KOL Event

Sep 2, 2025

Our second webinar. I will do a very brief intro and recap of last week and then lead into today's topic and presentation. Today we have Dr. Hans David Olmert from UCLA. Very happy to have him here. Thank you, David, again. Thank you, Cristian. Thank you. Last week we had two presentations and a very nice discussion following. The first presentation was by Dr. Oliver Sartor, second by Dr. David Piwnica-Worms. Dr. Sartor gave us an overview of the prostate cancer treatment landscape, the unmet medical needs, and emerging new treatments, including, of course, radiotherapy such as the combination of radium-223 with enzalutamide, and then more targeted approaches, of course, like PSMA radiotherapeutics such as Pluvicto. These treatments, and in particular, of course, Pluvicto, have changed the landscape of prostate cancer treatment very significantly over the past years. Pluvicto has demonstrated efficacy in prostate cancer patients before and after chemotherapy with the PSMA-4 and the VISION trial, respectively. Now, also very recently in June, in earlier stage of disease, in other words, in hormone-sensitive prostate cancer with the PSMA addition trial. Following these important achievements, of course, considering that all patients who have in the past received some form of PSMA targeting treatments will relapse, it is very clear that there is still a big medical need for new therapies, in particular, new targeted radiotherapy. From there, we went to Dr. David Piwnica-Worms' presentation. He introduced us to a very exciting new target, B7-H3, which is an immune checkpoint inhibitor that is expressed in many different cancers, including prostate. Dr. Piwnica-Worms presented an array of preclinical data demonstrating very convincingly the efficacy of Betabart. We call this agent Betabart. It is Radiopharm Theranostics' monoclonal antibody for the clinic. It is a modified antibody to have a shorter half-life and reduce side effects such as organ toxicities while maintaining a very strong affinity for the target. We will be using Betabart in our upcoming study, having it linked with Lutetium-177. We will enroll in a basket study patients with different tumors with relapsed refractory disease, including patients with prostate cancer who had prior Pluvicto or did not have prior Pluvicto or any other PSMA targeting therapies. Since this is going to be a new target in prostate instead of going after the same PSMA target as many other companies in various iterations, we believe it does represent a promising new approach. We are really very much looking forward to run the Betabart study. We will run this study in the U.S. and plan to enroll the first patient at the end of this year. Today, as I said, I have the great pleasure to introduce Dr. Hans David Olmert. Dr. Olmert is a researcher and academic, currently Associate Professor in Residence in the Department of Molecular Medical Pharmacology at the David Geffen School of Medicine at the University of California, Los Angeles, in Los Angeles, California. He is also the Director of the UCLA Preclinical Theranostics Program and a member of the UCLA Johnson Comprehensive Cancer Center. His research focuses on developing novel targeted therapies and molecular imaging strategies for cancer. He has a particular interest in prostate cancer, studying risk factors and biomarkers. His work involves using radiolabeled antibodies to target specific proteins in cancer cells, like human kallikreins, such as KLK2 and our KLK3, for image-guided diagnosis and therapy. In addition to these, he has also been awarded a grant to advance targeted therapy for osteosarcoma, which is a form of bone cancer. Prior to his current role, Dr. Olmert was affiliated with institutions such as Memorial Sloan Kettering Cancer Center in New York and Lund University in Sweden, where he also received his M.D. and his Ph.D. Dr. Olmert will tell us about another new target in prostate cancer, which is KLK3 or PSA, that he has studied very extensively. He basically came up with this particular therapeutic approach. He studied this very extensively, as I said, in the preclinical setting. We, Radiopharm Theranostics, will study this in the clinic in prostate cancer patients. In contrast with many other companies who are going after a new target, not another PSMA iteration. You will see that this new target, KLK3, is very specific for prostate as opposed to PSMA, which, despite its name, is expressed in many different other tissues or organs such as kidneys, salivary glands, or the lung, accounting for some of the toxicities that have been observed in the past. Our KLK3 is, of course, going to be, because of that, we believe, a very promising approach. We will run this study with our KLK3, 100% in Australia. We plan to enroll the first patient sometime early next year. With all that, I'll stop talking and hand it over to Dr. Olmert. David, take it from here. Looking forward to your presentation. Thank you so much for the kind introduction. I'm going to show you the rationale for targeting prostate kallikreins and specifically KLK3 or PSA. To give you a little bit of a background on human prostate kallikreins, KLK2 and KLK3 are the genes for HK2 and PSA. They're only found in humans, dogs, and old-world monkeys. Interestingly, we are also the only species who spontaneously develop prostate adenocarcinoma and BPH. Both of them are specifically expressed at very abundant levels in prostatic tissues, both healthy tissues and malignantly derived. The expression is governed by the androgen receptor, which is the key driver of adenocarcinoma, which has been targeted with other types of therapies, such as AR inhibitors, etc. KLK2 and KLK3 are very similar in terms of sequence identity. They have 80% AA sequence identity. KLK3 is a duplication of KLK2 phylogenetically. However, even though they're very similar, they have different enzymatic activities. HK2 has a trypsin-like activity and PSA has a chymotrypsin-like activity. What's interesting with HK2 and PSA is that they're both very tightly confined within the prostate gland. Even though we measure PSA and HK2 in blood, it's only every millionth molecule that is secreted when there is a prostate pathology ongoing in the gland. What's also interesting is that when we are measuring PSA, we are actually measuring PSA complexed with protease inhibitors because as soon as they are entering the blood circulation, since they're enzymes, they are immediately inhibited and complexed with protease inhibitors. We are going after the catalytic cleft of these two proteins. The specificity is quite spectacular when it comes to expression levels of KLK2 and KLK3. Compared here to FOLF1 or PSMA, we see that we only have expression in prostate tissues, both healthy and malignantly derived. We have a higher expression of KLK3 compared to KLK2. We made antibodies for both of these enzymes. We're specifically targeting the catalytic cleft of HK2 and PSA, respectively. We're doing that in order to avoid targeting PSA that is measured and found in serum. If we start with the HK2-targeted approach, here are our preclinical assessment in subcutaneous tumors. As you can see here, the HK2 antibody is labeled with zirconium-89, which is a positron emitter, so it can be utilized for PET imaging. As you can see in these subcutaneous mouse models, the antibody is specifically going and retaining in the tumor tissue. We also see that if you have a higher expression or higher production rate of KLK2, you have a higher uptake of the antibody. Same goes for PSA. As mentioned before, it's only dogs, old-world monkeys, and humans that express prostate kallikreins. In order to study this in more efficient ways, we have to develop genetically modified mouse models that then have the full immune system and also that they're spontaneously developed adenocarcinoma. If we have the zirconium-labeled antibody targeting KLK2 and we inject that into a mouse, we see that we have no uptake at all in the body of the mouse. In the middle here is a mouse model that expresses KLK2 specifically in the prostate under the androgen receptor. We continue to see quite clearly the uptake of zirconium-labeled KLK2 antibody. To the right, you can see when we cross this model that is expressing KLK2 with a Hi-Myc model, which is spontaneously developed aggressive form of adenocarcinoma. As you can see, the PET picks up where the KLK2 cells are located, which is specifically in the prostate tissue and malignantly derived prostate tissue. We also know with PSA and KLK2 that we can target very late disease, meaning that when the patient, for example, has metastases to the liver, we are able to become enzalutamide resistant. We're able to target these forms of prostate malignancies, as seen here with PET and PET MRI. When we are evaluating the therapeutic efficacy of KLK2-targeted therapies here, when we labeled it with Actinium-225, which is an alpha emitter, we utilize these advanced models in order to evaluate the efficacy. As you can see here on the MRI images, this is as pre-treatment. We have a massive tumor amount in the mouse. We give a single injection of alpha-emitting KLK2-targeting radiation immunotherapy. As you can see, after four weeks and after eight weeks, the tumor basically disappears. You also see up to the left to the right graph where you have a Kaplan-Meier plot for survival of the mice over a longer period of time. From a pathobiological perspective, both PSA and KLK2 are highly interesting. The radiation immunopathobiology is something that we are exploiting in this type of treatment. What happens in a tumor when you are applying irradiation is that the cells that are not dying are trying to repair the DNA in the cells. When those DNA damage responses are induced, we also see that we also know that AR is increased. That's been pretty elegantly shown by both Knutson and Falkenhorn about 10 to 15 years ago. Since AR is upregulated as a response to DNA damage, when AR is upregulated and since both HK2 and PSA are governed by AR activity, what happens in the tumor is that the tumor gets smaller. However, given the surviving cells are trying to repair their DNA, AR goes up and then HK2 and PSA increase as well. The tumor gets smaller, but the amount of target is increasing in the tumor over time. As you can see through the graph number D, we see that AR is upregulated. We see that KLK2 is upregulated twofold, while KLK3 is upregulated almost fourfold, while PSA or FOLH1 is decreased. It's something that we see in patients as well when you're giving a dose of PSMA targeting Lutetium therapy. We see that the therapeutic efficacy is decreasing over time. One theory behind this resistance mechanism is that when they're trying to repair their cells, AR is upregulated. Given that FOLH1 is negatively driven by AR, the amount of PSMA is decreasing. The HK2 antibody has been licensed or sold to Johnson & Johnson, who had taken this to the clinic. They started by evaluating it by labeling the antibody with indium 111. What you can see from the SPECT images here and the evaluation and the results from these clinical trials is that the HK2-targeted imaging picks up all tumors that could be found by combined imaging, such as PSMA imaging, CT, and MRI. After this study, when this phase zero study was done, they moved forward and they then applied it as an actinium-targeted radiation immunotherapy. What we can see here through these results from the phase one studies is that most of the patients are responding really well. We see that they have deep and durable responses. What's interesting here also is that, as you can see to the right, when you give a dose, the PSA levels in the blood are decreasing. When they go up again, you give a second and a third dose, they are responding. The response is not decreasing over time. If we should then summarize HK2-targeted radiotheranostics, it's that we have developed an antibody-targeted cleft of HK2. We have labeled it with zirconium and evaluated that preclinically, both in advanced mouse models, normal subcutaneous models, but also in monkeys. We know that the AR reaction towards as a response to irradiation, that we are benefiting from that, given that AR goes up, HK2 goes up. The tumor decreases over time, but the avidity or the amount of available target is increasing. We can deliver, have utilized this to deliver both alpha and beta particle radiotherapy. J&J has then evaluated as an indium-labeled compound and is currently evaluating in a phase one as an actinium-labeled compound. Now, why is KLK3 or free PSA-targeted radiotheranostics a more advanced or better approach? It has to do with that you have a higher expression level of KLK3 compared to KLK2. When you look at levels in tissues, the HK2 levels are often 10 times lower. The KLK3 levels are 10 times higher. Only 2% of the total PSA levels are found as HK2 levels when evaluating it. PSA and KLK3 is a much more studied biomarker. If we look at PubMed, there's over 27,000 publications, while there are only a couple of hundreds on the KLK2 and HK2, which is then, and of course, PSA is the gold standard biomarker for screening, diagnosing, and monitoring, one of the most well-studied biomarkers for cancer that exists. Utilizing all of this, the higher expression, the know-how of PSA and HK2 or PSA, and that we're targeting the catalytic cleft, meaning we are not targeting the PSA that is in the main form in the circulation. If we look at other PSA-targeted strategies, they have shown safety and some efficacy in phase one and phase two trials. Not only are we benefiting from Janssen looking at the HK2 targeting antibody and seeing that there are therapeutic effects and that the antibody is going where it should go, we're also benefiting then from other studies as well, which is then de-risking the project when going into the clinic. If we then look at the differences here in terms of expression levels in different tissues, as I've showed you before, the scene here is that KLK3 expression is very specific and expressed at abundant levels in prostatic tissues compared to, for example, PSMA. With the antibody that we developed for the PSA targeting approach, we've evaluated with as a zirconium PET agent, as an actinium-225 labeled radiation immunotherapy. We also compared it to yttrium-90, which is a pure beta emitter. We also assessed it with Lutetium. We evaluated that as well, the PSA targeting antibody as well in genetically modified mouse models, very advanced models with the full immune system that spontaneously develop adenocarcinoma. As you can see to the left of these images, these are PET images, zirconium-labeled PSA targeting PET. You can see that specifically the uptake is specifically in the prostate where you have the expression of PSA. We can also see that we have, it's a subtle academic sort of thing to look at, but we see that we have in some of the mouse lobes higher expression of PSA than other lobes. We can see in this autoradiography that is below the PET image that we have a higher uptake in the glands and the lobes that have higher expression of PSA. We also see that when we're comparing zirconium, actinium, and yttrium biodistributions, they're very similar. You can rely on, for example, zirconium-labeled antibody in order to do dosimetry for actinium-labeled variants of it. What's great with the 5A10 antibody is that it's internalizing, meaning that when the antibody is binding to the catalytic cleft of PSA, the cell is taking in the antibody, which then is carrying either a diagnostic radionuclide or a therapeutic warhead. You see that here is that the blue is then the DNA. The red is the filaments that are making the cell stable and working as a scaffold for the cell. The green dots here are then the 5A10 antibody. We can clearly see here that it is internalized in these advanced models. If we then compare free PSA-targeted radiation immunotherapy and we compare actinium versus yttrium, so pure alpha versus a pure beta, we see that we have a faster response with the beta emitter, but we have a longer durability when we're applying it as an alpha emitter. We've also studied this in monkeys. Here are some caveats that we need to keep in mind when we look at these images. The PSA levels in the monkeys are about 500 to 1,000 fold lower compared to humans. We also know that if you look at the amount of PSA in the ejaculatory mix, it's about 5,000 times lower than in humans. On top of this, two alternative splice variants of PSA are expressed in the monkey, and one of these is not targetable with the PSA antibody. It's also unclear how the other differences between monkey PSA and human PSA, how much that is affecting the binding as well. Regardless of these thousands fold lower expression levels of PSA, when we tested it in monkey as a zirconium-labeled free PSA targeting imaging agent, we can clearly see that despite the much lower expression levels in monkeys, we see that the uptake in the prostate is clearly visible. As you can see here on the series of images focusing on the prostate, we start to see uptake after an hour and the retention is then in the prostate for many days while it's decreasing in other organs. If we then look at the other benefits of and utilizations of PSA-targeted radiation immunotherapy, it is that, as we've explained before, PSMA-targeted therapy, we see that the efficacy is decreasing over time and that AR is increasing. We're benefiting from a PSA prior to patients that are prior PSMA treated because they have potentially a higher level of PSA in the prostate and in the malignant tissues that are producing PSA. We're also then relying on a small molecule that is targeting PSMA, which has a different excretion pathway. We have uptake in both PSMA expression in the kidneys, and there are PSMA expressions in the salivary glands. Going with an additional small molecule that is then also excreted via the kidneys could potentially be troublesome. Moving on and utilizing an antibody instead and switching then from Lutetium-177 to Terbium-161. Why it's important to point out and why Terbium is very interesting in this case is that the antibody, as shown before, is internalizing. We're both relying on beta particles, which is then not only retained in the PSA-expressing cell, but it's also giving off radiation that will then affect and have therapeutic effect on the neighboring cells. However, with Terbium-161, we also have R-share electrons, which are only effective if it's very, very close to the nuclei. Again, we have an internalizing antibody. You can see this as a very robust and intense burst that is pinpointing sort of like an explosion within the cell, which is then damaging the DNA on top of the emitted beta particles. In summary, we made and developed an antibody that specifically targets the catalytic cleft of PSA, so the free form of PSA. We are then avoiding targeting PSA in the blood. We know that through evaluation in monkeys that it's safe and specifically targets PSA-expressing tissues. We also know that the therapeutic, when we're looking at alpha and beta emitters, that both are very effective. We are exploiting and harnessing the therapeutic activity by the upregulation of PSA that occurs as a response to DNA repair mechanisms. The tumor becomes smaller, but you have a higher expression over time of PSA, which is then increasing the retention in the tumors and increasing the efficacy. If we compare to KLK2 to KLK3, it's again that we have a much higher expression level of KLK3 compared to KLK2. Not only can we rely on and look at how the Janssen's evaluation of the therapy in humans where they see effect, and that it's safe, it's also that we then have a higher expression. We assume that we will also see a much higher tumor-specific uptake compared to what we'll see with the KLK2 or HK2 targeting therapies. Thank you very much for letting me present the summary here. If there are any questions, I'm more than happy to discuss them. Thank you, David. That was really amazing. Thank you for this so comprehensive overview of the landscape with the kallikreins. Very happy to open the Q&A. I would like to ask people who are in the meeting to submit your questions in writing, please, so that we can really try and answer them in the way they come in and try also to look at similar questions. The first question, which I guess is in many people's minds, for those who have observed the Janssen study with the KLK2 and the actinium, where do you think the reported ILD is coming from? Is it from the actinium? Is there an aberrant expression of KLK2 in the lung interstitium? I think that maybe they started out with seeing that they first didn't see any toxicity. They increased and increased and increased the dose. That could be one rationale for why they saw some ILDs. Again, we expect that we will have a, given that antibodies are circulating for a long time, we know that the higher amounts of expressed target that we see, the faster we'll also have an uptake in the tumor. It's anticipated that the targeting and circulation time will be shorter, given that we have a higher expression. Thank you. Another question is behind the rationale for choosing Terbium over Actinium to label the KLK3 antibody. I mean, I believe you already answered that, but I guess it's the combination of the beta and the OG. Maybe you want to expand on that again briefly. It's a two-hit sort of approach where we are not only utilizing the specific tumor retention, we're also then utilizing the fact that the antibodies internalize to getting close to the DNA. Not only are we getting therapeutic effect from the beta and destroying the cell that the antibody is taken up in, but also harming the neighboring cells. On top of that, we have then a sort of a small explosion very close to the DNA, which then increases the therapeutic efficacy as well. Thank you. Where do you see, I mean, you spoke about KLK2, but where is the KLK3 competition right now? Is there any other KLK3 targeting compound out there? No. From my knowledge, it's not. I won't go into the full academic mechanistic answer of how the antibody is internalizing. Together with Jeff Ravitch's lab, we evaluated how the antibody is internalized, and it's internalized through an FC mechanism. It's hard to get an internalization with a small molecule, for example, or a smaller version of an antibody. You have to rely on an antibody. Great. Thank you. Just looking back at last week, there's a question whether there's any correlation between B7-H3 and KLK3. I will say that the correlation with KLK3 is more correlating with AR activity. It's two different beasts. One is a checkpoint inhibitor, and the other is an enzyme that is specifically expressed under AR at very, very high levels. There's a difference in how the expression is regulated. Thank you. When you, I mean, you're not, you're more a researcher than a clinician, but when you think about the landscape, the clinical landscape, how would you see that KLK3 would fit into that current landscape after what standard of care therapies, for example? I think personally, and again, that's my personal opinion, I think it would fit in really well after patients that have been treated with Pluvicto. They are tired of having their salivary glands destroyed. They also have potential risks with kidney toxicity. The AR is increased. Benefiting from the high AR output and increase of AR activity, and then utilizing an antibody which is excreted via the liver, not only decreases to change the landscape of the toxicity, but also benefits from how PSMA is regulated. Yeah. Thank you. That's great. Going back, maybe another question, going back to the asset of the Terbium, I guess, you know, it's a relatively new kid on the block, so to speak. Do you expect that we will see more with other targets? You know, any particular targets that you would think would be appropriate for Terbium? Or it's simply that, you know, it's new. I mean, there have been, of course, the studies or the VIOLET study that was recently published out of Australia, of course, with great success. From your perspective, is it just something that could be combined with other agents in the same way as, for example, Lutetium or? I think that's a question that is better answered by a physicist than me. Yes, from what I see, I think that we are benefiting from the internalization of the antibody and that we have sort of a two-hit approach to make it more efficient compared to if we had gone with Lutetium, for example. Okay. Very good. I think we're at the end of the questions. Is there any other in the chat? I believe I answered all the questions in the chat right now. If not, then again, thank you so much, David. For the people who are online, if there's something that comes to mind after we're done here, please reach out also via email. We would be, of course, more than happy to answer any additional questions in writing if there's something that you forgot to answer or something that comes to mind later tonight or tomorrow. With that, David, again, thank you so much. This was extremely interesting. I can only say that, you know, we, as Radiopharm Theranostics and I personally, as the Chief Medical Officer, we're super excited about this compound. Very excited to get it into the clinic in prostate cancer patients. I've myself been working on and off prostate cancer since radium, so since like 15 years or so. I'm very excited to get this going and have patients in Australia hopefully benefit from that. Thank you again for pointing out the great preclinical data. With that, I'm closing remarks to Riccardo Canevari. Riccardo Canevari is our Chief Executive Officer. He would like to have the last word. Thank you. Thank you, Dimitris. I think it's been two great webinars. Thank you to David Piwnica-Worms and Oliver Sartor last week. Thank you to Hans David Olmert today and to you, Dimitris, for running the show and all the people attending. We really were positively surprised that we have more than, well, above 100 people, close to 200 people for each webinar, both from Australia, where it's morning now, and the U.S., where it's evening. By the way, today is still Labor Day evening. It's a national holiday. Thank you for being with us. I really just took some notes. I think that I have only four take-home messages from these two incredible webinars. The first one is that in the metastatic prostate cancer space, the arrival of radiopharmaceuticals has changed the landscape. It is incredible the added value that we saw today with patients with metastatic prostate cancer. We can say from a statistical point of view that now they live longer. This is a great achievement. The second bullet point is that despite Pluvicto is a very good product, it's not perfect. This is normal from every first-in-class or for every standard of care. We need additional science. We need to do something more because unfortunately today, patients with metastatic prostate cancer still die from their disease. The third bullet point is what can we do? Can we go to the same target, switching isotope? Can we modify maybe the molecule a little bit? Can we try to go to new targets and new approach? What oncology, most of the time, has shown is that people, patients need a second target, a second approach to have higher chances to respond to a new therapy and live longer. Here is our role as radiopharmaceuticals. We are extremely involved in prostate cancer. We had two amazing compounds, the B7-H3 targeting molecule called RV-01, and the KLK3 targeting molecule called RAD402. Both of them will be available to patients in the clinical study before the end of the year. The B7-H3 in the U.S., the KLK3 in Australia. For us, for our team, having the possibility to go from testing this molecule in the preclinical setting to offering those to patients is a great reward. We are very excited. We are very positive. We think that these are the two most promising or among the two most promising molecules in metastatic prostate cancer that are coming to clinical. Again, fully motivated, fully excited. I just want to say a big thank you to all the scientists, the investigators, and the team that made this possible. We just cannot wait to do the first patient before the end of the year. Thank you very much to everybody for being with us. We hope to deliver short-time interim data quite soon. Thank you very much. Thank you, Dr.