Radiopharm Theranostics Limited (RAD) Earnings Call Transcript & Summary

Welcome, everybody. Welcome to our second webinar. I am Dimitris Voliotis. I'm the Chief Medical Officer for Radiopharm and it is a great pleasure for me to have you with us either for the first time or if you're already there last week, then welcome you back to, as said, our second webinars. I will do a very brief intro and a recap of last week and then lead into today's topic and presentation. Today, we have Dr. David Ulmert from UCLA. Very happy to have him here. Thank you, David, again. So last week, we had 2 presentations and a very nice discussion following. The first was -- first presentation was by Dr. Oliver Sartor, second by 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 vision -- with the PSMA 4 and the VISION trial, respectively. And now also very recently in June in earlier stage of disease, in other words, in hormone-sensitive prostate cancer with the PSMAddition trial. Following these important achievements, of course, considering that all patients have -- that have received some form of PSMA targeting treatments will relapse. So it's very clear that there is still a big medical need for new therapies, in particular, new targeted radiotherapy. So from there then, 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, and Dr. Piwnica-Worms presented in array of preclinical data demonstrating very convincingly the efficacy of BetaBart. So we call this agent BetaBart. It is RAD's monoclonal antibody for the clinic. It is modified. It's 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. So we'll be using BetaBart in our upcoming study, having it linked with Lutetium-177, and 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. And since this is going to be a new targeted 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. So we're 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 Ulmert. Dr. Ulmert 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. He is also the Director of the UCLA Preclinical Theranostics program and a member of the UCLA Jonsson Comprehensive Cancer Center. His research focuses on developing novel targeted therapies and molecular imaging strategies for cancer, and he has a particular interest in prostate cancer setting risk factors and biomarkers. His work involves using radiolabeled antibodies to target specific proteins in cancer cells like human kallikreins, such as KLK2 and KLK3 for image-guided diagnosis and therapy. In addition to this, 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. Ulmert was affiliated with institutions such as Memorial Sloan Kettering Cancer Center in New York and Lund University in Sweden, where he also received his MD and his PhD. Dr. Ulmert 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 started this very extensively, as I said, in the preclinical setting, and we, RAD, will study this in the clinic in prostate cancer patients. Again, in contrast with many other companies, we 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 kidney, salivary glands, or the lung, accounting for some of the toxicities that have been observed in the past. So 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 and we plan to enroll the first patient sometime early next year. So with all that, I'll stop talking and hand it over to Dr. Ulmert. David, take it from here, looking forward to your presentation.

Thank you so much for the kind introduction. So I'm going to show you the rationale for targeting prostate kallikreins and specifically, KLK3 or PSA. So to give you a little bit of a background on human prostate kallikreins. KLK2 and KLK3 are the genes for HK2 and PSA and they're only found in humans, dogs and old world monkeys. And interestingly, we are also the only species who spontaneously develop prostate adenocarcinoma and BPH. They are -- both of them are specifically expressed at very abundant levels in prosthetic tissues, both healthy tissues and malignantly-derived. It's governed by -- 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, et cetera. So KLK2 and KLK3, they are very similar in terms of sequence identity, they have 80% AA sequence identity. KLK3 is a duplication of KLK2 philogenetically. However, even though they're very similar, they have different enzymatic activities. So 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 are secreted when there is a prostate pathology ongoing in the gland. What's also interesting is that we are measuring PSA, we are actually measuring PSA complex with protease inhibitors because as soon as they are entering the blood circulation since their enzymes, they are immediately inhibited and complex with protease inhibitors. So we -- and we are going after the catalytic cleft of these 2 proteins. The specificity is quite spectacular when it comes to expression levels of KLK2 and KLK3 compared here to FOLH1 or PSMA, we see that we only have expression in prostate tissues both healthy and malignancy-derived. We have a higher expression of KLK3 compared to KLK2. So we made antibodies both -- for both of these enzymes, and we're specifically targeting the catalytic cleft of HK2 and PSA, respectively. And 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 is then the HK2 antibody labeled with Zirconium-89 which is a positron emitter, so it can be utilized for PET imaging and as you can see in these subcutaneous mouse models, the antibody specifically going and retaining in the tumor tissue. We also see that if you have a higher expression or higher production rate of HK2, we 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 a genetically modified mouse models that then have the immuno -- full immune system and also that they are spontaneously developed in [indiscernible] carcinoma. So if we have the zirconium-labeled antibody targeting HK2 and we inject that into a mouse, we see that we have no uptake at all in the body of the mouse. We have then in the middle here is then a mouse model that express HK2 specifically in the prostate and the androgen receptor. And then indeed you can see quite clearly the uptick of zirconium-labeled HK2 antibody. And to the right, you can see when we crossed this model that is expressing KLK2 with a high MYC model, which is spontaneously developed aggressive form of adenocarcinoma. And as you can see, the PET picks up where the HK2 cells are located, which is specifically in the prostate tissue and malignantly-derived prostate tissue. We also know with PSA and HK2 that we can target very late disease, meaning that when the patient, for example, has metastasis to deliver, we are able to -- and become enzalutamide resistant, we're able to target these forms of prostate malignancies as seen here with PET and PET MRI. When we are then evaluating the therapeutic efficacy of targeted -- our HK2 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 pretreatment, we have a massive tumor amount in the mouse, and then we give a single injection of alpha-emitting HK2 targeting radio immunotherapy. And as you can see, after 4 weeks and after 8 weeks, the tumor basically disappears. And you also see up to the left -- to the right graph, we have a Kaplan-Meier plot for survival of the mice over a longer period of time. From a pathobiological perspective, both PSA and HK2 are highly interesting and the radio immunopathobiology is something that we are exploiting in this type of treatment. So -- what happens in the tumor when you are applying irradiation is that cells that are not dying, they're trying to repair the DNA in the cells. And when those DNA damage responses are induced, and we also see that -- we also know that AR is increased. That has been pretty elegantly shown by both Knutson and Polkinghorne about 10, 15 years ago. So 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 the DNA, AR goes up and then HK2 and PSA has increased as well. So the tumor gets smaller, but the amount of target is increasing in the tumor over time. As you can see to the graph #D, we see that AR is upregulated. We see that KLK2 is upregulated twofold, while KLK3 is upregulated almost 4-fold while PSA or FOLH1 is a decrease, and it's something that we see in patients as well when you're giving a dose of lutetium -- PSMA targeting lutetium therapy, we see that the therapeutic efficacy is decreasing over time. And one theory behind this persistence mechanism is that when they're trying to repair their cells, AR is upregulated. And given that FOLH1 is negatively driven by AR, the amount of PSMA is decreasing. So the HK2 antibody has been licensed or sold to Johnson & Johnson, who have taken this to the clinic. They started by evaluating it By labeling the antibody with Indium-111. And what you can see from the SPECT images here and the evaluation on the results from these clinical trials is that the HK2 targeted imaging picks up all tumors that, combined with that -- that could be found by combined imaging such as PSMA imaging, CT and MRI. So after this study, when this Phase 0 study was done, they moved forward, and they then applied as an actinium-targeted radio immunotherapy. And -- what we can see here through these results from the Phase I studies is that most of the patients are responding really well. And 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 and when they go up again, you give a second; and the third dose, they are responding and the response is not decreasing over time. So if we should then summarize HK2 targeted radio theranostics, it's that we have developed an antibody targeting catalytic cleft of HK2. And we can -- we have labeled it with zirconium and evaluating 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. So again, the tumor decrease 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. And J&J has been evaluated in the Indium -- as an Indium-labeled compound and is currently evaluating in a Phase I as a actinium-labeled compound. Now why is KLK3 or free PSA targeted radiotheranostic a more advanced or better approach. It has to do with that you have higher expression level of KLK3 compared to KLK2. So it's almost a -- when you look at levels in tissues, the HK2 levels are often 10x times lower. So the KLK3 levels are 10x higher and only 2% of the total PSA levels are found as HK2 levels when evaluating it. PSA and KLK3 is much more studied biomarker. If we look at PubMed, there is 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 a gold standard biomarker for screening and diagnosing and monitoring one of the most well-studied biomarkers for cancer that exists. So utilizing all of this, the higher expression, the know-how of PSA and HK2 or PSA. And 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 I and Phase II trials. So not only are we benefiting from Janssen looking at the HK2 targeting antibody and seeing what -- that there are therapeutic effect and that the antibodies going where it should go, we're also benefiting then from other studies as well, which is then derisking the project when going into the clinic. So if we then look at the differences here in terms of expression levels and different tissues, as I've showed you before, and as seen here is that KLK3 expression is very specific and expressed at abundant levels in prosthetic tissues compared to, for example, PSMA. So here with the antibody that we developed for the PSA targeting approach, we have evaluated with -- as a zirconium PET agent, as a Actinium-225 label, radioimmunotherapy. We also compared it to Yttrium-90, which is a pure beta emitter, and we also assessed it with Lutetium. And we evaluated that as well with the PSA targeting antibody as well in genetically modified mouse models. So very advanced models with the full immune system that are spontaneously developed adenocarcinoma. And as you can see to the left of these images, these are PET images, zirconium-labeled PSA targeting -- and you can see that is specifically -- the uptick is specifically in the prostate where you have the expression of PSA. We can also see that we have it's subtle academic sort of thing to look at, but we see that we have in some of the mouse lobes that have higher expression of PSA than other lobes. And 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 has higher expression of PSA. We also see that they are -- when we're comparing Zirconium, Actinium and Yttrium by distributions that they're very similar. So you can rely on, for example, zirconium-labeled antibody in order to do dose inventory for Actinium-labeled variants of it. What's great with the 5810 antibody is that it's internalizing, meaning that when the antibody is finding to free -- to the catalytic cleft of PSA that the cell is taking in the antibody, which then is carrying a either diagnostic radionuclide or a therapeutic warhead. And you see that here is that the blue is then the DNA, the red is the filaments that are sort of making the cell stable and sort of working as a scaffold for the cell and the green dots here is then the 5810 antibody, and we can clearly see here that it is internalized in these advanced models. So if we then compare free PSA targeted radioimmunotherapy 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 have also studied this in monkeys and here are some caveats that we need to keep in mind when we look at these images. It's that the monkey levels -- the PSA levels in monkeys, they are about 500 to 1000 fold lower compared to humans. We also know that if you look at the amount of PSA in the ejaculatory mix, it's about 5,000x lower than in humans. And also on top of this, is that two alternative splice variants of PSA has 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 PET imaging agent, we can clearly see that despite the much lower expression levels in monkeys that 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 that we start to see uptake after an hour and that the retention is then in the prostate for many days, while it's decreasing in other organs. So if we then look at the other benefits of utilizations of PSA-targeted radioimmunotherapy, it is that as I've explained before that PSMA-targeted therapy, we see that the efficacy is decreasing over time and that AR is increasing. So we're benefiting from -- 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. So we have uptake in both PSMA expression in the kidneys and there are PSMA expressions in the salivary glands. So going with an additional small molecule that is then also excreted via the kidneys could potentially be troublesome. So moving on and utilizing an antibody instead and switching then from Lutetium-177 to Terbium-161. And why it's important to point out on why we -- why Terbium is very interesting in this case is that the antibody, as shown before, is internalizing. So we're both relying on beta particles, which is then not only retained in the PSA expressing cell, but it's also then -- is then also giving off radiation that will then affect and will have therapeutic effect on the neighboring cells. However, with Terbium-161, we also have Auger electrons, which are only effective if it's very, very close to the nuclei and again, we have an internalizing antibody. And you can see this as a very robust and intense burst that is pinpointing sort of like an explosion within the cell, which has been damaging the DNA on top of the immediate beta particles. So in summary, we have made and developed an antibody that specifically targets the catalytic cleft of PSA to the free form of PSA, so 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 -- are very effective and then that we are exploiting and harnessing the therapeutic activity by then the upregulation of PSA that occurs as a response to DNA repair mechanisms. So again, the tumor becomes smaller, but have a higher expression over time of PSA, which is then increasing the retention in the tumors and then increasing the efficacy. If we compare then KLK2 to KLK3 is, again, that we have a much higher expression level of KLK3 compared to KLK2, so not only can we rely on and look at how that the Janssen's evaluation of the therapy in humans, we're going to see effect. We also -- and that it's safe. It's also that we then have a higher expression. So we assume that we will also see a much higher tumor-specific uptick compared to what we see with the KLK2 or HK2-targeting therapies. So thank you very much for letting me present the summary here. And if there are any questions, I'm more than happy to discuss them.

Thank you, David. That was really amazing. Thank you for this comprehensive overview of the landscape with the kallikreins. I'm 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.

So the first question, which I guess is in many people's mind, so we have observed the Janssen study with the KLK2 and Actinium. Where do you think the reported ILD is coming from? Is it from the Actinium? Is there an apparent expiration of HK2 in the Lung [indiscernible]?

I think that maybe they started out with seeing that they first didn't see any toxicity, so 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 the antibodies are circulating for a long time, we know that the higher amounts of an expressed target that we see, the faster we'll also have an uptick in the tumor. So it's anticipated that the targeting in circulation time will be shorter given that we have a higher expression.

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, and maybe you want to expand on that again briefly.

It's a 2-hit sort of approach where we are not only utilizing the specific tumor retention, we were also then utilizing the fact that the antibodies internalized to getting close to the DNA. It's not only are you getting therapeutic effect from the beta and distorting the cell that the antibody is taken up in, but also harming the neighboring cells. And on top of that, we have then a sort of a -- sort of a small explosion very close to the DNA which gives -- which then increases the therapeutic efficacy as well.

So where do you see -- I mean, we spoke about -- 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 sort of the full sort of academic mechanistic answer of how the antibody is internalizing, but together with Jeff Ravetch's lab, we evaluated how the antibody is internalized. And it's internalized through an FC mechanism. So 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.

Just -- looking back at last week, there was a question whether there's any correlation between B7-H3 and KLK3?

It's -- I would say that the -- the correlation with KLK3 is more correlating with AR activity. So 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. So there is a difference in the -- how the expression is regulated.

So 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?

Well, 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 are also at potential risks with kidney toxicity. The AR is increased. So benefiting from the high AR output and increase of AR activity, and then utilizing an antibody, which is excreted via the liver, not only decreased -- sort of changed the landscape of the toxicity, we're also benefiting from the -- how PSMA is regulated.

Yes. That's great. So going back -- maybe another question going back to the isotopes of Terbium, I guess, it's a relatively new kid on the block, so to speak. Do you expect that we will see more with other targets? Any particular targets that you would think would be appropriate for Terbium or it's simply that it's new. And I mean, there have been, of course, the studies or the VIOLET study that was recently published with -- out of Australia, of course, with great success. But any -- 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 that's a question that is better answered by a physicist than me. But yes, on -- from what I see, I think that we are benefiting from, again, the internalization of the antibody and then we have sort of 2-hit approach to make it more efficient compared to if we have 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. And for the people who are online, if there is something that comes to mind after we're done here, please reach out also via e-mail, 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. So with that, David, again, thank you so much. This was extremely interesting and I can only say that we, as RAD, and I, personally as a CMO, we're super excited about this compound. Very excited to get into the clinic in prostate cancer patients. I have myself been working on an off prostate cancer since Radium. So since like 15 years or so. And I'm very excited to get this going and have patients in Australia hopefully benefit from that. So thank you again for pointing out the great preclinical data. And with that, closing remarks to Riccardo. Riccardo Canevari is our Chief Executive Officer; and he would like to have the last word.

Thank you. Thank you, Dimitris. And I think it's been 2 great webinars. So thank you to the David Piwnica-Worms and Oliver Sartor last week. Thank you to David Ulmert 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 U.S., where it's evening. And by the way, today is still labor day evening, so it's a national holiday. So thank you for being with us. I really just took some notes, and I think that I have only 4 take-home messages from these 2 incredible webinars. The first one is that in the metastatic prostate cancer space, the arrival of radiopharmaceutical has changed the landscape. It is incredible, it 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 and this is a great achievement. The second bullet point is that despite Pluvicto is a very good product, it's not perfect. And this is normal from every first-in-class or for every standard of care. So we need additional science. We need to do something more because, unfortunately, today, patients with metastatic prostate cancer still die from their disease. So 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? Or can we try to go to new targets and new approach? And what oncology, most of the time, has shown that people, patients need a second target, a second approach to have higher chances to responding to a new therapy and live longer. So here is our role. As Radiopharm Theranostics, we are extremely involved in prostate cancer. We had 2 amazing compound; the B7-H3 targeting molecule called RV-01 and the KLK3 targeting molecule called RAD 402. Both of them will be available to patient in the clinical study before the end of the year; the B7-H3 in U.S., the KLK3 in Australia. And 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 and we think that these are the 2 most promising or among the 2 most promising molecule in metastatic prostate cancer that are coming to clinical. So again, fully motivated, fully excited. I just want to say a big thank you to all the scientists, the investigator and the team that made this possible, and we just cannot wait to dose the first patient before the end of the year. So thank you very much to everybody for being with us, and we hope to deliver short time interim data quite soon. So thank you very much.

Thank you, Riccardo.