Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Good morning, good evening or afternoon, depending on where in the world you are. My name is Ky Williamson. I'm SVP of Investor Relations and Corporate Communication at Telix. Very pleased to welcome you all today to our webinar with some key opinion leaders and special subject matter experts to discuss a physician's perspective on innovations in PSMA PET CT imaging for prostate cancer. Today's format will be a moderated panel discussion hosted by Dr. David Cade, MD, Chief Medical Officer -- Group Chief Medical Officer at Telix. I'm very pleased to welcome our speakers. We are joined by Rodney Hicks, Professor of Medicine at the University of Melbourne and Monash University, Founder and Executive Chairman and Chief Medical Officer at the Melbourne Theranostic Innovation Center. and by Dr. Paul Yonover, Chief Data Officer and Director of Clinical Navigation at UroPartners, a division of The Specialty Alliance, Chief of Urology at Ascension Saint Joseph Hospital from Chicago. Thank you for joining us. And last but not least, Darren Patti, the Telix Group Chief Operating Officer. Today's format will be a moderated panel discussion, as I said. [Operator Instructions] If we can't answer your question during the session, we'll follow up after the call if necessary. With that, I would like to hand over to David Cade.

Thank you, Ky, for the very gracious introduction and very excited to be here today to discuss what I think is a critically important topic, which is the future of prostate cancer imaging. We are joined by 2 of the global leaders in the field, Professor Rod Hicks, who is an esteemed nuclear medicine physician and Dr. Paul Yonover, who is a leading surgical urologist based in Chicago. We're going to cover 3 very important themes today, namely the current clinical landscape of how we image prostate cancer. We're going to also cover the supply chain, which is an important consideration, as we aim to serve patients across geographic expanses. And I think most excitingly, we're going to address a key question, which is what are our needs for the future. We've made some very significant advances in the last 5 years, but where will we go over the next 5- to 10-year period. So to kick things off, I'm going to ask Professor Hicks. Professor Hicks, you installed the first PET/CT camera in this country in Australia and one of the first in the world at the Peter MacCallum Cancer Center in 2001. It's almost a quarter of a century ago. And then you commenced our specialized PSMA PET imaging and therapeutics, which is what we call today theranostics at Peter Mac around 2015. So that's over a decade ago. So could I start by asking you to provide an overview of PSMA PET imaging and some of the key data that supports Gallium PSMA PET and how Gallium PSMA PET has changed the way we manage men with prostate cancer. So what really matters to physicians today.

I think we've seen over the last decade, David, a really strong clinical support for the use of PSMA imaging in the urology community at 4 different stages of the process of diagnosis and therapeutic planning. In the diagnostic setting, although MRI has a pivotal role in localizing prostate pathology, it's a technology that is firstly very difficult to read. The MR radiologists, who are good at prostate, they are, in my mind, the idiots of the [indiscernible] imaging world to bring together an incredibly complex set of images to make a diagnosis. And they use a scoring system called PI-RADS, the prostate imaging radiology diagnostic score, which I sometimes tongue-in-cheek renamed the poorly informative, really accurate diagnostic score because it's really very observer dependent. Men hate prostate MRI. I can tell you that, and there are many who can't have it. And in that setting, PSMA has a very high acceptance by the patients. It's got a very good sensitivity for the detection of disease. And it also moves on to the next phase when you've already made the diagnosis of prostate cancer on clinical grounds and biopsy. it's excellent for staging the disease. It has a high true positive rate, high diagnostic performance with diagnostic micro metastases down to very small levels. And that becomes particularly important in the next phase, which is in the biochemical recurrence after definitive treatment, the PSA hasn't gone away. We know they have disease. We have a very sensitive and specific biomarker for the presence of residual disease and that biochemical recurrence, we can see disease down to very small levels with PSMA PET scanning. The next level is after patients have developed metastatic disease, determining their therapeutic pathway and particularly selection for radioligand therapy theranostics, the pathway of -- if you can see it, you can treat it and high PSMA expression is [indiscernible] for selection of those patients. And the last phase, and this is something that's just coming along and recently been incorporated into the prostate working group for assessment of response to therapies is the use of PSMA for monitoring therapeutic response. The principle, if you can't see it, you can't measure it, you can't monitor it. And at all stages, we've been able to show that PSMA outperforms CT bone scan. So why would you use a technique that can't see the disease in the first place to monitor that disease. So it's really having a fundamental role at all stages of the evolution of the prostate cancer spectrum.

Thank you, Dr. Hicks. Now if we go to the next slide, please. Dr. Hicks, this is the most recent Phase III study. So it's a Phase III study of Gallium PSMA PET. In fact, this was in a Chinese population that's a pivotal registration trial intended to see Illuccix approved in China. That's in 140 patients. And really, this is a very positive Phase III trial. The results came out recently a couple of months back. And really, the headline results was that it showed that there's a very high positive predictive value of gallium PSMA PET across high to very low PSA strata. And it also showed very high positive predictive value across different anatomical locations of disease in Chinese men. So did these results surprise you? Or are they otherwise what you would expect?

Yes. They don't surprise me at all. I think we've got now a very large body of data from around the world with a whole variety of different quality of imaging technology that have shown very high positive predictive values and pathologically validated studies as well, demonstrating a high positive predictive value. The area, I guess, that we're seeing the greatest impact, however, is actually below in those very low PSA levels, where traditionally people haven't been doing it. The whole point of doing PSA after biochemical failure is to identify a subgroup of patients, who are potentially salvageable by local regional therapies. And so we've seen our population, referral mix move increasingly to below PSAs of 0.2. And in that population, we see, firstly, with the protocols and the technology that we use a very high detection rate of disease, but more importantly, a much lower rate of disease outside the prostate bed that could never have been controlled by local regional therapies, which often applied now empirically in that low PSA level.

Thanks, Dr. Hicks. If we go to the next slide, really leads me on to a technology question. Dr. Hicks, you were -- you've installed, I think, one of the first Siemens Quadra whole body PET/CT cameras in Australia at the Melbourne Theranostics Innovation Center, which you established a number of years ago. I think a fundamental question, this is a truly fundamental question is where will the next major innovation come from in the way we image men with prostate cancer? Do you think it's better tracer drugs? Or do you think it's the evolution of the capital equipment, the cameras? What's your perspective on this?

I think it's a bit of both, David. The performance of PSMA has been excellent with what I would consider last century technology in many ways that people were using analog, sometimes time-of-flight, sometimes non-time-of-flight cameras, which have rather low sensitivity for the detection of disease. The advantage of the Quadra having a field of view of over a meter and very high time-of-flight resolution and very sensitive digital detectors is that it's about tenfold higher than the best digital camera that Siemens themselves make, which itself is about twice as sensitive as most non-digital time-of-flight cameras, which are themselves twice as sensitive as analog cameras without time-of-flight. And so you're getting somewhere between 10 and 40-fold higher sensitivity. And that makes a big difference in terms of the signal to noise, which is particularly important to detecting small volume disease. So this is a patient who was planned for salvage pelvic radiotherapy on the basis of an elevated PSA of around 0.4 thought to have perhaps a false positive in the rib. We do see some false positive uptake in rib lesions and with any of the PSMA agents more with some than others. But this patient was still going to have an attempt at cure or at least delay of need for systemic therapy by pelvic radiotherapy. And they came to us for some therapeutic radiotherapy planning and had PET imaging on the Quadra. The image on the left in red, it was the conventional scan done outside our facility, a 32-minute scan on a standard field of view digital camera. And the images on the right are the same acquisition, but then passed into shorter and shorter aliquots of the acquisition time. Our standard acquisition is 4 minutes for that partial body, but we've processed it down to just 30 seconds of that acquisition. And you can see that what was perceived to be local retinal disease clearly isn't. There's widespread disease. This patient never would have benefited from pelvic radiotherapy. But more importantly, around the pelvis, we can see with late diuretic imaging, post-diuretic imaging, there's almost no or very low activity in the bladder, but there's no evidence of recurrence in the prostate bed. All of the toxicity from radiotherapy comes from irradiating the prostate bed. And in this patient, not only was it not necessary, but because there was disease outside the pelvis, there was no potential long-term progression-free or overall survival benefit in this particular patient. So huge impact on patients. So that idea of the reasons we don't see disease, 3 reasons: too small, too close, too close to the bladder, too close to the major blood vessels, waiting longer, imaging later allows clearance of blood pool, and you can see very small nodes close to the blood vessels or too little expression of the target. Technology helps with too small, the Quadra and other extended field of view digital PET scanners are going to make a big difference and AI processing of those data are going to make a further jump in the improvement in the sensitivity. To close, it's about technique, imaging before the urine gets in the bladder dynamically, which we routinely do in our biochemical recurrence or imaging late post diuretic. And again, more sensitive scanners allow you to go longer into the decay scheme and still have high statistical quality scans. The last question is too little target, you need different tracers, new PSMA tracers aren't going to make a big difference if the target isn't expressed anyway.

Maybe just while we're on that topic, you could touch upon the loss of the PSMA target from a prostate cancer and what other tracers might be required to hit other alternative targets that are manifest on a prostate cancer cell.

There's sort of 2 different scenarios wherein PSMA is not expressed. The most important one is where the disease becomes highly differentiated and disorganized and loses the basement membrane, where PSMA is expressed. And that's Pattern 4 -- sorry, Pattern 5 Gleason score. And so that gets into the very high isotope grade group, so particularly grade group 5, where either 4 plus 5 or 5 plus 4 or 5 plus 5, depending on the proportion of that classification of 5, which often lacks PSMA you'll get very low uptake. 4 has high generally PSMA expression. 5 has -- can have none. And if there's a high proportion of Patent 5 disease, those cases can be relatively negative on -- in terms of expression on staining. And so those patients, they're genuine card-carrying cancers that use glucose and FDG PET has been shown to be very, very useful and an adverse prognostic indicator. I actually believe they're the subgroup of patients, who benefit most from chemotherapy. So if you've got one of those very high Gleason score in a negative PSMA, I think it's really important to do an FDG scan in those. At the other end of the spectrum, as you get into clinically significant prostate cancer that transition from 4 -- sorry, from Gleason 6 to 7, for example, some of them have relatively low PSMA expression, particularly if the percentage of Pattern 4 is relatively low. And that may have prognostic significance, but there are other targets that are overexpressed in that group and particularly GRPR sensitive, which is the gastrin-releasing peptide receptor. And I think there's some exciting work going on in that area of new tracers that may have both diagnostic and therapeutic applicability in terms of target. But there are other targets that people are obviously looking at both stromal as well as epithelial that may be important.

Yes. Thanks, Dr. Hicks. I mean it's evident that you're operating at the bleeding edge of technology and camera equipment and that's really manifest itself in the success of your theranostics practice in Melbourne. I'd like to now transition to the surgical perspective. Dr. Yonover, you're a very busy surgical urologist at the largest private urology practice group in the world based there in Chicago. So we've gone from Melbourne to Chicago just now. You're also effectively a business owner in which your practice currently has 4 PET/CT scanners. And I believe you're investing very heavily with your partners in more cameras. Your practice group currently sees and images over 1,000 patients a year in providing a PET/CT scan and you treat those patients under your own care. So how has PSMA PET imaging changed your practice? And what's important to you in your U.S. high-volume practice setting?

Sure. And thank you very much for having me. It's a pleasure and certainly an honor to be with somebody like Professor Hicks. So thank you, Dr. Cade. Yes. So I represent, I think, a growing sort of segment of the U.S. health care system. I'm in a private practice, essentially single specialty group. We're now fairly massive. We're national. So those scanners that we're putting up are in towns like Detroit, Michigan, Philadelphia, Chicago, New York, et cetera. I think by 2026, we should have 13 or 14 scanners up. And that's with the idea that a large group like us in the United States is sort of a closed ecosystem, at least that's what we aim to be. And that -- and PSMA PET molecular imaging really plays a sort of an integral role of that because we're part of the gatekeeping. We're the ones who screen for prostate cancer. We diagnose the patients. We have our own pathology lab. We have our own in-office dispensary because we deliver those therapeutics. We also have our own linear accelerators. So we deliver the radiotherapy, brachytherapy, we do theranostics. So we really try -- we've attempted to have a relatively closed ecosystem, where we're really going from cradle to grave, if you would. And molecular imaging has had a massive -- I mean, it's hard to overstate from a clinical perspective from prostate cancer as a clinician, the impact it's had just in the last 4 or 5 years when it's really come to fore here in the United States and how it's been disruptive in a good way, right? Right now, we're seeing it in the -- of course, in the diagnostics space, in the therapeutic space and of course, in the advanced prostate cancer space, what we're looking towards, what we are hoping for is expanded indication, getting a lot more clinical data and an expanded indication so we can bring molecular imaging, Gallium PSMA PET into the pre-diagnostic space in the screening space, in the active surveillance space and the focal therapy space. And of course, as Dr. Professor Hicks alluded to, response to therapy, right? When a patient goes for radiation therapy, all we have really is following serial PSAs, conventional imaging doesn't do much and having some assessment of response will be sort of key. But your question was how is it impacting us as a business owner, right? Because it's impacting me as a clinician, how do I approach my patients, the confidence I have in being able to truly understand do they have localized disease? Do they have locally advanced or metastatic -- cold metastatic disease? What's the volume of their disease, PSA as a biomarker, we could have hours of conversation just about that. But the impact on a -- such a large group as ours, the operational economic impact, right, profound, right? It's actually becoming integral to our business planning. And because having access to our own scanning lets us control things, which is a good thing most of the time. quality control, we can stay ahead of things as far as technology, and we can, of course, leverage this from an economic perspective. But as a large group here in the United States, large private groups outside of academia is actually probably one of the largest sources of clinical research, clinical trials. We have a lot of very busy, very sophisticated clinical trialists. And so it's sort of that 3-legged stool, right? There's a clinical piece to this that is immediately, tangibly impactful both to the physician and to the patients that we treat. It is certainly impactful to a large for-profit company like ours, where we're looking to the economic benefits of having this in our ecosystem. And then there's the clinical research piece. So I would say that's having access to PSMA PET scanning really has been quite disruptive to all 3 of those pillars.

Yes. Thanks, Dr. Yonover. What I'd like to do is maybe delve a little bit deeper on 2 elements of what you raised, namely the business model, but also the clinical research that you contribute. So we'll just address those. Maybe you could talk a little bit about the requirements of a high throughput 6-day a week business model where you're clearly investing very heavily in camera capital equipment. What are the requirements of that and the requirement to have reliable clinical efficiency? And then we might talk about some of the patients that you might even have seen today on BiPASS, which is a rapidly enrolling trial that you and Dr. Hicks are both co-investigators on?

Right. So I mean, I can't again overstate the importance of efficiency. This is the word as a business owner, right? Anything that kills efficiency is something that's sort of an enemy to our mission. And so we've had to spend a great deal of capital, both tangible capital as well as just labor on operationalizing a high throughput system, right? We have a massive footprint. So just our subpractice here in Chicago has a massive geographic footprint. And so we've got patients. It's a spoken wheel sort of referral. We have one scanner. We're hoping soon to have another just locally. And -- the coordination of care, quite considerable. These patients are of various ages and capability as far as transportation and mobility and getting patients scheduled, getting the prior authorizations and the other issues with insurance that we deal with here in the United States, getting a patient there, getting them scanned, getting them home, getting the scan, getting the data. I mean it's a -- when we're doing just on our 1 camera, 1,000 to 1,200 scans in a year, then of course, there's force multipliers, right? As you get bigger, those small changes in efficiencies you bring up, anything that can hinder efficiency is something that's something we try to eliminate, right? So we have to get a lot of patients through. It's logistically quite challenging. It's -- we have here in Chicago O'Hare Airport. And it's nothing short of that, right? So no-show rates are a big problem that we want to eliminate, right? And it's same-day scanning. That's really the only way we can really truly achieve sort of our high throughput. And from our perspective, right, we are always looking for optimization, right? Any business, whether non-profit or profit driven should always be looking for optimization. We've made a choice to go with gallium-based isotopes in our scanning protocols. And as Professor Hicks so eloquently sort of pointed out and just demonstrated, right, the optimization opportunities are in our technologies, our techniques, our acquisition protocols, the application of AI-assisted interpretations. That's what as a group, we're going to be looking to as we scale and as we try to get that 6-day a week. I hate the visualization, but we got to pack them in, right? That's a group like us, that's what we have to do here in the United States. That's -- those are the -- we're under the same economic pressures as anybody else. And so, we have to live within the physics of gravity and the physics of economic pressures. And so we obviously don't want to cut any corners clinically quality-wise, we want the very best. We want the very cutting edge for our patients. But we need to do that in the most cost-efficient way in a way that's not going to be disruptive to our overall very complex ecosystem that we've built. So we're looking towards those improvements in technology that Professor Hicks went through so that we can get better scans. And in the same vein of trying to provide cutting-edge, high-quality care, we are participating in the BiPASS study, which I have great cautious optimism that based on already published data, but also just from my clinical experience, that if you're able to bring in a PSMA PET into the pre-diagnostic screening space, Professor Hicks, of course, made me laugh about his descriptions of the PI-RADS reading system as a clinical urologist whose job it is, is to find prostate cancer and only find clinically significant prostate cancer and only treat appropriately. The advent of MRI 3, multiparametric 3 Tesla MRI was a huge advance, right? We all understood and we were sanguine about its shortcomings, but it was -- really came to the fore in essence of a vacuum. And it was game-changing, a little bit of a trite saying, it was game-changing, but we were fully aware of MRI negative -- MRI-invisible disease and sort of the ambiguities of a PI-RADS 3 lesion. And so we've already gotten the sense that a PSMA plus an MRI, they're very complementary. They're actually not exclusionary. They're complementary in many respects. There are 2 different modalities and prostate cancer is a heterogeneous disease, PSMA expression. We're just at the surface of understanding the biology of PSMA expression. And so if on an MRI, we can image and understand the ADC and the other areas, where the prostate -- how it looks under MRI imaging. And then we're able to use a molecular target like PSMA PET. You put those 2 together, you look for congruence -- incongruent areas. It should in theory, and I think it will bear out, be able to allow someone like myself to have a more effective biopsy, a higher yield and/or -- and sort of the other aspiration is biopsy avoidance, right? If you have great clinical data, particularly given the pretest probabilities, some of the clinical parameters, if you have a negative MRI and a negative PSMA PET scan, the hope of the BiPASS trial and other data is that perhaps we can avoid biopsies in certain patients. It will also be interesting to apply that in the active surveillance space. And my hope is on that end, right, to be able to avoid biopsy in certain patients of mine, but also be able to do a better biopsy for patients of mine, where I'm able to have a higher yield that's more efficient. And then if I have a biopsy that tells me a little closer to truth what's going on in that prostate, that's where I can help guide a patient make better therapeutic decisions. Is a prostatectomy or radiotherapy or metastatic-directed therapy, systemic therapy, clinical trials. When you're getting closer to truth, right, you can actually just make better decisions. And so that's -- I did 2 BiPASS biopsies today. These were 2 gentlemen's actually who had negative MRIs, and they had minimally avid areas of disease, one that I'm suspicious, I covered it pretty well on the biopsy. And it's an area actually that I would not have ordinarily gone and biopsied on a normal template transperineal biopsy on a negative MRI. So obviously, I'll be very curious on my own experience. I'm also obviously going to be very curious about the readout of BiPASS when it's available. But I think there's really no doubt that the data that comes out from the BiPASS trial is going to be highly useful. There's just really no doubt about that, particularly based on some of the stuff that's come out of Australia already in that space. So I'm -- and as a business owner, right, I'm looking for -- I've got a scanner, I've got a tracer that works beautifully. I'd love to find more applications in the screening space, in the advanced therapeutic space and in that response to therapy space.

Yes. Dr. Yonover, thank you very much. Look, that's a very comprehensive overview. I think to summarize, as a surgeon, your raise on [ detra] , if you will, is to do a complete cancer surgery on a patient and make sure that you have cleared the patient of all prostate cancer. You've also made the point that you've got a lot of patients to serve. You've got an extraordinary high throughput clinic with your partners and you've got a significant requirement for PET camera uptime to make sure that you aren't seeing those assets not run to their full extent. So that really moves us on to the second theme, which is supply chain and making sure that the ability to use those cameras to image patients to be able to take them to surgery is maximized. So we'll move across to my colleague, Darren Patti. Darren, prior to becoming the Chief Operating Officer at Telix, you were instrumental in the leadership team at Sofie as well as before that [indiscernible] PET trace and manufacturing business as well as their radiopharmacy networks in North America. Today, we've got 2 isotopes, obviously, Gallium-68 and Fluorine-18, effectively serving the PSMA PET market. Perhaps, Darren, you could start by talking about the supply chain for gallium and how that's supporting the broader patient access as well as production flexibility, which is what Dr. Yonover just talked about.

Yes. Thank you, David. Yes. When you look at the gallium landscape, you find that there's really a -- what we have now is a mature and robust supply chain. Now that we have multiple commercial products on the market for a number of years now, this has really given opportunity for the gallium isotope supply chain to mature. And because of this, I think there's a few notable things to call out. And this includes that now we have multiple generator manufacturers that have demonstrated consistent, reliable access and delivery. And this is something we expect to continue to expand with additional product offerings in the future. Additionally, the beginning to end supply chain of generator production has become more vertically integrated with various manufacturers. So that further ensures uninterrupted supply. So that includes starting material germanium that's needed for the generator manufacturing And then we talked about the flexibility and access and then just the inherent nature of having a generator on site or nearby essentially provides on-demand access, and that really affords the kind of ultimate flexibility for patient demand and access. And then finally, with newer generators having higher capacity, this availability in the market further drives that flexibility and additionally provides greater access. So we've established that we have a very solid and consistent gallium generator supply chain that's available for patients. So -- but now we can take a look and augment that or scale that even further now that we have commercially available cyclotron produced gallium methods. So that really allows us to ratchet up isotope production even further. And this includes things like the ARTMS technology via the QIS system, and this allows large curie amounts of gallium to be produced. And again, this is using a very secure end-to-end supply chain, so we know it's reliable. And so when you sum up the parts on the isotope side and then couple it with a higher capacity kit as an example, like Gozellix, you really have that higher flexibility solution that can easily scale to meet patient demand. So on the next slide, it's just really an illustrative example of when you look at the over 250 partners that are producing Illuccix and Gozellix on a daily basis and then you add on capacity afforded by Gozellix in conjunction with high-capacity generators or cyclotron produced gallium, and you can see how it really opens up access with the associated flexibility to a very broad customer base So I think the take-home message here is that with Illuccix and Gozellix, paired with an extremely reliable gallium generator supply chain, including generators of various sizes, and the option for a high-scale production via gallium production on a cyclotron using something like the ARTMS technology, there's a flexible option that can be tailored to a specific market need. And I think that's a very unique offering.

Yes. Thanks, Darren. I think obviously, let's put it this way, gallium and fluorine have been workforce isotopes over the last 5 years during the advent of PSMA PET. There are also exotic isotopes, if you will, copper, zirconium and others. So now we possibly have 2 providers aiming to bring copper-based tracers to the PSMA PET market. In your view, I mean, you've got over a decade of experience in meeting demand and doing so with very high reliability. Are these providers with copper going to be able to replicate or meet the reach of the existing gallium and fluorine supply chains? What's your view on that?

Yes. So it's a really good question, David. And obviously, supply chain success is a prerequisite to deliver commercial success and patient access, right? So -- and we saw some of those challenges early on in the gallium market. And as time has progressed, the market has grown to meet that demand. And I think we're a little bit early in that phase with copper. There's just some product attributes that make it a little bit different to look at as well. You have a longer half-life. So conceptually, you can have more centralized manufacturing, but that doesn't come without fair logistical risks and limitations as well. So in my view, it's still better supported with maybe a more regional model. But to your point, that's -- there's up-and-coming products, but I don't feel the -- really the supply chain is quite there yet, and that's from starting materials all the way through finished product. So with the gallium, it's truly something we've seen that's battle tested and really pressure tested through -- in a high capacity and high demand mass market. So I think it will take some time to get there. There's emerging technologies and things that are being done, but that's going to take some time to develop further.

Thanks, Darren. Well, let's assume they do get there. I might direct a question back to Professor Hicks. Professor Hicks, in your mind, in your experience, given the background of what you described was possible with improved camera equipment. Is there a role for new or novel isotopes? And if so, what might they be? Are they niche roles? Or can you see a broader application?

Yes. I can talk, I think, to some extent around the copper development because the agent that's currently in clinical trials, the bisPSMA was actually developed through my lab in collaboration with Professor Paul Donnelly from the University of Melbourne, and we did a lot of the preclinical and some of the earliest imaging of that agent. And the advantage in the preclinical model was we saw as a companion for the therapeutic application of copper 67 that the long half-life of copper 64 of 12.7 hours allowed you to get a time activity curve that could do predictive dosimetry for the first time, a long enough uptake and clearance curve to estimate the dose that would be delivered to tumor into normal tissues. And we saw a major advantage in that, particularly in the patients who are a bit borderline for selection of PSMA-targeted therapy where the intensity of uptake is not particularly high, and you worry about the therapeutic index between radiation delivered to tumor versus to normal tissues like salivary glands, like the kidneys. So we certainly thought there was going to be a significant advantage there that the ability to image late would allow that issue of being too close to blood vessels or bladder would be addressed to some extent by late imaging. And from that point of view, the long half-life being able to image at 24 and we've imaged here out to beyond 48 hours, which on the Quadra because it's so sensitive with copper, you can go very, very late in your imaging protocol. But it's -- if you look at the sensitivity of the gallium PSMA and the convenience that in most patients within 1 to 2 hours, you've got all the information you need for therapeutic pathway planning. I was struck by what Paul was saying about how it's impacting management. Before PSMA and even with multiparametric MRI, surgical planning and medical therapy planning, radiotherapy planning was treatment by Braille. You were treating completely blind. And by -- the real impact is not just simply the positivity negativity, it's where the disease is that's critically important. We found that between 30% and 40% of even pelvic confined nodal disease is outside traditional empiric radiotherapy treatment volumes. They're not areas that surgeons like to go, but they can go if they know that the disease is there. And so it's making a huge impact on that planning piece. And so I think that these agents are going to have a role. And increasingly, people are also using tracers for radio-guided surgery, where you use a probe on a robot often increasingly as well as optical imaging, and this is work that we're doing with Telix, as you know, David, to combine radioisotope and optical probes for imaging-guided surgery, the macroscopic planning with the PET scan, the microscopic at the level of the operating microscope and robot.

Yes. Thanks, Professor Hicks. I might just move to the final sort of theme, which was do we need a new tracer. And I might direct this question to Dr. Yonover. Given the discussion up to now on the current clinical landscape and the supply chain aspects that Darren covered of the U.S. PSMA PET market. In your practice setting, a very large or the largest private urology group in the world, let me pose a question to you. Do you need a new tracer? And if so, what for? And what might be the necessary conditions in which to implement it? Does it have to be same day? Or can you accommodate second day, third day, fifth-day imaging? How would it work in your practice?

Well, in a short answer, no right now. In 2026, particularly because we've already created a business plan around gallium scanning, right? The bar would have to be set extremely high for us to not only change and adopt a new isotope, but if that comes with a whole different logistical landscape, right? That -- those logistical challenges, while not insurmountable, certainly are a barrier that would give us pause. And for those -- from that pure business model perspective, I know that it would be very challenging and it would create sort of -- it would create a big problem for us. And so I go back to -- we hope to optimize things with technology. I'm -- as a clinician and a business owner, I'm much more interested in novel targets because I know I've seen it myself with my own patients, the shortcomings of PSMA targeted imaging, both in the theranostic space, of course, but in the newly diagnosed space. So I think that's what we're going to be looking for in sort of a short answer. The other thing from the clinicians and certainly, Professor Hicks could speak much better to this than I, but these tracers are not interchangeable. This is not -- we have -- as a clinician, as a non-nuclear medicine doc, as a urologist, we've had to ingest all of the molecular imaging and most of that is gallium-68-based literature over the last 5 to 10 years, of which there's a great depth and breadth. And any new tracer is going to have to not only show clinical utility, it's going to have to show not only change in management, but it's going to have to show the impact on outcome, right? And that takes quite a long time. And until we see that proof, right, it would be hard for us to justify from a logistical challenge, a business challenge to make those sorts of leaps. I see -- and again, just from the clinician's eye, not as from an expert in isotopes, but I see something like copper as a niche product, right? There are instances, where our gallium 68, which I see sort of as our daily workhorse. There are going to be times, where I think it's probably going to be useful in that space. But I'm personally much more interested in different targets than I am in different isotopes.

Thank you, Dr. Yonover. Look, I think that's a very comprehensive answer. And I think we will conclude the formal session there and move to questions-and-answers. So I would like to, on behalf of the audience, thank Professor Hicks and Dr. Yonover and my colleague, Darren Patti, who are really sort of apex predators right at the top of their fields, as I think you can determine from some of the discussion. I will now -- perfect timing, it's 10:20 here in Sydney. I'd like to leave 10 minutes at the end for questions-and-answers, and I'll do my best to direct the question to the appropriate respondee. What I'm going to do is I'm just going to go through the questions as they come in. The first one is there's a lot of noise around BCR sensitivity. I think what that means is that people are asking questions about the sensitivity of different tracers in the biochemical recurrent setting. On the weekend, we saw POSLUMA head-to-head versus PYLARIFY. In a few weeks' time, we'll see full data from copper versus gallium. That's obviously at the EAU conference. What are those strengths and weaknesses of head-to-head study designs in the BCR setting? I might direct that to Professor Hicks, if you --

Yes. I think it's a really important question of what are the selection criteria of the patients entering into those head-to-head. I think the data actually has been already presented around the gallium PSMA 11, the Illuccix versus the copper agent of Clarity that my colleague here in Australia, Professor Louise Emmett presented at [ EUA ] (sic) [ EAU ]. If you look at the data, and this was in a group of patients, where I think the median PSA was about 0.4 with an interquartile range between 0.3 and 0.6. If we go back to that data that you present from the Chinese study, the positivity rate in that series for that range was over 90% in Louise series, it was 28% for Illuccix, which is just completely out of keeping with that data, but also out of keeping with her own data in 3, I think, published studies, where she's published her results with Illuccix, where in that sort of range, she was getting well over 50%, closer to 75% of a positivity. And to me, that speaks to the potential of this group being subject to a selection bias that because they have the Illuccix first, and I suspect they either had negative or equivocal scans or their PSA was out of keeping with the level of disease detected on their scan and remembering that, that scan was done probably around 45 to 60 minutes, not at 60 minutes, not beyond 120 minutes, not with diuretic, not with dynamic imaging. And so they're the very group of patients, where the technique and the technology is going to make the biggest difference in detecting them. And of course, if you then have late imaging in those patients, you're going to see more disease. But how much does it benefit you to go to 24 hours when we know that the uptake kinetics really plateau off at about 3 hours. And if you can image at 3 hours going to 24 hours or you lose the statistical quality in your image. The other limitation of that approach is that because of the long half-life, we're restricted in how much we can inject into a patient. The administered activity for copper within the radiation guidelines are much less than for gallium and also for fluorine, which have a much shorter half-life. So you're starting from a lower statistical background and imaging later. And so there are significant offsets as well as the supply chain issues that Darren brought up that I think are going to really mean what Dr. Yonover was talking about. There is going to be a place for this and it's in exactly the kind of patients that I think Louise is may be inadvertently preselected those who have a negative scan on a conventional PSMA agent or the extent of disease just doesn't seem in keeping with the PSA level that's extent in that patient.

Yes. Thanks, Rod. That's a very comprehensive answer. We are being very egalitarian here because this is obviously a surgical question for Dr. Yonover, which is nice to see. Thank you to the questioner. The question, would PET-guided biopsy reduce the number of cores required and the number of cores required to calculate the Gleason score and does higher yield mean the ability to acquire more cancer cells per core due to PSMA PET guidance. How would you tease that out, Dr. Yonover?

That's an excellent question. I'm still -- that's sort of to be -- I don't mean to be cute, but I think that's to be determined, right? One of the things in our MRI fusion experience, meaning we -- our MRI experience of whether we do a template biopsy, basically a systematic biopsy, where we're taking cores from various regions and then also targeting the region of interest. That is, I wouldn't say controversial, but that's batted back and forth. And I think we're going to be facing the same sort of conversation with PSMA. I don't know if the number of cores will be reduced. It's not really impactful as far as morbidity. The number of cores taken don't particularly increase risk of infection bleeding or patient discomfort, to be honest. It's more of biopsy, no biopsy. Once you're starting to biopsy, that impact is de minimis. What I'm more interested in from a yield perspective is the reduction of occult disease, right? We do an MRI fusion biopsy. We think the patient has a Grade Group 3 disease. Thankfully, we have molecular imaging now so that I can avoid therapeutic futility. We know if the nodes are likely to be positive. We certainly have ruled out metastatic patients so that we take the patient to surgery. We're confident that at least they don't have metastatic disease. And lo and behold, what we want to reduce are the surprises in surgery, right? We want to know going into surgery, what is the most likely grade group and where it is? Is there SV involvement? Is there extra capsular invasion so that we can do a wide dissection on that side. Those are the things that we're hoping that PSMA plus MRI, we're going into surgery with more certainty. That's where I'm hoping for higher yield. The other area, right, is if there is -- and this gets into a little wonky into the biology of prostate cancer, but if you have, say, Grade Group 5 non-PSMA excreting disease, right, that has some neuroendocrine features, that may not be responsive to the radiosensitivity of that disease, it may not respond, right? The advantage of surgery is that it's agnostic to the biology. If it's localized and you take out the prostate, it's gone. If you go for radiotherapy, you have to apply various levels of boosting, radiotherapy, systemic therapy and the response to radiation is variable because we know the heterogeneity of prostate cancer is variable. And then if I may, just for a moment, from a surgical perspective is focal therapy has been underutilized, and that's partly because surgeons like myself are very reluctant. We know it's a heterogeneous disease, where we always want to avoid missing disease. And if I have a higher yield, more accurate biopsy, particularly if there's congruence between my molecular image and my MRI, I think the field of focal therapy will start to bloom, which is going to be an advantage, particularly for our younger patients if we can go into focal therapy with more confidence. And that confidence is borne out from a better biopsy. That's a long-winded answer to your short question, but hopefully, that's the promise of where we can get from the intraprostatic findings of Illuccix.

Thank you, Dr. Yonover. I think Professor Hicks you --

I just wanted to add a very quick thing to that. There are areas, where I think both MRI and biopsy are very difficult. One is the anterior fibromuscular stroma, which can be hard to get to with the biopsy needle. And it's also a more difficult area to interpret on MRI. And we've seen a very significant impact of PSMA in that particular area, identifying the other areas right up at the very base, close to the bladder where the needles -- they're a little bit reluctant to go so high. And we've certainly seen cases where biopsy negative, but strongly positive on PSMA because they -- it's just a sampling error. And so I think that there is a big advantage there. We've -- I think, today doing our 51st patient on the BIPASS study. And the fact that this has been run by the Australian Prostate Cancer Center Urologist shows that their enthusiasm for this technology as part of their diagnostic workup because not only do you get a better assessment of the extent of disease within the prostate, at the same time, you're getting staging information, not only about the pelvis, but about the whole body. And in the higher PSA, higher-risk patients, there's a significant yield of staging information, not just diagnostic information.

And that's efficient for a large practice like us, right? That efficiency, the "one-stop" shopping, right? The number of visits a patient -- if we can cut down on the number of patient visits if we can -- part of our business model is navigation, right, navigating these patients. And that's one of the reasons why we've adopted molecular imaging internally and just helps us navigate these patients. And what Professor Hicks is talking about, I'm glad to see that the enthusiasm I have no doubt would be in Australia would be as great as it is here in the United States about getting PSMA PET in the pre-biopsy space. I think there's just --

I don't want to scare you, but last year, we did over 5,000 PET scans with a single PET scanner and approximately half of those were PSMA scans. So it's going nuts.

All right. Thank you very much, Professor Hicks and Dr. Yonover. We've got time for one more question. We will take any residual questions and answer them separately. This is for Darren. Darren, could you please address the breakdown between cyclotron produced versus generator-produced gallium PSMA. And could you possibly talk about the scale-up of gallium production, as we anticipate the scanning volume to potentially double by the early 2030s, which is sort of 5-odd years from now?

Yes. I think that's the scale-up is where the cyclotron production really comes into play, right? So right now, the majority of the gallium production, the vast majority is done via generator-produced gallium. And I think there's always going to be a place for generator produced gallium, right? So there's really not a one size fits all. But the cyclotron technology gives us, as I mentioned earlier, that opportunity to really ratchet up the amount of activity we can make. So you're talking going from 50, 100 millicurie generators to curie amounts of gallium on a solid target system via cyclotron production. So you're talking 10x to 20x the amount of isotope. So that really opens up a lot of flexibility in terms of how radiopharmacies and those producing finished drug product can address the market. There could be a fractionation of the isotope feathering out to other centers, just opens up a new world of opportunity. And something like that is cyclotron produced gallium is something that really does move the needle to meet that surge in demand.

All right. Thanks, Darren. Well, we are just over time. I would like to, on behalf of the audience and all participants, thank Professor Hicks from Melbourne, Dr. Yonover from Chicago; and my colleague, Darren Patti, who's also in Chicago. Colleagues, thank you very much for your extraordinary insights. I've learned a lot today, and I believe the audience will have as well. So thank you kindly, and I appreciate the audience dialing. I hope it's been valuable for you. Thank you.