Hey, so hi everybody, welcome to our third Radiopharm Theranostics webinar. I am Dimitris Voliotis, I am the Radiopharm Chief Medical Officer, and I can see that we still have people joining, so let's give it another, like, 20 seconds or so until everybody, until the counter stops. I think we're good now, so again, welcome everybody, I'm Dimitris Voliotis, I'm the Chief Medical Officer of Radiopharm. Good morning to the folks joining in Australia, good evening to everybody on the East Coast, and if somebody is joining in from Europe, it's in the middle of the night, so I hope you're having a good night, so welcome, as I said, to our third webinar. We want to discuss here the unmet medical need for patients with suspected rare metastases from solid tumors. Our first webinar, which was about four weeks back, was around prostate cancer and our new agent, B7-H3 targeting agent, which we call Betabart, that will go into the clinic and clinical studies very soon this year, which also is treating prostate cancer patients. The second webinar, which was a week later, was around KLK3, which is another agent, very specific this time for prostate cancer, a very, very interesting, very specific target, as I said, in prostate cancer. And now I'm just very thrilled to have the opportunity to share some data and some thoughts around our, first of all, the unmet need for those patients, and also our thoughts about our own development compound, which we believe has the potential to hopefully sometime in the future address some of those needs. I am super excited to be able to welcome Dr. Ramji Rajendran as our key opinion leader here. Dr. Rajendran is a highly skilled radiation oncologist with a pretty unique background in both clinical practice and research. He completed his MD and PhD in a combined program at the University of Illinois at Urbana-Champaign, and his doctoral research focused on molecular mechanisms and cell biology of hormone-dependent tumors such as breast and prostate. After that, he completed his residency at the Hospital of the University of Pennsylvania in Philadelphia, and he has dedicated really his career to advancing the treatment through radiation therapy primarily, and he currently serves as the director of the Department of Radiation Oncology and the Illinois Gamma Knife Center at the Ascension Alexian Brothers Medical Center. His expertise spans a really wide range of advanced therapeutic techniques, including SBRT and Gamma Knife, and his research contributed to publications in prostate, proton radiation therapy, and radiation therapy for breast and thoracic tumor, so I'm very thrilled to have you here, Dr. Rajendran. I will open the slides. It is a pleasure to be here, and good morning, Australia. It's a pleasure to be here with you. Today, I would like to talk about challenges and unmet needs for radiographic detection of relapsed brain metastases from solid tumors and consequences for therapeutic approaches. So again. Sorry, Ramji, just one second, one second. I'm sorry to interrupt you. Of course. If the people on the webinar have questions, please do submit those questions in writing through our chat function. We cannot take questions verbally. So we have a chat function where you can submit all of your questions, and we will address them at the end. Apologies, Ramji. Go ahead. No, not at all. It's a pleasure. So again, I'm Ramji Rajendran. I'm a radiation oncologist in community practice at Alexian Brothers Medical Center in the Chicagoland area. We have a unique opportunity that we've had a Gamma Knife program for over 20 years, and I haven't made it to Australia, but as close as I've gotten is to Guam, so I'd like to share some sunsets from Guam in the South Pacific. Next slide. So it's important to know that brain metastases are a huge portion of cancer care today. They're five times more common than primary brain tumors. Next slide. So as cancer treatments improve, patients are living longer, and brain metastases are increasing in number. A large part of this is due to the fact that patient survival is greater, and advances in systemic treatment have extended the life expectancy for many cancer patients, giving the disease time to spread to the brain. The brain is a sanctuary site where it's difficult for chemotherapy and other systemic treatments to go, and we're now better to diagnose those tumors, even as small as two millimeters, especially with MRI and gadolinium contrast, and they can detect brain metastases that were previously too small and asymptomatic to be found, and overall, there's an increased cancer incidence, and so the overall increase in cancer incidence contributes to a greater number of patients who have brain metastases. Next slide. Almost all cancers can spread to the brain, but lung, breast, colon, kidney, and melanoma are the most common ones that spread to the brain. Next slide. I think that we really need to rethink how brain metastases are thought of. It used to be a terminal disease, and this was the end, and whole brain radiation was sometimes offered or just hospice care. But I think we need to rethink this because really metastases grow from inside to cancer and then cause an invasion of the lymphatic system and eventually the bloodstream, and there's arrest and extravasation into the watershed areas of the brain causing tumors to form, but these tumors really do not invade the brain tissue itself, and they're still able to be treated in a way in which just the tumor can be treated and normal brain can be minimized with radiation dose. Next slide. The way that we do this is called stereotactic radiosurgery or SRS. It's a great way to treat brain metastases. It uses a highly precise, high dose of radiation to target and destroy tumors. I don't know if any of you have ever tried playing with a magnifying glass in bright sunlight, where if you focus the beam of radiation, in this case, light radiation, onto a piece of paper, you can have a very dramatic effect. In fact, you can burn a hole in the paper. However, just next to that, there's no effect at all, and the paper is left undamaged. Next slide. So our sort of baby, what we use to really do this is called the Leksell Gamma Knife, which is a tool and sort of the gold standard for radiosurgery for brain metastases. It's used to treat malignant and benign tumors, vascular malformations, and functional disorders. It's about 7:00 P.M. here, but this morning I was treating patients, and the treatment times ranged, in fact, for today, between 40 minutes to up to three hours for a patient with multiple brain metastases. The patients communicate by a microphone and camera. Patient planning software allows for conformal shape of radiation treatment. I kind of describe it as each metastasis is sort of like a little bag, and then we fill that bag of marbles of radiation or shots of radiation that allow to just treat the tumor and still leave the normal brain untouched. It's a fully automated system, and it uses 192 beams of radiation, each of which can be in eight sectors that have different sizes. The accuracy of this, because it can have a frame, is less than a millimeter, 0.5 millimeters, and the stereotactic frame allows for maximum precision, even to treat the fifth cranial nerve, for example, for trigeminal neuralgia. While everyone else sees this, next slide, we see this. It is a really amazing machine that can really deliver very precise doses of radiation to make sure that we are able to treat tumors with complete confidence and with the ability to tell the patient we have greater than a 90% chance that this tumor will be gone. Next slide. Here is a couple of examples. This is a 60-year-old patient with non-small cell lung cancer treated to a single metastasis, here shown on the left at initial treatment, both in the axial and coronal sections. On the right, you see six months later that tumor is just a piece of scar tissue left in the brain, and eventually that gets smaller and smaller over time. Next slide. Here's another example of a 52-year-old woman with a melanoma that started with a very large metastasis, but this dramatically shrank just five months after treatment. Again, these are the pre-treatment or day of treatment on the left in axial and coronal, and on the right, five months later, you're left with a little scar. Next slide. It's really treatment of brain metastases involves a neurosurgeon, a medical oncologist, and a radiation oncologist, and it is absolutely a team sport, and it is multidisciplinary care at its finest. Next slide. Sometimes we see patients like this that has a large single brain metastasis in the frontal lobe, causing midline shift, causing a significant amount of edema. A patient like this would not receive Gamma Knife upfront. They would typically receive a resection of this metastasis and then Gamma Knife radiosurgery to the tumor bed to prevent local recurrence. Next slide. However, a patient like this with one to three small to intermediate-sized brain metastases can be treated with Gamma Knife radiosurgery alone, and there's a greater than 90% chance that those tumors will never recur. Next slide. However, when you have multiple tumors like this, one may require whole brain radiation therapy or discussions with the medical oncologist to see if systemic treatments would be appropriate. Next slide. However, when you have a patient after treatment with Gamma Knife, this is a patient, again, with the axial and coronal slices. On the leftmost is the initial treatment day where a tumor was clearly circumscribed with a radiation dose and treated. Three months later, there was a dramatic effect. I've shown you that there's just a scar tissue left. However, at six months, there's an increase in size. Not quite as big as the original treatment day, but by nine months, there's a significant increase in size. There's also central necrosis in the middle, where the gadolinium contrast for the MRI cannot go, and so we're left to wonder, is this true recurrence? Did Gamma Knife fail, or did Gamma Knife work so well that it recruits inflammatory signals causing swelling of the tumor and swelling of the normal brain in addition? Do we place the patient on steroids after, or do we have the patient be considered for resection by a neurosurgeon? This is where we're left to wonder what next step should be. The best we really can offer the patient is to do another MRI maybe in six weeks. If the patient is symptomatic, we have to empirically put them on steroids and see what happens with time. In the meanwhile, the patient also may be on immunotherapy where the steroids are contraindicated. The patient may also have symptoms that need to be managed and controlled. We're often at this point stuck. An imaging agent that would be able to discern whether this is radiation necrosis or whether it's tumor progression would dramatically improve clinical care and allow us to appropriately select those patients for the appropriate next steps. Next slide. That may be the last slide. So can a PET radiodiagnostic distinguish radiation necrosis from progression in patients with suspected recurrent brain metastases status post radiosurgery? Now, this is the question. It's a common clinical predicament, and it's one where the whole multidisciplinary team is left to wonder, and most importantly, the patient is left without a clear answer. Thank you. Thank you so much. That's such a great presentation. Just one question maybe while I pull up the slides that we have on RAD-101. So this was a great example, I believe, the patient that you showed earlier or the last patient that you showed there. So how would you, if you knew that you would have a metastasis there, how would you treat such a patient? So this was a patient from last Tuesday, and we saw this patient, and we elected to place her on steroids. So she was given 4 milligrams of dexamethasone twice a day. Fortunately, she was not on immunotherapy, and she was able to tolerate the treatment. And we have to image her brain again in six weeks. And if she was symptomatic, if this was a melanoma and the patient was on immunotherapy alone, it really leaves us to wonder if we're doing the right thing, and we would be very much stuck. We're hoping that an imaging agent such as a PET agent will allow us to better discern whether this is one or the other and allow us to immediately have a better, more appropriate clinical answer for these patients and not just have them wait. Thank you. Yeah, I believe it's also very important for people, whether it's the audience here or patients and doctors who are not treating brain metastases patients every year, to, as you said also in the beginning, to realize that there are treatment options for these patients. Because up until very recently, it is what you said that many times those patients were left to hospice care, and especially if there was a reduced patient with less who was less well as a general condition, and people were afraid to give them some sort of radiation or systemic therapy, they were just left without any treatment, and I think it's important to realize that there are, in fact, treatments for such patients as long as you can identify these lesions early enough, right? I agree. Historically, there were patients that had a single metastasis that was completely resected and then received whole brain radiation, and we were still left to express to the patient that at that time, given the systemic treatments available, those patients that were ideal patients today, no evidence of disease, on average lived about 11 months. All right. Good. Thank you so much. So I'm taking over here for a short outline of what we at Radiopharm are trying to do to maybe help patients and treating physicians to really get to the point to be able to distinguish between what you said. Could it be necrosis? Could it be an inflammation pseudoprogression? Or do we have a case with really a true progression that might be amenable for additional treatments such as surgery or stereotactic radiosurgery, right? So our agent is called RAD-101. It does have the potential to address a really, as you already saw, I believe from Dr. Rajendran's presentation, a huge unmet medical need. In the U.S. alone, there are 300,000 new subjects diagnosed with brain metastasis every year. So it's very far from being a rare condition. And it is important that we as treating physicians are able to identify and treat such recurrent brain metastases early enough. And the standard of care for such patients is MRI, which is not sufficient, as I believe you saw very, very nicely presented from Dr. Rajendran, in especially the case of patients who have undergone surgery or especially stereotactic radiosurgery. So we have published positive phase two data that I will share with you that demonstrate that we have a high tracer uptake in all patients that underwent the study, and regardless of the origin of the primary tumor. Further, that there was, at least in the sample size or in the study, a correlation between a high SUV, which is the uptake essentially of the tracer that you can distinguish in the PET, and the short survival, which could be, if it's confirmed in the larger study, of course, be a non-invasive way to predict survival. We at RAD have currently a phase 2 study ongoing that's really recruiting very, very well. Dr. Rajendran is part of this study, and it's going really well, and we will be able to finish that study hopefully very soon. The agent that we have, RAD-101, is a small molecule, which with the linker we have attached to the radioactive isotope, in this case, F-18, which of course we use for the diagnostic purpose here. The target of this whole construct, RAD-101, is fatty acid synthase, which is a very important enzyme for brain cancer cells to survive in the brain microenvironment, so by targeting and disrupting fatty acid synthase activity, we are able to impair the growth and of course also making it visible to the eye through the diagnostic imaging as a PET agent. This is a first-in-class phase two imaging study. As I said, there's a very high unmet medical need for those patients in this not very rare condition, actually, and we don't currently have any other competitors in the field, so what exactly is behind fatty acid synthase targeting? Very briefly here, a couple of slides on the mechanism of action. What happens is basically that patients need to be able to upregulate their own lipid synthesis because in the brain itself, the microenvironment is actually not nutrient-rich in terms of the lipids that those cells need. So there are certain cells that are pre-activated to have this lipogenic program switched on. When those patients metastasize to the brain through the bloodstream and then the blood-brain barrier, they are able to develop brain metastases through their own upregulation of the synthesis of lipids that they need to grow in the nutrient-poor brain microenvironment. This is not just a metabolic adaptation for the cancer cells to survive, but it can make cancer cells also more aggressive and then also resistant to various treatments. Okay. So in addition to what I already explained in terms of the lipid synthesis, fatty acid synthase has also a very relevant pro-oncogenic function itself in the sense that it leads to the cancer cells being able to avoid immune destruction. It activates invasion and metastases. It induces angiogenesis, induces resistance to cell death, deregulates cellular energetics, and sustains the proliferative signal that many of these cancer cells have activated de novo. So it's involved in sustained proliferation, dysregulation, resistance to cell death, activation of invasion and metastasis, and prevention of immune destruction. So it's not just that it leads to the cancer cells being able to produce their own lipids. It is itself also contributing to sustained tumor growth. So being able to target this, of course, makes a whole lot of sense, right? So this is one slide where I can just hopefully summarize for you the preclinical data. We were, in our collaboration with Imperial College London, able to generate an enzyme or a target against this enzyme, which is metabolically very stable. You can see that here. A single peak, as you can see here in the various organs, including the plasma, means that there are no metabolites. So it doesn't change when it's being injected into a patient. There's a rapid accumulation of pivalate. So pivalate is another name for RAD-101 or 18F-FPIA, so pivalate or RAD-101. When we implanted it in vivo into mice using human and murine adenocarcinoma cells, we saw a rapid and very extensive tumor localization. Being a small molecule, of course, it is taken up and cleared through the kidneys. It is superior in many of the brain cancer models that were studied, superior to FDG PET. You know that FDG PET is another very popular method for PET detection of metabolic activity of cancer cells. However, it is not appropriate for brain metastasis because not so much of less detection, but because the brain itself has a high baseline of glucose metabolism. So you cannot detect the difference. Our agent, RAD-101, has a very superior tumor-to-brain ratio compared to FDG. They were able to very, very well localize brain metastasis in these preclinical models. As we discussed already a few times, brain metastases are actually, or unfortunately, a common occurrence. You can see here on the left side that 10%-20% of all lung cancer patients, up to 50% of triple-negative breast, up to 50% of HER2-positive breast, and 15%-60% of all melanoma patients can develop brain metastases. Among those who have developed metastasis to the brain, accordingly, the majority is lung cancer, breast cancer, and melanoma. We discussed already how those patients are being treated. This is one example on the right hand from a breast cancer study where you can see that in comparison with whole brain radiotherapy, stereotactic radiotherapy does lead to an improvement in survival. Now, these are old data. Newer publications are able to show that even for patients with a larger number of metastases, this is an active treatment. The survival has improved somewhat, but it's still, of course, a very difficult medical condition. But the earlier this is detected, and especially the earlier the relapse is detected, the better are the treatment modalities. So this is, in a nutshell, the therapeutic approach. Patients are being screened for that. The MRI is good. Then they're being diagnosed here in panel number B. They do receive, as we already saw very nicely from Dr. Rajendran, their stereotactic radiosurgery or surgery. And then it is important at that point, the patients, of course, continue to get additional, after the procedure, additional imaging. And the MRI is, as I said, not very good in detecting that. So monitoring the treatment effect and being able to early detect metastases versus necrosis or pseudoprogression is obviously very, very important. The study, this compound has been studied in phase one and phase two through the Imperial College London. These were studies conducted in the United Kingdom. We are currently running our own phase two B study in the U.S. And the phase three study would be a truly global study going forward. So short summary of the existing phase two data. The objectives of this trial were selective to identify the selective uptake in brain metastasis to understand the impact of stereotactic radiosurgery after four to eight weeks in two cohorts of patients, patients who were both treatment naive and SRS pretreated. In summary, the study results showed that there was a very high uptake independent of primary tumor, that there was high uptake in all patients compared to contralateral brain matter. And patients with an SUV uptake and SUV max of more than two showed a particularly short overall survival as opposed to patients who had a lower SUV. Three slides on this study very briefly. Again, the first question was, is the agent able to identify all patients, all brain metastases, irrespective of the type of tumor? And you can see the brief response to that, whether patients were treatment naive or SRS pretreated, and whether they had lung, breast, melanoma, or colorectal. Basically, you can see all the values here are similar. So the SUV max and also the tumor-to-background ratio do not show a difference between lung, breast, melanoma, and colorectal cancer metastases, which are, as I already said, the most frequent ones. The other question is, can we differentiate with this agent between patients who had received prior treatment and those who were treatment naive? And the answer is yes. I believe you can see this very nicely on the upper two images being a patient who is treatment naive. So this patient had a relatively similar expression in terms of both the MRI and the PET. The PET is green. The MRI is red. So they do show pretty similar activities here. But when you then looked at a patient that was pretreated, you see a substantial difference here. So the PET here and here shows an area that is larger than it was identified with the MRI. In other words, this patient, if this patient would only be treated on the MRI identifiable lesion, they would probably receive treatment that's not enough to cover the entire tumor area. And then the last finding that I already mentioned, which is very interesting and very important, obviously, is the potential of non-invasive prediction of survival. So the upper panel of three images shows a patient with a high SUV over two, 3.3. As an example on the lower part of the slide, these are lesions from another patient who had a low uptake. You can see here that the patient with the high uptake had a progression-free survival of only one month, an overall survival of only four months, as opposed to the other patient who had an overall survival of 34 months. The study was conducted, as I said, by Imperial College London. They did the statistics. Of course, this is still a small study, and we will have to see if we can confirm those results in a bigger study. I believe the results are very striking, as you can see. It's a very, very clearly statistically significant effect. Where are we now in terms of our own study? As I said, the study is running. Patients are eligible if they have brain metastasis from all these tumors shown here and suspected relapse. They then receive whole brain PET with a low dose of our agents, and the endpoints are concordance between PET and the MRI, and the patient also receives then a six-month longitudinal follow-up. We're enrolling the study. We will have early interim data end of the year or second half of this year, of course, and then the last patient dose at the end of this year, beginning of next year, and we'll be able to have a phase two readout then in the early half of 2026. So the design that we have, as I already mentioned, subject with advanced solid tumors with no history of brain metastasis and suspected relapse following stereotactic radiosurgery. To conclude, and this is my last slide, the early identification and treatment of recurrent brain metastasis is an area of really high unmet need with standard of care imaging such as MRI being insufficient. RAD-101, we think, has the potential to address this medical need. The existing and published preclinical and clinical data clearly demonstrate that the technology works. We do have clinical proof of concept in the phase two A. We have those positive phase two data published, and they demonstrate a high uptake in all subjects irrespective of the primary tumor. We can show better differentiation of pretreated lesions versus the MRI. We have a potential correlation between high SUV and short survival, which could indicate the potential to have a non-invasive OS prediction. Our study is well underway, recruiting subjects very well with the phase two B readout being the first half of next year. We are in the planning stages of the phase three to address this existing gap, and as already said, because there is no other competitor, a potential approval would be for us, of course, a unique position of leadership in the field, so that's all I had, and I'm very happy to hand over to Riccardo. Thank you, Dr. Rajendran. Thank you, Dimitris. Let me share my slide. I have a few minutes of a presentation, and then I'm happy to, of course, go to the Q&A in a moment, so from a Radiopharm Theranostics point of view, RAD-101, the products that we are discussing today is our most advanced technology in phase two B. I saw a question in the chat asking, what is the difference between a phase two A and phase two B? In our specific case, the phase two A was in 22 patients, but only half of them were post-SRS. The trial was performed in a single academic center. 11 patients in a single center. Our phase two B is 30 patients, so three times bigger in five different centers under the regulation of FDA. It's a very different validation, of course, before you can go to registrational trial. Today, the focus is 101, as I said, but I just want to take the opportunity to thank you, the team and everybody in Radiopharm for the great progress in the last months. We now have five clinical trials ongoing, and we will have the sixth clinical trial ongoing by the end of the year. The full pipeline will be in the clinics. That, of course, for a company that is only four years old, is a major achievement, but let's stay on RAD-101. This is a slide that Dimitris already showed. I just want to focus your attention on two elements. There are ongoing imaging trials in glioma, high-grade glioma, but there are no advanced trials in brain metastases. We are by far the first and the only ongoing late-stage development to image brain mets, and this is a unique and a very positive competitive situation, considering that there are so many patients affected by the disease. It's around 300,000 new patients every year, only in the U.S., as Dimitris was stating before, but I would like to go a little bit deeper in terms of expectation and timelines, so we started this trial in the first half of 2025. That's when we dosed the first patient. We are well on track. It will always take a little bit of time to set up the center and to start, but the recruitment that we saw, in particular during the month of September, that is not finished yet, is really great. So we believe that we can be at least at 20 patients, if not the entire 30 patients, by the end of the year or the end of January. Then we need some time to put together the data and the readout. But what we have decided as a team, that considering the positive data of the phase two A and the early positive data that we have seen in the phase two B, we have decided to start the preparation of the phase three. We think that these products have very good probability of success that can be proven in a registrational trial. We are preparing at risk. That doesn't mean that we will go full speed in a month, but we will prepare to be ready to go full speed as soon as we have visibility in a little bit higher number of patients. But what we have seen is very, very important and highly, highly promising. So we think that we can start the phase three next year at the end of 2026. You should assume a trial of about 150 to 100 patients. So between 12-18 months recruitment. So this will give us a unique opportunity for an NDA submission at the end of 2028. So that means that the product is ready to be approved by FDA for a commercial launch. Why we decided to accelerate the development and the preparation of the phase three? We recently saw great success in the market of two imaging agents in a completely different area that is prostate cancer. Illuccix from Telix, Pylarify from Lantheus are now called blockbusters of products with a yearly sales that is above $1 billion per year. We asked an independent company to do an assessment to tell us where Pivalate stands if we are able to successfully image the brain metastasis in the patient that we discussed during this webinar. We were very pleased when we saw that Pivalate or RAD-101 has the potential to be the third largest imaging agent on the market. The assessment, again, was not our forecast. It was an independent assessment that was telling us that the potential is above $500 million per year, AUD 750 million per year. This is only in the U.S. So this is not including Europe, Australia, China, Japan. That's U.S. only. So this number, of course, is very important and are giving us the confidence that there is a unique opportunity to take. I always like to say that the sales are the results, are the outcome, but what is more important is our ability to serve the patient. There is a huge medical need here as been described by the speaker before, and we are very highly motivated to give our contribution in the space and as a result to capture, of course, the commercial opportunity. And with this, thank you from my side and all of you that are attending, but we don't want to miss the opportunity to answer to all your questions. So I give it back the ownership to Dimitris to select the right people to answer your question. Thank you very much. Thank you, Riccardo. So I'm going through the list of questions here. A few are for Dr. Rajendran, a few that we can address from our end as read. So again, Ramji, I believe people are asking, you know, how many patients do you really see with brain metastasis in a busy clinic every year? Some people, I believe, still think that this is not a very frequent condition. So if you could maybe repeat some of the things you've said around the prevalence, the incidence, How often this happens. We treat with Gamma Knife Radiosurgery, and I'm in the Gamma Knife Center once a week. We typically treat about three patients to six patients every week. And I would say altogether, we have approximately 150 patients that we treat per year specifically with Gamma Knife Radiosurgery. That's very different than patients that receive whole brain radiation and other treatments. Sometimes we observe patients, especially if they're amenable for immunotherapy such as melanoma patients. But this is a frequent issue and a frequent problem with the most prevalent of cancers, lung cancer, breast cancer. And so I think that it would be wrong to say that this is not a frequent occurrence and something that we encounter very regularly in the clinic. I'm not in an academic institution. I'm at a community health system. And I feel like I represent the majority of radiation oncologists in practice. And so I may see more because of the fact that I do Gamma Knife Radiosurgery and I'm sort of top of mind for the neurosurgeons that I work with, but it is very common. Thank you. Yeah. I mean, I agree. As I hopefully was able to show, when you have tumors where half the patient has, let's say, triple-negative breast cancer or melanoma or more than half metastasized to the brain, I don't think you can call that a rare condition. So it's really not. And indeed, I wish it wasn't as common, but it's also it leads to very poor quality of life. I mean, nobody wants to die a neurologic death. Yeah. Thank you. One question that we had around the phase two versus phase two B study. So the difference between the phase two A, that this was an investigator-initiated academic study conducted at and by Imperial College London. They treated patients who had treatment-naive patients, but also patients who were pretreated as opposed to our study that is obviously a study conducted by us, by a biotech company. We only exclusively include patients with prior stereotactic radiosurgery. Another question, maybe again for you, Ramji. What's the appropriate treatment if a substance like RAD-101 identifies early brain mets? Does it vary by tumor origin, or are they basically the same, or how do you differentiate what treatment those patients need? It's typically surgical resection. The earlier you're able to resect, you'd imagine if you can resect a smaller tumor because you see it sooner and catch it sooner, there's less morbidity and mortality associated with resection of a smaller tumor. Furthermore, there are in development treatments that penetrate the blood-brain barrier and systemic treatments that are options that are available. I think those are also going to be potentially alternatives for such patients. Great. Thank you. Another question maybe that you and I can jointly answer is what gives us the confidence that this technology could work? So maybe I can start and then you chime in. So I was hopefully able to show you that we have an agent that is very specific targeting an enzyme that is key to the survival of brain metastasis. And we have demonstrated in preclinical experiments that we can do this very successfully with an agent that is very, very specific targeting those cancer cells that express this enzyme. And we have a very strong proof of concept in the clinic also from the Imperial College London data. But maybe, Ramji, also from your end, you're part of the study. You enrolled a few patients. Tell us a little bit about your experience and your perspective. I mean, recurrent tumors light up. It's that simple. I don't know if I'm giving away any secret, but I find that recurrent tumors are shown to be active on PET with this agent, and the study is not yet meant to change treatment, but it sure does give me pause, and I want to act sooner for those patients because I think it's the right thing to do clinically, but I think it's effective, and I think this is why we do the trial, this is why we do the study, and we're just at the cusp of a theranostics revolution, okay? This is going to be an amazing opportunity to kind of be one of the early movers and really be able to capture a large portion of clinical practice and ultimately affect the lives of multiple patients and provide a way in which we can have them live with a better quality of life for whatever time they have left. Yeah. What about survival benefit in patients who are detected early enough? I think survival benefit is always harder to prove when you have so many different tumor types, when you have so many different treatment options. I think that we have to take it on a case-by-case basis. Ultimately, you would want an agent that you know could change practice. Even radiation to the brain is still considered palliative because you have a metastatic incurable patient. It's just that the systemic treatments are so much better now that this ends up being their rate-limiting and life-limiting issue. So I think that it is hard to prove overall survival in this setting, but ultimately, it does dramatically affect clinical practice. Thank you. Yeah, and as we saw from the phase two now, of course, there seems to be a very strong correlation between a high SUV and survival. So obviously, this is going to be something we will investigate in the phase three. The phase two data are very promising. I mean, it makes sense, right? I mean, if you have a tumor with a very high metabolic activity, you have a high SUV, and it would be logical to assume that in a patient with a very aggressive tumor, very high expression levels of fatty acids intake, that that patient would have a shorter survival. I have also two questions for Riccardo. Riccardo, I believe we answered the question around the start of the phase three when we will have the phase two complete and the data. But two questions also for you. Here is about the competition to Pivalate and the other one, whether we would consider partnering out licensing at the end of the phase two. Yeah. Thank you, Dimitris. If you don't mind, I'd like to start with another question, and I will immediately answer to those that I see on the chat because the question, I hope I don't disclose anything unfair. I saw a question from Dr. Pisaneschi. Dr. Pisaneschi was at Imperial College London, and she was co-inventing RAD-101 or Pivalate. So thank you, Dr. Pisaneschi, for being with us. Your question about other indication, well, we know the data that probably you contributed to generate in glioma and in solid tumor for Pivalate due to the, of course, presence of fatty acid synthase, not only in brain mets. For the time being, we like to stay focused on the brain. Brain mets is the primary important area of focus. But we are aware of some preliminary data in particular in glioma, high-grade glioma. We cannot exclude that this is an area where we want to go after brain mets. Back to the question of Dimitris, will we partner Pivalate after phase two? Doing a phase three trial is a very important investment. As I mentioned before, we have the intention to prepare and to start this trial, but we are definitely very open to consider the support that we can have from larger organizations if there is a strong interest in conducting a global multi-center phase three trial that can be faster than what we can do alone because at the end of the day, we want these products to be to the market as soon as possible for the patient benefit. So we will definitely be open to partnership. Sorry, Dimitris, what was the other question apart from the partnership? Was about I forgot what you asked me. The partnership and out licensing potentially and the market size we covered. Yeah. One other question is, what is the we covered it, but maybe clarify again what the competition is for Pivalate at this point. Yeah. So look, there has been a trial that tested a different agent in phase three in the last couple of years. Unfortunately, that trial was not successful. It was a different molecule with a different mechanism of action. So due to my knowledge or due to the public information, I'm not aware of any agent that is currently in clinical development as an imaging from brain metastasis. So from this point of view, if there is no agent that is even in phase one and we are in phase two B and potentially less than a year from registration or trial, that means that we have a number of years of advantage compared to any other molecule in competition. That's why we want to maximize this opportunity. That's why we are open even to partnership, as I mentioned before, because we would like to go full speed. We just want Dr. Rajendran to give us even more beautiful images and data on his patient that will further increase the confidence that we are in the right trajectory. Thank you, Riccardo. So another question is that the next data update, how many patient data will we be able to present? Yeah. Well, Dimitris, maybe I agree. I think it depends on what we mean data update. If you follow how the trial has been designed, there are the data that you can have right away, like 24 hours after the patient is dosed. And then there is the six-month follow-up. You want to check if comparing with MRI or standard of care, Pivalate keeps saying and keeps giving the correct answer. So on the short term, we are very fast. As I said, the trial is evolving very well. But if we want to give the patient data that includes the six-month follow-up, even if we are highly advanced in the recruitment, we need some more months to get there. What I'm saying in this complicated answer is that we likely have three to five patient data very soon, and probably we will have 10, 15 patient data in a few months from now before the final readout. So I expect to have a couple of interim before the full and final readout. Thank you, Riccardo. So obviously, that was another question. How's the enrollment going? I believe we answered that. We have very enthusiastically enrolling sites and investigators. But we also need to have the six-month follow-up for every patient to understand really whether they indeed have a progression or if they have a biopsy, what the result of the biopsy is. So to keep that in mind, that's part of the study as well. And that's what makes it actually six months longer, right? Dr. Rajendran, another question is really interesting, more practical, whether RAD-101 or Pivalate can be detected or whether it can be used with regular machines, if you need any specialized equipment, anything that you don't have in the clinic. We don't have anything special. We're a community hospital. We have a regular PET scan that's used all the time for FDG PET, for PSMA PET. And so there's nothing unique about what we can offer. There's no special technology. If you have a PET scanner, this works. And it's pretty interesting. My radiologist actually called me when we had the first few of these patients just because it was exciting to see something different. It was really neat to hear directly from a person that wasn't necessarily involved in the trial to say that this is a really cool thing. It's exciting. Thank you. Another question that we had is, what is the smallest tumor size that you can detect? That's an interesting question because I believe it shows some of the ideas behind. Or, answering this, we can illustrate some of the benefits of the technology. The MRI is an anatomical imaging where you look at the anatomical size of the lesions, less than one centimeter, more than one centimeter, and so on. PET imaging is functional. You can have a lesion that appears bigger in the PET scan even if the anatomical size of the lesion appears small because the PET does not show anatomical but functional imaging. That's really the key difference. We differentiate between very active and maybe less active lesions. And again, that's also the point of what I said, the correlation that we saw or that actually the colleagues at ICL saw with the survival between the SUV and the survival. Another question maybe that we got is whether we could get an early approval after the phase two B. That is unlikely because for diagnostic agents, the standard, there is no accelerated approval as you have for therapeutic agents with a very strong response rate. You could maybe go down the path of an accelerated approval. So the agency, the FDA, that is, is still using sensitivity, specificity, and accuracy as the primary endpoints, especially for imaging trials. However, the size of such an imaging trial is typically much smaller than that of a therapeutic study. So we believe that the study can be as small as 150 or maybe 200 patients, which is actually the size of a large randomized phase two B with the therapeutic. So unlikely based on the phase two B, but the phase two B will be very informative, of course, for us planning the phase three, and the phase three is not going to be a very large study. I'd rather have a very strong body of data and body of work and really trust that we have a good agent than try to rush it. Yeah. Good point. Another question. Let me go through this. Whether we have to show superior outcomes or as good as standard of care? Well, essentially, yes, we need to be better than standard of care. But the way that the trial will be designed is that we have certain cutoff values agreed upon with the agencies that we can show the sensitivity. We can show the specificity. Those analyses, for example, include patients identify the number of patients who are false positive or false negative and the direct comparison between the MRI and the PET. Let me just double-check. Maybe, Dimitris, the question on the therapeutic side. Yeah. Yeah. Yeah. Well, maybe one more for you, Riccardo. Many investors focus on the therapeutic radiopharmaceuticals. Why should investors be excited about the diagnostic technology? Look, this is absolutely true. Many times when we spoke with investors, their first focus is on the therapeutic agent. But at the same time, we saw an equal number of investors that have been aware of how transformational the imaging agent in prostate cancer has been for companies like Lantheus and Telix. So this is really changing the valuation of the new imaging agent. Until that day, the largest imaging agent was probably NetSpot for neuroendocrine tumors in around $100 million. And now we are talking products in the $2 billion range. So we believe that in the current environment, if you can offer a very specific imaging agent that can be combined with a therapeutic option like it is SRS, and this can help patients to be diagnosed and treated earlier, the value is recognized. It's recognized in the products, and this translates in the future potential. As a company, we believe that the imaging agent has the opportunity to be faster to market, less expensive to develop, and still have a very important potential. At the same time, we are also working on therapeutic agents because we definitely see the value of radiopharmaceutical therapies as a new approach to targeted therapy. And maybe this is a good continuation to the question that I see below saying, have you considered making Pivalate a therapeutic agent in addition to the current imaging? And the answer is yes. We tried once about two years ago, and we failed. Pivalate is a small molecule, and when we attach an isotope, the isotope was too potent, and the molecule was not stable. But we learned from it, and now we are making a second attempt. We modified the molecule in a way that is not changing its ability to interact with the fatty acid synthase, but can support a stronger therapeutic isotope, so we are working on preclinical on a project to do a Pivalate therapeutic. We don't know if the right indication will be brain mets or glioma, but as we have such a molecule with such a strong ability in terms of having tumor uptake, why not to think about a therapeutic option, so it's not something that we can present data in six months. It's a longer-term project, but we definitely are working on it. I mean, forget about brain metastasis for a second. There are things where we can't help patients. There are things like leptomeningeal disease where we're left to really just patients go to hospice like they did for brain metastases. A therapeutic agent would be a huge, huge benefit, so. Thank you. Very good. I think, oh, maybe one additional question at the end. Dr. Rajendran, just out of interest from the audience, if the immune system is any different within the blood-brain barrier as opposed to outside in terms of how the immune system tackles potentially brain metastasis. So the brain is a sanctuary site, as I mentioned. Therefore, a lot of the molecules that work great in the body don't work as well in the brain, including larger molecules such as antibodies. So I think it's really imperative that both diagnostic and therapeutic opportunities are available. And I think that it's just different. Being a sanctuary site, there are differences in the brain than the rest of the body. And we see immune dysfunction in the brain, right, with disorders like multiple sclerosis, which we still have a lot to understand. But the simple answer is yes. And just as much as I respect that what we do is pretty cool, there's still a lot we don't know, and we have a lot to learn, so. Thank you. Thank you so much, Dr. Rajendran. I think we have answered all the questions. Of course, if there are any additional questions that come up from the audience, we are obviously all available by email. Do not hesitate to contact us. If something comes to mind, please let us know. But at this point, I'm happy to say we are, well, almost 15 minutes over, which I believe just is a testament to the great interest. Thank you, Dr.Rajendran Rajendran, for this absolutely outstanding presentation, which I believe was able to showcase not just your personal interest, but also why this is so tremendously important for patients and for their benefit, for their survival, for their therapeutic options, and us collectively, you, yourself, personally, the other study investigators, me as a CMO, and the entire team, CEO, Riccardo, the entire team at Radiopharm, we are really excited about this compound. We are excited to finish the phase two and hopefully bring this to a point where it can be made available for patients. So thank you, everybody. Thank you for your help with the webinar here, Ramji, and we'll stay in touch. Thanks for having me. Thank you, and again, to the audience, if you guys have a question that we didn't answer or you have a new question, then please let us know in writing by email. Thank you so much. And everybody, have a great day and a good evening. Thank you.