Greetings. Welcome to Isoray and Viewpoint Molecular Targeting Investor Webcast. At this time, all participants are in a listen-only mode. If you'd like to ask a question during the presentation, please click on the ask question box on the left of your screen. Type your question and hit Submit. Please note this conference is being recorded. I will now turn the conference over to your presenters. Please go ahead. Good afternoon. Thank you for joining us today. I'm Lori Woods, CEO of Isoray, and joining me today is Thijs Spoor, the CEO of Viewpoint Molecular Targeting, Michael Schultz, Co-Founder and Chief Scientific Officer of Viewpoint Molecular Targeting, Dr. Jeffrey Johnson from the Mayo Clinic, who will be speaking on his experiences with metastatic melanoma, and Dr. Vikas Prasad, who is working at Washington University in St. Louis and will discuss his experiences imaging and treating neuroendocrine tumors in animals and humans. First, I'd like to take a couple of minutes and give you an overview of Isoray. Isoray uses the radioisotope Cesium-131 in the form of brachytherapy seeds to treat a variety of cancers, including our primary market, prostate cancer, and other cancers including brain, head, neck, and lung. We're the only company in the world who manufactures and distributes Cesium-131 brachytherapy seeds. Cesium-131 has two important characteristics when compared to the competing isotopes. It has high energy, which allows it to aggressively kill the tumors, and a short half-life, which means it leaves the body quickly after delivering the therapeutic dose from the inside out. Although prostate cancer has been the primary focus of the company, due to the unique characteristics of Cesium-131, we have been approached by leading cancer institutions to discuss combination therapies, which we believe will be the future value drivers for the company. I'd like to highlight two of our current immuno-oncology clinical trials that we're very excited about. The first is with the University of Cincinnati and Thomas Jefferson University and is the first brachytherapy PD-1 inhibitor combination study in recurrent head and neck cancer, combining Cesium-131 with Keytruda. The second trial with another leading cancer institution combines Cesium-131 with nivolumab to treat metastatic melanoma. These clinical trials have already led to discussions with other research institutions regarding how Cesium-131 can be used in combination therapies to treat difficult cancers. Turning to our interest in the targeted alpha therapy market, we began due diligence in this market about 18 months ago, comparing 6 potential isotopes that included Lead-212. It quickly became apparent to us that Lead-212 had distinct advantages over the other isotopes we reviewed. We engaged a leading industry research firm to take a deeper dive into this market, and they confirmed our conclusions. We then profiled the companies in the space, and that led to our meeting Viewpoint. In speaking with Viewpoint, we quickly discovered we shared common beliefs of how to best deliver radiation therapy. We share the belief that radiation should spare healthy tissues and be delivered from the inside out. We also believe in a targeted, personalized approach to treating each patient's cancer. These shared beliefs, along with business synergies, bringing together two organizations that have very little overlap. Isoray has sales and marketing, finance, quality and regulatory and HR departments. While Viewpoint brings access to laboratory space, project management, and strong technical and scientific teams, really creating a world-class organization in the delivery of personalized, targeted inside out therapies. I'll leave you with this last slide that provides a stunning visual on what we mean when we say inside out. This slide shows two patients. The patient on the left who had whole brain radiation. Please note that the areas in black and white did not receive radiation. On the right is a patient who received a Cesium-131 implant at the time of surgery. The radiation was delivered exactly where the neurosurgeon wanted it delivered, right around the edges of the resected tumor bed, sparing most of the brain. This slide highlights our belief in treating cancers from the inside out and why we're so excited about our merger with Viewpoint, whose technology will treat patients in need on a molecular level. I will now turn the presentation over to Thijs Spoor, CEO of Viewpoint Molecular Targeting. Thank you, Lori. We're really excited to talk about Viewpoint Molecular Targeting today, and I know that we've had a lot of questions as to who we are. Viewpoint is a University of Iowa spin out. We have an amazing development team in-house. We have a great team of scientists, PhDs and chemists and physicians who all together work on really developing the best possible tracer for patients' unmet medical needs. What's really exciting about the story is that we've actually developed a lot of IP in-house to really look at the isotope supply chain, to look at how to sort of chelate these isotopes and combine these metals safely, to then turn them into targeted drugs. What's so exciting about our progress so far is that we actually have two clinical stage programs right now and actually an amazing pipeline right behind it. We haven't stopped with our current successes. We keep innovating as we go, and we're very excited as to how it all moves forward. One of the things that any drug company really tries to think about is what are those unmet medical needs. We're not that excited about doing, you know, me-too products or generics. That's not our business. What we're excited about is it's dealing with unmet medical needs. For example, there's something called a neuroendocrine tumor that represents an extraordinary opportunity to make a difference in patients' lives. Currently, this opportunity is valued at over $5 billion in terms of global sales for these kinds of products. I think everyone has heard about melanoma and its risks, and we actually have a very interesting drug in metastatic melanoma that we think also represents an extraordinary opportunity. What's nice for me is I look at the team of Viewpoint scientists that are working together to build this program forward, as we've been recognized with actually quite a few grants from the NIH and the NCI, you know, the National Cancer Institute, and that's been around $18 million to date. We really appreciate the scientific and financial validation of where we're going. In order to sort of talk about the development pipeline on the slide that we have here, it's really important to think about these are all different kinds of drugs, and each drug has both an imaging and a therapeutic portion. The lead program is targeting neuroendocrine tumors. The second program is targeting advanced melanoma, and we're gonna have some world-leading physicians talk about that later on in this call. Our scientists keep innovating, and behind the scenes, we also have additional programs in place where we're looking at breast cancer, prostate cancer, pancreatic cancer, and a whole range of other tumors, and really trying to take personalized medicine into a very sort of, you know, clean level for patients to understand. If we can actually visualize the patient in advance with a therapeutic, we think that we can give them some of the best possible treatment options. Then last, underpinning it all, we have a core technology with a nuclide generator system. There's a lot to understand there, but what it means is we're taking a lot of risk out of the radioactive material supply chain and developing that for easy access so that patients can get drug as needed and when needed. Just thinking about what radiopharmaceuticals are, and on this slide, what we go through, what we wanna highlight is that this is really emerging as the new pillar in oncology. There are many, many opportunities across many tumor types for how molecularly targeted radiation can make a difference. The idea is that, as Lori mentioned, we're not gonna hit cancer from the outside in and run a higher risk of hitting healthy tissue. We wanna target cancer from the inside out, and we think that doing molecular targeting is another approach that can do this and actually get the patient's cancers treated inside out and having pre-screened who's the most relevant patient for that. By having these companion imaging agents, we actually think we can actually choose the right patient. Before a patient gets dosed with a therapeutic, we can see in advance that they actually have a scan that shows that we have a really good probability of success of the therapy going exactly where it's supposed to. The therapies that we're developing can either be given as monotherapy or as combination therapies, and we have great animal data that implies that we can go in either path. We still need to do the development work with the FDA's guidance to make sure we find the right way to image a patient and treat a patient. We've seen an awful lot of synergies coming out of the research that we've done in our lab. The nice thing about these technologies and therapies we're developing is that we think they're really outpatient-friendly. The fact that you've got somewhere in the range of 20-30 million patients a year in the U.S. who receive nuclear medicine procedures currently. There's a well-established infrastructure that actually lets patients get access to the products. There's the supply chain that offers this to physicians in a way that is friendly to their locations. We actually think that given the overall global supply chain and the ease with which physicians have access to isotopes, we've taken a lot of risk out. Patients get access to isotopes in whatever hospitals or regions of the country where they are based on the very well-established discipline called nuclear medicine. A lot of patient scans and scanners and departments are well suited to actually offer our therapy to the patients that they see in front of them. I've mentioned to you previously about types of radiation and alluded to it, and I wanna really kind of zoom out to first principles and really explain what's going on. On this slide, you know, this a cartoon that shows the differences between alpha, beta, and gamma radiation, and they're not interchangeable. Gamma rays are what everyone thinks about usually when they think about X-rays. They'll penetrate through a lot of different surfaces, and they'll deliver energy gradually across their path. What we're really excited about is some of these subatomic particles, alpha particles and beta particles. As we look at these particles, that's where things get really interesting. Betas, it can actually penetrate about 200 cell diameters. They'll go through paper and skin and go a certain distance before they deliver their energy. We're really excited about alpha particles. Alpha particles travel about two cell diameters only, and they're massive. They're about 8,000 times as massive as a beta particle with thousands of times more energy that gets delivered into the tumor. Our whole approach is getting radiation to the tumor and targeting it from the inside out. As we think about how to apply this, though, I wanna turn the microphone over to Dr. Michael Schultz, who's one of Viewpoint's co-founders and inventors of some of the technology. Michael? Thanks, Thijs. I really appreciate the conversation. You know, if the forms of radiation were one of the fundamentals of the technology that we're developing for therapy for cancer, then the selection of the isotopes is another very important fundamental. On this slide, we talk about sort of the two-step approach that really represents the foundation for the theranostic approach to cancer therapy. In step one, we do an imaging scan where we use an isotope that emits a gamma ray that we can use for developing a detailed understanding of the biodistribution of the drug and tumor accumulation and clearance from other organs. Then we can use that information quantitatively in step two to develop a treatment plan that could be used for delivery of the, in this case, Lead-212 for delivery of alpha particles to the tumor microenvironment while monitoring the distribution of the dose clearance out of the body. In our case, we chose Lead-212 and Lead-203 as elementally identical isotopes. That we can be confident that the Lead-203 diagnostic scan will give us quantitative and accurate information about what the biodistribution of the Lead-212 will be in the cancer therapeutic stage. There are several isotopes that could be selected for this type of therapy, and I mentioned that we're looking at these elementally identical lead isotopes. What you might not know is that you know there's a long history of the use of isotopes for cancer therapy, beginning with Iodine-131 for treatment of thyroid cancer. Followed by that was a beta emitter called the Lu-177 that turned out to be easier to produce and easier to ship and it's a good isotope that has provided benefit for cancer patients. Over the recent years, it's really emerged that alpha particle emitters have the potential to truly be transformative to cancer patients. That leads to some more decisions. And there's really two isotopes that you know that have emerged as the front runners here. One, Actinium-225, you see there with a 10-day half-life, versus our selection and what my research led me to choose as Lead-212 with about a half a day half-life. There's a real reason for choosing Lead-212 over Actinium-225. You know, the molecules that we designed to target cancer cells, we've designed them so that they rapidly accumulate in the tumor microenvironment, and the residual dose is rapidly cleared from the rest of the body. Biologically, it just didn't make sense to me to have a radioactive isotope with a 10-day half-life that was bound to a molecule that cleared through the body so quickly. I felt like, you know, the idea here is to deliver the highest effective dose that you can to the tumor and the lowest dose to all of the other organs and tissues in the body, and Lead-212, you know, was the choice. I guess the second part of Actinium-225 that really led me in this direction of lead isotopes for alpha particle therapy for cancer was this idea of daughter radionuclides. Here on the left-hand side, you see that Actinium-225 decays through a series of other isotopes. When actinium, there's a key fundamental property here of alpha particle decay that leads to the decoupling of the daughter radionuclides from the chelator that's supposed to deliver the therapeutic dose. Those daughters, in the case of Actinium-225, also have decays of radiation, and those decays then will be deposited in other parts of the body that aren't targeted to the tumor microenvironment. This really led me to think that Lead-212 had a much higher probability of targeting the alpha particle dose to the tumor microenvironment with minimum dose to other organs and tissues. If you know, if radioactive decay is one of the fundamentals, of course, then you know, the third fundamental that we're gonna talk about here is this idea of the development of the targeting ligand. A great amount of my research in my laboratory has been around development of the targeting ligand. On the right-hand side of the screen here, you see this cancer cell with its cell surface protein that's found in high concentrations in cancer cells, but not on normal cells. We have a targeting ligand that we link to a proprietary chelator that binds tightly to the Lead-203 and the Lead-212 to deliver that radiation dose and to help us to ensure that that radiation dose is being delivered to the tumor microenvironment where we're killing the tumor from the inside out, as Tas and Lloyd mentioned, rather than from the outside in. My laboratory, as Tas also mentioned, has two of these targeting ligands that we've developed that are going into clinical trials. We have two world-leading experts in the development and clinical translation of this type of therapeutic agent that are with us today. Jeff Johnson from the Mayo Clinic in Rochester, Minnesota, will speak on metastatic melanoma, and Vikas Prasad, who is now with Washington University in St. Louis, will speak on neuroendocrine tumors. Now I'm gonna turn it over to Dr. Johnson to talk to us about the work that we're doing to target melanoma cells. Thanks, Michael. I'm gonna talk to you about the promise of alpha particle radiotherapy for melanoma. Melanoma is widely known that once it goes metastatic, it is basically a death sentence. We have a multiple different therapies, including immunotherapies, that we can try to slow down the disease and aid in patient comfort. But we have very few things we can do that could potentially lead to cure. Alpha particle therapy is a promising new option, and Viewpoint is leading the way. I do have some disclosures. I wanna highlight that I do have a know-how agreement with Viewpoint. This is the core team from the Mayo Clinic that brought the study forward, funded by the NIH, where we used imaging versions of the therapy to show the promise of the potential therapy to kill the cancer. What is the basic concept here? On the left, you have a cancer cell in green, and you can see that it has multiple proteins on its surface. Those proteins or targets are chosen because they're expressed on the surface of just the cancer cells and very few of any other cells in the body, so that when you inject a medicine that's designed to stick to that target, it only sticks to the cancer cells. What doesn't stick washes out of the body quickly. The medicine or radiopharmaceutical is designed to be injected into the vein, circulate through the body, stick to the cancer, and kill it. You can see in here that there are four components to the design of these medications. In green, the circle you see is the ligand. That's designed to bind to the target, and Viewpoint has created its own specific ligand. There's a linker which holds the molecule together and carries with the ligand a chelator or a cage that you can see in the circle on the right. That is designed to hold a radioactive atom. We can put two different kinds of radioactive atoms in there. We can put a radioactive atom that gives off photons or radiation that can be seen by a scanner, such as a PET scanner or a SPECT scanner, that lets us see where in the body the medicine went. Once we've identified that a patient is a good candidate, we can inject a different version of the drug that's therapeutic, and in that case, it would contain a lead-two-twelve atom, which gives off alpha emissions and kills the cancer. Here is an example to show you why I and many of us in the field of nuclear medicine and in oncology are excited about alpha emitters in particular, compared to the current standard of care beta emitters. This is not the same technology that Viewpoint is developing. This was the image of the year from a group in Germany based on what the Society of Nuclear Medicine voted on at the time, because it shows the promise of alpha emitters where beta emitters fail. On the left under A, you can see a three-dimensional image. You could rotate this around in 3D if we were looking at a PET scan. You can see all of these black areas, which are areas where the PET radiotracer or radiopharmaceutical went in the body, and those are sites, in this case, of prostate cancer. What was injected is a Gallium PSMA-11 radiotracer. Unfortunately, this patient continued to progress, and then they received two doses of lutetium PSMA. This is now known as Pluvicto. It was FDA approved in March. In many patients you can see a response, but in many other patients like this one, the cancer continues to progress because the cancer for some reason is resistant to the beta emissions coming off of the drug designed to kill the cancer. This patient then switched to an alpha emitter, so instead of lutetium, which is a beta emitter, they loaded the medication with actinium, which is an alpha emitter. You can clearly see that after that injection in image C, the cancer is almost gone. After one more cycle of therapy, the cancer is gone. This, together with other data, has led to a lot of excitement that alpha therapies are the future. There are a number of issues with actinium, and Lead-212 is a different alpha emitter that Viewpoint has decided to move forward with, which has some distinct advantages. Beta versus alpha. Let's go into it in a little more detail for those of you who don't understand. On the left, you can see that's the listing for beta emissions, which is beta is another term for an electron. It is a very tiny subatomic particle coming off the nuclide. It doesn't have much power. You need many electrons to hit the cancer cell to kill it, and it also has a range of 2-12 millimeters, meaning it's gonna kill cells around the cell the medicine's bound to, not the actual cell it's bound to. It only causes what are called single DNA strand breaks. Why does that matter? A single DNA strand break in the core of the cancer cell won't kill the cancer cell by itself. It has to have multiple of them to die, and the cancer cell can turn on defenses to protect itself like we saw in the patient we just looked at. In theory, if the cancer cell repairs itself but repairs itself incorrectly in its DNA, it can mutate further and become more malignant. You could even have new malignancies that start in the bone marrow, which is a problem with our current beta emitters. An alpha emitter by comparison is a much larger subatomic particle that's emitted from the medicine. It's actually a helium atom's core. It is orders of magnitude bigger. It is much more powerful, and it travels a much shorter distance. Therefore, it is much, much more precise. It literally kills the cell it's bound to or a couple cells nearby, and that's it. It causes double DNA strand breaks, which the cancer cell can have no defense for. It literally kills the cell that it radiates, and it can even therefore kill tiny tumors and potentially could lead to a cure in some patients. Viewpoint developed the technology of a specific ligand that targets the melanocortin 1 receptor. Okay, what is that? It is the target on the melanoma cancer cells that we are trying to use to bind our drugs and kill the cancer cells. It's a particularly good target because it is highly expressed or abundantly on the surface of cancer cells, and it is almost nowhere else in the body. Having said that, not every melanoma expresses this receptor target. Therefore, we need to use imaging to select a patient and say, "This patient is a good candidate," versus, "That patient is not." Another thing that Viewpoint did, which is critical to this development, is they developed their own chelator. On the left in green and blue, you can see some standard chelators for holding on to lead, and it can be either Lead-203 for imaging or Lead-212 for therapy. Their particular chelator holds on to the lead much more tightly in the body. Therefore, the drug doesn't fall apart after you inject it, which is critical because you want the radiation to go to the tumor and nowhere else, if at all possible. The two different medicines or radiopharmaceuticals that we studied already in our practice funded by the NIH were both for imaging. We're getting ready for the therapy in the next phase. The top one you can see is with gallium-68. This is used for PET imaging. We use this for patient selection. It's very precise at being able to see a very small amount of the pharmaceutical in such cancer to identify a candidate. The bottom one is with Lead-203. This is identical in structure to the Lead-212 version, which is used for therapy. It's not necessarily as good for imaging because it has to be imaged with a SPECT scanner, which is a lower quality technology. It allows us to have the exact same biodistribution in the body as the Lead-212 imaging or Lead-212 therapy. We can accurately predict how much of the therapy we're gonna need to have a good effect in a given patient. Here's a preclinical animal. It's hard to see because almost all of the medicine that was injected into this mouse went into a tumor, a melanoma tumor that you can see circled with a T. What else didn't go to the tumor is being washed out of the body. You can see it in the kidneys. It's going out in the urine. Very precise to the tumor and very few other tissues. This is a description of a study that we had funded by the NIH, where we're imaging. I can tell you that our internal safety review committee, which is independent from the study, concluded there were no side effects from either imaging agent in any of the human patients we tested. We enrolled seven patients. One withdrew because of personal reasons and their cancer. We had six that we imaged, and half of them were positive, which is similar to what we were expecting based on what we know about expression of the tumors. The positive patients on imaging are the ones you select for therapy. I'm gonna show you a few of them. Patient five, 65-year-old woman who had melanoma in the eye that 20 years later came back and metastasized to the liver. She was on immunotherapy. You can see on this MRI image on the right, the white rounded areas in her liver, which is a classic appearance for melanoma. We also did an FDG PET/CT. FDG is sugar. It's a radioactive sugar, and when the cancer cells consume it lights up. It lets us know that the tumors are alive. Now, here down below, you can see with the gallium VMT01, the first research test product here, that the tumor is expressing the melanocortin receptor, and the imaging agent is binding to the cancer, meaning that this patient is a candidate for the therapy. Patient six, 39-year-old man diagnosed in 2007 with a BRAF mutant melanoma on the skin on the back and metastatic to lymph nodes. The patient then later had a number of metastases of cancer in the right pleura. On the right here, you can see a PET scan from the vertex of the head all the way to the toes. This is an FDG PET scan. This is the glucose PET scan. The brain lights up, that's normal on this type of scan because the brain consumes a lot of energy. You can see a number of black spots to the right of midline in the patient's chest. Those are cancer metastases in and around the lung in what we call the pleura. The patient was on chemotherapy between that scan and the subsequent images on the right, which are the VMT-02 medicine that we're using to select the patient. Some of those tumors may have died, but you can clearly see that many of them do light up. I've got three images here at one hour, two hour, and three hours. You can see the dark spots in the pleura continue to hold onto an increase in the amount of radioactive drug that they have bound while it's washing out of everything else from the kidneys and the bladder and leaving the body. This is what you wanna see with a theranostic when you're selecting a patient for a therapy. If we do a cross-sectional image where you have a CT in black and white showing the anatomy of the patient, and in red and white, you can see the radioactive medication we injected. Again, on the left, this is in the pleura, you see one lesion where the arrow is pointing to a live tumor consuming glucose. On the right, you can see it's taking up a significant amount of the VMT01 imaging radionuclide. That tells us that this patient again has fairly high expression of the melanocortin receptor on their tumors and is a good candidate for therapy. Patient seven is a 67-year-old man diagnosed in 2021 with a different mutation, NRAS-mutant melanoma. This patient had widely metastatic disease. The patient was on a number of therapies, and unfortunately, after the imaging was completed, the patient did pass away due to their cancer, unrelated to the imaging medication. On the left, you can see an FDG PET scan. Again, the brain is normal, but almost all of those black spots are active live tumors. On the right, you can see that the lymph node just underneath the right shoulder and a number of the liver metastases are clearly visible. As we scroll through the images in more detail, some of those smaller lesions also show up. Having said that, likely all of them express the melanocortin receptor, and the reason you can't see them has more to do with the resolution of the scan than has to do with whether they express the tumor target. On the left, now you see a cross-sectional image through the chest with the arrow pointed at a large, FDG avid or glucose-consuming tumor. On the right, you can see that the patient again, has uptake of our research radiopharmaceutical, the VMT01, saying that they're eligible for therapy. I'm gonna show you also here that the patient, this is the Lead-203 VMT01 SPECT CT. This shows you that even though it's a less, SPECT is a lower quality scan type, the molecule that's absolutely, that is structurally identical to the therapy also clearly shows up in the tumors. That allows us to calculate how much medicine we should be giving to these patients. With that, I wanna say thank you for your time and say, next I'm gonna pass it off to Dr. Vikas Prasad, who's gonna talk about alpha therapy and imaging in neuroendocrine tumors. Thanks, Jeff. That was a nice overview on the melanoma. I am going to speak on the Pb-203, Pb-212 VMT-α-NET in the management of somatostatin receptor-positive neuroendocrine tumors. Just briefly about me, I'm not going to take a lot of time. I am a professor of radiology and director of clinical diagnostics in the division of nuclear medicine of the Mallinckrodt Institute of Radiology. I just arrived a few days back in the U.S. What I'm going to briefly walk you through is the journey of a neuroendocrine tumor patient, as well as the outcome and the symptoms which these patients have to deal with. I'll also explain why we think there is an urgent need for a very effective therapeutic option. You Neuroendocrine tumor is a highly heterogeneous kind of tumor. It has its origin from the abnormal neuroendocrine cells in the gastrointestinal, pancreas, and lung region. There are other places where they can actually originate, but these are the major ones, gastroenteropancreatic neuroendocrine tumors, as we call it. They have different grades, slowly proliferating, the G1, mild to moderately proliferating are the G2, and aggressively proliferating are the G3. If you only look at the life expectancy of the patients with G1 and G2 neuroendocrine tumor, somewhere around 30%-70% if the tumor is already metastasized. It's also important to remember and to stress upon that already approximately 175,000 people are living with this diagnosis, and 12,000 patients are adding up every year. The symptoms, apart from those caused by the metastasis, the symptoms of these neuroendocrine tumor patients are also due to the functionality of neuroendocrine tumors. What do we understand by the functionality? It means that these tumors actually produce a lot of different kinds of hormones, and that makes a patient's life only a problem. For example, patients having diarrhea or flushing. Sometimes some of the patients go 10-20 times a day. The other hormonal symptoms which make their life not that easy, although the life expectancy 5 years, say, it's good enough in metastasized stage, but the quality of life suffers significantly, and that has an effect on the economic and psychological well-being of that patient as well. Despite significant advancement, specifically, for example, with the Lutathera approval, and other new treatment options, despite the significant number of drugs which are already available, the patients are still suffering. We really need to develop and make these patients a different and new kind of treatment available. Alpha particle therapy is actually one of the most promising treatment options for the somatostatin receptor-positive neuroendocrine tumor patients. Before I explain how it actually works and which data we have, I would like to stress that, probably, the reason why we are still seeing lot of escape from those already effective treatment options available is that we are using those treatment options in the last stage of second or third or fourth line of treatment. I think radioligand therapy has a potential to be moved upfront at the first line as soon as the patients are diagnosed with a functionally active neuroendocrine tumor or somatostatin receptor-positive metastasis all over the body. These patients should be treated in the first line. It's my personal opinion. Which kind of radioligand should we use for the first line of treatment? Not all. Well, these patients also live for a significant period of time, so we want to have a treatment option which does not lead to an increase in toxicity and thus decreases the quality of life for patient because that's very important for the neuroendocrine tumor. We need to have an ideal radioligand which can be defined as having a very high therapeutic index. What do we mean by therapeutic index? That means that the dose delivered by these radioligands to the tumor should be significantly higher as compared to the dose, radiation dose being deposited in the normal organs, and this is a therapeutic index, the ratio between tumor to the non-tumor tissues radiation dose deposited there. When we deposit and inject the radioligands in a patient's body, sometimes some of the radionuclides may actually get free at the location of their emission. That actually can theoretically, and in some cases it has been shown, that can actually lead to an unnecessary radiation exposure to the normal tissue. You actually need to have a very good chelator, which keeps the radioligands tight and bound within itself. Because this therapeutic index is very important, there should be a way to assess the amount of radiation dose delivered to the tumor and the amount of radiation dose delivered to the normal organs. This can be divided into micro and macro dosimetry. Let's not make it very complex dosimetry. It It means that the dose is delivered in and around the tumor and also in the normal organs. There should be a way to calculate it. An ideal radioligand should be a radioligand which gives us a very good quality of image for allowing us, our medical physicists, to do this calculation. Of course, any kind of treatment has to be very effective because these tumor cells are quite smart. You really need to kill those tumor cells. It should have very high killing property for those tumor cells, right? These are the ideal radioligands which are properties of an ideal radioligands which should then allow us to move up in the first line. Before I go on to the imaging study done in a patient, I will just briefly highlight the extremely interesting and extremely important preclinical data which actually compared the already approved Lutathera treatment in the mice containing the somatostatin receptor positive neuroendocrine tumors. These results are then compared to the Pb-212 VMT-α-NET, which is a neurotherapy. The results here on the left-hand side, on the upper one you are seeing is the vehicle. What do you mean by vehicle? It's like those mice did not receive any treatment. Of course, if you don't treat, these tumors grow. Again, this just shows that we really need to treat those patients. That's true. Then we look on the right side, upper panel, graph, which you are seeing is that these mice are treated with three cycles of 500 microcurie. Actually, it was planned to treat with four times 500 microcurie, but as you are seeing those three red arrows from zero until 20 days, within the 28- 29 days, the tumor progressed so rapidly that the animals had to be killed so those animals could not receive the fourth treatment cycle. Then on the left side lower panel and on the right side lower panel, you are seeing what happens if you treat these mice bearing somatostatin receptor positive neuroendocrine tumor with one cycle of the Pb-212 VMT-α-NET, that's on the left-hand side, or four cycles of Pb-212 VMT-α-NET on the right-hand side. You see those graphs, these dots which you are seeing, if you follow the curve, you are seeing that immediately, only after the first, I'm going to stress it again, only after the first treatment cycle, the tumor size has disappeared. It has gone significantly and very quickly down. Even more important is on the left-hand side that even when the treatment was stopped and no further treatment cycles were given, there was no escape. The tumor did not come up. On the right upper panel in the Lutathera arm, you are seeing that there was a rapid escape after 28 days. The dosimetry was of course performed and an assessment was done. I can tell you that the results are extremely positive in favor of the Pb-212 VMT-α-NET. That again stresses upon using such kind of treatment in the first-line treatment. We performed or injected in a patient with a functionally active neuroendocrine tumor with very significant amount of metastasis in the liver. These metastases in the liver were producing a significant amount of hormones, and these are the serotonin hormones. They actually led to a damage of one of the valves on the right-hand side of the heart, which led to a kind of a heart dysfunction. The patient, who was only 45, 47 years old, actually, had very poor quality of life. In this stage, the patient was not responding to any other treatment option. The patient came to us when I was at Ulm, and I injected in this patient the Pb-203 VMT-α-NET, which is the diagnostic component of the Pb-212. Why is it diagnostic? Because it gives gamma rays, which can then be captured. On the middle panel, this black and white images you are seeing, on the right-hand side also, the 1-hour and 24-hour images are the whole body images acquired because the gamma emission of the Pb-203. Those arrows which you are looking at on the upper side, they are actually the tumor. You can see immediately within one hour, on the lower side, there's a fast renal clearance, and majority of the activity was already out into the urinary bladder. In the kidneys, there was hardly any significant amount of uptake. On the 21 hours, you can see that there was an even faster clearance from the kidneys. Most remarkably, and this is again very important, it's not only that the radioligands clear themselves, they should stick on to the tumor, and that is their purpose, to treat. How can you treat? You only can have a good response when you achieve a significant amount of radiation dose. How can you achieve a significant of radiation dose in the tumor? By having a radioligand which sticks onto the tumor cells and bombards it internally for a significant period of time. On the left side, what you're seeing, we have got four images, axial slices, from the PET CT on the left-hand side and from the SPECT CT on the right-hand side. The SPECT CT is the one which was the scintigraphy, Pb-203 VMT and from that images. Those white arrows where all you are seeing, those are the tumors which were present, which could be seen on PET as well as on the SPECT CT. Mind you, PET has a much higher resolution than the scintigraphy images. Still, because of a very good target to non-target ratio, because of the extreme excellent clearance from the normal organs, we could actually see that the tumor showed a very good uptake immediately within one hour and persisted for 21 hours. If you treat using this VMT-α-NET peptide combining with the Pb-212, you're going to achieve a very high radiation dose from the alpha therapy. This alpha therapy will lead to significant decrease in the tumor size. If we are lucky, in some of the patients, we can achieve complete remission as well. In some of the patients, we can really make a very big difference. I'm pretty sure this kind of treatment is going to move upfront in the first line of treatment of the gastroenteropancreatic neuroendocrine tumor. With that, I would like to thank you for your attention. Great. Thank you, Vikas. With that, we'll turn it over to Q&A. Certainly. Ladies and gentlemen, you can submit a question at any time by clicking on the Ask Question button on the left of your screen. Type your question into the box and hit the Send button to submit your questions. Thank you. Great. Thank you. Looks like we have a lot of questions here. The first question is actually for Dr. Johnson. In the melanoma patients, not every tumor was positive on the experimental scans. Does this mean that only the positive tumors will respond to treatment? Thank you for the question. Hopefully, you can hear me okay. When you look at those scans, one of the things I mentioned was the FDG scan with a glucose scan was done prior to the VMT-02 scan. Like the one in the pleura where I mentioned that the patient was on chemotherapy, those tumors had decreased in size. Some of those tumors that were VMT negative, if you will, where we didn't see the melanocortin receptor radiopharmaceutical that Viewpoint has designed in the tumor, was probably because the tumors were dead. This is an early proof of principle concept here. We were able to show that there's proof of principle that it's binding with tumors. We will need more data to go out and say whether or not all tumors in a given patient take up the target. You're correct. If there was a patient who had mixed disease, who actually had live tumors that were VMT negative, where we expected to see it, they were big enough, we should be able to see them with the resolution of the scanner, the patient would probably be a poor candidate for the therapy. Great. Thank you. Next question. Actually, there's a few questions I'm gonna combine together and ask each of you. The first is, are these radiotherapies that approved in the U.S.? And then that'll be for Dr. Johnson and for Dr. Prasad, can you tell us what the landscape is in the European Union in terms of adoption of this type of therapy? Is there infrastructure and is reimbursement in place, I guess, in both geographies? Jeff, do you wanna take the first one? Yeah, sure. In the US, there are about six different radiopharmaceutical therapies that are currently in use. Two of them you heard mentioned, lutetium dotatate or Lutathera, lutetium PSMA, which I mentioned, which is Pluvicto, and I showed you a slide of. There are some other older ones like Radium and Zevalin for hematologic disease, and then a really old one, the iodine for thyroid cancer, which is just simply a free atom. Those are all reimbursable, used in our practice commonly. We give about 35-40 doses a week of these various medications in cancer patients. When you look forward and you see all of the investment coming with a number of different companies, there is a clear wave, a growing wave of investment in this space because of the recent successes of the lutetium drugs and the kind of data you just saw from Prasad showing just how effective these alpha therapies can be. Thanks. I think the most important point to stress over here is that the alpha therapy and the radioligand therapy has seen a real push in the last 5-10 years, and I can see the landscape from the European perspective that there's a really an exponential growth in the demand from the patients as well as from the oncologists, not only for these 5 or 6 indications which Dr. Johnson mentioned, but also for pediatric patients, but also for brain tumor, but also for first line treatment of the prostate cancer, as well as many other hematological diseases as well. Regarding the reimbursement, I can tell you about from the European and specifically from the German perspective, of course, as long as you are in Germany, you get a treatment. If the treatment is effective, people get this kind of treatment, get it reimbursed. In other centers, depends upon where you are, sometimes they reimburse, sometimes they don't reimburse. In general, there's a very great acceptance and extreme enthusiasm amongst the clinical oncologists that probably it is the equally as important as the growth of immunotherapy in oncology, the radioligand therapy, the alpha therapy. I guess I didn't comment on the reimbursement in the U.S. These are well reimbursed. In other words, Medicare reimburses for these, and third-party payers reimburse for these. We have these extensive therapies, so we track it very closely, and our institution has been quite happy with how that has gone. Great. Thank you. Question from the analyst at Oppenheimer saying, "One of the critical challenges of radiopharmaceuticals is the logistics of delivering, you know, radiopharmaceuticals to the patient before the isotope decays, and this gets challenging when half-lives are shorter versus longer." The question is, how do you manage this challenge when you have a half-life of only half a day? I'll take that one and ask Dr. Schultz to layer in as well. You know, the reality is you need to have sort of local regional manufacturing and production, and thankfully there's a large established infrastructure of facilities that produce, you know, radiopharmaceuticals for both single photon imaging through nuclear pharmacies and also manufacturing sites producing positron emitting drugs. There's also been a lot of investment in infrastructure, as the prior panelists discussed, that have created manufacturing sites all across the U.S. that are all trying to deliver this isotope to quote just in time. Just in time means within sort of in some cases, 6-8 hours of manufacturing and distribution. Dr. Schultz, anything to add to that? Yeah. You know, no, that's a nice summary of, you know, the situation for the shorter-lived isotopes. I think the, you know, as you mentioned, there's, you know, an increase in infrastructure that continues to build off the back of, you know, what is an industry that has been around for a long time in radiopharmacies. Also I think that there's a misconception, you know, that the last mile logistics won't be the most important thing in delivering these radionuclide therapies to the clinical centers. Even with isotopes that have longer half-lives, you know, those last mile logistics are turning out to be, you know, super important, and that's the reason that, you know, the industry is building manufacturing facilities to handle radiopharmaceutical production on this local regional, you know, sort of platform. Great. Thank you. Next questions actually come from the analyst at B. Riley. First is for Dr. Johnson. Can you elaborate on the beta therapy resistance mechanisms, and if any of these mechanisms can be overcome with alpha therapy? Sure. First of all, when you look at it from a clinical perspective, you know, you look at a patient who you do a PET scan on, and all of their tumors light up with the imaging version of a drug, and then you give them the therapy, and you expect or hope that you're gonna have a good response. We can't really predict it right now. Some of the patients have a great response, some of them have stable disease, and some of them, like the one I showed in the earlier slide, just progress right through the beta therapy. We don't really know yet exactly what differentiates those two. However, the growing experience is that when you switch to an alpha emitter, you can take those patients that had progressed on a beta emitter, again, presuming their tumors all light up, meaning that the drug gets to the target, and you can get a therapeutic benefit. The clinical data tells us that they work better. When we go and talk about mechanisms, we're now trying to look at the mechanism to explain what we already know clinically. What are some of the things that can happen? Well, when you have a hypoxic tumor, we already know that hypoxic tumors, where there's not enough oxygen because there's low blood flow to the tumor, they turn on genes to protect themselves from what are called free radicals or ions. Those free radicals are molecules that have broken apart that can combine with the DNA and break the DNA. Okay? If you're deciding to give somebody external beam radiation and you know the patient's hypoxic, a radiation oncologist knows they have to up the dose because the cancer is gonna be resistant because it turns on a bunch of genes in the DNA that actually produces proteins that scavenge all these free radicals. That actually protects the cell, the cancer cell, from the beta emitting radiation and blocks that mechanism of cell killing that we're trying to use with the beta emitter. With the double DNA strand break of an alpha emitter, it doesn't matter if the cell has turned on those defenses, because when the double DNA strand break happens, it's a direct hit from the alpha particle to the DNA that rips through it. With the double DNA strand break, there's no mechanism that we know of that can significantly repair that cell's DNA, and the cell basically is lost, just go right on to die. There are other mechanisms that we can get into more details, and we can have a whole hour discussion about bystander killing and other ways in which alphas may be killing cells. At its core, that's it. It's the turning on of genes in a hypoxic environment and the protection of the cell from the single DNA strand breaks and the free radicals that cancer cells can do against the beta therapy. Great. Thank you. The last question is for Dr. Prasad. As it relates to having, you know, VMT-alpha-NET in clinical trials for first-line NET patients versus last-line, you know, what do you think the challenges will be in actually either identifying and/or enrolling those patients? I think the major challenge would be to look at and select the right patient. Other than that, if you ask me, we are already thinking and I can tell you from my experience from some of the guidelines where I have said to the committees, we are actually thinking of these, bringing these kind of alpha therapies in the first line, for example, in patients with a functionally active neuroendocrine tumor right after one of the approved or even before one of the approved somatostatin analog. I think the challenge would be mostly about how do we expand the number of skilled people who can manage the huge amount of patients which will be needing such kind of treatment. If at all, that in my opinion, is the only challenge. Otherwise, the acceptance from the clinical and the pharmaceutical, radiopharmaceutical, as well as from the insurance side is pretty high. Great. Thank you. Unfortunately, we didn't get through to all the questions here, but we're out of time. First, I'd like to thank all the presenters and Dr. Johnson, Dr. Prasad. We really appreciate your sharing your thoughts and your experiences so far in patients with the drug so far. Thank you. Thank you. Thank you, ladies and gentlemen. This concludes today's event. You may disconnect at this time and have a wonderful day. Thank you for your participation.