Morning, everybody. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communications at Telix . We're very pleased to welcome you today to our investor call and webcast to present the results of the ProstACT Global phase III study, Part 1, safety and dosimetry lead-in. I'm just looking to the next slide. Just ask you to take a moment to have a look at our disclaimer. Then moving to the next slide. Very pleased to introduce today's speakers. Dr. Christian Behrenbruch, our Managing Director and Group CEO, will make some brief introductory remarks. Our Chief Medical Officer, Dr. David Cade, will present the data. Then I'm very pleased to welcome our guest speaker, Dr.
Pedro Barata, Medical Oncologist with the University Hospitals Seidman Cancer Center, and Associate Professor of Medicine at Case Western Reserve University School of Medicine in Cleveland, U.S.A., and also a ProstACT Global Steering Committee member and investigator on the trial to also share some case studies and his perspectives. Following the presentation of the data, we will open the call up to questions from analysts. These through the conference call line. These will be focused on the clinical data. For the questions that we don't get to or questions on the webcast, we will respond to you at the conclusion of the call if we can't get to your question. With that, I'd like to hand over to Chris.
Thanks very much, Ky. I'm gonna actually hand over to my clinical colleagues in relatively short order, but I would like to make a few brief introductory comments. We're delighted to present the results of the ProstACT Global phase III study Part 1, and we thank you for your patience as we closed out the study and completed the data and dosimetric analysis in preparation for engagement with the FDA. As a reminder, this Part 1 study is a specific requirement of the FDA in order to proceed to Part 2 in the United States. ProstACT Global is a highly innovative trial that is designed to integrate with current standard of care in the castration-resistant metastatic prostate cancer setting, including in combination with androgen deprivation or ARPI switch. ARPI switch is the preferred standard of care in this patient setting in the United States.
However, this study design also reflects the fact that in many parts of the world, patients still receive chemotherapy following treatment with an initial ARPI, largely due to its cost-effectiveness. As such, both approaches are permitted in this study. The data that is presented today confirms the safety profile of TLX591-Tx in the combination therapy setting, and while an important milestone for investors, is not an entirely unexpected outcome given that we had an independent data safety review committee grant clearance last year to progress to Part 2 randomization in the ex-U.S. jurisdictions where we already have regulatory approval to proceed. Having now formally closed and read out the study, this enables us to go back to the FDA to obtain an IND amendment to include American patients in Part 2, subject, of course, to agency approval.
As a reminder of the purpose of this gating study from the FDA perspective, the agency is looking for us to demonstrate safety, dosimetry, and feasibility with combination therapy, and particularly the comparisons between the different ARPI combos. As you will see, the data indicates that TLX591-Tx can be integrated with standard of care, both ARPI and taxane, no observed drug-drug interactions, and no new or unexpected safety signals. Drug is well-tolerated on top of standard of care in all three treatment arms. Additionally, and this is very important, based on the adverse event profile and specifically recovery from treatment-related AEs, there would be no impediment to patients receiving further treatment upon progression, including, if required, taxanes. We're now focused on enrolling Part 2 of the study globally as quickly as possible.
Part 2 has quite a different recruitment cadence than Part 1 due to the more streamlined nature of the second part of the study. It is our belief that in the not-too-distant future, combining TLX591-Tx with standard of care in the first and second-line metastatic setting will give physicians new options to treat patients and potentially better outcomes after failing first-line therapy. Finally, before we move to the specific study outcomes, I want to acknowledge with gratitude the patients, their families, and our clinical collaborators that continue to support this important trial. I'd like to especially acknowledge one of our key investigators, Dr. Barata, who joins us today as a speaker alongside Dr. David Cade, our Chief Medical Officer. With that, I will hand over to the clinical team to go into the detail of the study outcomes. David, over to you.
Thank you, Chris. If we go to the next slide, today, together with Dr. Barata, I'm gonna take you through the outcomes from Part 1 of our phase III ProstACT Global study, in which we set out to evaluate the safety and the dosimetry of our lead prostate cancer therapy agent, TLX591, in combination with the androgen receptor pathway inhibitor agents, either abiraterone or enzalutamide, or the chemotherapy agent docetaxel, which we evaluated in three separate cohorts of patients. In essence, really all of the Part 1 study objectives comprising the safety of the three combinations, very clear pharmacokinetics, and a favorable dosimetry were achieved. Specifically, I'm delighted to see that there are no new safety signals that were identified, and the hematologic or the blood events were both transient and manageable, as we'll go into a little bit more detail later in the discussion.
The tolerability of TLX591 plus ARPI or docetaxel given sequentially following TLX591 was supported by the dosimetry and the low grade of non-hematologic events. The lesion dosimetry demonstrated very meaningful uptake in the lesions, and there were no significant differences in the absorbed dose profiles across the three cohorts of patients that we studied. Finally, there were no adverse drug interactions observed in any of the TLX591 combinations. If you put this together fundamentally, these Part 1 results demonstrate the feasibility of integrating TLX591 with contemporary backbone standards of care globally is a feasible approach to undertake. If we go to the next slide.
As a brief recap of Telix's therapeutic candidate, TLX591 is a highly differentiated PSMA targeted radiopharmaceutical that employs a monoclonal antibody to very selectively target prostate cancer express PSMA while avoiding the PSMA that is natively expressed on some of the normal tissues. What this does is it enables a very precise delivery of the, to the cancer tissue, which is where we want it to go, of that radioactive payload. Now this approach, you know, really addresses a number of clinical needs that we need to address. You know, particularly a 2-dose 15-day schedule that enables a much more feasible integration with standard of care, either ARPI or chemotherapy agents that we otherwise want to continue to, offer patients.
A very low radiation dose is imparted to the salivary glands and the kidneys, which are the two main organs that may be injured when we use small molecule agents, as well as a very transient and manageable hematologic profile that we'll get into a bit more detail later on. There's very specific internalization and thus a prolonged retention within the prostate cancer cell, which is clearly evident on some of the post-treatment imaging which Dr. Barata will show, a number of case studies on. Finally, you know, there are some real potential, you know, real-world advantages from the lower administered activity and lower radiation doses being directed at the normal tissues, particularly the kidneys, which may in future enable the patient to have additional forms of radiation therapy if necessary.
If you go to the next slide, you know this slide really nicely illustrates the fundamental differences between TLX591, which is a radio antibody-drug conjugate, and a first-generation small molecule radioligand therapy, for example, Pluvicto. I think the key takeaway here is that the dosing schedule is markedly different, with TLX591 being dosed as two fractions two weeks apart, compared to up to six fractions every six weeks with the small molecule. What this means is that the total amount of radioactivity that has to be delivered to a patient is much less with TLX591. This is because the antibody delivery vector is specifically immunoreactive with the tumor-expressed PSMA site, following which it internalizes into the tumor cell and maintains a prolonged retention, which the imaging shows.
I always like pictures, so on the right you can clearly see the biodistribution and the clearance of the two different approaches and the advantage of the radio antibody approach, where the liver, which is a relatively radiotolerant organ, is the primary clearance organ, followed by the large bowel and ultimately fecal elimination. The other image obviously shows the small molecule on the other hand, which is primarily cleared from the blood circulation via the kidneys, which really aren't so welcoming of radiation, followed by the bladder, which you can see very clearly, and ultimately urinary elimination. You can also see significant off-target uptake in the salivary glands, which leads to dry mouth, which can be quite problematic, leading to a reduction in quality of life in a quite a significant proportion of patients.
If we go to the next slide, let's move on to the study design and I'll summarize the patient population. Go to the next slide, please. Now here you can see why we designed ProstACT Global, the study the way we did. It's a very pragmatic study design that aims to evaluate whether adding TLX591 on top of standard of care can improve progression-free survival and overall survival. What it does, as Chris mentioned at the outset, was that it aims to accommodate the different backbones of standard of care that are most commonly used by and are familiar to oncologists either within or outside of the United States.
Specifically, you know, this chart of the world indicates that in the United States, when a patient experiences prostate cancer progression while receiving their first ARPI drug, the predominant clinical practice is then to switch the patient onto a second ARPI drug. Very, very established practice in the United States. Whereas outside of the U.S., the more common practice, and this is reflected in the clinical practice guidelines both in Europe, such as ESMO and the EAU guidelines, but also those guidelines in China and Korea and Japan and elsewhere. The prevailing practice is to switch the patient onto a chemotherapy agent. The most common one of those, that's used is docetaxel. If we go to the next slide. This is the, overall design of ProstACT Global, the phase III study and its current status, which is very nicely summarized on the top right.
As you can see, Part 1. Sorry, Part 2, which is the randomized treatment expansion, is enrolling 490 patients, and that enrollment is occurring currently in Australia and New Zealand and Canada. Following the independent data monitoring committee review in October of last year, that the study also now has the regulatory approvals enabling Part 2 to commence randomization of patients in China and Japan, Korea, Singapore, Turkey, and the United Kingdom. That's underway at the moment. Part 1. Back to Part 1. Part 1, which is now complete, was a prerequisite of the FDA that was required by the FDA before we were given permission to commence Part 2 in American patients.
We're really encouraged by this data from Part 1, and we look forward to engaging with the FDA with this data at the earliest opportunity, while continuing to obviously enroll into Part 2 in those regions where the study's been approved to do that. Now, if we go to the next slide. This is a brief CONSORT, what we call a CONSORT diagram, that really outlines what has occurred so far in Part 1 as we've completed Part 1. You can see that, starting at the top, there were 57 patients screened. 36 patients who each progressed while receiving a prior ARPI agent were deemed eligible, and all 36 of those eligible patients received 2 doses of TLX591 as planned according to the study protocol. You can see the breakout below that.
11 patients were allocated into the abiraterone cohort, 11 to the enzalutamide cohort, and 14 to the docetaxel cohort. I think it's a very positive sign that there were no treatment-related deaths on study, and 32 of those 36 patients enrolled remain alive, as well as 26 patients that continue on the study as at the time of the data cut, back on the 12th of January. Let's move on to what these patients look like. Next slide. These are the demographics and prior treatments of those 36 patients that we enrolled for Part 1 at baseline. I think in summary, really nothing is especially remarkable about the demographics or baseline characteristics of the patients that were enrolled to Part 1 of the study.
As you can see, the majority of patients in Part 1, almost 3/4, were receiving second-line therapy in this study, and their median age was 77 years, which is somewhat older compared to other studies where the age is typically around 70. For example, in VISION, it was 71. This is a relatively advanced group of patients. In terms of prior treatments, most patients, just under half of them, had enzalutamide as their prior ARPI agent. Most patients, almost three-quarters, had not had a prior taxane chemotherapy agent in the earlier metastatic castration-sensitive setting. When we look at some of the prognostic factors, a subset of which are on the right, the median PSA was similar to other studies and their ECOG performance status was good.
In Part 2, as we proceed to enroll, and ramp up enrollment to Part 2, maybe we'd expect the age to come down slightly, but otherwise it'll be a very similar set of demographics in the second part of the study. Next slide. Let's now look at the safety. Next slide. The primary objective of Part 1 of ProstACT Global was obviously to assess the safety of TLX591 when either administered concurrently with standard of care, abiraterone or enzalutamide, or followed by standard of care docetaxel chemotherapy. Overall, the three cohorts demonstrated an acceptable safety profile with no new safety signals when compared to the prior studies, including the most recent ProstACT SELECT study. You can see in the table on the right the most common treatment emergent adverse events comprised fatigue and nausea and dry mouth.
Almost all of these non-hematologic adverse events were Grade 1 or Grade 2. In other words, they were mild, with the exception of one patient who had a Grade 3 dizziness event. The hematologic adverse events, as we would expect, comprised Grade 3 and Grade 4 thrombocytopenia, which is a reduction in the platelet counts on a lab test, which occurred in 14% and 31% of the patients respectively. As well as Grade 3 and Grade 4 neutropenia, which is a reduction in the neutrophil count, which occurred in 22% and 25% of patients respectively. I think it's important to say that these hematologic events were certainly in line with the profile that we would expect for this class of radio antibody-drug conjugate, and they were transient and manageable, as we'll discuss in a bit more detail on the next slide. Next slide, please.
The question that comes up, of course, is when you have a hematological event, what happens? As I mentioned in the prior discussion, the hematological events are the main adverse events of interest for this radio antibody drug class of therapy. Now, in terms of thrombocytopenia, which is the most important of these events, as you can see here, the platelet counts were very consistent across the three cohorts. With the nadir or the bottom point in the platelet count occurring very consistently at an average of 43 days, which is about six weeks after the first dose of TLX591. What's most important is what happens from here. From the nadir, you can see that the platelet counts recovered to Grade 1 or better at an average of about 15 days after the lowest point.
From there they continued to revert back to the normal range in the majority of patients. Importantly, no patients experienced any febrile neutropenia related to TLX591, which is a relatively common adverse event that patients may characteristically experience from conventional chemotherapy. In summary, the hematologic adverse events, which are very well characterized and understood from prior clinical studies with this agent, were self-limiting and may resolve spontaneously without intervention in the majority of patients in Part 1. This is very encouraging. Let's move on to next slide, please, the dosimetry. Next slide. While safety was the primary objective of Part 1 of ProstACT Global, the main secondary endpoint was to assess the pharmacokinetics, biodistribution, and the radiation dosimetry of TLX591 when administered concurrently with those standards of care. Overall, the three cohorts demonstrated a very predictable pharmacokinetic profile.
If you think about where you want the radioactivity to be, you either want it circulating in the blood pool so that it's available to be taken up by the tumors. You want it in the tumor lesions themselves, or you want it in the liver as the drug is cleared from the body, as we saw in those earlier images. Now, the importance of these two graphs, and I'll explain them to you, is that the graph on the left demonstrates the blood radioactivity concentration, which as you can see from the curves, is sustained but declining over time.
In the right-hand graph, what we see is essentially the reciprocal of that, which I think very nicely demonstrates the tumor radioactivity concentration, which increases early and then is sustained over time through the antibody's specific binding, its internalization, and its prolonged retention on site within the tumor. These, exposure and washout kinetics were very clearly consistent across the three cohorts, as you can see by the oversitting of the lines, which indicates that there was no evidence of TLX591 interacting with any of the ARPI drugs when we co-administered those agents with TLX591. Next slide. Now, let's move on to the normal organ dosimetry. This is very important. This is those organs that we want to keep the radiation away from.
As you can see very clearly, this part of the study confirms that the radiation exposure to those normal organs was very low and certainly well below safety limits that have been determined from the external beam radiation and the radioligand therapy literature. In a particular note, you can see that with TLX591, there's a very low radiation dose imparted to the kidneys and the salivary glands, which are the two normal tissues that small molecule radioligands tend to hit the hardest. This reduces the risk of developing kidney impairment or dry mouth, each of which may vary significantly impact patient quality of life, both during treatment and in the out years to come. You can see on the right-hand side of this chart, the liver, as I highlighted earlier with the images. Well, it's a relatively radio tolerant organ.
It makes sense that this is the primary clearance organ and therefore it receives the highest dose, which, you know, it is capable of doing. From there, the activity is cleared from the body via the right colon, the left colon, the rectum, which is sort of downstream of the liver, and ultimately via fecal elimination. Next slide. Finally, Part 1 studied the lesion dosimetry, which again was highly consistent across the three cohorts of patients. It showed that following the administration of two doses of TLX591 14 days apart, there were consistent and meaningful physical radiation doses imparted to the tumor target lesions across all of the main anatomical sites of disease, the three main ones being the skeleton, which is where prostate cancer goes, the lymph nodes, and the soft tissues.
I do think it's important to note that while these radiation doses are meaningful, radio antibody drugs possess a different mechanism of action compared to small molecule ligands. As a recent dosimetry think tank at the ASCO meeting concluded, it's important to be mindful that tumor dosimetry is measured differently from trial to trial. While it's available for go/no-go decisions in radiopharma development, we ultimately still rely on objective clinical measures of efficacy such as PFS and OS, which of course what ProstACT Global Part 2 is already underway to evaluate. Now, I would like to hand over to Dr. Barata. We're very fortunate to work with investigators of the caliber of Dr. Barata. Dr. Barata is gonna take us through a couple of typical patient cases from Part 1 of this study.
Dr. Barata, over to you.
I appreciate it very much, David. I hope you and everybody can hear me okay. Pleasure to be here with you all. Can you show me next slide, please? We have a couple of cases here, part of this component of the study for you today. What we're looking at is actually our first patient case. This case, in brief, kind of illustrates a 64-year-old patient known to have metastatic prostate cancer involving the lymph nodes who got treated with TLX591 in combination with abiraterone. Just for context, this patient had evidence of mCRPC, so castration-resistant disease. Previously got treated with enzalutamide and ADT, and the investigator decided to choose abiraterone as standard of care along with TLX591 and end up enrolling in that cohort.
Baseline gallium PSMA PET did show disease in the lymph nodes, as you can see here on the left, including subcarinal, para-tracheal, abdominal, pelvic lymph nodes. You know, extensive nodal disease, if you will. He did receive a single dose of 177Lu-TLX591 at approximately 2,780 MBq, and then was followed by a serial SPECT to evaluate biodistribution. I think what we can see is here early images at four and 24 hours show kind of an expected distribution of the radiolabeled antibody within the vascular compartment and also the liver, which does reflect what David presented before, that systemic circulation and hepatic clearance. Importantly, by 96-168 hours, we do see a clear uptake, and which I think demonstrates effective targeting of the PSMA expression lesions.
I think it's relevant to note the persistence in the signal even at 360, highlighting, I think, to me, the prolonged tumor retention of this antibody-based radiopharmaceutical. So I think, you know, this prolonged residence time, I guess, you know, supports this radiation delivery to tumor sites, and I think it can reflect the potential advantage of this approach compared to small molecule, for example. I should note that this patient remains on study at 279 days at the time of data cutoff, and this was, you know, last January 12, 2026. Thank you. Can we move on to next slide? I'm gonna show you a little different case. This is an older patient, 83-year-old patient, also known with mCRPC.
Predominantly bone disease, as shown in the baseline gallium PSMA PET that includes the disease in the vertebrae as well as in the ribs. This patient was also previously treated with ADT and enzalutamide and at, the investigator determined that the patient should receive docetaxel as standard of care, following TLX591. Patient did receive TLX591, approximately 2,890 MBq, and again, got serial SPECT imaging in that context. As with the previous case, we see early images there demonstrating the same type of distribution, which is again consistent with the pharmacokinetics and of the monoclonal antibody-based radiopharmaceutical.
By 96 hours and beyond, we do see a clear localization of the radiotracer in the skeletal mets, which I think confirms the uptake of the sites of the PSMA-expressing tumor in the bone. It's also relevant one more time to note that we do see activity detected through the 360 hours, which again demonstrates this prolonged tumor retention, and sustained radiation exposure. You know, this patient also remains on study at 160 days at the time of the data cutoff, same day, January 12, 2026. In this context, you know, it's, I think, important to highlight the feasibility of sequencing TLX591, you know, with docetaxel, while maintaining effective, you know, tumor targeting and favorable biodistribution.
Two cases, one standard of care, abiraterone the second standard of care docetaxel, they received sequentially. Both cases, patients remained on study at the time of data cutoff. Thank you, and please show me the next slide. I'll give it back to you, David, and thanks so much. Happy to take questions.
All right. Thanks, Dr. Barata. Next slide, please. Let's summarize and then we'll move on to we're very happy to take questions. To summarize, you know, Part 1 of ProstACT Global really has confirmed for us that TLX591 plus the most common standards of care has an acceptable safety profile. It's got favorable normal organ and meaningful tumor dosimetry. You know, in particular, I think these findings were consistent across the three cohorts. That's a very important finding across those three cohorts that we studied. As expected, there were no new safety signals identified. There were no drug adverse interactions, and that was shown very clearly in the behavior of the agent when it was combined with the ARPI agents.
A low radiation exposure to the salivary glands and to the kidneys are very important, and I think attractive features of this agent, which really support and explain its tolerability among the patients that sort of received the agent, the 36 patients in Part 1 of the study. Really, you know, we're very encouraged by this data from Part 1. I think they're sound, and we do look forward to engaging with the FDA at the earliest opportunity, while of course, at the same time ramping up enrollment into Part 2, which is the exciting part of the trial, the randomized treatment expansion in all of those regions where the study has already been approved. I'd like to thank you for dialing in. Thanks for your attention. I hope that's been informative.
We are very happy to take any questions.
Thank you. Your first question comes from Andy Hsieh from William Blair. Please go ahead.
Oh, great. Thanks for taking our question. Maybe a couple of just quick ones for Dr. Barata, if you don't mind. Just from a patient baseline characteristic, I noticed that the visceral metastasis rate is about 36%. Can you comment on that, whether that's kinda high compared to other prostate cancer studies like a PSMAfore or a VISION study? Also before the CONSORT diagram, it seems like the screen failure rate is also a little bit high, about 37%. I'm curious about what the most common reason for not meeting eligibility and have a quick follow-up in terms of maybe absorbed dose.
David, I'll defer to you. If you want me to address the visceral question first or vice versa, I'll defer to you.
Yeah. Dr. Pedro Barata, you go ahead. I can add a little bit of color to it as well.
Of course. Thank you for your question. Really relevant. I think you're quoting several datasets, trials and real-world data regarding the prevalence of visceral disease, right? Which usually lands in up to 20%. You are right. When we compare things, you know, the number needs to be higher. My interpretation is twofold. Number one, I think it's an advantage of this design, is the ability to offer chemotherapy as part of the cohort here, which is different from other studies. What that means is, this tells me that the investigators around the world were very comfortable offering this protocol because they have the option of going with chemotherapy, which is a standard of care, in many parts of the world, particularly for patients with aggressive disease such as visceral disease.
The other piece is definitely the stance from the investigators that if you have a positive PSMA as a tracer, even though you have visceral disease, you do believe that radiopharmaceutical is playable. In my opinion, the higher rate than expected, it's a good thing for this particular study design because it reinforces the opportunity to run this study in the context of more or less aggressive disease, but to your point, in the context of more aggressive disease as well. It does play relevant in both scenarios. In a scenario, of course, a crossover to a different ARPI or the scenario of going with the chemotherapy. Fantastic point that you raised.
Yeah. Maybe, Andy, look, you've got a very sharp eye, so I'll answer your the second part of your question. Just to repeat it, you asked in the CONSORT diagram why was a significant number of patients excluded, 57 screened, but 36 enrolled. It's an excellent question. Primarily that's because of the 21 patients excluded, 18 of them didn't meet the eligibility criteria. Within that 18, the vast majority were because there's a baseline independent radiology review that looks at the PSMA positivity of these patients. Obviously, you wanna have a high PSMA positivity, in other words, a high expression of the target because they're the patients that ultimately stand to benefit from therapy.
Whereas those patients, excuse me, with a low PSMA expression are very likely to respond. We select patients quite heavily on that basis, and that's why patients that don't have high PSMA expression are weeded out and thus excluded. Does that answer the question, Andy?
Apologies. Andy has dropped off the line. Your next question comes from Laura Sutcliffe from Citi. Please go ahead.
Hello. Thank you for taking my question. Since Andy just dropped off, I might follow up to his question first. Do you envisage that initial baseline screen in any way becoming part of who is eligible for this in future? Would you be cutting down your eligible patient population by means of a required PSMA expression level? And then I'll come back with another question.
You know, Laura, look, that's a great question. The answer is yes. In the entry criteria into the study, patients have to have lesions or at least one lesion that has PSMA positivity that is twice the liver. That is a requirement to enter the study. That's for sensible reasons because PSMA positivity is a sort of an indicator of how much the radioligand therapies, the radio antibody drug conjugate will go to those lesions. If a patient has a very low PSMA positivity, there'll be much more off-target uptake and won't hit the tumor target. That's why that is set. That was used in the VISION trial.
We've increased the requirement for PSMA positivity in the study and typically the eligibility criteria guide the ultimate label discussion with FDA. That's a matter for that discussion in the future.
Okay, thanks. My other question is if you've broken down in your presentation the dose absorption characteristics of the three groups, and they're quite similar, but the safety profile is not broken out by cohort. I was just wondering if you could comment on how the groups differ and in particular, any differences in Grade 3/4 adverse event rates between the groups.
Yeah. Look, they're actually very similar across the three groups. Very similar. The most important adverse event is the hematological adverse events. Of those, the most important of those is the thrombocytes. You can see that those three curves for the platelet decline to nadir and then recovery from nadir back to Grade 1 and then, you know, beyond that, recovering back to normal. Those three curves, you know, when I first saw them, I was very pleased to see that they almost sit on top of each other. That behavior for thrombocytes, platelets, but also for neutrophils, is very consistent across the cohorts, and it's the same for all of the other non-hematological toxicities as well.
Laura, that would be a, you know, if FDA would want to see that'll be a detailed discussion with FDA. But they, across all three cohorts, they're very similar.
All right. I'll leave it there. Thanks.
My pleasure.
Thank you. Your next question comes from Tara Bancroft from TD Cowen. Please go ahead.
Thanks very much. This is Nick on for Tara. Given these data, what is your level of confidence that patients can remain on drug to experience longer rPFS than Pluvicto does in the PSMAfore trial at 12 months? Or do you believe there is a different bar to use for ProstACT Global given the combination approach? Thanks very much.
Yeah. Look, the statistics of this study basically requires, you know, nine months versus six months, but that's not an assumption of efficacy, of course. That's just simply for the statistical planning for the sample size, you know, based on an assumed treatment effect. So that's the assumption for the sample size planning. Now, that's not to say that's what we'll demonstrate, but obviously there needs to be a meaningful progression-free survival and a meaningful overall survival. And that'll be first gauged. We don't have any reading on that at the moment. That'll be first gauged as an exploratory endpoint from Part 1. Progression-free survival and radiographic progression-free survival are exploratory endpoints.
We anticipate that they will probably be available later in the year, second half of 2026. Obviously, that's a time to event, which is guided by how the patients perform, and so longer for each patient is better, and that obviously pushes that out. The next inflection obviously is guided by the interim analysis of futility, which is a pre-planned inflection, but after 81 progression events. That's where we're headed.
Thanks very much.
My pleasure.
Thank you. Your next question comes from Shane Storey from Canaccord Genuity. Please go ahead.
Thank you. Good morning. David, I'm gonna continue just there with that statistical route, please. I anticipate that we'd probably see quite different activity and maybe effect sizes between the three controls in the second component of Global. So just curious about how that might be handled. Maybe another way of asking that is whether any of the individual standard of care arms might themselves overpower to that primary endpoint, please. Thanks.
Yeah, Shane. That's a well-directed question. There's an assumption of no significant difference in the effect size between the ARPIs and the sequenced docetaxel. However, you know, per the protocol design, and this is obviously up on ClinicalTrials.gov. There are these stratification factors, you know, between whether they were selected by their investigator to have either ARPI or chemotherapy. That's a stratification factor, which means that both sides will be balanced, and that's how bias is dealt with. Yeah, really, I think that answers the question, hopefully, Shane.
No, it does. They're stratified first and then randomized second.
They are, yes. The stratification balances out to make sure that there aren't more patients in one arm compared to the other getting chemotherapy or ARPI, and that's how that bias is mitigated. Pretty conventional sort of statistical approach.
Thanks. Got a couple more just back to this morning's data. You mentioned the, I guess-
Homogeneity of the safety sort of across the different cohorts. Could you speak maybe to a little bit more detail on the management of the Grade 4 hematologic events? I wondered whether in any of those situations whether transfusions and growth factors were necessary, please. Hello?
Sorry, just take myself off mute. All of those thrombocytopenias were self-limiting and resolved spontaneously. Two patients received platelets, and two patients received red cells. But that that's very similar to prior studies. Yeah, two patients received platelets, two patients received red cells. Now, that is pretty consistent as you would expect in patients receiving chemotherapy or receiving other cytotoxic agents or radiation therapy as well. There's not really a difference in the rate at which blood products were received compared to other studies. Yeah.
My last question, David, and thank you for that answer. My last question really and I know it perhaps might go a little bit beyond the duration of interest that we're dealing with this morning, but maybe some comments on how many cycles of docetaxel, you know, those patients went on to receive after TLX591. I just wanna kinda rule out the idea that there were any sort of serious deviation from the dosing protocol for docetaxel. Thanks.
Yeah, sure. That's a relevant question, Shane. In standard practice, when we use docetaxel, the median number of cycles that a patient with advanced prostate cancer would get is typically five to six cycles. In this study, we're very confident that we've got enough patients receiving enough chemotherapy to take to the FDA. That's what they asked us to show. We didn't go into any detail on that because that is really a question of treatment intensity. Treatment intensity, the number of cycles that the patient gets is not obviously an endpoint of Part 1, and it's typically discussed when we get into efficacy discussions.
You will see that in the Part 2 results, but it's not an endpoint and not really that relevant for Part 2. We're very confident we've got enough data on the docetaxel protocol to take to the FDA and have a meaningful discussion.
Thanks, David. Thanks, team. That's all. That's all my questions.
Thank you. The next question comes from Dave Stanton from Jefferies. Please go ahead.
Good morning, team. Thanks very much for taking my questions. Just to follow up on the previous question from Shane then. Can you perhaps outline for us the next steps and potential timelines for that for FDA engagement?
Look, I'll also invite Chris to comment on that as well. I think these data, Dave, these clinical data are exactly what the FDA prescribed us to collect. We've now completed that, and it is, I think, you know, we're overwhelmingly encouraged by this data, and we're really keen to put it in front of the FDA. Chris, I might, you know, ask you to sort of add any additional color to that that you would like to add.
No, I don't. I mean, this is the first time that we've had the completed CSR from the study, which is why we've disclosed it in a timely fashion, and the team's working really hard to get the package in front of the FDA in a timely fashion. It's high priority to get U.S. patients into the randomized Part 2.
Understood. Thanks. Perhaps, you know, just in the real world, can you talk about potential treatment options for, you know, TCP, Grade 3 or Grade 4 that a clinician might look to use and how to mitigate, you know, any that decline in a Grade 3 or 4 situation in the real world? Perhaps it's a question for Dr. Barata.
Maybe Dr. Barata, you'd be welcome to answer that question of Dr. David Stanton.
I appreciate that. I think I was having some trouble hearing the question till the end. I think real world management of significant side effects. Is that what I heard? I'm sorry.
In particular, Grade 3 and Grade 4 thrombocytopenia, please. How would you manage that in the real world to get patients through?
Yeah. Got you. Yeah. I think what we've, you know, we've done in the protocol it's pretty much aligned what happens in real world. I can tell you that most of the times, unless you have below 10,000 platelets where transfusion, platelet transfusion is recommended, because you can develop spontaneous bleed. Numbers above 10,000 usually under close monitoring with repeat labs on a regular basis, and observation is what we tend to do. You know, the protocol in terms of managing and watching the numbers on a regular basis, repeat labs, is what we would do in clinical practice. You know, that the periodicity or the schedule of those checks, lab checks vary. You know, some folks will do a little bit more often.
You know, every week to every other week. I would say the protocol allows you that flexibility. What you're seeing here is really pretty much what we would have done in the real world outside a clinical protocol.
Understood. Thank you very much.
I'll just add to that. You know, it's certainly not an acute event. You know, we know the behavior of the platelet profile. And, you know, most patients in the study, as you can see, I think it's in that graph very clearly articulated that they get just below Grade 1. Grade 1's between lower limit of normal and 75,000 platelets. Patients spend a very short, you know, fleeting time below Grade 1, and then they recover, almost all of them just by themselves back to Grade 1, which is sort of, you're an M.D. I know as well, but, Grade 1's obviously the safe zone. In fact, Grade 2 is quite safe as well.
They get back into the Grade 1 very safe zone very quickly by themselves, and then from there, most of them recover, you know, pretty quickly. It's really, really predictable, and it's only the, you know, the outlier patient that might need the hematologic support with units of platelets or red cells. Now, obviously red cells declining is very, very common in radiation therapy and chemotherapy. You know, anemia is one of the most common side effects, but it's not characteristic with this agent.
Thank you.
Thank you. Your next question comes from Melissa Benson from Barrenjoey. Please go ahead.
Hi, team. Thanks for taking my question. The first one, just a quick one on the non-hematologic events, just the dry mouth, all Grade 1. Should we think of that as really attributed just to the ARPI combination contribution?
Melissa, look, as I mentioned, all of the dry mouth events were Grade 1, Grade 2, in other words, mild. They were a very short duration as well. Now, attribution is, you know, performed by the investigator. All of the attribution for dry mouth was not attributed to TLX591. So it was, it's not attributed to TLX591. The occurrence of it has not been specifically attributed in the study, so the investigator basically says that it's not attributed. I guess the encouraging thing is that.
Okay.
Yeah, none of the patients had, you know, Grade 3 or Grade 4 dry mouth, and none of the patients had Grade 3 or Grade 4 dry mouth that was, permanent, which it characteristically is with small molecules. Always Grade 1, always Grade 2, and always fleeting.
Great. Thank you. Just one further. You've spoken to, you know, FDA next steps. You know, later last year, you mentioned that you need to file a CTA with the European regulators to kind of open Europe sites. I guess just help us understand, I guess, next steps there. Are you kind of waiting first for FDA and then you'll file with Europe, or that's a kind of a parallel process? Thanks.
Yeah. Thanks, Melissa. Yeah, FDA was the regulator that said, we want to see Part 1 done and bring it back to show us, and we'll, you know, we'll have that discussion for an IND amendment. European regulators did not specifically ask for that, but of course, the regulatory authorities in Europe and the United States communicate. In fact, all global regulators communicate on a regular basis. When the European authorities saw that the FDA wanted Part 1 completed, the European agencies also wanted to undertake that approach as well. Now that we've got it'll be going to the European authorities seeking permission, very similar, you know, to the FDA's approach to open the study to Part 2 in the European sites.
Great. Thanks.
Thank you. Your next question comes from David Bailey from Morgan Stanley. Please go ahead.
Thanks. Good morning. Just the SELECT trial was ARPI's only, and in this one you've added docetaxel. It's a broad question you've kind of answered already. But how would you expect adding docetaxel to impact the hematologic events? And is there anything from a data perspective between ProstACT Global and SELECT that you think might be explained by adding docetaxel into the treatment arms?
Yeah, good question. You know, David, in Part 1 of the study, docetaxel is not given concurrently, as you know. Docetaxel is nominated by the clinician, and it's started after five-one-one, typically within a 10-week window after TLX591 second dose has been given. Now, you know, there are patients that have had many cycles of docetaxel in this study. There are patients that have the sort of median number of cycles and so forth. As I said earlier, we've got enough. We believe we've got enough of that data to take to the FDA and have a very meaningful discussion. A lot of patients don't want to start docetaxel when they're feeling great after a therapy, so a lot of patients will actually decline it.
I would like to invite Dr. Barata to maybe comment on how his patients view docetaxel versus ARPI. You know, their willingness to start it. Maybe, Dr. Barata, you could comment on that.
Right. It's a fantastic question and a fantastic point, David, that you raise. You know, I think it's common, it's known to all of us that patients don't want chemo, right? They're looking for non-chemotherapy options. Perhaps that's one of the reasons why there's, you know, so much ARPI switch is done, at least in the United States, where we can actually do it. From that perspective, when you give a therapy that works and you're doing well on it, you will, you would expect or you will expect some pushback, you know, from patients and and quite honestly, also from providers, right? 'Cause they won't feel as strongly regarding bringing the chemo right now as per protocol is defined versus upon progression. It's almost like you're buying time, you have tumor control.
The more you have an active agent that provides you tumor control, evident in scans, PSA, patient doing well. Actually, I would argue it would not be residual, the amount of patients who say, "You know what? Give me a break. I'm doing well. Cancer is not progressing. Can we do it at a later time?" I would anticipate in these kind of designs, the n-amount of people who end up not getting the sequential intervention without progressive disease is not necessarily a bad thing. It can be a consequence of patient preference because he has that ability to push back because tumor is not getting worse.
We do see that in clinical practice and so it's something that on one end, we're assigning it to chemo because we think it's aggressive disease, we wanna do chemo. On the other hand, if TLX591 is effective, some of the patients very likely can push it back for a later time.
Thank you.
Now, David, I'll just add to what Dr. Barata said. I think, you know, we've articulated the purpose of Part 1 of this study. FDA wanted to see specific information on the priority combinations of ARPI plus TLX591 when they're intended to be given together or TLX591 sequenced with docetaxel following. ProstACT SELECT, as you might recall, no, I don't expect you to remember all of these details. You've got a lot of things that you're thinking about, no doubt. ProstACT SELECT, the primary objective that, as the title of that study said, was to demonstrate that gallium PSMA tracer indicated where lutetium and rosopatamab therapy was likely to go.
In ProstACT SELECT, you know, we didn't specify that the patients had to have an ARPI or a chemotherapy agent. We allowed it, but the vast majority of patients in that trial were treated as monotherapy with TLX591.
Thank you. Your next question comes from David Low from UBS. Please go ahead.
Thanks for taking my question. Just going back to slide 15, we saw enzalutamide group showing platelet count continuing to decline after 150 days. Just wondering, you know, what, you know, how we should understand that, and do you think that platelet count is manageable after day 350?
Yeah. Thanks for the question. That sort of decline, if you look at where it's happening in the platelet count, it's a long way out to the right. If you look at the sort of, I guess, the scale on the bottom, you know, the patient's heading out, you know, up to a year and beyond. Really, in this advanced metastatic castration-resistant population, where they're being treated, as I mentioned in the baseline demographics, they're being treated as second-line patients. The median age of 77. This is a pretty advanced group of patients. That lab profile is certainly not uncommon in the broader population of patients.
Now, whether it's any more marked with abiraterone or not, I don't think these data can conclude that for us. That behavior of that decline sort of out beyond, you know, 250-300 days is pretty characteristic of what you'd see in the blood counts if you took them and sent them to the lab in the average patient who was off study. Maybe Dr. Barata, you could comment in your own clinical experience, you know, what happens to the lab counts after long exposure to abiraterone.
Yeah. No, that's a fantastic point. I would argue as well, you know, you have 25% in the baseline patients previously exposed to taxane-based treatment, right? Elderly population, median age close to 80, 77, which is definitely higher than the overall population, if you will. We see some cytopenias with ADT and ARPI. I don't, you know. If you look at the numbers, you know, the numbers is definitely within the safe zone for us to definitely consider subsequent therapy. You know, it wouldn't guide our eye in terms of concerning at this point with such a good, I mean, a follow-up of a year as David alluded to. It's kinda reassuring thinking that they got therapy a long time before these last cutoff.
That's in my view. You know, it's aligned with what we would anticipate for this patient population.
Okay. Thank you. Just the other one I had, with the next steps with the FDA, what are your thoughts on what their safety criteria might be to proceed to Part 2?
Really, look, I think this will be the last question, but it's an important one. The FDA were crystal clear. FDA wanted to see safety on the concurrent use of TLX591, plus very conventional agents in the U.S., which are primarily abiraterone or enzalutamide. Or, if a clinician like Dr. Barata wanted to provide docetaxel after TLX591. They were the three dosing regimens that the FDA was crystal clear on. It was pre-specified by the agency. Go away and do 10, and 10. We've actually done 11, and 14, so we've done a little bit more than what the FDA asked for. That was pre-specified, pre-agreed with the FDA, and we look forward to taking it back.
The only other thing that the FDA would wanna make sure is, you know, that the agents don't preclude, subsequent treatment with chemotherapy, and we've got that data as well, and we look forward to presenting that to the FDA. We've done what the FDA agreed, all pre-specified, and we're about to take it back and show it to them. I think that's the.
Okay.
Yeah. Yeah, no. Thank you. No, great question. I think we're out of time. I'll hand back to the operator.
Thank you. Yes, that does bring us to the scheduled finish time. I'd now like to hand back to David for any closing remarks.
I'd like to acknowledge obviously the patients that have come into this trial, all 36 of them, including the 57 that were screened. But of course, the dedicated clinicians that we are thrilled to work with, like Dr. Barata, you know, very esteemed investigators across North America, Europe, and Australia, and New Zealand. I'd like to thank those for dialing in. We hope it's been informative to you. Thank you very much.
That does conclude our conference for today. Thank you for participating. You may now disconnect.