Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Good morning. This is Kyahn Williamson, SVP of Investor Relations and Corporate Communications from Telix. Thank you so much for joining us on this special call today. I think as everybody is aware, the results from the ZIRCON study were presented at ASCO GU in a symposium over the weekend in the U.S And I'm really pleased to welcome today Dr. Colin Hayward, our Chief Medical Officer; and Associate Professor, Brian Shuch, MD, Director of Kidney program at UCLA Institute of Urologic Oncology in Los Angeles, California. He was also a principal investigator in the ZIRCON study, and delivered the presentation over the weekend. A bit more about Brian. He's a urologist and urologic oncologist who has spent much of his career working in the area of kidney cancer research in clinical practice. He is the Director of the Kidney Cancer Program at UCLA and the Alvin & Carrie Meinhardt Endowed Chair in Kidney Cancer Research. He completed his urology training at UCLA, followed by a urologic oncology fellowship at the National Cancer Institute. He's an accomplished surgeon and clinical translational researcher. He's served in leadership positions within various kidney cancer research organizations such as SWOG and the Society of Urologic Oncology. He is recognized an expert in genetics of kidney cancer and runs a translational research program with over 140 peer reviewed publications in prestigious journals. Previously, Dr. Shuch was at Yale from 2013 to 2018 where he was an Associate Professor of Urology and Diagnostic Radiology, Director of the Genitourinary Cancer Genetics and the Director of the Genitourinary Biospecimen Repository. So thank you, Brian. We really appreciate you joining us today. I will hand over to Colin to make a few opening remains, and then Brian will deliver the presentation.

Thank you, Ky. Look, we're very excited to go through this with everybody today. And this is a big step, our first positive Phase III study that we have, and very excited to just let Brian take this forward and let the results speak for themselves and really get to understand the clinical utility of this product, and then listen to what your questions are about this. So Brian, why don't you take it away?

Great. Thanks, Colin. Thanks, Ky. I appreciate it. Excited to be here today to discuss the results of this trial. Unfortunately, there has been limited advancements in the field over the past 10 or 15 years in the localized disease space. And I think this is the most exciting advancement we've had in a very long time. So if we could just start from the beginning of the slide deck. Okay. Let me just see if I can get it in full mode. Okay. So we have an unmet need in our field to non-invasively characterize we call indeterminant renal mass. We see about 70,000 to 80,000 new diagnoses a year in the United States, but there's another 10,000 benign tumors, another 10,000, 20,000 cystic tumors, and anatomic imaging currently cannot really reliably distinguish between benign and malignant renal masses. Despite excellent work trying to characterize what tumors look like on imaging, the characteristics of CT scan and MRI for specificity and positive predictive value are pretty poor to modest for clear cell kidney cancer. This leads to about 20% to 30% of our tumors that undergo a partial nephrectomy, ultimately being found to be benign only after treatment. And unfortunately, we know all forms of therapy have morbidity. Actually, about 1 in 500 patients will ultimately die within a month of a partial nephrectomy, usually from medical complications. You might say, "Well, why don't we stick a needle and biopsy." So a biopsy is invasive. It's actually performed infrequently in the United States, about 10% to 15%. A lot of radiologists don't feel comfortable with some locations. Some patients are on blood thinners. And it's often nondiagnostic up to 10% or 20%, especially for cystic lesions, they won't even try it because it's so poor in its accuracy. Regarding clear cell, clear cell kidney cancer accounts for 75% of the tumors we see, and it causes about 90% of the deaths from kidney cancer. And you might say, well, what about those who just get observed? Well, we know that those with clear cell kidney cancer do progress more rapidly than other flavors of kidney cancer. So if we had an accurate noninvasive method for really stratifying patients before treatment, it'd really help us guide management. And this would be akin to PSMA, which has really revolutionized the management of prostate cancer. And this has long been hoped in kidney cancer. Next slide. So what is CAIX, carbonic anhydrase IX? This has been a 20-year journey in the field of kidney cancer to really operationalize this. It's a cell surface protein. Basically, it's induced by hypoxia. With hypoxia or with loss of the VHL gene, which is seen in about 90% of our clear cell kidney cancers, CAIX is upregulated. The exciting thing here is that it's not really seen in most normal tissue. There's very low expression in biliary epithelium, but it's not really expressed in normal tissues. In the normoxic state, VHL will bind to this HIF protein, and HIF gets degraded. But with true hypoxia or with loss of VHL, basically HIF translocates to the nucleus, and it leads to a whole upregulation of about 140 different genes. One of them being CAIX. This whole pathway is actually what led to the Nobel prize about 2 years ago to try to drug this pathway by 3 investigators. So CAIX gets upregulated, it may contribute to tumor genesis or might serve a way to maybe therapeutically target or image clear cell kidney cancer. Next slide. So how can we get there? Well, if we had an antibody-based imaging agent, maybe we could detect clear cell kidney cancer. Well, that's where girentuximab comes in, and this is an Ig Kappa Light Chain chimeric monoclonal antibody, which is highly specific for CAIX. And when girentuximab binds to CAIX and gets internalized, there is extensive safety data with this antibody in previously performed imaging studies or therapeutic studies, the very large ARISER study where this was used as a therapeutic agent, there was very low toxicity. So we know it's safe. The exciting thing here is it's also not excreted through the kidney. There's hepatobiliary excretion. So for patients with kidney tumors, we don't have to worry about issues such as renal excretion in the urine. Now this can be chelated with desporoxamine. It can then have a payload with attachment of zirconium. And zirconium is a very exciting positron emitter. It's been used in a lot of different imaging studies with PET scan. Half-life is about 3 to 4 days, and is very well suited to be chelated and bound to a lot of antibodies, and it's also hepatically cleared. So this serves as a really exciting agent to bind to girentuximab and image clear cell kidney cancer. Now other studies have used zirconium, desparoxamine girentuximab, it's been shown that it can image CAIX-positive tumors with SPECT CT or PET. And the dose which we'll talk about used in the ZIRCON trial was previously shown to be safe and allowed for imaging of clear cell kidney cancer between days 4 to 7 after administration. Next slide. So ZIRCON was a large pivotal Phase III study where patients who had an indeterminate renal mass that was 7 centimeters or less, as seen on either CT or MRI that was deemed suspicious for clear cell kidney cancer, were eligible if they were scheduled to have surgical removal. And the way the trial worked is that patients on day 0, they had dosing. And then on day 5, plus or minus 2 days, they had the PET scan. And this was reviewed by 3 central radiologists to characterize the lesion. And then within 90 days, patients had a partial or radical nephrectomy, and their tissue was sent in for a central histology review. Now the endpoints of this trial, we're looking at 2 co-primary endpoints, both the sensitivity and specificity. And the goal was to try to show that the floor of the confidence interval was well above any other previously performed metrics with other agents. So with sensitivity, hoping it was above 70% the floor of the confidence interval and the specificity above, I think, 68% the floor of the confidence interval. And this was using the central histology, the resected specimen as the truth, the gold standard. Now the secondary endpoints, we're also looking at how this will perform in very small renal masses. In the T1a cohort, also looking at safety and also things like positive and negative predictive value. Next slide. So this was a global study. So kudos to the Telix team and their partners to get this imaging agent all over the world. It was in 9 countries, 36 sites, and 300 subjects were enrolled. So this is the largest molecular imaging study ever performed to date in patients with localized renal cell carcinoma. Next slide. Now there were 371 patients screened and 332 patients enrolled. There were patients, who were too early, either they got cold feet, withdrew consent, maybe they didn't go for surgery or they didn't go through with the imaging. And there's really 2 data sets which will be looked at, is the safety analysis set, really anyone who got dosed, see if it's safe. And two, the full analysis set, which is looking at those who had both central radiology review, and central pathology review looking at the truth of the gold standard. And that's 284 patients in that full analysis set. Next slide. Now the problem we have in kidney cancer is a lot of our patients are older, and they have some comorbidity. So what you'd expect in a series of patients with small renal masses, T1a, T1b, is you would have patients in their 60s. So the median age here of 62 is what we'd expect. This is very generalizable. And we do know that more patients are men than women, about 68% to 70% depending on the series. The median lesion size was 3.7 centimeters, and we had 179 T1a and a large number of T1b. Unfortunately, there is enough very, very small lesions here, the less than 2-centimeter ones, which made up about 1/8 of the cohort. And what you'd expect in a cohort such as this is you'd have enrichment for clear cell kidney cancer, which was seen in 2/3. And again, patients had to have suspicion of clear cell. But there were other renal lesions as well in 1/3, which were largely the non-clear cell kidney cancers, capillaries, chromophobes, oncocytomas and some other subtypes. Next slide. Now what we would expect is that the tumors that are larger would have an enrichment for clear cell, because clear-cell is more aggressive than some of our other renal lesions. Next slide. Now this is the meat of really the presentation of really, how did it do? Well, it really crushed any prior imaging metrics ever performed in a series of patients with localized renal tumors. And with all 3 reviewers, the radiologists, they had very high sensitivity and specificity. And if you look at their confidence interval, again, looking at the floor of the confidence interval, it greatly exceeds that 70% sensitivity threshold and the 68% specificity. But pooled, the sensitivity was 85.5% and specificity of 87%, which again is much higher than any other type of imaging study, CT, MRI, ultrasound. And the positive predictive value in the overall cohort was 93%, and the negative predictive value was quite high at 75%. Very high to have near 100% for both positive predictive value and negative predictive value, but this is a quite exceptional accuracy at 86%. Next slide. Now you might say, "Well, what about the very small tumors, is this going to be performing worse because they're smaller lesions, it's hard to characterize? Well, actually, I think the data is actually even better. And again, all 3 reviewers here, the lower bounds exceeded what was set as the floor for the confidence interval. But if you see, again, sensitivity pooled 85%, the specificity was close to 90%, so even higher. And the positive predictive value was 93.4%, with even higher negative predictive value, and accuracy at 87%. So I think, again, even in the small lesions, which again, a large number of them are less than 2 centimeters here, there is outstanding performance. And the final publication will look at how they did in 1 or 2-centimeter lesions, and the data is similar and very consistent, whether they're 2 or 4 centimeters. Next slide. Now again, for safety, there were very few adverse events related to the zirconium/desporoxamine/girentuximab imaging agent. And most of these were mild. There were 18 patients who had grade 3 treatment-emergent adverse events, meaning they signed consent and the next day they can have an adverse event, and that counts. However, if you look at most of these adverse events, most of these are related to the nephrectomy. Okay, things like wound infections, hernias, bleeding, they're not related to the administration of the agent. And there's really no unexpected safety signals observed. And this is really consistent with the hundreds of patients who've been given girentuximab, either as a therapeutic agent or in prior imaging studies. So I think just confirms that it has outstanding safety profile. I think I had 1 patient who accounted, she felt a little warm after the agent. A big deal. She was fine. She went home. And then care. But a very, very safe imaging agent. Next slide. Now here's just some cases here. This is a patient who had a 3.1 centimeter renal lesion. It is interpolar, is partially endophytic, and this cystic lesion was PET-avid. So clear cell kidney cancer was very, very PET-avid. And at the site, they did a radical nephrectomy, and on central pathology review is confirmed to be clear cell kidney cancer. And then the IHC expression, it wasn't a very high expressing tumor, showing that even tumors with lower focal CAIX expression can be positive. I will tell you that urologists absolutely hate taking out kidneys and then finding out the tumor was benign. And that does not happen infrequently. But that is really a punch in the gut to the surgeon, and it's really horrible for the patient. So in this center where they deem this patient a candidate for radical nephrectomy, very, very fortunate for the patient, it wasn't a benign lesion. It was clear that this was a clear cell kidney cancer. Next slide. So for the -- again, I think this was one of my patients, very anxious, small renal mass, 1 centimeter, 57-year-old. You might say, "Well, couldn't you watch this?" Well, yes, you can watch small tumors. Small tumors that are clear cell are going to grow quicker. I will tell you, very frequently, I have patients say, "Well, doc, I'm healthy now. I'm worried about what's going to happen in 3 or 4 years. I'm going to be less healthy. Should I get treated now before I'm not a candidate for treatment later when it's growing bigger?" Well, as you see this 1 centimeter tumor where you think that maybe it's below the limit of detection, very, very PET-avid here. This patient had a partial nephrectomy, and it was confirmed to be clear cell kidney cancer. So again, this just demonstrates that very small tumors can be very PET-avid, and it's a very clean tracer. Next slide. So really, the summary, I think this pivotal Phase III trial shows it really met its end point. It exceeds the sensitivity and specificity thresholds that were defined at the start of the trial. And then looking in the T1a cohort, it performs just as well, if not better, in the patients that have very small renal masses. And then the safety profile, again, has confirmed this is a very safe imaging agent. There's no toxicity that is really thought to be new or really concerning here, consistent with prior work. Next slide. And then I think really, this, compared to conventional cross-sectional imaging, I think that this imaging agent really improves our identification of clear cell kidney cancer. It really greatly exceeds what is seen in a classic series of CT and MRI by really outstanding expert centers of really amazing GU radiologists, but this was something performed at 36 sites. And even with that, in many centers, it greatly crushes those imaging metrics of sensitivity and specificity. I think this has the real potential to improve care. It's a molecular biopsy. I think it really can select the ZIRCON-hot patients for treatment. And I think the ones that are zircon-cold, again, you could potentially, depending on the patient, you might want to do further imaging, maybe those are the ones you'd want to intelligently decide on maybe a biopsy or maybe say, "Hey, there's likely to be a more indolent lesion here. Maybe I feel more confident doing surveillance on that patient." And I think overall, girentuximab as an antibody holds extreme promise to not just help the localized renal mass, it potentially can help us improve staging. It could be used maybe for routine post-op surveillance. I think for treatment, there's exciting trials that are obviously ongoing with radiopharmaceuticals. If you see it, you can treat it with radiopharmaceuticals or maybe antibody drug conjugates. And then obviously, other solid tumors that have the potential to be hypoxic, this potentially can serve as an imaging agent for those. So again, I think this is really the most exciting advancement that I think we've seen in the past 10 or 20 years, other than really the introduction of robotic surgery to early-stage kidney cancer. And next slide, again, all the patients and the sites, obviously, and the partners deserve a thanks. And the Telix team really made this happen to bring this agent forward to our patients.

Brian, thanks for that excellent summary, and thanks particularly. Obviously, it's a challenge for you because of the high number of patients that you recruited into this study in UCLA. So thank you for being that leading recruiter and recruiting all of those patients at your site. Thanks for going, again, through the burden of this disease that you see out there, the potential future utility as well as that current clinical utility. So I think we'll now hand over to the moderator and take questions.

[Operator Instructions] The first question comes from Shane Storey from Wilsons.

Thanks for making yourselves available to discuss these results. Perhaps I can start just as you finished your presentation there, you began to sort of think about different ways that the CAIX scan might be used. Presumably, there's a large population of patients out there today who are in that surveillance category, whether they've been managed that way initially or whether they have been treated and then subsequently worried about recurrence. I mean, with the availability of the CAIX agent, I mean, is there any justification in calling any of those patients back and scanning them?

So absolutely. So I follow probably half of the small renal mass patients I see. I see probably about 300 or 400 new patients a year. And of the small ones, about half of them I actually put on surveillance initially. If someone has been stable for 5 years on surveillance, probably not much clinical utility. But again, we have a large population of patients, they start on their imaging. And year 1, year 2, they've had a little bit of slight growth. We know that the rate of metastasis greatly varies by histology. So I'd be willing to follow a patient with clear cell kidney cancer only up to maybe 3 centimeters because there's data they can metastasize. Some of these non-clear subtypes like papillary and chromophobe, I would watch a patient like that much longer, because the incidence of metastatic dissemination is clearly very, very different, especially obviously benign at 0. So I think all those patients who are on surveillance that are in the first 1 or 2 or 3 years, I think those patients, you've seen a little slight growth. They're a candidate for treatment if we would want to get them reimaged with this agent. And again, the surveillance after treatment is where I see this holding promise for serial imaging following those patients longitudinally with an agent, which I think is probably going to have a higher rate of detection of small lesions, which are indeterminate.

You also mentioned on the call that -- and I appreciate that this will be -- the data will come in a publication, that it seems that the diagnostic performance sort of really held up across the spectrum of small tumor. Maybe before that data, though, maybe if you could give us a sense for whether, I guess, the clinical -- how the clinical decision-making challenge sort of sits today when you're confronted, say, with a 4-centimeter tumor versus a 1-centimeter tumor or mass, I guess, before you characterize it. Just a sense for whether your decision making becomes materially harder with decreasing size?

Yes. I mean, again, for like a 4- or 5-centimeter tumor, if I'm going to consider a radical nephrectomy on that patient, I do not want to take out a benign tumor. I do not want to have them lose their kidneys. So I'm going to clearly use this scan to get more information, and I feel more comfortable counseling a patient that they're going to lose their kidney because they have actually a kidney cancer. And again, what was not mentioned on this call, but was also brought up at GU ASCO is even though the positive predictive value is 93%, 94% for clear cell, you might say, what about those false positives? Well, I think 10 of the 11 false positives were cancer. So I would argue that the positive predictive value is 99% of having a cancer diagnosis, only 93% to 94% for clear cell. For 1-centimeter renal mass, clearly, if you're in a wheelchair, I'm not going to want to treat you. But when the average or median age is age 60 to 70 and a lot of patients have 5 or 10 years of life expectancy ahead of them, every patient always asks me, I'm not sure I'm going to be healthy in 3 to 5 years, why don't I try to get treated now. And again, I think I can give them more information and say, listen, the median rate of growth is actually maybe up to 3 millimeters a year. And for a 1-centimeter mass, if you're going to be living 10 years, I'm going to want to treat you in the next 5 to 10 years. So why don't I just treat you now where it's much easier.

Last question for me, and then I'll get back into the queue. I did notice just in the abstract that it said that there were, I think, 2 cases of adverse events that may have been related to the treatment. Just wondered specifically what you saw there.

So I mean, I think that it's kind of hard. Once they sign consent to the time of their nephrectomy and then they get post-op imaging, that's a treatment-emergent adverse event. I will tell you that I have plenty of patients who have imaging with CT scans and MRIs that are allergic to contrast agents. But Colin, if you want to chime in about what we think is really related to the tracer.

Yes. And look, Shane, I think this is more of a technicality in terms of how we report safety within in clinical trials. We see these events really, as a company, as related to the surgery. So we see a lot of postsurgical events. When we look at what the real window is adverse events after the injection and immediately after the injection of the zirconium girentuximab we see very little. We see some minor injection site reactions that we'd expect. We don't really expect to see anything serious with this product. And I think -- but just to also add, this product has been more used in hundreds and hundreds of other patients as well in other studies, both in real cancer and also previous imaging. So we're pretty confident in terms of the track record and the exposure of the patients with girentuximab to date.

Your next question comes from Dennis Hulme from Taylor Collison.

Good morning. Dr. Shuch, thanks for your presentation. I was just wanting to drill down a little bit further into how clinicians will use this information. We see that if they've got a positive PET, that's really useful information over 90% clear cell. But if you've got negative PET scan, my estimate it's around 40% of patients, 25% will be clear cell, probably over half of them will be renal cell carcinoma of some sort. How are clinicians going to deal with those negative patients? And how useful do you think they'll find that information when they've still got this relatively large pool of patients they're not sure what's going on with?

So I label those patients zircon-hot or zircon-cold, okay? And the zircon-cold patients, again, statistically are more likely to be enriched for papillary, chromophobe kidney cancers or an oncocytoma. I think in those patients, again, you could do further imaging. You could do a triphasic scan, and you're pretty good at picking out the papillary renal cell cancers, which have a slower rate of growth. And again, the incidence of metastasis is very, very low until around 4 centimeters or greater. If you actually had a CAIX-negative scan or again, zircon-cold and then you did maybe a triphasic scan or what's called the sestamibi scan, which is not available, it's not on any guidelines, but it's being used off label for a lot of different patients, you might then say, "Well, that patient is more likely to be chromophobe." I think it really will have a lot of enrichment for those who get biopsied. A lot of people are biopsy never and a lot of people are biopsy always. I think while there's going to be consensus that in the zircon-cold group, there's going to be a lot of patients who probably go for a biopsy to get more information if their radiologists are not really attuned to really try to pick out what is the subtype or flavor of non-clear cell kidney cancer or benign histology. So again, I think that we would use additional modalities to better risk stratify. Again, this is all about getting patients more information, not overtreating, and not unnecessarily treating patients.

And also I was wanting to ask, I noticed in this trial, all the patients had to be going to surgery. We saw 13% of patients had a lesion under 2 centimeters. If we didn't have that restriction, it was just the general population of patients with suspicious lesions, what proportion do you think would be under 2 centimeters in that population compared to the 13% seen in this trial?

That went on surveillance or went on -- or went for surgery?

Well, I guess more who would be candidates for the scan but weren't eligible to participate in this trial.

Well, again, these are patients who were very interested in having surgery. So again, there are plenty of patients who are less interested, and I was able to talk them off the ledge about initial surveillance. So it's very center-dependent about who goes on surveillance and who has surgery. There's actually data from a registry in Michigan where depending on who you saw, your rate of active surveillance could go from 10% all the way up to like 80% for a patient with a 2-centimeter or less lesion. So I don't know if that covers the question, but again, it's dependent on the physician and also the patient. But these are patients who are very motivated to have surgery, and they weren't able to get the scan and then, like, changed their mind.

Right. So would it be reasonable to think that, that under 2 centimeters number might be double if you included all those who actually go to active surveillance?

Double in terms of what, the number that went on to get scanned?

Just the number of patients who are out there who would be eligible for scan if you're thinking about active surveillance.

I mean there's going to be exponentially larger -- so T1a versus like T1b, it's -- the ratio is much higher. So about 50% of the new diagnoses are T1a. So T1b are going to be much lower. So there's going to be a lot more of those patients out there, and this is not representative of the -- of who we see in clinic.

Okay. And I was just also wanting to talk briefly on the utility of checking for metastases on initial staging. I know that wasn't part of this trial, but how useful do you think the imaging agent is going to be for that staging?

So I think it's going to be incredibly useful. The problem is if you're negative, you're not really sure. And if you're positive, are you going to give patient systemic therapy upfront. So we're excited and we're appreciative that the Telix team is supporting a trial, which we're going to do at UCLA, which is going to use it for post-op staging. And I really see this as you know it's clear cell, you know it's CAIX positive, and then you're going to do a scan. And if they have metastatic disease rather than go on adjuvant therapy or be surveyed, you get full systemic therapy. And if you're actually negative, the question would be, would you actually put them on adjuvant therapy, which is now approved in the U.S. and also in Europe? So I think it's going to -- it's going to be the Will Rogers effect really kind of the patients who are zircon-hot outside of their kidney are going to have probably worse, obviously, of outcome. And those who are negative are going to do better. So I really think this holds a lot of promise. This cohort was not advanced stage kidney cancer. Again, I think if it was a Stage III cohort, we'd be confused about exactly what to do with those patients. Do not image them. So I think this was a nice clean cohort to get the answer about first the kidney, and then subsequent data will get -- prove staging. And I'd be very confident based on other work from other investigators that this can pick up sites of disease well.

Your next question comes from Steve Wheen from Jarden.

I just had a question around -- I'm just curious as to why the sensitivity and specificity of the diagnostic dosing that you did was more pronounced in the smaller lesions than the larger ones? Do you have any sort of explanation as to why that was the case?

Well, the outcome was great for both, and the confidence intervals will overlap. So I think you'd probably show that statistically, you're not going to do better for the T1a versus the T1b. It's just that you were looking at 89% versus like 86%. So I think the confidence interval would be overlapping if you were to compare.

Yes. Got it. Okay. And then the second question I had was just with regard to given the age of these patients, did you -- was there any other sort of observations around the diagnostic picking up other cancers, because I believe Telix is pursuing other cancers with regards to this agent?

Yes. I would tell you that they would have been on the trial. So if we did a scan and we saw like a liver lesion or, let's say, something in their pancreas, we probably -- they weren't eligible, I think, to be on a trial if they had a second malignancy that needed to be treated. But again, occasionally, you see that, and it would have been interesting to have those patients to see because you can image. Even though they're not VHL deficient, a lot of tumors have hypoxia. And this is really upregulated focally with hypoxia. And I think the 10 of the 11 false positives were papillary kidney cancers, which are not VHL deficient, they're just hypoxic, and that's a sign of probably a more aggressive malignancy.

Yes. Maybe I can add just a comment on that one as well about the conduct of the study. It was really very focused on patients who had a potential renal cancer, and that was the whole aim of the study. And the source of truth was the nephrectomy, of course, so patients have to be planned to go on and have an nephrectomy. Now, we did allow in those smaller patients whole-body scans, as well whole PET scans. And I think 85 patients had the whole body scans. We did see around about 30 patients who had what looked like extra renal disease. But of course, in terms of how we followed up and what was the clear primary endpoint for the regulators for this, it was just about comparing the image in the kidney with the histology in the kidney. So I think, they are all questions that we can look at in future studies.

There are no further phone questions at this time, I'll now hand over for webcast questions.

So our first question is from [ Johan Z. ] at B. Riley Securities, asking, knowing how PSMA-targeting imaging agents, such as Illuccix, changed the practice in prostate cancer treatment management. Can you put into context how do you view the results from ZIRCON study in renal cancer detection and treatment management?

So for PSMA targeting, again, I don't know if we're going to be using any CAIX targeting agents in the kidney specifically, but it would be very interesting because it is potentially feasible. But again, I think we can show we can clearly detect clear cell kidney cancer. And if you can see it, you can potentially target it with radiopharmaceuticals or like with lutetium. So I think the trial, which is ongoing, led by Darren Feldman at Sloan Kettering, I think, is extremely exciting and that's with nivolumab. But there is, unfortunately, not that many exciting agents for treatment emerging. So I think this is one of the most exciting things that have potential for therapy in the clear cell kidney cancer space.

Brian, can I just ask a bit of a question and jump in there. Just because speaking to a lot of people at ASCO GU and people who treat both prostate and renal cancer, this is that the PSMA imaging has obviously brought people, like you said, the word is they're bringing patients earlier stage and detecting metastases that were already there at an early stage. Do you think this will bring about potential metastatic-directed therapy in those high-risk patients?

Yes, I think so. I think it will be something where instead of just following those patients and then having more and more lesions kind of show up, I would probably still do nephrectomy, and I would probably target those hoping with multimodal therapy, treating with SBRT, surgery, immunotherapy, would hopefully improve outcome rather than just later finding them developing widespread metastatic disease.

I have a related question to that, which is, could you elaborate on other use cases, including staging, e.g., will [ there be ] effect for more advanced tumors and post systemic therapy monitoring for this imaging agent.

So post systemic therapy monitoring is really exciting because never before, other than in the IL-2 era, did we really have complete responses. There are a lot of patients who get like ipi/nivo or cabo/nivo, all the dual IO/TKI therapy, and they have really, really deep responses. There's plenty of patients who have radiation to oligometastatic disease. And I think this will show whether those lesions, which are still visible on the scans, we're actually probably living. Because we don't routinely biopsy them, sometimes the medical oncologists are afraid to stop therapy. But if you had a scan that showed that probably they were CAIX positive and then they reverted, and they had a very small amount of disease, maybe those are the patients you would either de-intensify systemic therapy on or stop therapy altogether. Again, it's really hard to biopsy 3 or 4 lesions, but when you do focal therapy, ablations, radiation and you have still visible disease, you really never know what you treated if it's really dead. And I think if this was hot and then became cold, this would be really promising for that systemic therapy monitoring. And the other question, I forgot. It was 2 parts.

Yes, it was just really more general about other use cases.

Yes. So again, we have a lot of patients who have cystic renal masses. We really have no idea the number of them, but I think it's probably, in the U.S., at least 10,000 or 20,000 patients because I think it's at least double or triple the number of benign renal masses that I see. And for Bosniak 3 renal mass, that means it's a moderately complex renal cyst that has maybe thick walls, some nodules, 50% of those are kidney cancer. And 50% of those are benign. And as you'd expect, the same thing holds true, is that 70% of those to 75% of those are actually clear cell kidney cancers. So there were patients -- and then for Bosniak 4, about 85% of those are also going to be kidney cancer and 15% are going to be benign. And again, 70%, 75% of those are going to be clear cell kidney cancer. We would never biopsy a cystic renal mass, not because we're afraid of the tumor popping and spilling, we just have such inability to get a piece of the wall of that cystic lesion. And there were patients on this study that actually had Bosniak 3 or 4 lesions that were imaged and we're very PET-avid. So I think we -- it holds promise for the large number of patients with Bosniak 3s or 4s to know that we can potentially better inform them about their disease and then do a more intelligent treatment. Because we can't biopsy them and we just usually just take them to surgery. Now, we can have a more intelligent selection for surgery.

Great. The next question. Could you talk a little more about the false positives in the trial, and how much of a concern these represent for treating physicians?

So again, there were, I think, 11 falls positives. And I think 10 of the 11 were kidney cancer. They were papillary, I think, mostly. And again, we know that some papillary tumors are aggressive and some papillary tumors can have focal hypoxia or CAIX expression. So again, to me, for a treating physician, if you add those numbers in, the positive predictive value of diagnosing a cancer is going to be nearly like 99%. I don't consider that a bad thing. I consider that, yes, it is -- there may not be always going to be a clear cell kidney cancer if there's occasionally some false positives. But again, I would have no concern resecting those tumors or using it as an upfront modality to select patients. And Colin, if you want to weigh in about the maybe 1 patient that was incorrect, I think we're doing pretty darn well.

Yes. Look, I mean, I think, as you say, there's -- and the previous question, CAIX is expressed in other malignancies, particularly in those that are hypoxic. And so we don't really understand fully the expression of CAIX in other malignancies, in other renal malignancies. In addition, what we certainly saw throughout the histology was some mixed cases. So I think we've got something here that we can feel confident that we're at least as accurate as the histological sample itself. Bear in mind, histology is looking at a mass, and you're trying to hit a very, very fine needle into very heterogeneous tissue. And so I think what this imaging does is give us a perspective of the whole tumor as well. So we have to use histology as the standard of truth. That's the standard within our regulatory studies. But for me, I think this data gives us very good confidence that we're at least as good as biopsy.

I have a question about the NCCN guidelines and whether the results from, say, a comp would warrant amendment? You may not want to predict that, but perhaps you might want to talk, Brian, to just the process of the NCCN Guideline's admissions.

Yes. So I am, for disclosure, I am on the NCCN Guideline panel, and I would say that a lot of companies come to the NCCN with submissions that don't have large Phase III trials that are positive. They have smaller series trying to get their drug or trying to get like sestamibi imaging approved, and there haven't been something this robust that really hasn't probably gone through. So again, you have a large positive Phase III trial, and when you have people hungry to advance the field, I can see this easily sliding into the guidelines, again, but is a committee vote.

And I just have one last question at the moment, which is what, if anything, would impede the rapid uptake of the use of this imaging agent by urologists?

Again, it's probably just getting access to this. But again, this trial was conducted in 9 countries. And shipping this agent all over the world, the Telix team has been doing that for PSMA. So I think there'd be a very rapid uptake amongst urologists to have this use. And patient advocates are really -- speaking to them after the meeting, they were very excited. And there's a large patient community, guiding other people on the Board of Directors for the Kidney Cancer Association, which there's nurse navigators. I think that there's going to be a lot of interest among patients telling other patients about this scan, so I think it's just a matter of operationalizing it and knowing that when the CEO has been in Indianapolis working on those logistics, I'd be very confident that the Telix team can bring this all over the world very quickly.

Thanks, Brian. And certainly, in this prelaunch period, we'll be out about doing scientific education with centers. And of course, we'll be having a whole range of other studies as well in which people can gain experience in terms of expanded access programs, your study, for example, and other studies where we'll be using this agent, both in clear cell renal cancer and beyond.

Thank you. So that brings us to the end of our questions. Brian, we really sincerely appreciate the time you've taken to take our investors through this presentation. I know that it's been greatly appreciated by some people I've heard from. Colin as well, thank you. So with that, I think we'll draw the call to a close. And again, thank you, and we look forward to working with you on further studies and the rollout of this product.

Perfect. Thanks, Ky. Thanks, Colin.

Yes. Thanks very much. Take care. Bye now.