Telix Pharmaceuticals Limited ($TLX)

Thank you for standing by, and welcome to the Telix Pharmaceuticals Limited Unlocking the Potential of PSMA Therapy: A Next-Generation Portfolio. [Operator Instructions] I would now like to hand the conference over to Mr. Stewart Holmstrom, Director of Corporate Communications. Please go ahead.

Hello, everybody. My name is Stewart Holmstrom, Director of Corporate Communications at Telix. We're very pleased to welcome you today to our educational webinar to present on unlocking the potential of PSMA therapy and Telix's next-generation portfolio approach. We can just move to the next slide, please. I ask you to take a moment to look at our disclaimer. Next slide, please. I'm very pleased to introduce today's speakers. Dr. David Cade, Group Chief Medical Officer at Telix, will present on Telix's PSMA targeting therapeutic portfolio. And then I'm delighted to welcome our guest speaker, Professor Louise Emmett, Director of Theranostics and Nuclear Medicine St Vincent's Hospital in Sydney, a Conjoint Professor of Medicine at the University of New South Wales and Clinical Research Leader at Garvan Institute of Medicine Research and also the principal investigator on the OPTIMAL-PSMA trial that she will present today, along with case studies and perspectives based on her experience with TLX597-Tx. Following the presentation, Dr. Cade will take questions via the conference line and webcast Q&A function. Professor Emmett, who has been very generous with her time already whilst presenting in Europe, will be available afterwards to respond to questions via e-mail. And with that, I'd like to hand over to David.

Next slide, please. Well, thank you, Stu. Today, together with Professor Louise Emmett, who is one of the globally recognized pioneers in the development of radiopharmaceutical therapies for prostate cancer, I'm hoping that we'll be able to enable you to gain from our discussion a useful understanding of 3 important themes. And the first of those is we'll briefly discuss the current first-generation small molecule radioligand therapies and where in the treatment cascade, they've established themselves for advanced prostate cancer. Secondly, we'll also discuss some of the challenges that have emerged in applying first-generation small molecule agents earlier in prostate cancer where patients tend to be fitter and healthier, and why Telix is taking a portfolio approach based on very distinct mechanisms of action with TLX591, which is a radio antibody drug conjugate being developed for advanced metastatic castrate-resistant prostate cancer in the ongoing Phase III ProstACT Global trial. And with TLX591, which we haven't really talked a lot about previously. This is a highly targeted second-generation small molecule radioligand, which has demonstrated a favorable dosimetry profile with a very minimal salivary gland and kidney dose, but a very high tumor dose, which really makes it uniquely positioned for use in earlier metastatic hormone-sensitive prostate cancer. And then thirdly, I'm looking forward to Professor Emmett, who will discuss her St. Vincent's Sydney group's rapidly growing experience with TLX597, which Professor Emmett and her team are studying in the OPTIMAL-PSMA randomized Phase II trial, which Professor Emmett presented very recently at the IPCS Congress in Lugano in Switzerland. So if you go to the next slide, please. So I think this slide really very nicely summarizes on the left-hand side there, how we would typically treat prostate cancer once it's broken free from the prostate gland and it's become metastatic. And what you can see is that for early metastatic hormone-sensitive prostate cancer at the start of the disease journey, we would typically use androgen deprivation therapy to block testosterone and/or would use the newer androgen receptor pathway inhibitors or we may use a taxane chemotherapy, especially if the patient has high-volume metastatic disease. But then what invariably happens is the prostate cancer learns how to progress despite the testosterone tap having been turned off, which is what we call metastatic castrate-resistant prostate cancer, we see that PSMA-617, which is Novartis' agent Pluvicto, is appropriately established for advanced metastatic castrate-resistant cancer over on the right. And this was established 3 or 4 years ago when the VISION trial showed a 4-month extension in overall survival with PSMA-617 when compared to conventional standard of care. And from here, of course, a very logical next development of such an agent is to undertake trials in earlier disease settings, which is what the PSMAddition trial sought to do. But what PSMAddition also showed is that there are emerging concerns when we try to treat earlier, healthier patients. And the 2 main concerns really could be summarized as the radiation dose to the salivary glands that tends to lead to dry mouth that then degrades patients' quality of life as well as the radiation dose to the kidneys, which may lead to long-term kidney injury. So in other words, we're probably overtreating these patients with a first-generation radioligand therapy, whereas what we really need is a second-generation agent that exhibits a very low dose to any of the normal tissues if we're truly going to be able to deploy radioligand therapy widely in early mHSPC. So if you go to the next slide, I think this really does nicely summarize those points that were made at the ESMO Congress in Berlin last October, where Dr. Tagawa from Weill Cornell, he presented the interim data from PSMA addition and Dr. Azad from Peter MacCallum in Melbourne was the discussant, and he critically discussed the results from PSMA addition and the take-home messages that we in the audience should take away for our clinical practice. And -- what he concluded were really 4 key take-home messages. The first of those was the PSMA addition is the first randomized Phase III trial demonstrating efficacy of radioligand therapy in mHSPC. And ultimately, the progression-free survival benefit will probably lead to regulatory approval in multiple jurisdictions. But to date, there's been no improvement in overall survival really shown. And to date, lower quality of life has been exhibited with PSMA-617 in this disease setting. So that's a very important point. Secondly, he reminded us as we sometimes forget that he reminded us that the goal of any cancer treatment is to make patients not just live longer, but also live better, and the discussions view was that this was not achieved in PSMA addition. Thirdly, he indicated that he wouldn't currently recommend the widespread use of PSMA-617 in mHSPC at this stage. And the final point he made, which is very, very important, was that to deliver the best outcomes in mHSPC, it's going to take a really patient-centric approach focused on avoiding overtreatment while minimizing the impact on quality of life and minimizing those late toxicities. So if you go to the next slide, please. And so if we took all that we've learned from the last few years' experience gained with first-generation small molecules and say we were to draw up a wish list, if you will, of those characteristics that a second-generation radioligand therapy would need to succeed. These can be summarized, I think, very simply. So firstly, we would absolutely demand a very low radiation dose to that organ that's responsible for clearing the radioactive drug from the body, which for small molecules is typically the kidney or we prefer the clearance organ to be the liver, which is an organ that is actually quite forgiving of radiation delivered to it. Secondly, we also demand a very low radiation dose to the exocrine glands, primarily the salivary and the T glands. Thirdly, would also demand a higher and more prolonged tumor retention. Especially given the relatively short retention time that characterizes first-generation agents. And then fourthly, we want to be able to apply a very patient-centered approach with both dose intensification, which is dialing up the amount of activity that we administer and adaptive dosing, which is administering only when the patient needs it to simultaneously improve both disease control and quality of life, which Professor Emmett is going to discuss -- she's going to discuss these concepts in a bit more detail shortly. And then finally, we'd ask for compatibility with alpha isotopes like actinium and lead. Next slide, please. And so with those attributes in mind, let's now move to TLX597 or Lu-DOTA-HYNIC-panPSMA to give it its full name. And what was evident right from the very early Phase I trial that was done by Professor Omar's group was that TLX597 is a highly targeted small molecule agent with a dosimetry profile that exhibits a minimal kidney and salivary gland dose while achieving some very significant PSMA -- PSA reductions in heavily pretreated patients. And you can see this in these 2 patients from Professor Omar study on the left-hand side there that he reported at the European Nuclear Medicine meeting just late last year. Now today, Professor Emmett's more recent randomized Phase II trial known as OPTIMAL-PSMA, that's about to complete patient enrollment has further demonstrated the very highly targeted behavior of TLX597, again, with really minimal uptake in the kidneys and the salivary glands, while in Professor Emmett study, additionally confirming very high radiation dose being delivered to the tumors, which is exactly what we want. Now if you think about these properties a little more deeply, they uniquely position the TLX597 agent for the important developmental objectives of, number one, dose intensification and adaptive dosing, which Professor Emmett is going to talk about shortly as well as use in earlier metastatic hormone-sensitive prostate cancer, and Professor Emmett will discuss this concept in a bit more detail as well. Next slide, please. So I think this is my last slide. And I think it really is articulate in its simplicity. And while I won't spend too much time here, this summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are tailored to both the disease state itself as well as the condition of the patient. And the way I would summarize it is TLX591, which employs the radio antibody drug conjugate mechanism of action, utilizes an antibody targeting vector to deliver that therapeutic payload, which enables long tumor retention with limited radiation to the healthy organs as we would want and that the short 2-dose regimen with 2 fractions, 2 weeks apart is primarily intended to allow this agent to be combined with the other standard of care agents that the patients is also going to be receiving in the mCRP setting. And that's the intent of ProstACT Global that many in the audience would be familiar with. Whereas on the other hand, there's a very significant opportunity in mHSPC for TLX597 due to its potentially best-in-class dosimetry profile that makes it uniquely suitable for earlier use in mHSPC as well as the dose intensification to achieve those further efficacy gains. So hopefully, that sets the scene nicely and clearly. And I think it's time I pass the mic to Professor Emmett, who's going to discuss some of the ground -- what I believe to be really groundbreaking work that she and her group has been doing at St. Vincent here in Sydney. So with that, I'd like to pass to you, Professor Emmett.

Thanks, David. So it's a great pleasure to be here and to be able to discuss OPTIMAL-PSMA, which we've been beavering away at now for about 9 months. So just next slide. The OPTIMAL-PSMA is a randomized Phase II trial, and it is about -- it's about dose intensification compared to standard of care dosing, and it really originated from this slight frustration, I guess, of the fact that we're dosing 6 doses, 6 weekly, most doses of 7.4 gigabecquerel, and we based that dosing on external beam dose constraints to the kidney. We haven't based it on efficacy. So we've done a number of randomized Phase III trials at the moment now where we haven't had a lot of significant kidney dose, but we struggled with overall survival. We have shorter progression-free survival than I would like to see with PSMA radioligand therapy. And the question is, are we actually optimally dosing? So OPTIMAL-PSMA is about evaluating the dosing interval and whether we should do short intensified dosing right upfront to attack the cancer cells when they're most vulnerable. And then have maintenance or why I call it mowing the lawn a little bit later. So we're doing 6 doses on each arm over 6 weeks, but we're dose intensifying upfront in just one of the doses. And it was very nice that we were able to really do some work on Lu-PSMA-597 before the trial started. So with safety lead in with the trial and looked at the dosimetry. Dosimetry is a big part of the trial, and we're doing a lot of translational work as well. But perhaps we can just look at the next slide and just have a look at the dosimetry. So this is dosimetry that's been derived from the safety lead-in first 12 patients of the trial. So single injection, so first dose of these patients, they had 3 time point dosimetry with the TLX597 and just compared to previous publications of PSMA-617 and PSMA-I&T. What we see with the dosimetry and it's been done twice. It's been done by our physicist and it's also been done formally by Ascinta Technologies. So I'm happy that these results in the nontarget organs are absolutely 100% correct. The kidney dose is 0.28 gigabecquerel, sorry, compared to 0.58 and 0.71. And then when you look in the lacrimal salivary gram, you've got significantly lower lacrimal salivary grand activity than either PSMA-617 or PSMA-I&T, but we don't have lower tumoral activity. So that's a really nice combination. Low salivary, low kidney maintained tumor, and that's really what you want to see. Next slide. So when we look here, we've got -- on the left, we've got the 4-hour, 24-hour and 120-hour delayed imaging, SPECT after a single dose of Lu-PSMA-597, 7.5 gigabecquerels. 4-hour image, you can see a lot of background activity. You can see some low-grade salivary gland activity, not very bright, really almost struggled to see the kidneys, but quite nice bright tumoral activity. 24 hours later, tumoral activity looks a bit brighter, salivary gland activity looks a bit less bright, once again, struggling to see the kidneys because there's quite a lot of bowel exclusion with this agent. And then 120 hours, really nice bright tumor. almost can't see the salivary glands at all and definitely can't see the kidneys. So on your right, similar time point, we're comparing this to PSMA-617, SPECT dosimetry. And you can see those salivary glands are really quite bright and they stay bright up to 160 hours following injection. Similarly with the kidneys, you can see quite bright activity within the kidneys, staying bright up to 168 hours post injection. So I do think that this is a very nice dosimetry, David. I actually think this is optimal dosimetry for a small molecule, right?

Yes. Well, I think Professor Emmett, it would be really interesting to sort of hear a little bit more about what prompted your -- I mean this is very intellectual thinking what you've set out to do in the study. It's one singular question you're aiming to answer, which is does dose intensification, which is really the constant tendering together of the first 3 fractions. So you're dosing day 1, day 3, day 15 very intensively. The underlying thesis that you formed in designing this trial was the upregulation of the PSMA target. So maybe you could talk about the data on that, the literature on that and why you thought that this approach might work.

Yes. So actually, it's the upregulation of the PSMA receptor with DNA damage is an appealing concept and there's some preclinical work on that and some work we did at St. Vincent's. But the other thing is we've got -- the radiobiologists tell us that when we hit with lutetium, it's all done and dusted within a couple of days. And there's some very nice work in lymphocytes that show that you have radiation induced foci for up to about 96 hours. But after that, it's all healed. So DNA damage repair heals at all. And so 2 things. What I'm really interested in is if we -- instead of just giving one big dose upfront, we split it up and we give it in a time fashion to when the DNA damage is not yet healed, do we get a deeper hit by hitting already damaged cells. That's one thing. And then Johann de Bono's lab, she and et al a couple of years ago published a very nice work that if you damage the cell -- prostate cancer cell, particularly mCRPC prostate cancer cells with radiation, you actually increase PSMA expression. And that happens in the first few days as well. And so we actually explored that last year, we presented at PSMA Theranostics Conference a series of patients where we did day 1, day 7 dosing with Lu-PSMA-I&T and 2/3 of those patients actually had increased PSMA expression. So putting the -- wanting to hit while the cell is damaged together with wanting to have increased PSMA expression, we came up with a day 1, day 3 dosing, but then we thought Scott Tagawa has got some great outcome data of day 1, day 15. So we did day 1, day 3 and then day 15. And so obviously, that's a brave trial to be doing because we would clearly be concerned about toxicity. So we have done a series of data safety monitoring Board meetings within the trial to see whether we ran into toxicity at all. But the idea is if we can intensify dosing and time it to the radiobiology and the PSMA biology, can we actually get really, really deep responses in these patients. So next slide.

Understood.

So this is actually the trial schema. It's a randomized Phase II, as you said, it's a 2:1 dosing. So we've got 80 patients in the dose intensified arm. We've got 40 patients in the standard of care arm. Patients had to have metastatic castrate-resistant prostate cancer. They have to have failed an ARPI -- they have to have failed docetaxel or be chemo ineligible for docetaxel, but a lot of patients on this trial have actually failed 1 or 2 lines of chemotherapy that have quite high-volume disease. And then in the first 35, 40 patients on the trial, we actually started at 7.5 gigabecquerels in the dose intensified arm. So we gave 7.5 gigabecquerels day 1, day 3 and day 15 and then 10 weekly in the experimental arm. And in the standard of care arm, it's 7.5 gigabecquerels, 6 doses, 6 weekly until no longer clinically benefiting, which is essentially standard of care. And all patients have a PSMA PET scan. So we started off using the vision criteria with the PSMA PET scan. We actually moved to the ENZA-p criteria after the first data safety monitoring meeting. And then we do a repeat PET at 8 weeks on all patients in the trial.

For these patients given your referral patterns from both metropolitan Sydney and regional centers, what is the patient population? What prior treatments have they been exposed to given that in Sydney, Australia?

It's a mix. The vast majority of patients have had docetaxel. A significant proportion of patients have had both docetaxel and cabazitaxel. All patients have received at least one androgen receptor pathway inhibitor, all patients are metastatic castrate resistant. I think we have a very high volume of disease on the trial because we don't have much access in Australia to lutetium PSMA therapy at the moment, we've deliberately made the inclusion criteria of this trial very broad. We take very sick patients. We take super scans. We take patients who are hemoglobins of 80 and falling and we get these patients on to this trial. So the primary endpoint, because we're looking about whether we can go deeper, whether we're going to be deeper in terms of our responses with dose intensified, the primary endpoint is PSA 90% response rate. I think that's quite a high bar in terms of primary endpoint. But we're also looking at PSA 50% response rate, PSA and radiographic progression-free survival, overall survival. And importantly, safety, quality of life and dosimetry. So we're doing multi-time point dosimetry in all the patients on the trial on both arms so that we get very good data about Lu-PSMA-597. We're going to be able to look at biologic effective dose of dose intensified dosing compared to standard of care dosing. We've also doing ctDNA on this. So we're doing ctDNA at multiple time points, so we can look at ctDNA clearance. So we're actually clearing cancer cells from the blood using a more intensified dosing than we are with the standard of care dosing. And because Lu-PSMA-597 is so new, the standard of care gives us a great opportunity just to see how it benchmarks compared to other lutetium PSMA agents, small molecules and antibodies in terms of toxicity and effect.

I think an obvious question is, given the extent of prior treatment that these patients in this trial have received, how are they in your experience so far? And I know you've recruited very rapidly, how are they tolerating that dose intensified regimen in the experimental arm? Could you comment on that?

Yes. So it's one of the things everyone thinks you're very brave and looks at you slightly a stance that we're even thinking about doing this dose regimen. And when I first put the patients on the trial, I told them they may need blood transfusions, they were going to feel terrible. They were going to have this, they were going to have that -- it's been very interesting in terms of the toxicity. The toxicity has been very low. We did the Data Safety Monitoring Board meeting with the 8.5 gigabecquerel dose intensified in March. And so we looked at the first 10 patients who had dose intensified Lu-PSMA-597, and that was after 10 weeks. And I think we had 5 grade -- so we had 5 grade 1 anemias. We had 2 Grade 1 thrombocythemias, we had 1 patient who had grade 1 xerostomia and 2 grade 3 lymphopenia. So it is well tolerated. I will say that with the dose intensification in patients who have very high-volume disease, we do make pain worse in the first couple of weeks. So they get a really big response to this dose intensification at their sites of disease. We do have to make sure they have a pain plan, and we do put them on dexamethasone for the first couple of weeks just to reduce the fatigue that they might feel as well. That's actually a treatment response effect. So get a bit of pain around the time of lutetium, that's a good sign. No pain is not a good sign. So -- and then their pain is great. They're coming off their opiates. They're feeling very good. What I really want from this -- so they're great. We're not having any problems on this trial, but what I really want to know is can we make it last longer as well?

Yes. Yes. Understood.

Next slide. So this is just a couple of the early patients. And it's one of the things that just showing what's happening between the day 1 and the day 3 dosing in these patients, and it's pretty uniform. So when we did the first injection, you can see here, it says dose 1, day 1 on the far left, the SUV max the salivary gland was 11, SUV mean 9.4 of the tumor. And this patient got metastatic disease in bone in their mid-thoracic spine, and they've got a series of lymph nodes in their paraaortic region that you can see there. And then if you go to dose 2, day 3, so this is the SPECT images taken after the second injection, day 3. You can see the salivary gland looks a lot less bright, right? So it's gone not as bright and the SUV max is 5. And then -- but the tumoral intensity has actually gone up. So the SUV mean and the tumor has gone up to 14, the SUV max has gone from 51 up to 124. So we're getting increasing intensity in the tumor, and we're getting reduced intensity in the salivary gland. And if you look at the next patient, you can see the same thing. So salivary gland activity, dose 1 day 1, SUV max 5.2, dose 2, day 3, it's gone down to 1.8, you almost can't see it at all. So it's super, super interesting that you are reducing salivary gland activity while increasing tumoral activity. And in this second patient with very high-volume disease, you can see the SUV mean's gone from 5.7 to 7.9, SUV max gone from 25 to 74 and the tumoral volume has gone from 2,379 ml to 3,977 ml. So whatever the mechanism, we're getting a lot more lutetium into those cells with the day 3 dosing. The question is whether we're getting more dose into those cells than we would dosing them week 1, week 6. And that's one of the big questions of the trial really.

And would you say that -- I mean, this is -- I don't know if you can answer this question, but would you say that there is a correlation between the low radiation dose imparted to the normal tissues that you don't want to hit and the tolerability, the tolerability safety profile of what you've seen? Or can you not come to that conclusion yet?

I don't think -- we'll do all 120 patients and draw that conclusion. We're giving -- we're giving 25.5 gigabecquerels in 2 weeks. And in that data Safety Monitoring Board meeting, we had 1 patient with Grade 1 xerostomia. So I'm super happy with that. I don't know whether that's because we're saturating. There's a different mechanism of uptake in salivary glands to tumor. We know that. And it looks to me like this dosing regimen is saturating the salivary glands, but it's not saturating the tumoral activity day 1, day 3. So we know if we gave cold PSMA and then gave an injection of lutetium PSMA, we would have reduction in salivary glands and we'd also have reduction in tumor. But perhaps the regeneration of the PSMA expression in tumor is so fast that we've still got saturation in salivary glands in day 3, but we've actually overcome the saturation that we might have had with the injection by day 3 in the tumor, and we've got increased expression in -- either in relation to DNA damage or because we're overlying dose and we've got persistent activity because this agent has got really nice persistence in the tumor cell. Either way, I don't care. It's looking really bright. I can see we're getting a really nice deep radiation dose to all of those sites of disease where we want it, and we're not getting it where we don't want it. So I'm happy with that. That was -- that's cool. Those images are really cool for me.

I like the images, too. Yes, thank you.

Next slide. So this is just one of the patients on the study, and these are 4 our SPECT images actually underestimating the volume of disease of these patients. This is a patient who's pretty classic for us post chemotherapy post 2 lines, obviously, post-op because that's an inclusion criteria, very high-volume disease. PSA is 1,380, hemoglobin 112, platelets 200. So what we have here is the day 1, day 3, day 15 dosing. And these are the SPECT images that are all taken 4 hours after each injection, and then we have the week 10 dosing. So you can see that in this patient, the day 1 dosing, high-volume disease, day 3, it looks -- the volume has gone up again. Day 15, you get the impression it's not as bright. There's things going down. And then by week 10, there's a marked reduction in the number of sites involved. So a marked reduction in the volume. And you can see PSA has gone from 1,380, day 3 has actually gone up, and that's something that we routinely see. Pretty mixed at day 15, sometimes it's up, sometimes it's down, but down to 40 by week 10. So really nice PSA response there correlating with the really nice SPECT imaging response that we see at the week 10 dosing. And very nice to me the hemoglobin is maintaining itself and the platelets are maintaining themselves. So we're not getting a lot of -- we're not getting extreme hematotoxicity at all in these patients.

Yes. It'd be interesting. I'll ask you at the end, but your view as you go through your view on where the behavior of this peptide small molecule lends itself to future development because you're going to touch on that with earlier use. So back to you.

Yes. So next slide. Yes. I think we're almost there. I mean I -- so the OPTIMAL-PSMA trial is a randomized Phase II. We're at -- I think we are randomized -- we possibly -- I think we randomized the 90th patient today out of 120. We are getting another site on board, but that's essentially 90 patients at a single site at St. Vincent's Theranostics department in Sydney. As you're saying, David, a lot of these patients are rural. They come from all over the place to receive this treatment. So it's wonderful that we've been able to help them with this trial and that they've tolerated it well enough. A lot of patients are getting to the end of treatment. So they're getting all 6 doses, which is also fantastic. The median number of doses in therapy was 4, and that's because patients progressed around that time. About 45% of patients have progressed by dose 3 in the therapy trial. And so to me, that's the thing to be keep them on trial longer and see how long we can keep them on trial, how long we can keep them alive and feeling well.

Yes. Yes. Well, as I talked about earlier in the intro, Professor or Dr. Azad, a colleague of yours from across the border in Victoria down to [ indiscernible ] made that very thoughtful discussion session of PSMA addition and talked about some of the requirements for an agent for metastatic hormone-sensitive prostate cancer. I think it would be very interesting to get your thoughts on the development in that disease setting and your OPTIMAL-E trial that you've already, I think, got IRB approval for.

We do. So I think one of the reasons why we had the baseline PSMA PET and then the week 8 PSMA PET was we're thinking with the intensified dosing, we might be able to stop treatment in some of these patients. And we do, do treatment pauses frequently with -- so they continue the ADT, but they pause treatment with lutetium PSMA until they get first confirmed right, most patients who have a marked reduction in PSA and volume on their SPECT or their PET images. We haven't -- we've had very high-grade aggressive disease in the patients here. A number of these patients are actually super scans. So we've had good deep responses, I believe. But we haven't paused treatment in any of the patients in mCRPC. But I think in mHSPC, you have much better behaved clonal populations. You have more sensitive disease. It's a combination. It's always combinations that you use. So PSMAddition is ARPI, so androgen receptor pathway inhibitors plus ADT plus lutetium PSMA. And we showed in the ENZA-p trial that if you use 2 effective agents together, your responses are massively deep. Our PSA 90% response rate in mCRPC in ENZA-p was 95%. So if you're using ARPI plus ADT plus lutetium very early, you're going to get extremely deep responses and a lot of patients will have no disease left. If you just keep treating them, then you're going to end up getting a higher dose to the non-target organs. So I think Lu-PSMA-597 does lend itself well to the earlier space. It's got low salivary gland, low kidney activity. We haven't seen a lot of hematotoxicity yet. But of course, we have to read out the whole of OPTIMAL-PSMA. And so it does lend itself to going earlier. But I think it also this idea of adaptive dosing in the hormone-sensitive space where you treat upfront, then if you lose the target, you stop, you continue the very active ARPI and ADT regimen. And then at first confirmed PSA, you retreat again. So next slide. I think we've got the OPTIMAL-E concept. So this is OPTIMAL-E. This is the version of OPTIMAL-PSMA accepted in the metastatic hormone sensitive space for patients who've got metastatic disease at diagnosis. You can tell it's designed by a nuclear medicine physician because it's dust full of imaging. And we really want to see what's happening to that target as we go. So there's a screening PET to make sure they've actually got disease. And then the patient goes on ARPI, so an androgen receptor pathway inhibitor, either enzalutamide or abiraterone or darolutamide. And then at day 8 after commencing the ARPI, they have a PSMA PET. And then we commence day 1 and day 3. So we do a dose intensification, 8.5 gigabecquerels of those patients on the trial. We do a 6-week dose. We do a 12-week PET -- and then if there is no residual disease on the 12-week PET with the lutetium PSMA ARPI and ADT on board, we stopped the LU-PSMA-597. So ARPI and ADT would continue until first confirmed PSA rise and then we would start administering again. If there is residual disease, then we give another 2 doses of Lu-PSMA-597 at week 14 and week 22, and the patient has another opportunity at 6 months, so week 24 to see whether there's -- whether all disease has gone on the SPECT as well as the PSA -- around the PET as well as the PSA. And if it hasn't, they get another 2 doses. So this is what we call adaptive dosing. We're trying to treat when the target is present stop if it's not present and then recommence again the minute target starts to come back. And we look at target coming back based on PSA rise. So the question is how long can we go in some of these patients with very well-behaved disease with a dose intensification upfront with the lutetium PSMA and then stopping if they've got well-behaved disease. Is it years? I hope -- I really hope that, that's years before that clonal population comes back. In the ENZA-p trial, which we did a similar thing, we did a PSMA PET so that we could start and stop treatment, some of those patients only got 2 doses, and it's 6 years now, and they still have no measurable disease. So can we treat multiclonally and actually eliminate whole clonal populations for these patients, potentially cure.

Yes. So in your mind, what would you want to see? Obviously, OPTIMAL-E in metastatic hormone-sensitive prostate cancer is really the first proof of concept with dose intensification and dose adaptation so that we don't overtreat blindly a patient that negatively impact the quality of life. What would you want to see from such a study if you were to say, right, based on achieving this outcome, this warrants a registration enabling pivotal trial in this early disease setting?

Okay. So I hope we get a number of patients with reasonably high-volume M1 disease in this small study. I hope that we see that the ARPI and the ADT and the lutetium PSMA are working extremely well together with the dose intensification such that when we get to week 12, 3 months, I'm hoping we have a very high proportion of patients who have a PSA of less than 0.2 and nothing left on the PSMA PET. A lot of the benchmarks for overall survival in mHSPC is around the week 24 mark with a PSA of less than 0.2. What proportion of patients can we get to that? So if you're just ARPI and ADT and you are using and you're not using lutetium PSMA, that's about 68% of patients you would expect to have a PSA of less than 0.2 at 6 months. What proportion can we get to without inducing a lot of toxicity just by dose intensifying upfront and then giving patients an opportunity to de-intensify their treatment and go back to the ARPI and the ADT again. And then how does our quality of life compare, say, to 6 doses upfront. There are other trials that are doing this. [ MPP ] has got a very interesting design. It's using -- it's giving baseline, it's giving day 1, day 7, 7.4 gigabecquerels of Lu-PSMA-617 with ARPI and ADT. And then 6 weeks later, it's giving day 1, day 7 again and 6 weeks after that, it's giving another day 1, day 7. So dose intensification is happening at day 1, day 7, not day 1, day 3. So I think they're beyond the window of the DNA damage. And then they don't have the adaptive dosing design. And I think the adaptive dosing design is something that patients want -- they will want that. And I do want to know whether it works. Certainly, in the studies that we've done in the castrate-resistant setting, we've see no disadvantage to stopping treatment with losing the PSMA target. Patients feel well. They're not coming in for continued treatment. They don't have the associated toxicity. They don't get the very dry mouth. Potentially, we're avoiding renal toxicity, and then we're treating when they really need it when the PSA starts to rise again and the clone is on the move.

Yes. That's very clear.

I think it's interesting. We've got different ways of doing it. But if we got to week 24, all of our patients had a PSA of less than 0.2 or 95% of them had a PSA of less than 0.2 and 70% of them have been able to stop treatment because they didn't have anything left on their PSMA PET. I think that would be amazing. We'll see.

Yes. You say that would be your benchmark for saying, right, it's pivotal trial time. Yes. Understood.

Well, that's my benchmark. Obviously, other people will have different benchmarks, but I would be pretty happy with that.

Yes, very clear. Very clear. Okay.

I just want to say one thing, David. And that is we're so grateful to do this trial. Our OPTIMAL-PSMA has provided treatment access to many men across New South Wales in Australia. They are very grateful. I'm grateful that Telix has provided this access to this drug. It's been fantastic. But I just want to shout out to my team. Putting 90 patients on as a single site with a randomized Phase II trial has been heroic, and I really want to say thank you to them.

No. I think Professor Emmett, that's a critically important point. I've never seen a single center trial enroll at the rate that you've been able to do. So you and team and your patients are truly something out of the ordinary. Thank you.

Next slide.

Okay. So look, on behalf of those who have dialed in to the webinar, I'd really like to thank Professor Emmett, who's, I think, evidently doing some of the most evolved thinking in prostate theranostics at the current time. These are concepts that take a lot of CTU cycles in an academic brain. And I think we're seeing that a lot of thinking is going into this, Professor Emmett. So I hope today's discussion has gone some way to look, clearly articulating Telix's portfolio approach based on 2 very distinct mechanisms of action, TLX591 in metastatic castrate-resistant prostate cancer, but now TLX597, which is exhibiting some best-in-class small molecule distribution and dosimetry and tolerability characteristics that we believe make it really uniquely suitable for achieving the requirements for metastatic hormone-sensitive prostate cancer that was so well articulated at ESMO last year, i.e., that the goal -- number one, the goal of any anticancer treatment is to make patients live longer and live better. One without the other is not sufficient. And i.e. that to deliver the best outcome in metastatic hormone-sensitive prostate cancer. It's going to take a really patient-centered approach, which Professor Emmett has really, I think, driven home about not overtreating and adaptive dosing, focused on avoiding overtreatment, focused on minimizing the impact on quality of life and focused on minimizing late toxicities. So with that, I'd like to thank you, and I'll pass back to the operator, and we'd be very happy to take any questions from the audience.

[Operator Instructions] Your first question today comes from David Dai from UBS.

So just on the safety, it looks like dosimetry of bone marrow is correlated to tumor lesion, whereas patients without extensive bone lesions have limited dosimetry of bone marrow. So based on this data, how should we think about the potential hematological toxicity for TLX597, especially in early line hormone-sensitive prostate cancer patients?

Yes. Thanks, David. Great question. I think as you've seen, Professor Emmett presented the preliminary dosimetry, and she was at pains to explain that, that was in the first 12 patients that were enrolled to the trial. Ongoing dosimetry work is being done. But it's very clear that the dosimetry is at a multiple PSMA-617. It's a multiple of that agent in the tumor lesions and it's a percentage or it's a fraction of relative to that agent in the nontumor compartment. And that's the salivary glands, that's the kidneys and that's the bone marrow. So Professor Emmett has not extensively reported on the bone marrow dose, but it is similar to the kidney and salivary glands, very, very low. And that's why the hematological toxicity with small molecules as a class of drugs, but in particular, with this second-generation agent, the bone marrow dose is also very, very low. And that's what's correlating with the low clinical expression of hematological toxicity. So it's a very consistent profile, David, across the tumor compartment and the non-target normal tissue compartment, whether it's salivary gland, kidney or bone marrow. Does that answer the question?

Yes, that's really helpful. And so maybe just kind of follow on the dosimetry. So I just want to kind of follow a little bit more. Just based on the SPECT biodistribution data, it looks like there is some dosimetry in GI. So maybe just talk a little bit more around what do you think potential GI tox look like, especially the constipation or diarrhea and vomiting that we're seeing Pluvicto. Do you expect this to be replicated in PLX-591 as well or 597 as well?

Well, we don't, no. And the reason we don't is that this is a -- we are developing -- just to be clear, we're developing a new radiopharmaceutical. It is not in any way a generic version of Pluvicto. So it's a new -- it's got a new structure to it. It's basically being designed with a different linkage to Pluvicto and PSMA-I&T and the other small molecule agents that fundamentally alters its chemical and its physiological properties. Unfortunately, I can't really disclose more than that, but those altered chemical and physiological properties govern its biodistribution, which is essentially where it goes. And ultimately, where it goes governs the dosimetry, the radiation absorbed dose that it physically imparts. And so all of the off-target or off-tumor tissues are touched by this asset very, very minimally, and that includes the GI tract as well. So the adverse event profile that Professor Emmett has observed in her 90 patients that she reports to her independent data monitoring committee have had very low constitutional side effects, fatigue, nausea, vomiting relative to the other small molecules.

Your next question comes from Andy Hsieh from William Blair.

Thanks for answering a very important perhaps long overdue clinical question about dose intensity and optimization. So I have a question about the patient enrollment criteria. I think for the OPTIMAL-PSMA, the enrollment criteria was VISION and then transition to more ENZA-p. And so maybe for the first part, I'm wondering if you could talk about why ENZA-p enrollment criteria is enriching patients who will be likely candidates for intensification.. AND also the rationale for the OPTIMAL-E, it seems like it went back to the VISION study. So maybe kind of the rationale behind that enrollment criteria. And then maybe a quick one -- so for docetaxel -- sorry, not docetaxel, for dexamethasone usage, I believe that dexamethasone also reduces PSA. So I guess when you look at the PSA reduction down the road, I'm curious how you would interpret the data delineating between the 597 contribution also the dexamethasone contribution.

Yes, Andy, basically characteristically solid question from you. So the first question, just to restate it is you asked about in Professor Amit's current on foot OPTIMAL-PSMA trial, which is enrolling 120 patients is the target, and she's done, she's enrolled 90 of the 120. During the trial, she increased the PSMA positivity criteria where she started with the VISION criteria and she tightened the criteria to the ENZA-p criteria, which is a study that she was the principal investigator on. Now the primary reason she did that was that these patients in Australia are very late stage, so metastatic castrate-resistant prostate cancer, very heavily pretreated, and they have failed or sorry, progressed while on or become intolerant to all of the conventional therapies, which is primarily and taxane chemotherapy, mostly cabazitaxel and docetaxel. So these patients are very heavily pretreated. And what Professor Emmett wanted to do was to evaluate in this trial whether she could -- she started with a dose intensified regimen. She wanted to further dose intensify, which she did during the trial with the permission of IRB. She went from 7.5 to 8.5 gigabecquerels. So she inject -- she is now injecting a much higher amount of activity at each injection and she's constant tendering the first 3 injections together, if you will, on day 1, day 3, day 15. So that's a very dose intensified regimen. And what she wanted to do was make sure that with that heavily dose intensified regimen and in the population of heavily pretreated patients that she was making sure that they were highly PSMA positive before they're enrolled as a means of making sure that they were appropriate patients. So that's why she's done that. In terms of what this OPTIMAL-PSMA trial has shown. It has shown that this molecule is -- it really facilitates 3 objectives. Number one is dose intensification and dose adaptation, which is only treating when the target is present and not overtreating when it's not present. Number two, this has shown that the off-target deposition in the normal tissues uniquely lends itself to the metastatic hormone sensitive prostate cancer setting, which is what this trial OPTIMAL-E will evaluate. And then thirdly, if you think more over the horizon, it lends itself to use with an alpha isotope again, because of the low deposition in the kidney in particular. So that slide Professor Emmett has already planned and got approval for OPTIMAL-E, which is the study she talked about, Phase II trial in 20 patients that is combining this agent with conventional androgen deprivation therapy and ARPI. Now I can't really comment on really the role of steroid -- concurrent steroid. But she will look at the 4 ARPIs. She'll start with darolutamide and enzalutamide and then expand this trial to apalutamide and abiraterone. So all 4 will be studied and then we'll be able to answer that question once those data are in hand. So it's a detailed answer to a very thoughtful detailed question, but I hope that addresses it, Andy. I think we've got time for a couple more questions. We've got about 2 or 3 minutes to go.

Your next question comes from Melissa Benson from Barrenjoey.

I just wanted to kind of step back and understand, I guess, the rationale a little bit more about the 2-product strategy. If it is kind of focused and it seems like it's based on this reduced salivary uptake, low renal clearance, those are kind of both attributes of 591, obviously, because of its antibody in nature. So trying to understand, is it perhaps that the heme tox profile is less acceptable in kind of earlier stage hormone-sensitive disease and that's kind of part of the rationale. But also, is there anything that -- I remember you had the prostate TARGET trial with 591, which was kind of in that earlier like a BCR setting, but some of those patients are effectively hormone sensitive. Is there anything you learned in that, that's kind of guided this need for kind of a 2-product bifurcation?

Yes. Thanks, Melissa. And I think it's -- that's an important question, but it warrants a thoughtful answer. And I think the key point is that we at Telix fundamentally focused on the patient and a focus on the patient requires a focus across the entire disease journey or spectrum. And you can see that in the prior composition of the therapeutic portfolio for prostate cancer. It includes TLX591, but it also includes the development of TLX592, which is actinium, an alpha therapy, which must follow lutetium, it can't go ahead of lutetium. And then after alpha, an agent for bone pain, which is a sort of a prepalliative stage of the disease journey. So we have -- we continue to develop 591. It's uniquely positioned as a radio antibody drug conjugate for metastatic castrate-resistant prostate cancer. And I think we've its unique virtues in a very detailed kind of way. It's the long tumor retention, it's the prolonged radiation dose deposition and the fact that it is able to be given as a 2 fraction, 2-week apart dosing regimen really lends itself to be intercalated or combined with conventional standard of care that a patient is going to get. So we're asking the question, can we layer on top of standard of care a radio antibody drug conjugate. From there, though, we have looked upstream to mHSPC. And we have really thought deeply about the findings of PSMAddition, and we have been thinking about this for a long time. And we don't believe that just treating blindly with 6 fractions when the target life disappear is in the best interest of the patient. So we believe that in that early disease setting, a mandatory condition is that you do not do 2 things. You cannot adversely affect the patient's quality of life by having significant off-target effects. And secondly, you cannot injure critical organs like the kidney and have long-term toxicities because these patients, we are aiming to help them live a long time, measured in years. So we cannot be allowing them to live for years, but with renal injury and potentially renal dialysis as a consequence. So that's why it requires a very patient-centric approach and a fundamental rule in medicine is to do no harm, first of all, do no harm. So that's why we think an asset like this is intended for metastatic hormone-sensitive prostate cancer in that early metastatic setting. That's what I would want if I was a patient. So I hope that makes sense, but that's our view of the world. And I think it's a very thoughtful view of the world. And I think you can hear the sort of ambition that Professor Emmett hands in taking this upstream to where she's currently studying it. I hope that answers the question. I think we're probably at time. But if there -- I just apologize if there's any other questions that we haven't been able to get to. We would be very happy to have those triage to our Investor Relations team. And Professor Emmett was at pains to say she'd be delighted to respond to any questions. It's 2:00 a.m. in Europe at the moment. So we can't ask her to do it right now, of course. But within sort of the next day or 2, she'll be very keen to respond. So I'll hand back to the operator with that. Thank you to the audience for dialing in, and thanks for your attention.

Thank you. That does conclude our conference for today. Thank you for participating. You may now disconnect.