Thank you for standing by, and welcome to the Telix Pharmaceuticals Limited TLX591 ProstACT Expert Forum. All participants are in a listen-only mode. Today's format is a fireside chat hosted by Dr. Colin Hayward, Group Chief Medical Officer at Telix. Please go ahead.
Great. Thank you very much, and welcome to this interesting webinar on PSMA targeting radiopharmaceuticals, the ProstACT therapy program, a first-in-class our ADCs, TLX591 or lutetium rosopatamab tetraxetan. Now, look, there's clearly growing interest in radiopharmaceuticals, in GU oncology as a whole, but especially in prostate cancer given recent data in PSMAfore, for example, the ongoing SPLASH study. But we, of course, have ongoing studies and a recent interim report of SELECT, ProstACT SELECT, and you have seen the news about ProstACT GLOBAL recruiting the first patient in Australia. So that's very exciting news for us here at Telix.
This, this gives us an opportunity to revisit and re-educate the extensive development program to date and the history and the data that it's gotten us here, and maybe continue to discuss and identify a few interesting points and maybe some key differences of the potential antibody-based therapy versus small molecules. If we can go to the next slide, please. This is the standard disclaimer slide. Then, what I'd like to do is introduce a distinguished panel, and there isn't really any more qualified people in the world to have a very good discussion on TLX591. We have a panel from around the world who I'll let introduce themselves. So, Dr. Tagawa, perhaps you could just start for me.
Hi. Thanks for introduction. My name is Scott Tagawa. I'm a Medical Oncologist at Weill Cornell in New York. Overall, globally, I'm gonna, I treat patients with GU malignancies and I'm involved in developmental therapeutics in GU malignancies with a focus in cell surface targeting, and I'd say, especially in that realm in the last 15+ years, focused in PSMA targeting with radionuclides.
Fantastic. Thanks, Scott. Dr. Lenzo?
Thanks, Colin. I'm Nat Lenzo. I'm a Nuclear Physician and Internal Medicine physician based in Perth, Western Australia. I've been involved with theranostics for many years, but I've been involved with administering lutetium PSMA-based therapies for prostate cancer for the last eight years. I'm glad to be part of the ProstACT SELECT trial. We were the number one recruiter for that trial in Perth, and glad also to be the PI on the ProstACT GLOBAL trial, and we're glad that we've enrolled our first patient just in the last few weeks on this trial. So, glad to be here.
Thanks, Nat. And, Dr. Sartor.
Hi, I'm Oliver Sartor. I'm a Medical Oncologist, and I'm currently at the Mayo Clinic and have appointments in the Department of Medical Oncology, Urology, and Radiology. I've long been interested in theranostics, going all the way to the days of samarium-153 and radium-223. I've been quite involved with the use of PSMA lutetium small molecules, and I'm simply glad to be here and to be able to contribute tonight, talking about the first antibody rotation trial.
Wonderful. Thank you. Thank you all. So maybe I could just open up and just say a few words of our progress recently if we go to the next slide. So as I mentioned, there's increasing interest in radiopharmaceuticals, not just in prostate cancer, but clearly prostate cancer is leading the way. Particularly, you know, the interest is there because of that high U.S., incidence of metastatic castrate-resistant prostate cancer. That's 42,000 and growing 5% a year, which clearly translates to a very high market potential. And that first PSMA-targeted therapeutic, that's, reaching over $700 million in sales, as of September 2023. So, so clearly a very large opportunity and a large opportunity for men with prostate cancer to help them live longer and live better quality lives.
Clearly, the small molecules have produced some fantastic data to date, but are there any differences or any other opportunities we can on improving therapy for men? We go to the next slide. The ProstACT GLOBAL, we'll go into in a little bit more detail. We can see that we've launched this with the first patient recruited in Australia, and there's some key learnings that we've done in terms of planning this study that we'll go into in a little bit more, learning from the other PSMA studies in similar populations, but how we designed this study. And if we go to the next slide. We recently announced some interim data from ProstACT SELECT.
Just as a reminder, ProstACT SELECT is a dosimetry bio distribution study, no control arm, really giving us an indication that Illuccix is highly effective as a companion diagnostic for TLX591, and showing that we can identify tumor and target tumor with the antibody. In addition, gives us a promising insights into this patient population in terms of the safety data as well. And if we go to the next slide, we can see some of that hematological profile that we see and how that differs from the original development work with Scott and maybe, you know, perhaps this is the population is a more resilient population, an earlier treatment population. And so not getting quite the same numbers in terms of thrombocytopenia and neutropenia in particular. And if we go to the next slide.
Some of the key areas, we've met the objectives in terms of that demonstrating the patient-friendly two doses, and tumor targeting in that population, looking at the uptake and the dosimetry in different organs to show the safety. Seeing that tumor retention is in there for, for you know, at least two weeks, and we've you know, taken out those imaging to at least two weeks. The hematology, the lower rate of hematological events, which I've just shown. Now, efficacy is very, very preliminary. There was a baseline drop in 64% of patients at some point of those patients who've had a baseline PSA and full dose.
But really, the PSA and most importantly, the longer-term outcomes, the rPFS are still ongoing, and we all hope to be able to present that data next year as the data matures. Next slide. So, my perspective, but I'm, you know, would say this coming from the company perspective, you know, is that this is promising efficacy demonstrated. And I think it's important to realize that the development program to date has had over 200 patients, many of whom, Scott has been involved in those initial studies. We've seen that patients with a high PSMA tumor antigen expressed on SUV, and we have that specificity in terms of antibody binding and an acceptable safety profile.
That simple two-dose regimen administered over 14 days may offer, you know, significant advantages in terms of patient convenience, but also in terms of the lutetium dose and the total lutetium dose that's needed for those patients. Next slide. With that, just quick introduction and quick overview to set the scene, I'd really like to hand over to Scott to talk through the development of TLX591 or lutetium rosopatamab tetraxetan, and give us his insights of that development to date. Thanks, Scott.
Thanks, Colin. Next slide. Disclosures. Okay. So, I suspect many of you have heard something similar in the past in terms of what is on this slide. mAb stands for monoclonal antibody, and ligand, generally speaking for PSMA, is gonna be a small molecule. The main differences in how they act in the body is really based on their size. That's for the most part, and that size changes their kinetics and their biodistribution. So kinetics, how long they're circulating around, and biodistribution, where they land. And you can kind of just read the data that's sitting in front of you.
You know, I think if you were to look up pictures of imaging of the antibody with PET, pictures of the small molecule with PET, you can see some differences in terms of where they land. And I would say their, their advantages and their disadvantage are quite similar. It's a little bit of spin. So antibody has the advantage of circulating for a long time. So I give an infusion today, there's more targeting of the cancer tomorrow, more targeting of the cancer the next day. And I think that is especially important for lower PSMA-expressing sites, but or whatever the target site's gonna be. But then the downside of that longer circulation can be an effect on the bone marrow. We can talk about, you know, that sort of toxicity.
Then it's cleared through the reticuloendothelial system, like any big protein, which is predominantly the liver. Those small molecules, an advantage is they rapidly go to any target site, so PSMA in this particular case, and then they're excreted, and that's very nice for imaging. An issue is that, you know, for areas that maybe have lower PSMA expression or that they're gonna wash away, maybe there's less that are there for a longer period of time. Then there's the, quote, "on target but off-tumor" uptake. Because of their size, they're able to get into the salivary and lacrimal glands, being the for the dry mouth and dry eye side effects, the intestine in terms of nausea. Then could there be more kidney toxicity? We don't know.
It's relatively early, and if that's gonna happen, it would be a late effect. But anyway, at least there's a risk. Okay, so that's all theory. Next slide. So another thing, this is—I mentioned this a little bit. So this is in different. Actually, okay, these two pictures are one cell line, but we've done this in low PSMA, moderate PSMA, and high PSMA-expressing cell lines. And at the very beginning, you know, there's good binding of PSMA with whatever it is, but there is superior internalization and, more importantly, retention with the antibody.
That, I think, is a key in humans, is that it gets to where it's gonna go, luckily, preferably tumor in this case, and then stay there for longer, and that allows this radiation to continue to affect, in this particular case, the whole construct with lutetium 177, the 1-week half-life. So sitting in those tumors for weeks allows that radiation to persist over weeks. Okay, slide. Okay, so this is another graphical representation of the retention that is there, and then I mentioned you can look at PETs. This is probably a PET at around a week, hard to tell without looking, but that's usually when this happens with J591.
Where we see clearly insights of tumor, it is there, and you know, we've looked at images of lutetium two weeks out, and there's a lot that is there in the tumors. What you may not recognize, unless I pointed out, is that the salivary glands, if you look at any PSMA PET, otherwise you generally see it's these dark spots in the salivary glands, in the cheeks. And same with the kidneys and the small intestine, that's a little bit more difficult for a non-radiologist, let's say. Okay, next slide. So this is, you know, a long and what I would say from a scientific point of view, kind of carefully done sequential phase I and phase II studies.
As investors maybe say, "Why don't you do a phase III earlier?" But this—we did this as academics. But what's nice is that we have all this available data going into the phase III. So different, different beta emitters as well as gamma emitters and PET emitters have been labeled to this antibody. So we know the safety, we know the biodistribution of the antibody, and then to kind of break it down just fairly quickly in terms of three major points specific to, lutetium J591 and TLX591. You can see, I guess, mostly around. I guess it's kind of going back and forth. So I was gonna say just the wrong one. So phase I and phase II studies of a single dose.
This is in the pre-PET era, so this is all comers, and actually, every single one of these studies is all comers. So you have to take that into account when you're looking at whatever endpoint you wanna look at for efficacy. But we arrived at what we thought was a very good kind of maximal tolerated dose recommended phase II of a single dose. That led to this fractionated or split dose. So another way of talking about this, I would say, is dose dense. So if we're looking to cure a tumor with radiation, we do that with prostate cancer. We shoot in over a period of time, a long.
But if we give it half in one, 1 time and half, 2 weeks later, with the half-life of a week, we're essentially getting a pretty high dose to tumor in a continuous fashion for a month. And that's what we do nowadays when we're looking to cure prostate cancer in the prostate. So we did that phase I + phase II study, where we arrived at what we thought was a good regimen and good dose, and it's been translated, slightly changed, but to make it, you know, kind of easier, to get a flat dose. But what that turned out to be was looking at around 4-6 weeks, some decrease in the blood counts, but we know when it's coming, and they come back up, and we support them if we need to.
But that was associated with a very long overall survival, and that's what, you know, we can talk about PSA and other things, but, you know, 42-month survival in heavily pretreated patients. That's something to keep in mind. And then the one that's on the bottom, which is called Docetaxel, you know, people worry about what's gonna happen to the blood counts. Well, with full dose docetaxel or Taxotere, we can give concurrent lutetium J591 with this fractionated pattern. So even with chemotherapy, which decreases the blood counts, we can figure out a way to do those together. So anyway, long history of the development. Next slide.
And this is that study that in the top left of the schema, that we did skip or delay one cycle of chemotherapy, but we're able to give essentially full dose of each drug concurrently. Okay, slide. Okay, and that's basically the summary. So in the era where we didn't have PET imaging, we kind of treated all comers. We could look at the SPECT scans, so that's looking at the lutetium itself, and about 90%, you know, lit up, which is, you know, very similar to what we think of in terms of what we might screen in or screen out of studies such as VISION or PSMAfore. We've seen some PSA decline. We've seen clearance of circulating tumor cell. What I would think, you know, in non-controlled study is fairly good survival.
I did mention the one randomized trial that was presented earlier this year, non-metastatic CRPC, secondary hormonal therapy with lutetium J591 or indium J591 control, and we were able to delay time until radiographically metastatic evident disease. So that is not exactly the same, but a little bit more analogous to this patient population of an earlier disease setting, where there's efficacy in the first randomized trial with available data. So anyway, I've been talking for longer than I intended to, so we can move on and maybe get to some questions.
That was great background. Thanks, Scott. I just wanna maybe open up to the panel to ask a couple of questions of your development plan today. As you said, it's a very extensive development plan, way over 240 patients that who've received J591, either with lutetium or other isotopes. Just quick question for me. You mentioned as well the condition of those patients going into the original studies of the fractionated that you saw. Were these really refractory to all chemotherapies?
Yeah, that, that's the way we designed our phase I and II trials, and the inclusion was, they either were not fit or refused other therapies. So there, you know, we do, we do have, and it's been published, that patients can get chemotherapy afterwards. So some patients didn't have chemotherapy, or let's say they came in after docetaxel in the pre-cabazitaxel era and then later could get cabazitaxel, so they were still fit for that. But not everyone had chemotherapy first, but many or most patients had multiple lines of hormonal therapy, and some other experimental therapies. And most did have chemotherapy, but it wasn't, wasn't all, but, but, you know, heavily pretreated.
I do think that you mentioned this already, but I do think that speaks, the fitness of the patient and their marrow speaks to the myelosuppression that might be seen. You know, just take the approved agent, lutetium PSMA-617, same administrative activity, same schedule, less myelosuppression in the PSMAfore data that Oliver just presented recently versus this. You know, the difference, I think, is the patient population.
Great, thank you. Oliver, any questions for Scott?
No, but I, I think one of the things that's interesting in this trial design, I'd like to comment on it now, perhaps we can discuss it more later, is that docetaxel is allowed, and it's allowed not only in the control arm, but it's also allowed within the isotopic arm. So we're trying to ensure that patients can get the best available therapies, and I think this trial design, which uses docetaxel and has the availability for docetaxel in both arms, is an important contribution. And if it's positive, then I think it can help really change the standard of care.
Great, thank you. Thank you, Oliver. Nat, any questions for Scott before I turn over to you?
No, I'd like to reiterate, though, what Oliver said, when we are talking about the trial design, it's been comforting for patients and also made it a lot easier in our discussions with medical oncologists, that there is the ability to have docetaxel as in different parts of the trial, both arms of the trial. So I think that was a very good move to put that in this trial.
Well, great. Thanks. Well, maybe I can then hand over formally to you now to maybe just delve into some of your own personal experience. As you mentioned, you're the lead recruiter in terms of patient, the SELECT study. You've been involved in an early study in combination with radiation, the ProstACT TARGET study as well, in very early BCR, as well as recruiting that first patient to ProstACT GLOBAL. So you've got a lot of experience, but also a lot of experience with small molecules in your years as a nuclear medicine physician, treating patients from around the world. So I'll hand over to you now.
Thanks, Colin. These are my disclosures. So, I've been fortunate enough to be one of the PIs on the ProstACT SELECT trial. The ProstACT SELECT trial, which is now closed, and as Colin said, was predominantly looking at, and it's a phase I biodistribution trial. But we were able to see in a number of patients very exquisite targeting by the antibody, and this is just some images performed with the TLX591 over a number of days. And you'll notice from the early four-hour image, where it's mostly in the blood compartment, over time, we get deposition within the PSMA-expressing metastases.
This correlates very well with the gallium PSMA-11 images that you can see on the left as the baseline, and out to 312 hours, exquisite targeting and retention within the tumor. So the hope is, as was said by Scott and also by Colin, that we're gonna. With this, a very good targeting and high retention of the antibody, that we will hopefully see improvements in efficacy, and, and that's hopefully what ProstACT GLOBAL will show us. Next slide, please. This is a patient who had nodal predominant disease as part of the SELECT trial. Once again, we see the targeting over time, clearance from the blood pool, clearance from the rest of the body. We do see retention in the liver. We don't actually see many changes to liver function, which is not uncommon.
I've been using a number of agents, antibody agents, for a number of years, and even though we see this, quite a lot of retention in the liver, we just don't seem to see any issues, either short or long term, which is encouraging. This patient here had previously been treated with enzalutamide and had nodal disease. From our past experience using the peptides or the small molecules, nodal disease is often very exquisitely radiosensitive, much easier to get persistent responses. So hopefully, we'll see that as well. In this patient, we did see quite a significant drop in PSA. Next slide, please. We've been fortunate enough to have a compassionate access program for the last few years, where we've been able to use TLX591.
And this is a case in point, similar to some of the patients that Scott has had in his trials. This is a heavily pre-treated patient. He is a gentleman who developed Gleason 4+3 prostate cancer in 2008, and he had locally advanced disease. So after his radical prostatectomy and salvage radiotherapy, he then relapsed in 2015 and 2017 and was actually diagnosed with pulmonary metastases in 2017. He then went on to docetaxel chemotherapy and then a number of different hormonal agents, but then relapsed again, and was lucky enough to get onto the therapy trial, which was a trial looking at lutetium PSMA-617 compared with cabazitaxel.
He was on the lutetium arm rather than the cabazitaxel arm, which was a multi-site Australian trial. He had a good response, a moderately good response to therapy. And when I say a good response, he did have a PSA drop, but more importantly, by the time he started the therapy trial, he had quite significant bone symptoms, and he did get very good palliation, which is one of the things that was well demonstrated in the VISION trial, the quality of life benefits of lutetium PSMA-617. Unfortunately, he relapsed. He then went on to cabazitaxel, which sort of kept his disease stable, but unfortunately, he was getting recurrent symptoms and then quite severe symptoms.
He had a trial of abiraterone, even though he had previously had enzalutamide, and then he came to us for compassionate access actinium, which stabilized the disease for a period of time, but then progressed, and then he was fortunate enough to be able to get access to compassionate use TLX591. By the time we had put him on the TLX591, he was in severe pain. He was on a lot of narcotic analgesics. He was quite limited by his symptoms, and we saw really quite a dramatic response in symptoms. And I'd have to say that anecdotally, I've been fairly impressed by the quick response I see with symptom control of patients who have bone pain with the antibody.
Hopefully, that will be borne out in data as it was in SELECT and also what we see in the ProstACT GLOBAL trial. He had a very good response, a PSA response as well to the 511. He did have thrombocytopenia, which it dropped. He never needed resuscitation initially, but he had quite significant anemia, which was a little bit unusual, and in fact, he then presented several months later with PR bleeding. A colonoscopy revealed actually an adenocarcinoma of the sigmoid. He was able to undergo a laparoscopic anterior resection, but his platelet count never dropped to a level where it was dangerous at that time. But then he did progress clinically.
He then developed neurological symptoms, cerebral metastasis, and then he passed away. But he did have a very good control of symptoms, and his main symptom was bone pain, and that lasted almost up until the time of his death. He and his family were actually very grateful at the quality of life that he was able to retain or get back after treatment with the antibody. Next slide, please. So the PSMA is actually scans are actually a very good marker of overall survival. Now, there's a lot of debate about PSA responses, and I'm sure there'll be discussions with the others about what this means and whether PSA is the be-all and end-all. Certain drugs have not shown that great a PSA response, but have shown improvements in overall survival.
But suffice to say that a PSMA PET is a very good independent predictor of disease. It actually is a predictor of aggressive disease, and it's also seems to be getting favor, and there are more trials coming out showing, and data coming out showing that, it's quite useful also in evaluating treatment response. And I think we'll see more of, more data coming out in the next year or so that proves that PSMA PET is really a very good and independent biomarker for this disease. Next slide.
So maybe just thanks, Nat, for that summary. It was very interesting hearing, you know, that patient experience. Is there anything else you noticed in terms of. You've treated many patients with small molecules over your time, many patients with antibody. Is there anything else you noticed in terms of the patient feedback?
Yeah, look, I think the small molecules are fantastic. You know, I've used them for many years. They're a great addition to our treatment armamentarium. Even those six-weekly or eight-weekly cycles are good. It's better than the three-weekly docetaxel, and we don't see a lot of side effects with the small molecules. I would have to say, though, we see less side effects even with the antibody. And as Scott said, the mild toxicity we're seeing, we know about it, we expect it, and it's reversible. So, we don't often have to intervene with that. We just need to monitor. We don't see any of the salivary gland toxicity at all. So in fact, I didn't mention with that last patient, the reason he didn't want any more actinium was his xerostomia.
He developed quite severe dry mouth and dry eyes and really did not want any more small molecule-based therapies. He'd had the six cycles of lutetium PSMA, and then, of course, the two cycles of the actinium PSMA. So I think tolerability, patient tolerability, the two weeks, two weeks apart is actually really. The patients like that. I have a lot of elderly patients. They realize they've got a terminal illness. They don't necessarily want to be stuck around hospitals, and so being able to have a treatment and then be able to go away and do things, as long as we're monitoring their blood counts, is actually very, very, very well appreciated by patients. The lower dose is also useful if you're running a busy theranostic clinic. We're only giving 2.8 megabecquerels.
They're only with us an hour or two. I can have multiple patients come through my clinic as an outpatient clinic. With the small molecules, they're very good, but at least in the Australian setting, they will be with us for several hours until they reach the safe discharge limit. So from a throughput point of view, from a radiation point of view, also for my staff, there's less exposure to my staff if I'm only giving 2.8 gigabecquerels of the J591. So there are a number of benefits, but, you know, the small molecules are great, and they have good responses. They've got good data, and the benefits we see with the antibodies, they're marginal, but useful.
Got it. Thank you. Thank you so much, Matt. That's, that's great insights. In particular as well, just a reminder in terms of that lower lutetium dose and, you know, the impact potentially in handling of patients and the potential waste as well, I think is important, right? Great. Look, Oliver, maybe I could. You've been involved in, in study designs for prostate cancer and other tumors extensively in the past. Maybe you could just give us a little bit more insights into the, the ProstACT GLOBAL study design and, and maybe some sort of similarities, but also some differences perhaps to other studies that are ongoing at the moment.
Sure. Thank you very much, Colin, and I'll go ahead to the next slide, and I do have some disclosures and worked with a variety of the companies in the space. There are differences in the ProstACT GLOBAL than the VISION trial, the PSMAfore, the ECLIPSE, and the SPLASH trial, which are other trials that have used, in a randomized way, the small molecules with lutetium. Now, one of the things that is actually not shown here is the definition of PSMA PET-positive disease, and there's some distinctions. The cutoff in the VISION trials and in the other small molecule trials have basically been an uptake greater than liver. Here, it's 1.5 times the liver uptake.
That could be important because we have analyzed the small molecule trials, and to some extent, those with more PSMA PET-positive disease are those that managed to do a little bit better. So here on the ProstACT GLOBAL, you're actually cutting out some of the low PSMA PET positivity and including only those that have a higher probability of response, in my mind. Now, another critically important variable is the actual use of standard of care. So if we go to the VISION trial, it was a standard of care plus or minus PSMA-617 lutetium-177. However, the standard of care excluded taxanes. If you look at the taxanes, they're known to be active, and I just finished another ad board where there was significant discussion about the control group, as well as the treatments that have been received in the PSMA lutetium patients.
There is, I think, a growing pushback against the exclusion of docetaxel, which is a known effective therapy in these trials. What we have here in the ProstACT GLOBAL is a standard of care that can include either an ARPI or a taxane, and it's going to be physician-designated, and it's going to be true in both arms. Now, let's look at the group A, which is the one with the lutetium, for a moment. If you're randomized to the standard of care, you could start an ARPI, essentially the same time that you would start the antibody. However, if you're going to receive the taxane, then you would need to wait until the lutetium is already in, and you make sure that the blood counts are such that they're eligible for taxane therapy.
But nevertheless, it is a standard of care plus the lutetium in this particular study. Now, in group B, the physicians can choose either an ARPI or a taxane, and they can start the taxane immediately if they so desire. But anyway, I think the bottom line is a little different in the selection, a little different in the standard of care, and the inclusion of taxane is actually a big difference to me. Now, next slide. We're going to be moving, for a brief moment into talking about Telix 592, which is not the same as 591. Telix 592 is an antibody that's been engineered for a more rapid rate of elimination than the standard antibodies, and as Scott mentioned, you end up with a prolonged retention in the blood pool with the standard antibodies.
So this is going to be one that would have a little bit more rapid clearance. Now, you could look at the 592 and look at the 591 in an animal model and be able to see that you end up with comparable tumor uptake, but a more rapid clearance. And the CUPID study is going to be looking at 592, and I'll just jump ahead for a moment. You're seeing the copper data here with the imaging, but I think the plan is to move this into actinium. Next slide. So a couple of things that I think distinguish the Telix 591. First of all, we have extensive data. Thank you, Scott Tagawa and colleagues in New York. And I think one of the things that is most promising is not necessarily the PSA decline, but rather the survival.
And the survival in heavily pre-treated patients has been much better than would have been anticipated with either a small molecule with lutetium or in fact, almost any other agent. Some of the survival data in these early phase Telix 591, J591 lutetium studies have been outstanding. Another thing is the dosing schedule. As Nat mentioned, and Scott had alluded to, there is a potential advantage from being able to give a couple of doses and then allow the combination with these concurrent therapies. Design really is the standard of care plus the Telix 591, and I think that's a good trial design and one that could have benefit for patients. For the patient comfort, we don't get the same degree of on target, but off-tumor effects. You don't get the dry eye, you don't get the xerostomia.
Nat had mentioned the PSMA-I&T actinium 225, where the patient actually declined further treatment because the dry eyes and xerostomia. There are implications, I think, for alpha therapy going forward, but that's not why we're here. I'm going to say that the 591 is not going to be associated with dry eyes and xerostomia we see with the small molecules. I think the patient-centric comfort is something that has been mentioned several times before. It's a 2-week course of treatment instead of a 36-week course of treatment. There is going to be close collaboration with medical oncology, but in my opinion, that is an asset. You end up with a short treatment duration, significantly fewer clinic visits, but I think incorporation with the medical oncologist for the inclusion of other standard of care therapies, as mentioned, is a significant positivity.
There's also reduced cost, reduced radiation protection implications, and I think there are many advantages for reduced radioactivity. We demonstrate efficacy of this particular trial, it'll change practice, and one I think that would be welcomed in the community. Colin, those are the issues that I wanted to cover. Now, back to you.
Thank you. Thank you so much. Thank you to the whole panel for great insights to date. Now, I wanted to just start a bit of a discussion, and we also have received a few questions from the audience that I will go through in time. But I wanted to go back to this PSA as a prognostic marker, and Oliver, maybe you could sort of open and comment on that.
Sure. PSA is a valuable biomarker, but it's not the end-all and the be-all. You know, one of the things that the VISION and the PSMAfore trial did not include was any PSMA PET imaging. But in studies where we've looked at PSMA PET imaging, it turns out that that's likely a better prognostic finding as compared to the PSA itself. Now, going to PSA just for a brief moment, let's remember that it is produced within the cells that are most differentiated. As you move into the higher Gleason scores, the 8, 9, 10s, on a cellular basis, the production of PSA is lower for a Gleason 10 tumor as compared to a Gleason 7. So what you're measuring with PSA is a more differentiated function, and that may not be the best measure of a biomarker when it comes to survival.
I'll take the survival that Scott has shown over the PSA declines, and I think that's where there could be some discrepancy. The small molecules, we've seen the PSA declines. With this particular molecule, we've seen the survival. I think the trial needs to be done, no doubt about it. It would be silly not to do the trial. Here, the trial is we're going to give a shot on goal and see what happens.
Fantastic. Any thoughts on other prognostic markers that you've seen during your investigations with 591, Scott?
Well, so in terms of prognostic markers, some of this, you know, there are known prognostic markers. Well, prognostic, I mean, it's independent of treatment, so, you know, things like LDH or you know, overall tumor burden, liver is not a great place for cancer. But in terms of other biomarkers that might be meaningful in terms of efficacy, in the more recent era, so these didn't really exist, you know, going back 15 to 20 years ago, but we've been looking at circulating tumor cells, which are in the process a couple of different platforms are in the process of being credentialed by the FDA as a potential approvable endpoint. And PSA has never been there is a major point.
So, starting off with a higher number or at least detectable and then coming down, has been associated independently, with overall survival across a number of different clinical trials, and we have demonstrated that, with lutetium JF-001 across the more, kind of more recent, era. So that's something kind of in addition to, just PSA, for instance.
Great. Any further thoughts to add on that, Nat?
No, look, I think I think Scott's right. I think the circulating tumor markers, circulating DNA, tumor DNA, I think are gonna add a lot more. We're starting to use it in other tumor types now. It's a valuable addition, I feel in other tumor types. I look forward to seeing that. And I think what Oliver said is completely correct. PSA can be actually very low in high-grade tumors. You know, it's one of the problems with some PSA screening, where you can have a quite aggressive tumor and your PSA is not very high. And even in some racial groups, we know that PSA is not often a good marker in certain races. So, it is what we have, it's what we use.
But I think in the era of PSMA PET, and we do a lot of PSMA PET in Australia. In fact, in Perth, we do over 100 PSMA PET a week, in a little town. So it's become a surrogate biomarker for us. You know, we are doing follow-up scans and routine scans. So I think PSMA PET has really changed the way we look at things, and I'm glad that PSMA PET has been included in this trial on an ongoing basis, because unfortunately, in the earlier trials, there wasn't that we didn't have the serial data, which we really need.
Fantastic. Thank you so much. Look, one of the questions we're asked often is, you know, are we, are we able to recruit for this study? Is two doses an attractive regimen for patients? Will we be able to recruit for this study? Oliver, what's your thoughts on that?
I don't think you'll have any trouble with recruitment. You know, first of all, the taxane-naive population has no radiopharmaceutical therapy approved today. So PSMA-617 is not approved. There's no reporting yet for Splash or Eclipse, and I think patients are anxious to get this type of therapy. And if you look at the accrual in a whole variety of the PSMA lutetium studies, they've been very rapid. I think accrual will not be a problem.
Great. Any further thoughts on that, Scott?
I completely agree. You know, it's. Patients are clearly interested in a way any non-chemotherapy regimen, especially some that have, you know, some data behind them, that's, you know, regardless if it's, if it's radioactive, if it's PSMA targeted, whatever it is, you know, I think patients are interested. And then, you know, in terms of the, on the practical basis, just the two-dose administration, it makes it easier. Of course, we're still gonna monitor them on an ongoing basis, both for safety as well as efficacy in terms of scans and survival. But in terms of overall treatment, it makes it easier on them.
Actually, one interesting thing, so with the segue, we look at CTCAE, that's the way, the technical term, how we look at adverse events, but we created a patient-reported outcome specifically for radio, radionuclides. It's because dry mouth is not very accurate on this. But one thing that came out was the feeling of isolation, and part of that came out from some questions about, well, worried about radiating my family, grandkids, et cetera. So there's less in terms of total amount of radioactivity that's injected, but it's also just twice rather than multiple times. So I don't know if that is gonna equal less feeling of isolation, but I know that did come out in this tool that we created for other reasons that just happened to kind of come out. So that's another interesting fact that is patient-friendly.
Mm-hmm. Very good. Look, Nat, maybe just, just something to put to you. You, you mentioned about the taxane therapy opening up recruitment, and in particular in Australia, where we know that's probably standard of care in that setting. Is that, is that right?
Yeah. No, look, I think the nice thing about this design is, well, you've got two arms. You can go on to a novel anti-androgen, which is good. And in Australia, the fact that Telix will cover a second novel anti-androgen because of our restrictive PBS criteria, it's often hard to go onto a second novel anti-androgen. So that's been welcomed. And also, the crossover design, I think, is also welcomed. It basically allows other therapies and other standards of care to be introduced. That's been one of the issues in the past.
So patients who I've spoken about the trial, even if they're, if they know that they get randomized to the non-radio ligand or the radioantibody therapy, know that there is the possibility to get that down the line. And that's actually very encouraging. In fact, I had a patient just very recently who has been randomized to the non-radio ligand arm, but he knows that that is in the background if he needs it, which is really very useful.
Yeah, and there's obviously there's slight nuances there because, you know, Australia can offer, you know, compassionate use perhaps more easily than other countries. In fact, you know, perhaps on the bigger scale, that looking at that crossover arm and taking that out might allow us to observe, you know, overall survival as an example. And moving forwards, you know, that was seen as a critique of PSMA four about the overall survival. There was huge crossover there, Oliver, right?
Yeah. 84% of the patients on the hormonal arm crossed over. I think that many people were aware that the intent to treat analysis had a hazard ratio of 1.16, but confidence intervals were big and clearly overlapped 1. In the pre-specified crossover- adjusted overall survival analysis, there was, in fact, a trend, 0.8, for the hazard ratio favorable for lutetium. However, again, the confidence intervals were large. The fact that the confidence intervals were so large, I think will be one of the reasons why there will be a little more scrutiny on that trial. I'll simply say that, nothing is approved in the space right now, and it'll require regulatory action before any of the other agents might be introduced.
Got it. Yeah, and, you know, obviously, regulators would like to see overall survival as a primary endpoint in a lot of studies in oncology, of course. But our PFS has been an accepted measure, but, you know, particularly overall survival will come in as we go forward, and particularly in terms of the reimbursement setting as well. I've just received an interesting question. At ESMO, I couldn't go to ESMO, but I know there was a lot of talk about quality of life and patient-felt quality of life factors. But this is one about synergy between PSMA-targeted agents and enzalutamide. But is there any data to suggest any synergies between 591 and taxanes at all? And, Scott, maybe your study gives us some thoughts on that.
Well, that's why we. I mean, some people would say oncologists have two drugs, and I was going to combine them in some sort of trial. But there was a scientific rationale for the regimen. One, because at least at the time, we thought, because we were coming from early studies where we used yttrium, which is a much longer path length, and lutetium, and the big bulky disease was better with yttrium. We said, "Okay, let's give a couple cycles to maybe cytoreduce." That was why we started with cycle three.
But the main reason that we wanted to combine them was because we know that taxanes, preclinically and clinically can radiosensitize. So, it can happen with hormonal therapy as well. But that was the idea, that can we safely deliver the two of them together, and, you know, get more bang for our buck? And that was the idea behind why we did that, that combination.
Got it. Thank you for that. Any other thoughts on that? Oliver, you wanted to comment?
Yeah. You know, you know, I think that there's not only synergy potentially between the taxanes but also with the hormonal agents. You know, within the VISION analysis, we looked at those who had the PSMA lutetium, with or without a hormonal therapy. And the truth is that those who were on the hormonal therapies did a little better. Now, in the PSMAfore trial, there was no hormonal therapy allowed in the. Excuse me, I should say no novel hormones, no abiraterone and enzalutamide allowed in the lutetium arm, and the FDA required the separation. I like the opportunity to use combination. I think if we had Louise Emmett here, she would agree with that, and she presented the ENZA-p data at ESMO as well, and that was indeed very interesting to me, showing interactions in a positive way for the hormones as well as the isotope.
Great. Thank you for that. There's a lot of interest in this, in terms of the clinical position. I guess, you know, if this study is positive, how would the potential indications be different with five nine one? Would it potentially end up in a combination with a taxane indication?
You know, I think your phase III trial will determine your indication, and here, by overtly including the taxanes and RPs in both arms, I think you could end up with a quite distinct label, which fits a little better with the way medical oncologists are treating patients. We do think about a single line of therapy, don't get me wrong, but we also think about combinations and sequences, and in the end, we want our patients to get as many of these life-prolonging therapies as possible. I think this trial design does have some advantages, and I think that's a little bit distinct from the PSMA for the Eclipse and the SPLASH trials.
Can I just ask, as a follow-on real question is like, you know, historically, and one of the reasons for this as a control arm going for abiraterone and then an enzalutamide-type control has been widely adopted because that has historically been a real-world practice in the U.S. But is the practice changing in the U.S., that taxanes are used in that second-line setting more often?
Well, you know, I think, I think there's an overall recognition of the limitations of the hormonal therapy in the second line. It's still quite commonly used, but everyone understands that the second-line hormone is gonna be less effective than the first, dramatically less effective than the first. And I think that there's a little more of a push these days to get in the docetaxel when you can, as opposed to pushing it to the rear. Docetaxel is acknowledged to be an active agent, and people want to use as many active agents as feasible for these patients. We're not curing them. We're trying to prolong their survival and fit in as many active agents as we possibly can. That's sort of a predominant philosophy, I'd say, today in the U.S.
That's great. And Scott, maybe you could comment on that, using taxanes in your daily practice.
Yeah. I mean, I'm an oncologist. We give chemotherapy, not only. You know, I think it depends. So, you know, part of it, I think you used the term era, but you might not have. I think it a little bit is the era. So in the setting where someone has had one AR pathway inhibitor, and then what do we have that really is proven overall survival, that is applicable to most patients, it really is chemotherapy. Because CPx-35 may be for a small subset, radium for a small subset, PARP inhibitors for a small subset. But taxane chemotherapy is, you know, more or less universally there, even though, you know, data will show only 50%-60% will ever get it.
You know, I think that, you know, certainly in my practice, I take the time to explain what's going on there. Most of my patients, virtually all, not just most, like 51%, but the vast majority, I would say, are taxane eligible. I may adjust the dosing schedule for them, but, you know, I think most can receive it. And, you know, when docetaxel is real, it improves survival as well as patient support outcomes, versus mitoxantrone, which is approved based upon patient outcomes. So it, you know, for symptomatic patients, I think it's great to have, but not everyone needs that as the absolute next line, and that's why people have used AR pathway inhibitors kind of back to back. I think that changes, but I mentioned ARs. That changes the new era where we start to have more options.
And even if, let's say, someone did a head-to-head against docetaxel, and there was no major difference, because for that minimally symptomatic patient population, and you still have the chemo toxicity, I think people might choose a chemo, non-chemo-containing regimen or one that's more delayed, you know. Let's say, with tissue and symptoms, J591, followed by docetaxel, and then in the real world, even if that was approved like that, patient doesn't necessarily get that second part right away. So, you know, we'd have to see what happens. You don't have that problem yet. You have to see what happens, and maybe that's a future issue to kind of bring up.
A nice, a nice problem to have, is what you're saying. Right. Look, we've come to the end of the hour, and I wanna thank the speakers for the excellent input and feedback. We've tried to cover a lot of those advanced questions in the discussion, in the presentations. Thank you for those who've just submitted questions, and I'm sorry if yours hasn't been answered, then, of course, we'll come back to you. But, you know, I think, you know, my excitement about J591 is the differences in terms of, you know, the dosing, the total lutetium dose, the side effect profile of the antibody. And also those two doses, which I think is patient-friendly. So I wanna thank you all.
We're excited to press ahead with ProstACT GLOBAL and really find out and get the data that we can use to take this asset forward. So, Oliver, Nat, Scott, thank you ever so much for your participation today. Thank you for those of you who've been able to join in, whatever time of day it is for you. So thanks, everybody. Look forward to meeting again very soon and discussing further data from this and other studies. So thank you.
Thank you, Colin.