEON is we have designed, in, I would say, very close collaboration or close consultation with the U.S. FDA, part one of this trial.
We are simply enrolling 20 and 20, so a total of 40 patients. DR1 and DR2 is dose regimen one and dose regimen two. We are really trying to work out whether one monthly or two monthly dosing is more optimal for the patient. This study is now enrolling pretty rapidly in Australia and Europe, and we have just opened it in the U.S. Once we have identified the winner of those two dosing regimens, you can see over on the far right-hand side, one of them will go forward into part two, which is the classic randomized treatment expansion against the investigator's selected standard of care.
It is a very elegant but simple design, picking which dose regimen is going to be the most tolerated, which one we can give the longest duration to, and we will take one of those, which will be the winner, forward into the randomized treatment expansion. There are many parallels between this and the way we have set up ProstACT Global. I would be very happy to take any questions, and I think Dr. Emmett and Professor Scott would be also very well qualified to talk about kidney cancer as well.
You go, sorry.
I have two questions just on Zircaix characterization is, I think, where it is at, is there opportunities for expansion for Zircaix down the track? My second question would be the ZIRCON trial, just maybe talk a little bit about what the change in clinical practice observations would be from that trial, and maybe link that through to what you have seen in PSMA-PET.
Yeah. I might, if I may, triage the first question to Professor Scott. Professor Scott, as I said, has got experience across the entire field and was one of the leading investigators on ZIRCON, put the first patients in at Austin Health, and I think was one of the highest recruiters. Maybe Professor Scott, if you could just talk about the evolution beyond the ZIRCON indication, where might we go with CA9 imaging?
The focus, of course, for CA9 so far has been in clear cell renal cancer because that's the greatest area of unmet need and where the CA9 expression is high and the VHL mutation can occur. There are many other cancer types which may be CA9 positive. They would certainly be suitable for potentially extending the imaging of CA9, I think more likely in the context of therapeutic approaches, where CA9 is being exploited as well, because we know that CA9 expression in clear cell renal cancer is extremely high, whereas in many other cancer types where CA9 expression can be seen, it's in a proportion of patients. It wouldn't be supplanting, for example, standard staging in lung cancer or colon cancer or many other cancers as well. If that's what you're asking, that would be my response to that.
Yeah, sort of more within clear cell renal carcinoma at the moment. It's a characterization. Is there a plan to go through staging and further on?
Oh, you're talking about just within clear cell? Yes. Clear cell, yeah. Of course. Yeah.
Did you do ZIRCON as well? I think you were involved in that as well.
Probably.
Yeah.
Probably.
Yeah. Would you like to cover that, or? Well, I would be very happy to. Because we got a key opinion leader here, and you want to hear from a key opinion leader, not me.
Yeah. I will leave that one to you.
Okay. The question was about ZIRCON. In the ZIRCON study, you are absolutely right, David, the CA9 PET scan focused on the pelvis, but at the investigator's discretion, they were allowed to expand what we call the axial field of view, and they could image the abdomen, they could image the chest, they could image up into the head and neck. What we found was that there is extensive value in expanding the axial field of view, what you actually look at, to look for metastases. You might want to do that if a patient has got a higher risk kidney cancer. The pathologist, when we send tissue off to the path lab, they look at the kidney cancer and they say whether it is high, medium, or low risk.
If it is a higher risk patient, you probably suspect that they might have distant disease that has gone to the lymph nodes in the chest or abdomen, or to other organs, like it might have gone to the liver or the adrenal gland or up into the lungs. Is there anything you want to add on that?
You have reminded me. Yes.
Oh, I thought—
If you have metastatic disease from clear cell, the retention of the CA9 expression is quite high. It does not down-regulate substantially. It is just as good at looking at sites of metastatic disease as it will be at the primary for CA9 expression and extent of disease.
Hi, David. On CA9 more broadly, the earlier topic, I think the basket trial was called STARBURST. Could you tell us what the outcomes of that was?
Yes. STARBURST was, as you say, a basket trial. Not only renal cell carcinoma, but other cancers. For example, mesothelioma has a propensity to express CA9. We did in that STARBURST study, that was an imaging study, we wanted to see exactly those things, S, P, and E, the specificity and the prevalence and the expression of some of these other cancers, because that would inform us where might we go, in terms of our life cycle management and other opportunities to help patients. We've got data from that. I don't know if it's been published extensively. I don't think it has. But it certainly informs us, beyond kidney cancer, where might we go next. But to get it approved, it's almost always approved by the FDA, it's almost still got to be disease-specific.
There's a number of basket trials that the FDA has granted approvals on, but the conventional way and the wisdom is to go for specific disease species. Things like mesothelioma are certainly worth investigating beyond kidney cancer.
Yeah, that's what I was wondering if there are further indications that will be pursued, targets.
Yeah, I think, we don't go into it in any detail today, but I talked earlier about fibroblast activation protein. That meets all of those SP&E criteria on a series of cancers, pancreatic cancer, ovarian cancer, and a few others as well. So we'll probably focus, that's more a pan-cancer target than CA9, even though CA9 is, FAP's probably even more so. Yeah. Okay. Laura.
Can I ask one more?
Of course you may.
Thank you. It's Laura at Citigroup. Could you talk about where you think TLX250-Tx, as in the therapeutic, has the potential to end up in the treatment paradigm? I assume you'll start with late-line monotherapy salvage option. Is it amenable to combinations with the sorts of class of drug that you would need to combine it with to see it move up the treatment paradigm? Move forward in the treatment paradigm?
Yeah, that's a great question. Dr. Emmett's going to talk a bit later in the prostate cancer setting how there is extensive synergism between ARPI drugs and radioligand therapy. But in kidney cancer, a very conventional, I wouldn't call it boring, but a conventional approach to developing a new first-in-class agent is exactly what Endocyte, Novartis did with PLUVICTO, which is use it first in patients that have exhausted all of the conventional options, so they're refractory to the usual treatment toolkit that we've got, and do that in late-line disease and try to show an overall survival benefit. I think it's critically important to get that overall survival benefit, and then from there move it upstream. It's sort of the asset earns its right to then go upstream in terms of development if it's shown a survival benefit in that last-line population.
Just in terms of your second question, which was about synergism, I think there's enormous potential, and we've got preclinical data on this, to combine the tissue-damaging effects of radioligand therapy with immune checkpoint inhibitors and augment the effects of immune checkpoint inhibitors like nivolumab and pembrolizumab. We've got some extensive preclinical data that shows that that's a very thoughtful strategy. That's got to be sequenced first. So radioligand therapy first, augmenting the immune checkpoint inhibitor in the following weeks. Yeah. Okay. Yep, let's All right, so, I think we're into prostate cancer. So we've gone from the pelvis, we've headed north to the cranium, we're going back south, back deep into the pelvis. So let's move on to TLX597-Tx and TLX591-Tx.
Now, before we discuss TLX591 -Tx and our TLX597-Tx programs, and Professor Emmett's going to talk about the emerging data from TLX597-Tx, a question that comes up, and it's a very, very important question is, why do we have both a small molecule and an antibody in our pipeline? We say it consistently, we are agnostic to the targeting vector. It might be a peptide, it might be a small molecule, it might be an amino acid, like Dr. Scott talked about, for the brain, or it might be an antibody or even an antibody fragment. So we are agnostic to it, but it's important to understand the main prostate cancer disease states, because this has implications for how we best manage our patients.
And while those little pictograms up the top left and top right, they are certainly highly simplified, they do illustrate, I think very nicely, the baseline characteristics of two distinct populations. And I know, Louise, you are going to argue with me on this, but we have got to try to make sense of the different populations. So on the left-hand side, this gentleman up here, we have got patients with early metastatic disease. That is what we call this new terminology, it is metastatic androgen pathway modulation-naive or sensitive disease. So just really briefly, androgen pathway modulation just means that we are trying to turn off the gasoline, turning off the petrol for prostate cancer, which is testosterone. So we are trying to either block or inhibit testosterone, just like in breast cancer. The petrol for breast cancer is estrogens.
So on the left-hand side, we have got early metastatic disease, and that is typically smaller volume, and it is responsive to switching off the testosterone, turning off the gasoline. So it is responsive to androgen pathway modulation with androgen deprivation therapy or ARPI drugs. These patients are otherwise fit, so they are like any of us, gentlemen, going about their daily lives. So really, our objectives for this group on the left with early disease is to maximize their quality of life, and we want to delay their progression into the androgen pathway modulation resistance state, which is over on the right. And really what we are trying to do is prolong their overall survival beyond five, six, or seven years as best we can. Now, over on the right-hand side, this pictogram is a gentleman with later metastatic disease. Their tumor burden is now increased.
His disease has now become resistant to androgen pathway suppression, so it is just going on its merry way regardless of turning off the testosterone. And so really, our objectives for treatment for this group is to optimize the combinations of therapy that we have remaining, controlling their bulky disease, and prolonging the remaining two or three years of survival that they would expect to have while keeping their quality of life optimized. So this slide, so keeping in mind those two sort of distinct groups, and there is clearly a lot of gray in between, but this slide summarizes our portfolio approach to metastatic prostate cancer, utilizing what are two very distinct mechanisms of action that we have adapted to each of these disease states within that continuum of care.
So, it is the first-in-class radioantibody drug conjugate, TLX591-Tx, that is administered as two doses two weeks apart, which really enables it to be layered on top of a backbone of conventional ARPI or chemotherapy that a patient with metastatic APMR disease would typically receive. So, so far, the safety of this approach has been confirmed in part one of ProstACT Global, as well as having confirmed from an earlier trial known as ProstACT SELECT, a radiographic progression-free survival of about 8.8 months, which is sort of favorable or compares nicely with PLUVICTO when it was at the earlier stage of its development. Now, TLX597-Tx, on the other hand, is a next-generation small molecule.
It is a next generation on from Novartis's PLUVICTO, and it is designed to enable dose intensification and dose adaptation in patients with earlier disease to both delay progression to the APMR state while at the same time maximizing their quality of life. We have in the room Professor Emmett, who is, I would not say probably, she is clearly the leading researcher in the field with this small molecule and the approach of dose intensification and dose adaptation, and we will hear from Professor Emmett in just a moment. I will not go into this in too much detail, but as a brief recap on TLX591-Tx, this is a highly differentiated PSMA-targeted, what we call radioantibody drug conjugate.
It uses obviously a monoclonal antibody to target tumor-expressed PSMA with a very high specificity, that word keeps coming up, which really enables the precise delivery only to tumor-expressed PSMA of the radiation and not the normal tissues. What this approach really addresses is a number of key clinical needs, and those are across four axes. The first of those is, as I mentioned, the two-dose, two-week-apart dosing schedule that really lends itself to be layered on top of conventional backbone care. Secondly, there is a low radiation dose that is imparted to the normal tissues, particularly the salivary glands and the kidneys, and usually a transient and mainly self-limiting hematological impost on the patient. An antibody very nicely specifically binds, it then internalizes, and has a prolonged retention within the prostate cancer cell.
We will look at some of the imaging in just a moment in a couple of case studies I will show you. It clearly shows that there is a very long retention of the radiation on post-treatment imaging. Then finally, I think there are some real-world advantages from using a lower administered activity, but it is particularly the lower dose that is imparted to the normal tissues that you do not want to hit. This is ProstACT Global. Again, I will not go into too much detail like I did on LUTEON. This is very familiar, I think, to most in the audience. This is our phase III ProstACT Global trial and its current status. As you can see, part two, which is the conventional randomized treatment expansion in 490 patients, is currently rolling. I think it is in about 35, it might be up to 40 sites now in seven countries.
The study has also recently received the necessary regulatory approvals in China and Japan, and we have just very recently aligned with the US FDA to commence part two shortly at sites in the United States as well. That will really see the study accelerate in terms of its enrollment pace next year. I thought I would finish up before passing to Professor Emmett. I would like to just show you three of the patients that have been enrolled into part one of the study. Obviously, I could not show these patients if they are in part two, because that is the main efficacy part. But these illustrate a very clear view of the biodistribution and the prolonged tumor retention characteristics of TLX591-Tx. On the right-hand side, you can see in the post-treatment imaging, that the radiation is present well out to 15 days post-treatment.
So this first case is an 83-year-old patient with metastatic mAPMR disease, mostly in the chest. He was diagnosed, and this is how long patients live with prostate cancer. He originally diagnosed in 2012, and he would have seen somebody like Dr. Phil Dundee, a urologist. He had a total prostatectomy, and he was essentially cured for a number of years. But as we've discussed earlier in the day, he had a recurrence, so he started on enzalutamide in late 2023, but he progressed despite that ARPI drug in mid-2025. You can see his baseline gallium PSMA-PET scan. It identified metastatic disease in his, over on the left here, in his thoracic vertebrae, so in his spine, and also in some of his ribs. He came into the ProstACT Global study. He received TLX591-Tx, I think, in August 2025.
He did have some grade 4 thrombocytopenia, but that recovered, fully recovered back to grade 0. He went on to receive his first dose of docetaxel chemotherapy about 10 weeks after the TLX591-Tx was completed, and he had six cycles of chemo. This patient was without progression at his last visit at the data cutoff, which is about 340-odd days after he started treatment. He's done very well in part one of the trial. This second patient, I've just got two more, was in the abiraterone cohort. He got abiraterone in combination, so simultaneously with TLX 591-Tx. Again, the imaging on the right-hand side shows sustained tumor retention over about 15 days after his first fraction of TLX 591-Tx. This gent was diagnosed, I think, 2019. He was previously treated with androgen deprivation therapy.
He had his first ARPI drug, which was enzalutamide, in the first-line metastatic mAPMR setting. As typical, he progressed despite receiving that ARPI drug. The investigator looking after this patient determined that he should receive abiraterone as his second standard of care in combination with TLX 591-Tx. Again, you can see his baseline gallium PSMA-PET on the left here, which shows metastatic disease really in his chest and abdomen and in some of his pelvic lymph nodes, as you'd expect. This patient ultimately did progress on study, but he only did so after just under 340 days of stable disease. He derived clearly disease control benefit for a long period of time. I think this is my last one. I wanted to not be selective.
This is a final patient from part one who was treated with, he had enzalutamide, this patient. He was diagnosed with metastatic disease in 2017, nine years ago. While he previously received docetaxel in 2017 and darolutamide in 2022, ultimately, he had disease progression in 2025. Again, he came into ProstACT Global. He received two fractions of TLX591-Tx in July of last year, and he remained on study until the data cutoff date at day 337, and he was without progression. Progression was not recorded in this patient. He's also done very well in this cohort. For me, when I wrap up, I think the key messages from these cases are that there's clearly very durable retention of the TLX591-Tx drug candidate in the tumor compartment. As you can see clearly on the post-treatment imaging, that's beyond doubt.
And it appears, again, this is part one of the trial where safety was the end point, there appears to be prolonged disease control in this very advanced patient population. I will pause there, which I am sure you will be glad of, and I would like to pass to Professor Louise Emmett, and I will just say a couple of things here. Our final key opinion leader speaker, Professor Louise Emmett, is the Director of Theranostics and Nuclear Medicine at St Vincent's in Darlinghurst. She is a clinical researcher at the Garvan Institute of Medical Research. And I think Professor Emmett is one of the leading clinician researchers in prostate cancer imaging, and theranostics in the country. Her research has helped really build the evidence base for the use of PSMA-PET across the entire prostate cancer journey from whoa to go.
Professor Emmett's work, I think in the fields, as I said earlier, in the fields of dose intensification, which is pushing the doses together and giving more activity, and dose adaptation, which basically means treating when the disease is there and stopping treating when the disease has dissipated. They are definitely leading the world. And every time I meet with Louise, there is something new that I learn. It is probably not reciprocated, I am sure. I do not think today will be any different. So over to you, Louise. Thank you.
Just—
Yep, just click on it.
Okay.
Yeah. Okay.
Oh. Okay. So, it is really good to be able to introduce TLX597-Tx today and talk about some of the work that we have been doing in TLX597-Tx. So I am just going to go back to Yeah. Okay. So, TLX597-Tx, unlike TLX591-Tx, it is a small molecule peptide, so it is very similar to PLUVICTO with Novartis or ITM, which is also extensively used in Australia and elsewhere as well. Very rapid uptake into the cell, very rapid excretion. So, you get less dose to marrow, renally excreted, renally and also in bowel. It is a DOTA-HYNIC linker, and that means that it has got a bit of a different biodistribution to either PLUVICTO or ITM, which is to the advantage of TLX597-Tx. So, really nice to be working with this very nice small molecule peptide that targets PSMA in the prostate cancer cell.
So, I started with the OPTIMAL-PSMA trial, February, well, sort of probably not February, it was about June last year. And we started that with a safety lead-in. Did not have a lot of data on PSMA-597, wanted to have a look at what it looked like in a patient. And so we did a series of multi-time point dosimetry in the first dose of these patients receiving lutetium PSMA-597. We actually have now multi-time point dosimetry in about 45 patients, which is very good. Very nice dosimetry. And I am actually just going to go forward a slide because I think it is. Do we have the. No, we do not have the images. Okay. So, basically what we look for in the dosimetry with these small molecule peptides in prostate cancer is we want to see very, what we call non-target organ doses.
We want to see very low non-target organ doses, so we do not want to have a lot of salivary activity. We do not want to have a lot of renal activity. We do not want to have a lot of marrow activity. And they are each a little bit different depending on their chemistry. And what we have here is Telix, so the PSMA-597 compared to PLUVICTO, which is the one in the middle, compared to ITM. So the two ones that are used mostly. And I am just going to point out the kidney dose there. You can see 0.71, 0.58, 0.28. So significantly lower kidney dose. And I had a nice image which you can see, actually see this on the right. If you use ITM and if you use PSMA-617, you see the kidneys very clearly on the SPECT images that we get.
You are getting a significant proximal tubular binding that increases the radiation dose to the kidney, and that is a long-term problem. If you have very low kidney dose, that is a great thing. It means you can increase the number of doses you actually give, and you can also increase the dose of each dose that you give without being worried about long-term kidney dysfunction, because it is a long-term issue. Similarly, salivary gland is important. Patients get dry mouth with PLUVICTO, they get dry mouth with ITM. If you have low salivary gland activity and good washout from the salivary gland, patients get less symptoms from the treatment themselves. So, looks really nice, low kidney, low salivary gland activity. With the OPTIMAL-PSMA, OPTIMAL-PSMA is a trial in theranostics in prostate cancer with lutetium and with actinium.
People have done pretty standard cookie cutter, giving a dose every six weeks, and they have given a standard dose. It was based on some old external beam dose constraint estimations that were and had not really changed. This was a wonderful opportunity to take a low dose, a low salivary and renal dose small molecule and test it, essentially, to see if we can actually get better treatment responses in our patients. We have had good responses with lutetium PSMA, with the VISION trial and other trials in the past, but can we actually do better by getting deeper responses in our patients? We did the OPTIMAL-PSMA study, and what we actually did was instead of giving a dose every six weeks, we are giving three doses in the first two weeks. We started with standard dosing at 7.5 GBq, day one, day three, and day 15.
Then we increased that from 7.5 GBq, which is standard dosing, up to 8.5 GBq, looked at the toxicity of that, and then sat at the 8.5 GBq dosing. We are giving about 26 GBq in the first two weeks in these patients, and then we are just treating 10 weekly. It is a randomized trial, so half the patients are receiving this dose intensification, and then the other patients are receiving standard dosing. What we are doing is we are comparing depth of response between the two arms, with lutetium PSMA-597 given two different ways. Also looking at safety of the DOTA-HYNIC-597 itself, and comparing that to each other. We are looking at progression-free survival, we are looking at depth of response, and we are looking at safety. In this trial, it is 120 patients.
We actually completed enrollment in June, July, and now we are going to be reading out early next year with the findings. This is the randomized trial that we have been doing. We have dose intensification on one arm, we have standard dosing on the other arm. Both arms are using lutetium PSMA-597. Both arms are treating for 30 weeks. Both arms are getting six doses. Really, if we just concentrate on those doses, do we get increased depth of response? These are patients who are end-stage disease, so 70% of patients have already had chemotherapy. All of them have had hormonal treatment, have failed hormonal treatment. A lot of these patients have very high volume disease. A lot of the patients come from the country. We do not have a lot of access to lutetium PSMA in Australia, so this has been wonderful for patients.
Just looking at this is one of our patients, pretty classic actually for our patients. A very high PSA, extensive disease, post-chemotherapy, and you can see we are getting quite nice responses in these patients. This is up to week 10, but we have actually got all patients now up to week 20 to week 30, and we will be reading out long-term outcomes fairly soon. One of the things we have done on the trial is treating very high-volume patients. These are patients, this is a 58-year-old, post-docetaxel and cabazitaxel chemotherapy. This patient would not get onto a standard trial. Their disease volume is too high, and they are excluded. But in fact, with the concertina dose, they have done extremely well. That is the week 20 PSA. PSA was 487. Week 20, it is 1.9. We are actually at week 40 now, and it is at 0.3.
The other interesting thing is we had to transfuse this guy to get him onto trial with the lutetium PSMA-597 dose intensification, but his hemoglobin now is about 120. Platelets were heading right down. Platelets now are in the 300s. So, we have actually got his marrow back with dose intensification with lutetium PSMA-597. That is a massive win for that patient, because he does not have any other treatments left, but this gives him the option potentially of going on another trial, which he did not have the option of before. So, very well tolerated, very nice in high-volume disease. Interesting to see what the results are like when we read it out. So, OPTIMAL-PSMA was just a joy to run, 120 patients. Toxicity has been extremely low, very low marrow toxicity in these patients, even with dose intensification, and we will report that.
On the back of that, we have been doing the OPTIMAL-e study with TLX597-Tx as well. As David was talking about, was this idea of moving treatments earlier in disease spaces to get better responses. The PSMAddition trial is a large trial by Novartis that was done very early in prostate cancer, and they essentially dumped six doses of the Novartis PSMA-617 with an ARPI and ADT in men with early metastatic disease. So this is a more refined approach, seeing if we can do a dose intensification, serial PSMA-PET, and then backing off when they do not need any more treatment in this group of patients, who really have a number of years to live.
Can we use a very low toxicity agent with very few symptoms and get good disease control, back off, using PSMA-PET to identify when we start and stop treatment? So, we have done 18 patients now on this trial in early metastatic hormone-sensitive prostate cancer. These are patients who are within 35 days of being diagnosed and starting on ADT, so these patients are really, really new. They have got quite extensive metastatic disease, a lot of them. This is one of the patients. This is their screening PET, so newly diagnosed. They have got 78 mLs, extensive disease in lymph nodes and in bone. They start on their hormone treatment. We do a PSMA-PET baseline, and eight days after starting on their hormone treatment, we start lutetium PSMA-597. We give that day one. We give a second dose day three.
We wait six weeks, we give a third dose, and then at three months, we do a PSMA-PET. If the patient's got a 90% reduction in volume on their three-month PSMA-PET, and a PSA also 90% reduction, we stop treatment with the lutetium PSMA. We just continue with the ARPI and the ADT. The trial will run for four years, and the hope is that these patients, we can time the dosing of lutetium PSMA-597 such that they get exactly what they need, not more, and then we can use it when they need it again. Because one thing about metastatic prostate cancer is no one's really got around to curing it yet. What we're doing is we're stretching things for as long as we can. We keep as many treatments for as long as we can.
We treat them when they've got volume, we don't treat when they don't have volume. As David said, this is sort of this idea of adaptive dosing and personalizing treatment, so we can extend, actually extend survival doing that. That's one of the cases. We've got about six patients now who've got to the three-month mark, and we've got two out of the six who have a greater than 90% reduction. We've got two patients who are sitting at 87% reduction, so they're going to get another two doses. But super interesting trial. Very grateful that we can do it. I think we're going to be increasing that number to 45 patients.
There's no thinking about it. It's done. Consider it done.
Okay, 45 patients, so that's fantastic as well. Get a lot of information on the PSMA-PET and the TLX597-Tx. I think that's the last slide.
And we will now move to questions. David, would you like to join Louise?
Yep. Just on the off-target uptake, TLX597-Tx versus PLUVICTO, just your thoughts there. There is a slide earlier on saying three to seven doses, and you get 230 mCi. Can you talk a little bit about, does that fit in with your personalized treatment paradigm? Is that you being more flexible with what you can do? Just thinking about, is this TLX597 -Tx something you can just turn up and down as you kind of want, without having that off-target uptake? Is that the way to think about it?
I think two things. One, TLX597 -Tx versus PLUVICTO. What I really like about TLX597-Tx, it is low salivary gland activity, and it is low kidney activity. So if you are thinking of bringing things very early in prostate cancer, you do not want patients to get kidney dysfunction early, and we know that with PSMA-617 and ITM, you can get this progressive slow reduction in GFR. So if you want to give it to someone who is going to live for 10- 15 years, you want to give a low kidney dose. TLX597-Tx does that. Then if you want to. Lutetium, we do not get a huge amount of toxicity in the salivary glands, but if you add actinium, you definitely do. So if you want to move to an alpha, a low toxicity salivary gland dose is also super appealing. So it is clean.
The thing I like about TLX597-Tx, it is in, it is out, and it concentrates in the tumor really, really nicely on delayed images, but not elsewhere. So I think that is super good. Then in terms of the number of doses administered, with adaptive dosing, we are actually in TLX597-Tx. Sorry, in OPTIMAL-PSMA, we are using six doses in six doses. But because it has got a low kidney and low salivary gland activity, you can increase the number of doses without increasing your kidney toxicity. So we can give more. Giving more is more disease control, basically, in a lot of these patients. Then timing when you get it also looks super important. It is not something we have done in prostate cancer very well, or in any theranostics actually, but we need to mix that up.
If we show deeper responses with OPTIMAL-PSMA, even though we are giving the same number of doses over the same period of time, just by changing when we are giving it, then to me, that is a game-changer.
Professor Emmett, you showed a slide with a case study just now where your patient had a dip in hemoglobin at week 10 and subsequent recovery. Was that observed pattern of events something you expected given the patient's history, or is this something that we need to look out for in general?
No. We haven't had toxicity. That patient had a hemoglobin of 81 to come on trial. We transfused them to get them on trial. Their hemoglobin would have been 60, 50, 40. It was still 60 at 10 weeks, but it is not subsequently. We got marrow back. I am super happy with that. That patient is a little bit complex in terms of the marrow. When we get marked responses in prostate cancer, you get sclerosis in the bone, and it can actually take up marrow and hemoglobin goes down. That 10-week mark, what we in fact did in that patient was put him on high-dose steroids, and hemoglobin came up. The hemoglobin came up because we got rid of cancer. It is not a toxicity from TLX597-Tx.
It is a reflection of the fact that they were transfusion dependent, and at the week 10 mark, they were still transfusion dependent.
Hi, Professor Emmett. TLX597-Tx, you said you like it. It gets in and gets out. Is that the reason for the choice of peptide instead of antibody? Otherwise, what is the reason? I noticed also on the slides the kidney function improving. Is that just because of a declining disease burden?
Kidney function probably is just improving that patient. They may have had a bit of obstruction of the kidneys as a result. In prostate cancer, they often get bulky nodes that can compress the ureters, and kidney function just improves if you get rid of the cancer. I like small molecules, because I am a big fan of combinations. I think they are clean. I think the future of theranostics in the long term is going to be combining things. We need to go for annihilation and then control, right? We are quite good at annihilation, but we are not so good at long-term control, and that is going to be with very careful combinations.
David, one for you. The TLX591-Tx stuff, ProstACT Global, and the earlier trials, you showed those images, and it shows really good uptake, the endocytosis, I guess. Is there much of a range in terms of how much is uptaken between different patients? I know that study is ongoing, but in earlier studies, does that correlate with outcomes?
Yeah, Andrew, that is a great question. In part one of the study, ProstACT Global, safety and dosimetry were the primary endpoints. The dosimetry was multi-time point dosimetry. They were scanned 5x after the dose was injected, so that we could construct a curve of how much dose. Dose is, it is not the amount of radioactivity that is injected into the vein. The dose is the amount of radiation energy imparted to the tumor tissue, and that is measured in gray, not gigabecquerel. What that showed was that the imparted dose across the three different cohorts of abiraterone, enzalutamide, and chemotherapy was very consistent. Yeah. So very similar. I do not think we know why, but it is probably related to the very high specificity for tumor-expressed PSMA and the internalization.
Once it is internalized, it is sort of Trojan horsed into the cancer cell, and it is residualized or kept there. That is probably the pathophysiological mechanism for why it is consistent dose.
We have an online question, asking how you derived at the 8.5 GBq dose in OPTIMAL-e.
We started at 7.5 GBq in OPTIMAL-PSMA. We had an independent data safety monitoring board meeting looking at the toxicity and early efficacy of 7.5 GBq, went up to 8.5 GBq. 8.5 GBq, second data safety monitoring board meeting, independent experts who approved it as looking promising and very non-toxic, which I have to say we have found throughout the whole of OPTIMAL-PSMA. With OPTIMAL-e, what we did was we took the dosing from OPTIMAL-PSMA, and we put the 8.5 GBq into OPTIMAL-e and did a day one, day three, and then a week six.
Thank you. Any other?
Hi, Professor Emmett. Thank you so much for your time. Could you just add some more color on the dosimetry that you're seeing for the additional patients that you treated in terms of the organs at risk and the dose to the target lesions? Given it seems like you're able to deliver very high dosing gray per gigabecquerel, it feels as if almost it's suggesting that you're delivering systemic SBRT at this point. Is that the way it's going?
That's kind of the plan. You're much more of a believer in dosimetry than I am. I don't think it's particularly accurate when it comes to tumor doses delivered. But what we're trying to do with the day one, day three dosing, as you say, is increase gray delivered to the tumor, and we're trying to do it within a window. When you look at lutetium, what it does is it causes double-stranded DNA breaks, and then they get repaired by the cancer cell, sometimes very, very quickly. The timeframe in which lutetium is known to cause double-strand DNA breaks within which it gets repaired is about 96 hours. We know that after 96 hours, basically everything's repaired by the cancer cell that's going to be repaired.
What you want to do is you want to kind of double down within that window, that vulnerability window, and double hit. The day one, day three is a double hit. The idea around that is that you're going to increase the gray or the, I would say, biologic effective dose, not gray. It's not gray. Biologic effective dose of the radiation dose that you're delivering. I think we definitely see that in OPTIMAL-PSMA. I think it's really exciting. The other exciting thing about doubling down on dose within a couple of days, and using a fractionated dose is we see a marked reduction in salivary gland activity at day three. I got a little bit thrown because I had that slide in there and then couldn't talk to it. But what we're doing is we're increasing activity within the tumor.
We're reducing activity in the non-target organs, so that we're treating within the vulnerability window, but actually increasing our therapeutic index as well.
Thank you.
Any other questions? All right. Maybe we will move on then. Thank you.
[Oh, sorry. Just go back one slide.]
Oh, back?
[You will finish off prostate cancer section.]
Oh, it is back here. Yeah, sorry. Okay, look, this room has been very patient with me. I mean, there is commerce degrees, there is masters of finance, and there is MBAs, and you have listened to this whole swath of science, and you have done it with a smile on your face. I am very grateful to you. I am going to hand to somebody who is a lot more familiar to you in a minute, a CFO, and that will make you a lot more comfortable. But before I do that, I got one last slide, and this really expresses the philosophy that I think we have, Chris, which is that our objective is to care for men across the entire prostate cancer continuum.
Dr. Emmett has articulated, I think, beautifully, the opportunities we have with TLX597-Tx to aggressively treat, but right up to a point and not over-treat. So that is dose intensification and dose adaptation in those patients with early metastatic disease. I have talked about why TLX591 -Tx clearly fits in the portfolio because of its two-dose, two-week-apart schedule that allows it to be intercalated with the sequencing of other backbone systemic treatments like ARPI drugs. I think it is fair to say that all men with metastatic prostate cancer, despite having access to radioligand therapy in wealthy countries like Australia or the U.S., will ultimately progress, so they need something after that, and that is where we believe that alpha therapies will be showing promise.
And that dotted line down the bottom shows that once alpha therapies, we believe, have proved themselves in men that have progressed despite earlier beta therapies like lutetium, there is certainly the potential to bring alphas into the frontline setting in early metastatic disease. But it needs to prove its safety in that late-line setting first. And then in the pre-palliative setting, men and other patients with cancers that go to the bones, like breast cancer does, bone pain is a condition that is really difficult to treat. And so we feel that the TLX090-Tx asset, which is a samarium-153 asset, is going to be critically important for bone pain palliation. So I will leave it there, and we have done Q&A. I have the great pleasure in passing to my esteemed colleague, Darren Smith, Group CFO. Sir, there you are.
Thank you very much, David. And as they say, now for something completely different. Maybe a too old a reference for this group. Okay. So, Telix's goal is pretty simple. It is to create long-term value for our people, our patients, and our shareholders. And our financial model is built to deliver that goal. We have been clear about the objective of optimizing our commercial engine, our precision medicine business, to generate capital that we then reinvest back into our theranostic pipeline and supply chain infrastructure. We do this sustainably, funding our growth largely from our own operations, and we do this with discipline. The key metrics that we have here at the top of the slide show that Telix continues to deliver against its stated financial targets and objectives.
The group is on track to deliver the top end of its guidance, and over the past year, we have steadily improved our gross margin for the precision medicine business to 65%. This disciplined performance gives Telix strategic optionality so that we can choose to invest in our development portfolio and supply chain infrastructure while minimizing the need to raise capital for our shareholders. And this is a clear point of differentiation from most of our biotech peers. Moving to the next slide. In our commercial performance, this chart clearly shows Telix's ability to execute. We have built a commercial business that has consistently outperformed its competitor, despite being second to market. In 2026, three initiatives have driven that growth. Firstly, product cycle management, with the launch of GOZELLIX in the late of 2025.
Secondly, the strong service focus of our RLS team, which have moved from being the fourth-largest distributor of the Telix product to now be the second-largest, all the while still maintaining its revenue from its third-party sales. And finally, geographic expansion, which includes the establishment of the commercial business at EMEA. Telix's commercial business is the engine of our financial model. Every dollar that we expand in our revenue increases our capacity to be able to invest back into the next wave of our products. Chris has spoken about our near-term and long-term growth opportunities earlier in the presentation, and we will shortly highlight Telix's 2027 opportunities and catalysts, which we are all very excited about. I will now turn to capital allocation and how we do this sustainably. There we go. As our business grows, we will continue to focus on maintaining the disciplined approach to our capital allocation.
Our capital allocation is focused across four main areas. The first is our commercial investments. We are investing into our commercial platforms to drive revenue growth and improve the economics of the business. Second is R&D. Across our therapeutic and precision medicine pipeline, we allocate capital with the same discipline. Investment is staged and flexible. We prioritize R&D by assessing each program against our strategic fit, degree of unmet need and competitive landscape, time to develop and the proximity to commercialization, potential for return on investment, and the probability of success. Third is our investment into our supply and production capabilities. When your product is quite literally the melting ice cube, the importance of supply chain execution cannot be overstated. That is why we have built a platform that gives us greater control of our critical components of supply chain, reducing the risk of execution.
Secondly, we secure scarce resources and capacity to rapidly grow the market so that we are ready to launch each product when it comes to commercialization. Finally, it improves profitability as we gain scale. Together, these build a durable competitive moat. The fourth part of our capital allocation, and we would be remiss not to mention it, is strategic M&A. Telix has a proven track record in identifying strategic opportunities, capabilities, and assets, and successfully bringing them in-house to strengthen our three pillars of growth. We remain open to strategic and very selective M&A, which strengthens our pipeline, lifecycle management, and/or our clinical supply chain capabilities. I will now turn to our R&D and drill into this. As the chart on the left shows, we have a disciplined approach to our R&D investment, managing as a percentage of revenue to ensure that our investment is sustainable.
More importantly, the charts on the right show our investment in R&D as a percentage of sales is estimated at 26%, well below therapeutic-focused companies with an average of 35%. Our investment has been highly productive, with three products now approved by the FDA, and three more are near-term on the horizon, which will continue to fuel our top-line growth, with more to come. In 2026, the majority of our investment in R&D has been directed to our therapeutic assets. This reflects the progress of our phase III ProstACT Global study, the development of TLX597-Tx, and the commencement of our phase III brain and renal cancer therapy trials. Once approved, the economics of our therapeutic products are expected to lift margins and to be a significant growth driver. This is the next stage of Telix's transformation. Now turning to ITM.
Earlier, Chris explained why ITM makes strategic sense for Telix, but I am sure you are asking, why does ITM make financial sense? First, ITM's business has an attractive growth profile. The value of the manufacturing business is underwritten by the long-term contract to supply commercial volumes of lutetium-177, and it is expected to grow at an 18% CAGR over the next five years. That contract runs into the 2030s. Beyond this, approximately 41 assets in development use lutetium-177. This includes four of our own, which are in late-stage development. Further, ITM can produce multiple clinical isotopes and creating future revenue opportunities. As a scaled business, growing volumes will further improve its current 40% margins. In short, this is a growing business that adds significant strategic value to securing our therapeutics supply chain. Second, ITM offers Telix near-term therapeutic opportunity that improves overall margins.
Finally, we expect to achieve approximately $50 million in synergies across the combined business within the first two years, ensuring that it will be an accretive acquisition. Before I hand it over to Chris for some final remarks, I will ask if there is any questions.
If you have any questions, please.
Thanks. David Low from UBS. Darren, just on the growth that you were mentioning there, could you just sort of run through that again? You talked about the CAGR into the future, and I was just wondering if you could sort of give us a little bit more detail how you are getting to that, please.
Yeah. I think Chris presented that CAGR earlier on, in an earlier on slide, where we showed that the potential $300 million raising to about, I think it was what, $2.1 billion for the lutetium asset, given that there is close on 41 assets in development. The current assets in development, our four assets that we will bring to market, TLX591-Tx, TLX597-Tx, TLX250-Tx, and obviously ITM-11. Then the potential of those other 37 assets that are under development and what they will bring to market. Further to that, there is also the opportunity we showed with actinium, and again, there was an opportunity there of up to $1.4 billion by 2035 or 2034.
All right. Let's ask Chris to give some final prepared remarks before we head to lunch. Thank you so much, Darren.
Well, thanks, everyone. I think you've battled well through the morning. I hope it was instructive and interesting. I'd like to echo David's thanks to our esteemed colleagues for coming in and giving you a bit of extra clinical perspective. I think that the data's exciting. There's lots of depth in our pipeline, and the investment that we're making into the therapeutic drugs is, well, it's not loved by everybody, but that's the mission of the company. That's it, simply, is to generate the revenue and the earnings to be able to build a pipeline for which the future revenue and earnings will exceed our R&D requirements.
Now, in this year and in next year, and particularly with the addition of ITM, we are going to continue along that throw the kitchen sink mentality at the business, because that's how you build a winning company in the current climate that we're a part of. It's a hugely competitive space, and the wheat from the chaff is going to separate very quickly over the next two years, and we think that that investment is really critical. In 2028, we expect to transition more to an earnings growth story, and that will attract a different cadre of investors, maybe a broader swath of investors. But today, it's really about delivering as a sustainable, self-powered biopharma company that, as Darren said, doesn't need to constantly dilute its shareholders just to do basic R&D. That's not what we think is the right format to engage with shareholders.
We've built an amazing company. As I said, $1 billion of revenue doesn't happen accidentally. It's a huge lift to have gotten here. We have three approved products. By this time next year, we'll have six approved products. So, you're going to see a step change, really, in the capability and the output of the company. These three pillars of building a commercial team, which we see as an asset, not an SG&A, a late-stage pipeline, which has no peer in the industry, and a manufacturing and supply chain that guarantees that we can get those products to market when the clinical data warrants it, I think it really defines and differentiates who the company is and how it stacks up against the competition in this space. I've called the ITM merger building a global radiopharma powerhouse. It's not the first transaction we've ever done.
I think we've demonstrated to investors that we can integrate companies and build value from the combined entities, and also nurture the talent that we bring in from other organizations. I am as excited about the people and the capabilities that come from that transaction as I am the financial trajectory and the patients that we can serve. Again, it's a race for talent, and I think that the ITM transaction really brings some amazing people that are just as excited about joining Telix as we are having them on board. Clearly, these little steps are not quantitative, so I just want to clarify. If we were to do it to scale, it would be a ridiculous-looking slide because everything on the left-hand side would get squashed down and you wouldn't be able to read any of it.
The point of it is that to some number, which will be given as guidance in the new year when our sales are out and we give you our forecast for 2027, there's a huge amount coming in behind. PIXCLARA, underappreciated asset. GOZELLIX will continue to grow. We are startlingly close to half of our business being GOZELLIX. It's been an amazingly successful lifecycle management with a big impact on ASP. BiPASS is going to potentially triple the volume of patients that we service, and it has a distinct market access strategy which allows us to control much more carefully the dissemination of that product. We will, of course, continue to expand our franchises globally. We genuinely aspire to make our products available globally. Then, of course, adding in the consequence of the ITM revenue, it's about a $300 million business.
You can see that we are, without too much mental gymnastics, tracking to $1.5 billion in revenue next year, AUD 2 billion, as a therapeutics company with a fully integrated supply chain behind it. So, it's an immensely underappreciated company in terms of what it's doing for patients and what its future trajectory is. But I think that maps it out really nicely. Then we're excited about the readouts that are coming. We have a huge amount of clinical data that's going to read out over the next 12 months. So, as you've seen from some of the data that's already coming out, there's really compelling evidence that the pipeline that we're developing is meaningful. So yeah, very exciting. With that, I'll conclude, and thank you for your time today.
I'm happy to take any wrap-up questions, or I feel like I've mistargeted questions so far. So if anybody's got a question that they'd like to throw at the Chief Executive, I'm happy to play. Of course, Andrew.
Thanks, Chris. Just the regulatory, I guess, delay or changes or whatever with Zircaix, and specifically, how has that impacted your thinking, if it has, on biologics more generally in the pipeline and the portfolio?
Well, I think the process that we've undertaken with the FDA has been very clarifying and has resulted in some very bright-line discussions that impact really the whole pipeline and the way we move forward. Biologics, from small formats to antibodies, have a huge amount of potential in radiopharma, just as they do in other areas of oncology, but it's a relatively novel area. I always listen to what KOLs say, and I do note Louise's comment about small molecules, and there are camps of people in nuclear medicine that think one is better than the other. The truth is, most academics can't develop biologics because they're too expensive, and that's the reason why historically they haven't been popular. To deliver things like actinium, lead-212, we are going to need to develop things that have really different pharmacology. That's why we did the TLX597-Tx program.
The actual question behind TLX597-Tx was, could we develop a small molecule that was the moral equivalent of TLX591-Tx so that investigators like Louise, who have a predisposition towards small molecules, I'll call it a predisposition rather than a bias, because bias is unkind. We should be able to have an open mind about what is the targeting agent. I'm not going to lie, chemistry can be easier sometimes, not always, mind you, but sometimes can be easier than a biologic. But biologics are also exquisitely tunable. It's a lot harder to make a small molecule do exactly what you want it to do. Because we're targeting agent agnostic, and we have the capabilities of doing all of those things, we should investigate the full gamut. But from a regulatory perspective, there's much less experience with biologics, and so it's been a steeper learning curve.
But I think that the Zircaix, notwithstanding the delays that we've had, I think it's been a very positive experience for the company, and I think that there's strategic knowledge that comes out of that that places us really far ahead. I think the best example of that is some of the pharma partnerships that we have, where we were able to build meaningful relationships precisely because of that experience. Not hypothetical experience, not one day, when our phase I program grows up and becomes a commercial stage asset, we might understand what a regulator thinks. We've had to, and of course, you, by consequence, have had to endure a bit of a journey on that one. But it's a journey that's well worth undertaking.
Despite the vertically integrated manufacturing model, I presume that the biologic targeting agent would. Sorry, although you are vertically integrated, I presume that a biologic targeting agent would continue to be manufactured externally.
We outsource, so we heavily rely on CDMOs, like all pharmaceutical companies do. I shouldn't be so definitive and give myself some wiggle room, but I think on this one, we can agree that we are not really in the business of making APIs. We are not really in the business of developing the basic pharmaceutical substrates. What we care about is that just-in-time manufacturing part at the end. It is not actually. If you take Zircaix, all right, the CMC package, let's visualize it as this big, okay? This much of it is the API, all right? But strategically, and from a customer perspective, the absolutely mission-critical part is that skim on the top, and that is what I think we have the appetite to fully control, whether it is in-house or with a mixture of in-house and really carefully selected partners.
For example, in the United States, we couldn't envisage a scenario where we wouldn't work with Cardinal Health. They are market leader, right? It is about having a comprehensive product offering for your customer base. The dynamics of selling in nuclear medicine is not about selling an individual product. It is a portfolio sell. Even the competitive landscape is a portfolio sell. You have to slightly disintermediate the commercial channels from the manufacturing and supply chain. What I would like to get to is the point where, from a risk management, from a quality perspective, from a patient access perspective, that we sort of share the load with carefully chosen partners. Of course, our relationships become more and more symbiotic with some of these distribution partners because we are also providing isotopes. It is not accidental, it is deliberate.
It is about making sure that we are part of that quality control and part of that value chain, right? That is a big shift for nuclear medicine. It has historically been, there is the underbelly of the industry that provides isotopes, and then there is another layer that provides distribution. Actually, historically, nuclear medicine companies never actually had responsibility for delivering products to a customer. They have been quite disintermediated from that. We see the importance of changing that as you have multiple products and you want to maintain decent product margins and decent pricing dynamics.
Thanks. You said at the start of the day that the strategy for how to win and compete in this space has changed drastically in the last five years. What are the biggest differences between what was required for success five years ago versus what's required for success today?
Well, first of all, other than Novartis, we haven't had any therapeutics come to market, so it's really about opening up a supply chain that is multi-product and multi-source, right? Because you got to have redundancy. There's a little bit chicken and egg. Part of the reason why we haven't had a lot of therapeutic nuclear medicine before now is because we haven't had the isotopes to then run the large multi-center clinical trials that are pretty accessible and have reproducible data, and that in turn then creates the momentum to be able to reinvest. So it's this kind of vicious cycle, and we're now truly in that cycle where if you've got a compelling late-stage pipeline, which we do, you're going to have to make a decision.
Either you're going to own the infrastructure and control your margins and your pricing structure, or you're going to hand that responsibility over to somebody else. I can tell you that latter decision is not for the faint-hearted, right? It's super expensive because all of those assets are trying to utilize the same path to market, and there's a lot of competition to get there. We really look at the space competitively, and we want to be the partner of choice for those earlier stage assets to look for a route to market. That's not a small biopharma model. The small biopharma model is- I'm going to develop two, three things. If one of them looks good, I might get snaffled up, right? Ideally, you're going to then go to a Cardinal Health and say, "Here you go.
Take 35%- 40% of my revenue, you look after my product. You do the sales and you do the marketing. But then you have no relationship with your customer, that doesn't lead itself to building a product portfolio with clinical strengths and clinical concentration, which is what we want. We have, in our strategy, decided that urologic oncology, neuro-oncology, certain areas of musculoskeletal disease, now potentially, let's call it thoracic, which means lung, these are some of the opportunities that radiopharma has to make a difference. We want to build concentration in those disease areas, we have to have then really meaningful commercial and clinical relationships with the key thought leaders in that space. You can't do that if you disintermediate yourself from the responsibility of delivering a product, right?
The other thing is we get I had to take a call, so I didn't hear all of Darren's presentation, but we get a lot of operating leverage as we build. If you have one product and one supply chain and one commercial team, then it all appears in the P&L of that product. But as we start to move now towards, as I said, by this time next year, we expect to have, subject to FDA approvals, six approved products, right? The operating leverage that we get on the commercial team starts to really play a profound role. That isotope supply chain cost now starts to get amortized across multiple product portfolios, that's when you really have a competitive advantage in terms of also your pricing modality, right? I think it's a very compelling approach. You can't just wake up one day.
We have literally just got our first four GMP licenses for Seneffe, right, in Europe for lutetium products. We started that project in 2020. It hasn't been a slow burn. It's been a full force, full investment, not drip feed, like big chunks of money put down every year. There are now 70 people working at that site, manufacturing drug product for clinical and commercial use. You can't wake up one day and just decide, "Oh, I'm going to make sure that my product has access." You've got to build infrastructure that takes years to install and get regulated. So yeah, it's a big lift. In some cases, we've bought the infrastructure. In some cases, we've built the infrastructure on an ongoing basis.
We will probably invest around $100 million a year in continuing to build and grow that infrastructure, putting in cyclotrons, putting in irradiation capabilities. But we've got an amazing baseline. I can tell you that there's no other company in the radiopharma space that comes vaguely close to the infrastructure that we have. Whether it's our pipeline or third-party pipeline that's attracted to that verticality of market channel that we have, I'm sure that infrastructure is going to get very well used. Yeah.
Yeah. Chris, just the Regeneron deal was pre-ITM. My question is there any additional benefits coming through as part of that that might help going forward? And equally, with the vertical integration, do you think those types of partnerships agreements are an opportunity going forward?
Definitely. We do have access to a commercial actinium supply chain through a couple of partnerships. But if we start to make a commitment to a pipeline around actinium rather than just early R&D proof of concepts, you got to have more than just the ability to buy the odd clinical dose of actinium. You got to have it on a regular basis. The Regeneron transaction is mostly focused on alpha or intended to focus on alpha. Being able to supply actinium, lead-212, and astatine. In fact, at our Trevose site just outside of Philadelphia, we actually have a facility that's dedicated to kind of alpha. This facility will process targets from Canada, from the ITM Actineer joint venture. It will produce astatine on site, and it will house one of our larger lead-212 generators.
The idea is that that's an innovation and clinical trial facilitation hub that can feed right into the can go as far up as Boston and New York, or as far south as Research Triangle. So you're covering that huge swath of East Coast clinical trial environment, which is just critical to running a decent clinical trial in the United States. Collaborations like Regeneron, which is, by the way, it's not the only collaboration that we have. It's just a public domain one. That is a great facilitator. Those assets that are being developed with Regeneron, some of them are moving at a very fast pace towards the clinic. So that supply chain needs to be ready. Anybody else have a question?
If no other questions, we'll thank Chris, and we'll thank everybody for joining us today. We have very important information that's coming from Charlene around lunch.
And that ends our webcast today. Thank you.
Yeah, thank you very much, everyone, for joining us, and much appreciated to those that attended online as well. Thank you.