Perspective Therapeutics, Inc. (CATX) Earnings Call Transcript & Summary

Good morning. I'd like to welcome everyone here. Thank you for joining us. I'm Thijs Spoor, the CEO of Perspective Therapeutics. A great audience here, some terrific key opinion leaders to talk about the space. We're so passionate about what we do and everything we do we think makes a benefit to help transform patients' lives. With that, let's take the chance to dig down a little bit and figure out what do we do? We believe we are one of the best at engineering the alpha advantage. And what does that mean for patients? And really, how can we deliver transformative therapies? This presentation is being live cast, and we actually will have a lot of slides. The slides will be available afterwards on the company's website and via the SEC as well. The agenda today is I want to talk to you about platform, pipeline, production, the things that really drive us how we do, things we're really, really good at. And then also then go back and say, right, what does this mean for patients? We have one of the world's experts on treating neuroendocrine tumors here. We'll speak about what that means. I'll be talking to you about our Phase I/II data of VMT-alpha-NET. But then there's also beyond the first-line setting, what can you do for patients as well. And we have 2 clinicians who have each treated patients post LUTATHERA. So post initial standard of care, what happens afterwards? Is there any hope? And they'll give their perspectives on that. And then I thought we'd zoom out a little bit, and Dr. Zan, who's Chair of Nuclear Medicine, Cleveland Clinic, will be sort of doing a little teaching. Does biodistribution tell you anything? Spoiler alert, it tells you just about everything, but she'll be able to kind of give that explanation and walk through what that means. And then we'll go on to sort of closing remarks and Q&A. So we have a lot of slides to go through here, but I want to sort of level set things right now. What do we do? So targeted alpha therapy. We are one of the only companies out there that's vertically integrated. We do everything from early production, isotope procurement, isotope stockpiling, all the way through to absolute innovation across the board. We are in a very, very strong position. When I joined the company 4 years ago, we were at 23 people. Now we're over 180 and growing. And a lot of that is thanks to the support of the people in this room who have helped us get there, support from the patients and clinicians. But with this sort of phenomenal pipeline that keeps growing and keeps building, we're actually in a very, very good position to actually go and be able to take things through. So we have multiple clinical catalysts coming up. And as we think about where things go, I want to walk through what it is to expect. We are increasing our manufacturing footprint. We do have many, many patients being treated in the U.S. We have over 100 patients now that have been treated in the United States with our various medicines. We have about 40 patients overseas that have been treated. We want to share some of those patient perspectives. But why do we do this? Is this a big market? Absolutely, right? I mean Novartis has done a very, very good job of saying you can actually take some clinically validated modalities. You can take basic targeting entities with betas, but the market keeps growing. And Novartis is just getting started. We're just getting started. What do we do to really differentiate? We think we've picked the right isotope. We actually have access to every single isotope in our labs. We can use actinium or lutetium or iodine or terbium. But we actually -- when we run the animal experiments, we realized the best results, meaning the best therapeutic window always has come so far with lead. And we do that because we do the animal biodistribution. We do the animal dosimetry. We do a lot of work to optimize the structural chemistry. If you don't invest in medicinal chemistry, you're going to get unwanted side effects, and you have to get it right because if you don't, then something else is going to get the damage instead of the tumor. These particles are so powerful. And that's a double-edged sword. Powerful particles absolutely will destroy cancer cells, but they will damage other tissues as well. It's one thing to take that approach. We actually have the advantage of being able to select in advance. We can use an isotopic twin or an elemental twin to actually figure out which patients are appropriate. But none of that counts if you can't make the drug and send it to the patients. And so we have multiple manufacturing sites and growing, and we're building our network across the board. And to do this, we actually keep investing. So we've been innovating, engineering, investing across the entire value chain. Is the market big? Absolutely. We are -- as we look at the addressable market, we know there's many solid tumors that we can address. We have not addressed liquid tumors yet. We think solid tumors are very exciting. We understand how to visualize those, what that means on the image, how we can quantify what we can address. We have an MC1R program targeting melanoma, which has a fairly strong unmet medical need as someone with a family history, I appreciate that it's more than just wearing a hat in the sun. You've got to do a lot more. And if you get the disease, you need to really get treated aggressively. NETs is a very interesting sort of one of several tumors that shows up with SSTR2 positivity. There are many other tumor types that also express SSTR2, and we want to find ways to help those as well. But if we get into much larger addressable markets, we think about FAP, which is a pretty amazing target. There is a pan-cancer target that we're going after. And there's a fourth program that we'll tell you about a little bit later today, which we think has also extraordinary potential to disrupt how we think about treating patients with these solid tumors. As we think about the field, some people in the room are experts about in radiopharm. Some people are naive to it. But the easiest thing you can do to the tumor, if you see it, cut it out, just remove it. If you can do that surgery, fantastic. It's curative. And as you go up, you want to try and throw more and more things systemically. If you don't know where the tumor is, then you have to not start guessing, but doing more broad-spectrum things. And so the evolution of chemo and external beam therapy, immunotherapy has done fantastic jobs, but it's not perfect yet. And ADCs as a targeted chemo have really innovated. But it's not a zero-sum game. We're actually trying to combine the things together. So just the same way you had chemo and radiation merging and you have chemoradiation combinations with IO, the same thing with radiopharms. And so if you have a choice of giving radiation to tumor, it shouldn't be a [ trick ] question. Is it better to target the cancer from the inside out or to have the radiation go through a lot of healthy tissue before it gets to the tumor itself, and that's what we're dedicated in doing and investing. We think Lead-212 is a fantastic isotope. It has a lot of advantages in terms of incredibly high potency by having a very low energy beta and a very powerful alpha. You then actually have the ability to give a very hard, fast burst. And radiation biology teaches us that if you give a hard, fast burst to the tumor with a particle, you can then create a neoantigen storm that should actually help the body do well on its own as well as killing the tumors themselves. On the supply production side, 10 years ago, when the founders started the company, you could only get a lead generator from the U.S. Department of Energy on the third Tuesday of every month. There are now 7 manufacturers, all supplying lead generation systems to the market. We're not a commercial producer of lead generators. We just happen to be really good at it. We've made about 400 generators so far. We make 3 or 4 every single week. We ship them around the world as a very, very reliable way of doing it, supplying isotope. We're not dependent on people in order to actually sort of satisfy what we need. We think there are a lot of conveniences for patients and hospitals for having a shorter-lived isotope, not having an isotope linger in the body, not having an isotope linger in the patient's urine after the fact, we think has a lot of advantages for just how patients get managed. And having the theranostic pair of Lead-203 and Lead-212 is incredibly elegant. We can perfectly predict biodistribution from the images, and that predicts the majority of side effects. So for the -- you'll learn a little bit more about that today. We do optimize our structural chemistry. We'll often get asked, well, what's the best isotope or what's the best linker or what's the best peptide? It depends, right? It's like saying, well, what's the best university program for your child. It really depends on what you're trying to do next. And if you can optimize things, we have that relentless drive to optimize, and we'll show you various images throughout the morning about that. The biggest innovation that we have to optimize the biodistribution is a lead-specific chelator. And so if you look on the left side, you'll see DOTA with a negative charge and TCMC with a positive charge. Charged proteins get picked up by the kidneys. And so one of the key innovations we've had is say, "Great, let's take the charge off the molecule." And if it makes neutral charge, the kidneys will not pick it up. But more importantly than that, this lead-specific chelator, it actually chelates the bismuth as well. So lead goes down to bismuth. The bismuth itself is where the alpha comes from. We chelate that as well. DOTA will leak about 30% of that free bismuth. We leak less than 5%. And so the ability to hold the lead and the bismuth together really means we're getting all the energy onto the tumor and minimizing as much as we can tumor to other parts of the body. The nice thing, too, is that using the identical composition matter, you can use Lead-203 or Lead-212. And 2 of the clinicians today will be speaking about what they've done to actually do that imaging and visualization and how that's really helped them. And the phrase, "treat what you see, see what you treat" is absolutely true. Here is a FAP patient. For the audience's benefit, I circled where the tumor is in the patient's shoulder. But you can see ahead of time that there is a lot of energy going to that tumor in the osteosarcoma, and you really don't get much distribution anywhere else. This should give a much broader therapeutic potential than if we had a lot of other normal tissue that was lighting up. And so we follow this relentlessly. We can follow the signal. If a patient has a very intense uptake, we'll treat them. If they don't have an uptake, we won't treat because it just -- it doesn't make sense. But I do want to take one victory lap and give credit to our team. So we've literally had over a decade of deliberate engineering. And it started with can we actually pick the right isotope. And then we said, if we're going to invest in that, then let's invest in a production system, which we've done. We actually have the ability to scale up at extraordinary levels with our Alpha-PRIME system, which is just a patent issued in Europe as well as the U.S. now. We've invested heavily in a proprietary chelator. This informs our discovery team. We've now invested into novel compositions of matter, and so we're pretty active filing new patents as it relates to compositions of matter and rolling things forward. And also, we've invested in methods of imaging and treating, and how to actually roll things earlier. And so all this is combined together with a very robust portfolio, but that doesn't work if we can't deliver the dose. And so now having over 150 patients treated at 30 sites and 3 continents, it feels pretty amazing to be able to bring this out. And as fast as we can roll things out, the demand is incredibly high. If we open up a cohort for enrollment, we get extraordinary physician and patient enthusiasm to actually go and move things forward. The one thing to understand about what Perspective does differently to others by not being dependent on people, we have a direct-to-hospital system. So we'll start with the thorium stockpile to get from the U.S. Department of Energy. We can stockpile the thorium. We keep it in-house. We then separate it in space and time from the radium daughter . And the radium daughter we ship to our manufacturing sites. Some of our manufacturing team are in the room right now. And every day, they make doses of our drug that are ready to use that day. Those doses are made at our manufacturing sites, labeled with the radioactive lead and shipped to the patient or shipped to the hospital for the patient to receive it. And so what does the day in the life of an employee look like at Perspective? For some of the team, they get up very early. And we're making sure we can elute the generator. In the early hours of the morning, we'll do the pharmaceutical synthesis at 2:30 a.m. or 3:00 a.m. We'll then go through quality control. We've actually invested in various QC techniques that allow us to shorten down our release time from several hours down to sort of 30 minutes in some cases. We package up in our site around 5:00 a.m. And then it starts showing up at the hospitals from 7:30 a.m. onwards. And the physicians and the facilities have all day to use that medicine depending when the patient is scheduled. But this is a system that isn't just on the slide. We're doing it every single day. We have a production site in Iowa that's shipping doses every day. We have a site in New Jersey shipping every day. We're building a flagship site in Chicago. We're building a complementary site in L.A., and we have plans beyond that as well. So you think about where we can get to, we want to get to where the patients are. The less time the dose spends in airplane, the better. We are right now covering from Washington State, California, New Hampshire, Florida and many places in between. And so we've actually had a fantastic reach across the whole country that we are literally delivering doses to on a regular basis and treating patients. The next objective for us is to scale this. And we're investing in that scale, and we are expanding our network. We have a fantastic portfolio. We have our NETs program treating SSTR2 expressing tumors. We have an MC1R program in melanoma. We do have the FAP alpha program. We have our currently undisclosed target for PSV594 as a new agent, we're actually now first in human images. And then multiple other programs behind that. We don't really want to announce our programs until we get first in human images. So we can really see what's happened. We've killed programs before. If we see the human image with the diagnostic version and if it doesn't match what we expect to see, and if that's the case, we don't go any further. You have to -- you can't just change the molecule, then it becomes a new drug. And back to the drawing board, do it right, and you have to get that biodistribution right. We are pretty excited over the course of this year. We're going to have Phase I/II data updates throughout 2026 on a NET patient, 68 patients dosed to date, 27 patients dosed with melanoma, and we'll be giving updates on their safety and efficacy and also the first experiences of the FAP as well. And so all these I think are pretty interesting for this year as we move forward. Thanks to people in this room. We also have a very, very strong financial position. We have no change to our guidance. This is our updated cash balance as of March 31, 2026. This will also be in our 10-Q. And so $271 million gives us sufficient funding to last late -- into late 2027. So if we think about the only company that's engineered across the board, the right isotope, optimize the chemistry, invest in the theranostic approach and deliver the product. These are major investments that we've made over the past decade, but that's turned in extraordinary results and implications for our patients to be able to actually get things done the right way. With that, I'd like to turn it over to Mary Maluccio, to tell us a little about what does it mean for neuroendocrine tumor patients? Is there any hope for a NET patient?

I'm not sure that I included the, is there hope for the NET patient part. And I'm very happy to be on the 7:30 a.m. part of that curve and not the 1:00 in the morning. So hi, I'm Mary Maluccio. I am a surgical oncologist by training, and I run a very large rare cancer and neuroendocrine program in New Orleans, Louisiana. So we see over 2,000 patients a year give a lot of theranostic treatments for both neuroendocrine and prostate. And what my goal today is to give you some of the clinical perspective. And for those of you that I have talked to, I feel like it seems like it is super complicated. And I think that how we make decisions in patient care can seem complicated. But for those of us that live in the world of neuroendocrine, which all of us here, it really isn't that complicated. It is very unique to certain patient and tumor variables, and I hope that we can get that across to you today. So theranostics in the management of patients. So this is kind of like the real-world experience. I'm a very patient-facing clinician. So my objectives were to at least describe the treatment landscape for neuroendocrine tumors, so you can understand where PRRT fits in that. Put treatment decisions in perspective, I have some patient examples that I can go over, highlight some of the medical decision-making using those patient examples, including patients that have been treated with both beta and alpha particle PRRT, and now define the current or evolving paradigms of radioisotope treatment because it is evolving rapidly. So the treatment landscape. So what is important for me to get across to you is that there are a number of treatments that we use for patients with neuroendocrine. I'm focusing on neuroendocrine, although this is really relevant to any somatostatin receptor avid tumors. So you've got the somatostatin receptor analogs. Those are injections that we give people every month, and their goal is to delay progression of disease over what can be a very long time. So there are liver-directed therapies. A lot of certainly the abdominal neuroendocrine tumors tend to spread to the liver. The liver is the major driver of mortality in neuroendocrine tumor patients, and therefore, how we treat the liver is super important. So liver-directed therapies in some way, shape or form have been part of the treatment for primary and secondary tumors that involve that site for probably over 5 decades. So we are very familiar with the expectations of liver-directed therapies. Surgical cytoreduction is when we will go in and take out a critical mass of the tumor. You do not need to take out all of the disease burden in this disease in order for it to be associated with a survival advantage. So surgical cytoreduction has also been a part of the management of neuroendocrine tumors for several decades. Chemotherapy, I think everyone in the room is familiar with chemotherapy. There are both cytostatic agents, meaning it doesn't actually kill the tumor, but it keeps it in check. There are cytotoxic agents. Those are the way patients think about chemotherapy. And those are the ones that have probably sizable side effect profile. And then there's obviously PRRT, of which we are focusing on the beta particle versus the alpha particle PRRT. So what is super important to understand is that none of these are mutually exclusive nor do we necessarily use them in a particular sequence. We can use them alone or in combination. And so in general, in neuroendocrine, we do not use the term alternative, we use the term complementary. So you could feasibly treat someone with liver-directed therapy, followed by PRRT done even a month later in order to better -- I think someone will explain biodistribution to you, to better biodistribute the radiopharm to some of the disease sites that are outside the liver. So it's really important to understand that all of these things are available to patients. I call it the menu of therapeutic options. And in general, since patients live a long time, you can often take a number of these things off of the menu over the course of that patient's lifetime. Important variables, the symptoms, patients with neuroendocrine tumors will often have functional tumors that give a lot of symptoms. Carcinoid syndrome can be as bothersome to the patient as the cancer growth itself. So some treatment options are going to be better at controlling symptoms than others. The location, do you have disease in the liver, the mesentery, which is the lymph node basin that is draining the small intestine or do you have multi-organ site involvement? Neuroendocrine tumors tend to spread to a number of distant sites, including the liver, lymph nodes, retroperitoneal lymph nodes, chest lymph nodes, bone and even the brain. Comorbidities, that's the little baggage of other health conditions that patients will bring to the table that may influence their ability to tolerate certain treatment options. And therefore, you will have to cater to those comorbidities in order to not make something a trade-off of one problem for a different problem that pokes the bear of whatever other medical condition they have. The primary site is also important. We treat -- oftentimes treat a midgut different than we would treat a bronchopulmonary neuroendocrine tumor even when they have similar somatostatin receptor avidity. The receptor density, which my much smarter colleagues will go over later, is sort of important when you are certainly looking at PRRT options. And then the disease interval, these patients can often live a long time. And therefore, is this a new diagnosis or is this someone that's had the disease for a long period of time? You got to play your cards correctly in the patient population that can live a long time and be exposed to a lot of different treatment options. So another thing that I would like to get across is most drugs have side effects. And so anticancer treatment has side effects. And so the investment in that to a patient, whether or not it be a physical investment or a financial investment or a side effect profile that pokes the bear of their other medical condition is that we can't focus so much on some side effect as being a dealmaker or a deal breaker. So surgical cytoreduction obviously has some significant adverse side effects in that the investment in the patient is an oftentimes multi-organ site resection and you have perioperative morbidity and mortality for the clinicians in the room. That is just the complication rate and/or the risk of dying as a consequence of that operation. But that for nonclinicians, it's really the significant investment that may be a trade-off of one problem for a different problem that they may have to live with for the rest of their life. Somatostatin receptor analogs, even though they are seemingly a very low-risk intervention, they do not come without their side effects. The hyperglycemia and elevated A1c is probably the most problematic thing. It is very difficult to manage patients that are already either prediabetic or diabetic because they often will need additional oral hypoglycemic agents or even insulin to manage the side effect profile of a somatostatin receptor analog. And so it becomes very frustrating if you are managing someone over 10 years of their life with a drug for which they need then insulin or multi-drug management of that side effect. You can get reactive hypoglycemia. That is when you have a trigger, food or otherwise, and you'll have sudden drops in your glucose. So somatostatin receptor analogs that can be very problematic for people because when those episodes occur, it can be difficult and unsettling, especially if you are driving a car. It will all burn out your gallbladder. We will routinely recommend taking out the gallbladder in patients that look like they're going to be on somatostatin receptor analogs long term. Cytotoxic chemotherapy has some obvious side effects that everyone is aware of. I don't think that too many people in the room probably don't know a single person in their life that has had to take chemotherapy and deal with some of the side effects. So the myelosuppression, the brain fog, the hand foot syndrome, the rashes. I don't think we need to see the picture of Senator Sasse on his pancreatic cancer treatment. There are some significant side effects associated with cytotoxic chemotherapy. Liver-directed treatment isn't generally well tolerated, but in people that have underlying liver function vulnerabilities or nontarget embolization to the gallbladder can cause cholecystitis or you can get infections in the treatment zones. So liver-directed therapies also have their side effects. And then PRRT, we focus predominantly on the myelosuppression and renal impairment. Some of the fatigue, nausea tends to be short-lived. But that, for the most part, PRRT comes with a myelosuppression or renal impairment, it is usually short-lived. So other factors that drive treatment, especially for me, I treat patients in the southern part of the U.S. Surgical cytoreduction is not available everywhere. You have a lot of even subspecialty trained surgical oncologists that are not feeling comfortable dealing with the complexities of these patients. So the availability of surgical cytoreduction is limited in the U.S. and comorbid conditions of patients that would influence their ability to recover from a very big operation will impact their ability to undergo surgery. The cost of somatostatin receptor analogs is becoming prohibitive. It is being pulled off of formularies and therefore becoming increasingly more problematic. I think for payers, they're even understanding that perhaps investing in some of the other treatment options that may have a different life span, they may actually ultimately save money in the long term because you have people in expensive therapy for what can be years to decades of life. They're straddled to an infusion center every month, and the injections are quite painful. Cytotoxic chemotherapy, it's usually medical comorbidities that will influence their ability to tolerate, and then it is an extended treatment. So this is unlike a patient that may get colon cancer and they're treated with chemotherapy for maybe 6 months, and then they're done and they're put into surveillance. These people can be on chemotherapy for 2, often 3 years of time. Liver-directed therapies are also not available everywhere. Even interventional radiologists will have their comfort level dealing with some of the more functional tumors and carcinoid crisis. Comorbidities will influence their ability to tolerate that treatment and certain liver function test vulnerabilities. And then PRRT, I've put in italics because I think a lot of the discussion today is going to be on renal impairment. But the PRRT in its current form, meaning the things that are currently commercially available, you will have the baseline or a renal impairment side effect. Availability of PRRT was very problematic probably 10 years ago. I think that it is becoming increasingly more available. So therefore, it is likely to be something that will expand rapidly in market share. And the amino acid requirement means it's a long infusion, it's probably around 5 hours of an infusion chair that actually adds to the cost of it. And so a lot of the platforms that are coming down the pike are focusing on the potential to be able to diminish the amount of time someone is in the chair, getting the amino acids and some of the platforms are even suggesting that we can get rid of the amino acids completely. So survival expectations, I think it's really important to understand that you've got to play the long game in neuroendocrine in terms of survivability. More than 50% of patients with metastatic midgut neuroendocrine tumors will live greater than 10 years. So that is a long life of being on some form of therapy. 50% 5-year survival in metastatic pancreatic neuroendocrine, they tend to be mixed grade and have a different biologic behavior. But even greater than 50% of people with bronchopulmonary neuroendocrine tumors will live more than 5 years. So then I did include some of the other tumors that are also somatostatin receptor avid because we are allowed, and I think that there are clinical trials that are currently available that will manage patients that are not necessarily the GI, pancreatic or bronchopulmonary neuroendocrines that are probably the market share that we currently have. But some of the rare diagnoses that we see like neuroendocrine of the thymic, paragangliomas, pheochromocytomas and recurrent meningiomas. Okay. PRRT is also part of our NCCN guidelines. So NCCN guidelines are what we are all expected to follow in some way, shape or form if we are going to practice cancer care in the United States of America. Now NCCN guidelines are not updated in real time to take advantage of some of the evolution of treatment, and they are definitely not updated at the pace at which we are changing the way we treat patients with neuroendocrine tumors. But the PRRT is well embedded in NCCN guidelines. So the only real change in what we're doing now is going to be the sequencing. When are we using PRRT now compared to when it first became commercially available. So these are just some patient examples that I have to go back. So medical decision-making. I was just going to go through my head and say, "Hey, on any given week, this is what my life might look like." So if you were to look at this woman here, okay? So this woman here was diagnosed in 2004 and we are in 2026. She has seen almost every treatment modality except chemotherapy. She ultimately was put on somatostatin receptor analogs. She underwent initial surgical cytoreduction. She ended up getting her initial beta particle PRRT in Basel in Europe. She came back here, was maintained on somatostatin receptor analogs, was shifted on to a capecitabine/temozolomide doublet of chemotherapy. She did not tolerate that. And now she has been treating -- she is being treated on an alpha particle clinical trial. This person is also a long timer. 2008 was her initial diagnosis. She has a mixed grade tumor, meaning some of her tumors have higher or lower somatostatin receptor avidity and a more aggressive or less aggressive biologic behavior. She has also seen almost everything under the sun, including cytotoxic chemotherapy. She was not able to get an alpha particle PRRT on trial just because there were no slots at the time. She was treated with 2 additional doses of beta PRRT. This gentleman is only 50 years old. This was his presenting scan 2 years ago. And if you were to look at these -- I don't have a pointer, so this right here is a lot of somatostatin receptor avidity within the liver, probably greater than 50% of his total liver volume was involved. The big black spot in the middle and all of those things in the middle of the screen are going to be in the midgut, the small intestine primary. He has a multifocal disease in that site, lymph node involvement, but limited disease elsewhere, unlike the guy that you saw with the shoulder. So we chose on him because I was not going to meet the surgical cytoreduction endpoint, which is 70% surgical cytoreduction that would be associated with him worth investing in that process. I ended up giving liver-directed therapies. I beat on the entire side of his right lobe of his liver, his liver function not only did not worsen, it actually improved. I then needed to take out the primary because he was starting to have intestinal manifestations of the primary site and not enough blood flow to his intestine. So we went and cytoreduced the primary sites, so we got rid of all the disease in the primary site. I cytoreduced the remaining disease within the left lobe, didn't have to touch anything on the right lobe, and he's being considered for an alpha particle trial. This young woman is only 48 years old. This was her presenting thing. So you can also see kind of mixed hotness. Some of them are darker, some of them are less dark, multi-organ site involvement predominantly within the bones. She had a lot of painful bony metastases, less involvement in the liver. Clearly, this is a situation where surgical cytoreduction is unlikely to be able to do anything for her. We are treating her with alpha particles on trial. And then the last lady is a 74-year-old, other comorbid conditions. She presented with not enough blood supply to her bowel. She presented with ischemic bowel. She had to go urgently to the operating room. We needed to take out the primary and the lymph node involvement. And then she has a lot of disease within her mediastinal lymph node basin, less disease within her liver. So therefore, I didn't have to consider liver-directed therapies. We are treating her with PRRT. This is the alpha particle PRRT. So this gentleman right here is now 74 years old. He was probably initially treated probably a metastatic pancreatic neuroendocrine tumor dating back to 2010. He had seen almost every treatment modality somatostatin receptor avid -- I mean, analogs, liver-directed therapies, but did not go on to chemotherapy. He's a type 1 diabetic, which made the somatostatin receptor analogs very problematic for him. And so he ultimately was treated on an alpha particle PRRT trial. This was his presenting scan before we treated him. This is the scan afterwards, and he was someone that had an excellent durable response to that treatment over 3 years. The reason why I'm showing you this because I'm sure there are going to be a number of questions about the toxicity profile of some of the alpha particles, but he paid the price. So he has had significant renal impairment after treatment to the extent where he is now being managed by a nephrologist. He has some liver impairment that is likely just because of being heavily treated over the course of his disease. And so it was a bit of a trade-off. It was a trade-off of a disease that was progressing and therefore, doing nothing was not going to be a great option for him. We chose what we thought was a great option. We had a side effect of a delayed renal impairment that we didn't necessarily expect. But I'm telling you, if you ask that guy whether or not he in any way regrets making that decision, he does not. He is alive with minimal residual disease 3 years after treatment and continuing to do everything that he wants to do. He's got a very good performance status. This woman here, multi-organ site involvement. It was the progression in the bones. It was prompting us to choose PRRT over liver-directed therapy. She ultimately also got an objective response right now, 3 years later. I think her disease probably goes back maybe around 8 or 9 years. I think some of our nuclear medicine people can talk about biodistribution. I couldn't have asked it to go to her bones instead of to the liver. She got a disproportionate response in the bones, which happened to be where I needed her to get the response. She is also now 3 years later with a durable response to that treatment, no renal impairment whatsoever, so a very good choice for her. And then the last gentleman is a metastatic rectal. Those just -- for those of us in neuroendocrine can be some of the most complicated ones to treat, they tend to be more biologically aggressive than both the midgut and the pancreas. And so they are more than 50% likely to need chemotherapy over the course of it. He had a number of comorbid conditions for which chemotherapy was not going to be a great option for him. So we charted him with alpha particle PRRT. He had an excellent durable response to treatment. He could not tolerate somatostatin receptor analogs and he has now been off of somatostatin receptor analogs now almost 3 years after the initiation of that treatment. So the evolution of the treatment continuum, how are we changing the sequencing of a treatment. This is how we used to do it. People would come in and sometimes if they went into a medical oncologist office, they may not have even had discussions of surgery if it was already multi-organ site involvement. But the question for almost every patient is, can you possibly remove this tumor and eliminate it as a variable. You have to remember in neuroendocrine, people with node positive midgut neuroendocrine tumors may live a long time, but they also have a greater than 50-50 chance of developing a local regional recurrence for metastatic disease over that lifetime. So surgical resection [indiscernible], can I meet the surgical resection endpoint? Then we would move on to somatostatin receptor analogs, and then we would usually not move past go until they had progressed despite adequate doses of somatostatin receptor analogs, and that could have been years on those drugs. Then you would do liver-directed therapy for liver only or liver-dominant disease in order to deal with the life-limiting component of their disease. Then we would shift because if they progressed after that, we have to be looking at chemotherapy, that was the fork in the road. And then PRRT came up dead last. And it was predominantly because we didn't have a lot of information about the sequencing of PRRT, especially the sequencing of PRRT relative to chemotherapy. That is probably the biggest change that we've made is that those have clearly flipped, and we would definitely choose PRRT over a chemotherapy in someone with a somatostatin receptor avid tumor. And now how we're shifting now is that we would still like to know whether or not we can remove at least a good chunk of the disease. And that has to do a lot with the biodistribution of a therapy and your ability to manage a much lower volume of disease in the longer term with whatever therapy you choose. Then now I put that in our [indiscernible] because now it's plus or minus somatostatin receptor analogs because now there are clinical trials where we're putting PRRT in that slot. So we're saying, hey, if we move PRRT up into that spot, then does everything else become a complementary or a salvage therapy after that. So you're putting your money down on the all over systemic therapy of PRRT with its targeted approach and then potentially using somatostatin receptor analogs as then the more maintenance therapy, not dissimilar to how we would use maintenance chemotherapy in someone with high-risk colon cancer. And then your plus or minus liver-directed therapy, meaning you would start -- potentially start with PRRT and salvage the liver with liver-directed therapy versus using liver-directed therapy to cytoreduce the liver component of the disease, follow that with PRRT to address the other sites of disease. PRRT would then have to deal with a less overall tumor burden or receptor density. And then as the PRRT is being sequenced either upfront or much earlier in the course of the treatment. And that is in general, as I think they're going to show you is that the objective response rate of a lot of the PRRT platforms is not only getting better, but that is now higher than the objective response rate you can expect with chemotherapy without the significant side effect profile. So in summary, PRRT is a standard of care, and it has been a standard of care for the last probably at least 10 years in the United States of America for patients with somatostatin receptor avid tumors. That includes not only neuroendocrine, but some of the other somatostatin receptor avid tumors. PRRT can be used alone or in combination. They are not mutually exclusive. Patients with low-grade tumors, which tend to be somatostatin receptor avid, live a long time. So you've got to play the long game. Most patients with SSR avid disease will be treated with PRRT over the course of their lifetime. So it's really just sequencing at this point in time because oftentimes, they will live long enough to show slow progression of disease where PRRT becomes relevant. Objective response is another thing that's asked a lot of me. Objective response is not the only variable we look at. And so we would not necessarily choose a 60% objective response rate over a 48% objective response rate if it's more fitting for the patient. So it is very patient specific on exactly how we make those decisions. And then the alpha particle platforms appear to be improving, and they are improving with respect to the most consequential side effects, which is on the kidneys. And that is for me.

Great. Thank you, Mary. So I don't need to explain now what neuroendocrine tumor is right now. I think you've had a nice presentation from one of the world's experts on it. There are a lot of patients that live with this disease. There's a big difference between the incidence and the prevalence and those that are progressing, and that's really on the patient's continuum, how do we actually think about them. And so we're focusing right now initially with the VMT-alpha-NET program on newly progressing patients. And so these are patients where whatever is happening, we know that tumors are starting to grow again. And we can see that on a scan. We actually initiated a trial a couple of years ago. We started dosing patients at 2.5 millicuries. We then started dosing patients at 5 millicuries. We had no safety issues with the 2.5 millicuries. And actually 2 years later, those 2 patients were doing incredibly well, stable disease, which is really what we're trying to do as an approval endpoint. We did something that no one else has really done. We actually broke through this hypothetical barrier of 23 Gray dose to the kidney by showing good data to the FDA showing that we could actually get a good clinical profile that would support potentially going 20% higher from 5 millicuries a dose at 4 doses up to 6 millicuries. And by doing that very cautiously, being really mindful of long-term safety issues, is that a better way to go? What do we see more of it at a higher dose? Do we see more sort of tumors being addressed? Do we see a faster tumor reduction? Do we see more safety signal? And that's really important to learn as drug developers. And we're also thinking about the additional SSTR2 targets. So in terms of what we do, we can scan the patient ahead of time. We can see the scan of the tumors. We can track them over time, see the shrinking of the tumors. That's fantastic, that helps drive response rate. We look at response rates not just on RECIST, which is does the tumor shrink, but if you see this tumor here between baseline and cycle 4, that mass is effectively the same, except now there's a white ring. So that's not counted as a response using RECIST, but it is a response in terms of the patient because eventually that tumor starts to shrink. And one of the big takeaways we'd like to share with people is that you need to wait for enough time to happen for the responses to show up. This is not the chemotherapy. We're looking to see right-away responders and seeing how long do they stay as responders. It's a different way of thinking about the disease. We have shared this data previously at AACR, which is these are patients that are fairly mixed group of patients that are representative of patients who are newly progressing. We're showing safety data across all numbers of exposures. We have a consistent pattern of disclosing whenever we can, all the patient safety data to date and sharing that across the board. We're really excited about what we don't see here. So we have not seen any DLTs. We've not seen any discontinuations. We don't see any grade 4 or 5 AEs. We have not seen any dysphagia and we've not seen any significant renal events. And so as we look at this profile for an oncologist, they think this is a terrific profile. This is something that's reasonable to present to a patient as an option. And then the question is what about kidney safety. And here, we're showing all the creatinine levels over time. If you look very carefully, you may see a subtle drift up near the end in patients that are aging, hard to tell. But at the very least, we're not seeing peaks. We're not seeing plateaus. We're not seeing anything that gives us immediate cause for concern. We want to keep watching this over time. This is a very important measure to assess patients' kidney health. But so far, no serious renal complications have been noted. If we look at the response rate and disease control, this approval endpoint. So now we're out to 104-week mark. It's great to see the patients. The 2 light blue at the top are the very first 2 patients that we actually showed. The important thing to note is that not all responses show up early, and I'll show this again in a different visualization. But sometimes, it takes out to the 56-week, 62-week, 74-week mark before you actually start to see all responses having shown up. And so we think it's really important to track real-time what's happening. The spider plots tell part of the story. The clinicians look at it and they look for patterns and say, are things sloping down to the right, and they appear to be. There's always lots of speculation as to what happens. We're right at that 30% mark. And gosh, will that patient go right below if it's minus 29.5%. Can we just round that to minus 30%? And the answer is no. You have to keep that. You can tell the patient, sorry, it's only minus 29.5% down. You haven't responded yet. As soon as we get that extra half point, then we'll count you. I'm not trying to make light of it, but this is -- we have to have a systematic metric to actually assess patients over time. What I do want to show you though is how you can get misled by the data if you look at it too early. And so this is patients that are 2 months on the study. This is all of those first group of patients we're talking about. This first cohort, 23 patients dosed at the 5 millicurie level. And so at 4 months, at 6 months, 8, 10, 12, 14, 16, 18, 20, 22, 24. Given that their first result showed at the 2-month or the 4-month mark, who would want to make their prediction as to if a patient is going to respond or not. You can't. And because if you look at this data, it's pretty amazing to see how that builds dynamically over time. And real world for the clinicians treating the patients, it's really obvious for them. They'll ask the patient, how do you feel? And generally, the patient will say, I feel so much better now. And that counts for a lot. And we track everything we can to make sure that they're okay. In our newly progressing patients, we show very strong disease control. And this is what we need to take to the regulators, the clinicians to understand where we're going and how we track it through. Our next steps is we are actually looking at the cohort 3 patients so the 6 millicuries times 4, but we're also looking at another cohort as well. They would be a front-loading. What is front-loading? It should be obvious by the name, but it means that if you think about the tumors, they're most like a sponge when they had the least exposure to any kind of targeted therapy. So the most receptor density that's possible and sort of the freshest receptors. And if you run the studies, you can actually see that you actually get almost 38.5% of the initial dose outcome in that first dose. So it implies that when the tumors are most receptive, that's when you give the most dose, knowing that it's the cumulative dose over time, the sum total of everything that's probably going to contribute to any kind of potential renal issues. And that's what we're trying to solve for with this approach. So we introduced Cohort 4 front-loading. So the patients still get 20 millicuries all together like Cohort 2, but rather than doing 5 times 4, it's 6 millicuries, 5, 5, 4. It seems very subtle, but it's ways that we want to really say, can we boost this even further and knowing that we keep the overall exposure to the patients consistent. We've shown with the Cohort 3 data that the 6 millicuries is actually a very safe dose to give as well. And so we feel this is a very safe, reasonable way to go forward and actually start treating patients a little earlier, a little better. But I want to be really clear. This does not slow down our path towards innovation and towards going to the FDA. And so we feel that this 5 millicuries times 4 or 20 millicuries in aggregate is a very, very compelling medicinal dose, and this is what we're taking forward and working full steam within our company to try and move forward with the regulator to get a registrational trial started as soon as we can. We are also looking at an indication for meningioma. And so meningioma is quite interesting, where it's not a standard tumor type. It doesn't respond the same way to things. It's pretty hard to get to it surgically. And so a systemic therapy could make a lot of sense. We know that a lot of meningioma is expressed SSTR2. There has been some early efficacy data implying that this could be quite interesting. And so there's -- this could be a whole separate R&D day, but I don't want to go there, but we actually are very excited about potential indications here and expansion indications and really saying, how do we actually improve on safety and durability of response? We know the medicines we make are as safe as we can think of how to do it. We broadened that therapeutic window out as much as we can. We're actually really excited that 72% of our patients remain progression-free with a year of follow-up. That's fantastic for the patient experience. And we also are thinking through how we're going to keep reporting on these patients that I just showed you and also the second half of the patients in the Cohort 2. So we want to report all the data when it's meaningful and when it makes sense. But it's almost like a sort of back to the future or let's go back to the past. I want to introduce Dr. Yusuf Menda, who's from University of Iowa. Perspective Therapeutics was formed as a spin-out from the University of Iowa. And so Dr. Menda, Dr. Schultz, Dr. Johnson were thinking about, is there a safer way to develop medicine for pediatric patients. And now the question is, is there a safer way to actually -- can you give something post LUTATHERA as well? And so I'll turn the microphone over to Dr. Menda. Thank you.

Thank you, Thijs. Yes, I've been fortunate to work with Mike Schultz, the Chief Scientific Officer of the company for many years. And I'm going to present some of our data here that is running separate from the registration of Phase I/II trials, another Phase I trial, and it is basically in patients who have previously received standard PRRT, what really the potential utility is. This was actually a study that we designed together with Mike Schultz at that time. I was fortunate to be there when he actually invented the product and went through the preclinical study. And it's basically, we're taking patients with neuroendocrine tumors who have previously received most of the time, it was LUTATHERA or other beta particle PRRT, and we are treating them in a slightly different approach in that we are escalating the radiation absorbed dose to the organ rather than the administered activity. And similar to -- consistent with what Thijs was saying, we actually were thinking about front-loading. In fact, we are treating patients in 2 cycles in this trial. So as part of the development of the product, we actually evaluated the targeting -- the tumor targeting, which we published and also looked at the tumor dose as well as normal organ dose because the kidney toxicity has been actually discussed widely. And so we actually looked what the radiation doses were for the kidneys and the tumors. And the way we actually approach that was, let's do the standard PET imaging and see how many tumors we see and how we can actually show that, yes, we actually can target these tumors with the lead and then treat them. This is one of those patients. You see the standard gallium image in the lower row and the lead image, the investigational product that shows a very nice distribution. And you can also see over time, the tumor uptake increases compared to background. So the tumor retains the dose, whereas the blood is actually clearing the drug. And because of the physical limitations of SPECT versus PET, it's probably most appropriate to look at the targeting for lesions greater than a centimeter, and 95% of lesions were easily visible on the investigational product. So one of the approaches is particularly in a patient -- in patients who are coming for a re-therapy setting is looking at what kind of radiation dose the normal organs will be getting because you may even undertreat because you're not really giving enough dose or you may overtreat. So we look at the normal organ doses, which really shows that they are widely variable. So it may not be the most personalized approach to give patients all the same dose because the tumor dose is also quite different. And one of the criticisms of doing dosimetry has been -- well, it requires multiple patient visits. But actually Lead-203 and VMT-alpha-NET has a very nice exponential clearance that you really can get away with a single time point imaging to really precisely dose the patients with a personalized dosing and be done within 24 hours. So this is our current active trial that is ongoing in patients who have received previous PRRT. So you can see the tumor doses are highly variable. We are increasing the normal organ dose. And I'm going to show a few examples. And the examples are the ones that have the highest tumor dose, which really show very nice tumor response. This was a patient who received previous Lutetium and received 2 doses of VMT-alpha-NET, and you can see the gallium image is showing very significant drop in tumor burden, which is also visible on RECIST, the standard tumor response assessment with a substantial reduction in tumor size in the liver that is also still happening as actually was also shown previously that the tumor response may continue for some time after the treatment is completed. Now in terms of -- this is also -- remember, these are also patients who have previously received PRRT. So the renal toxicity becomes more of a potential consideration. None of our patients so far have developed any renal toxicity that required an intervention. Some patients did have some drop in the eGFR, as you can see, and we are following them. And it's important, as Thijs was saying, to actually have long-term follow-up of these patients to know exactly what the renal toxicity profile will be. There were no instances of Grade 3 toxicity in terms of hematological toxicity. This is another patient, again, with extensive liver and bone metastases. The gallium, the standard imaging is on the left, the investigational imaging with Lead-203 VMT-Alpha-NET that is the right column. This was a patient who actually received cabozantinib, lutetium-DOTATATE, octreotide quite a number of different therapies and then was treated over two cycles with actually the total dose is similar to what the total dose is used in the current cohort in the other trial. This was close to 20.5 millicurie that was based on the dose to the kidneys, and this is already a response in 3 months, a significant therapy response. And this was actually the quality of life of that patient, the assessment and all quality of life measures were significantly better already at 3 months in terms of physical functioning, emotional functioning. And the symptoms, these neuroendocrine tumor patients have a lot of symptoms and the patient also did have diarrhea and also loss of appetite, and you can see the symptoms were also getting significantly better. So far, we have not seen a significant toxicity and the treatment is feasible with Lead-212 VMT-Alpha-NET after patients have received standard PRRT and we are going to the third cohort for dose levels actually in June. This is the group of physicians who actually are doing the study. You can see Mike Schulz's picture there, physicist, Dr. Graves, my colleagues, Dr. Bushnell [indiscernible] , Dr. Dhillon, endocrinologist and our regulatory manager, Dr. Bodeker. The study is actually supported by NIH as well as Perspective Therapeutics. Thank you.

Thank you, Dr. Menda. We've had a pretty decent results there from the patients that [indiscernible] treated. I'd like to bring up Dr. Bundschuh to talk about his experience with treating patients in Europe[indiscernible].

Yes. Thank you very much. Yes, I want to tell about the results of our compassionate use program in Europe. So we could start in March 2023 with Professor [indiscernible] who was the former Director of the Department of Nuclear Medicine. And meanwhile, 16 patients were included in this compassionate use program. All patients similar as before, heavily pre-treated and in this case, we have patients already treated with Lutathera as in the data before but we also had the patients pretreated with another alpha emitter, which is s actinium-DOTATATE, which was at that time standard of treatment in our department as well. So we have even 2 lines of radioligand treatment in the patients I will report on. Of course, all patients showed progression either in imaging or in a biochemical sense as a tumor marker, chromogranin A. And the decision for the treatment was always done in a multidisciplinary tumor conference. And as mentioned already before, we have here this very important theranostic pair, Lead-203, Lead-212. So all of our patients were examined with Lead-203 VMT-alpha-NET before. And this is really a very, very big advantage of this compound. So we have a true theranostic pair, not lutetium and gallium or something like that but we really have the same chemical behavior. We have the Lead-212 with the alpha emission for treatment effects but we have here also the Lead-203 where we have the possibility to do a very good imaging. It's not standard imaging. We have to do a little bit optimizing of the acquisition parameters but this is done by my physics tools very well. And then you can really do a very nice imaging with the Lead-203. Okay. So here, there is an example, and Lead-203 has a longer half-life time. So we have really the big advantage of doing the imaging over up to 48 hours. You see here one patient with a neuroendocrine tumor, liver metastasis. We have the gallium scan, and we have the different Lead-203 VMT-Alpha-NET scans, and this is done from 3 hours, 24 hours, 48 or 46 hours. And we really can predict very well the dose we can deliver to the patient with this treatment possibility as already mentioned by the previous speaker. So coming back to the results of our first compassionate use data. So we published last year the first publication, including 12 patients. These patients have a very various tumor entity, we read from that Grade I to Grade III. So very, very aggressive tumors included as well up to a proliferation index of 37%. And of these 12 patients, 8 patients were treated, two patients didn't show a good uptake in the Lead-203 scan. So this is why Lead-203 is that important for this because even if you have in the gallium PET a reasonable uptake, it may be that in the Lead-203, at least in the later images, the uptake is not sufficient to go for treatment. And 2 other patients dropped out due to a fast progression and they did not want to sign up for the compassionate use program anymore. If I look into the tumor burden for these patients, this is the waterfall plot for this. We have patients, which responded very well. The tumor load dropped down very much as we have seen also in previous data. This is one example where we see also this very extensive liver metastasis and really lose a lose of tumor load in these patients. So the patients reacted very, very well. Coming to the toxicity, as this is one of the most important things, especially if you have already Lutathera before and if you have another alpha emitter before. But still, we have never seen any grade 4 or 5 toxicity effects, 3 of the 8 patients obtained nausea and 2 of them vomiting but it was maximum of 24 hours. 6 of the 8 patients reported moderate fatigue, which is a Grade I to II toxicity side effect. And we didn't see any changes in vital parameters directly after the application or in ECG or any other parameters. We did a follow-up 3 months or over 3 months, each 2 weeks blood levels. And we did not see any change in the kidney function, at least not any statistically significant change. The eGRF in mean dropped a little bit but not relevant. Hemoglobin, thrombocytes and leukocytes were also quite stable. The only thing where we really found a little statistically significant dropdown were the lymphocytes, which dropped from 0.939 to 0.855, which is statistically significant. But still the maximum decline was in patient from 1.02 to 0.8, and this is corresponding to a grade 2 side effect. So still, we have even after 3 months, never obtained any Grade IV 4 or V toxicity. And this is comparable to what we have seen in the NETTER trial for the Lutathera. This was the Phase III study for Lutathera for the neuroendocrine tumors. And here, if you look at it into the side effects, it's absolutely the same range. But the difference is that these patients we are looking into, they already got Lutathera before and they got even at least 1 cycle of actinium-DOTATATE before. So they were much more heavily pretreated than the patients in the NETTER trial. And still, we do not have any more serious side effects. Since this first publication, we added 4 more patients to the compassionate use program, and we found more or less exactly the same toxicity profile, no Grade IV or V toxicity within the 3 months and stable disease according to RECIST criteria after the 3-month follow-up scan for all of the patients, chromogranin level. So the tumor marker was also stable for all of these patients. In 2 patients, we even got a little bit more advanced. So 2 of the patients who responded quite well to the first cycle got a second cycle of Lead-212 VMT-Alpha-NET at the first time, 7 months after the first cycle. Also in the second cycle, we didn't find any Grade III or up to V toxicity mildness, in one of these 2 patients. And in the follow-up of these 2 patients, here, I have it written down. The first patient was stable for up to 19 months after the first treatment cycle. So even after all other treatment options, including Lutatera and actinium-DOTATATE were used, we could add another 19 months or nearly 2 years and in the second patient, 21 months, another 2 years of stable disease to this patient history. The last -- one of these patients, I will report as a case example. So this was a 66-year-old male patient. It was a G2 NET. So proliferation was intermediate. So it was not the most easiest kind of NETs with the best prognosis but also not a very high aggressive one at the beginning. He had lymph node bone and hepatic metastasis when he showed up at the department. And as in the reports before, heavily pretreated octreotide, there was a partial resection. External beam radiotherapy was applied several times, treatment with everolimus, an mTOR inhibitor. Then he had Lutatera, a total of 15.8 gigabecquerel , and he had 1 cycle of actinium-DOTATATE with 7.7 megabecquerels. And this was more or less the PET scan when we started with the -- to include him into the Lead program. So you see it's a very extended bone metastasation but also lymph nodes and some smaller hepatic lesions. And we gave him these first 2 cycles of the Lead-212 VMT-Alpha-NET. And he -- there wasn't a real drop down into the tumor load. But as it was said before, it's in these patients more important to stabilize them and this we could achieve. So after these 2 cycles of VMT-Alpha-NET, he was then stable until the follow-up PET/CT 19 months after the first treatment cycle was applied. And there, we found a slight progression of the liver metastasis, and after that, that he reacted that very well on the first 2 cycles, we decided that we will also give him another 2 cycles of VMT-Alpha-NET. So at the end, he got 4 cycles. Unfortunately, due to the organization, it took a little bit time between the PET scan where we have seen the progression, which is seen on the very left side. And until we got the Lead-212 into Germany and settled up all of this for this patient, it took another 4 to 5 weeks. And in this 4 to 5 weeks, unfortunately, the liver metastasization exploded a little bit. So we have to guess that the tumor gained in aggressiveness. So it's not just anymore G2 tumor, perhaps it's changed a little bit due to the differentiation. And we did still the treatment, the patient reacted very well to the treatment. But unfortunately, it seems that the tumor changed a little bit in the biology, it's much more aggressive. So also, we slowed down, I think, with this third and fourth cycle, a little bit of disease progression. Still at the end, we decided that this patient has to switch to some more systemic chemotherapy as the tumor is much more aggressive. Unfortunately, the patient refused to do a re-biopsy of the liver because we wanted really to know what the biology was behind this fast progression but the patient refused this unfortunately. But still, we can report that even with the 4 cycles of rechallenged treatment with Lead-212 VMT-Alpha-NET, we did not find any Grade III to V CTCAE toxicities. The only minor dropdown was the hemoglobin from 8.0 to 6.6, which is according a Grade I toxicity and the lymphocytes dropped to 0.72, which is a grade 2 toxicity. So we have really seen that even with 4 cycles after Lutatera and after actinium-DOTATATE, we do not really experience much toxicity. Of course, these are case reports, and it's not a systemic data but we really can see that we can apply this also as a rechallenged therapy, very effective and very safe. And this was already mentioned before, the very big advantage is we can do imaging as well with the Lead-203 but also the Lead-212. So we really can do very, very precise dosimetric assessment. And this is also published by [indiscernible] in 2024. It was the first VMT-Alpha-NET imaging obtained in humans. So here, you see also very nice that you can compare the DOTATATE PET scan, the Lead-212 scans over 2.5, 5.5 and 20 hours. Unfortunately, a longer acquisition is not possible due to the half-life of the Lead-212 but it still remains very, very nice. And we did a very extensive dosimetric calculations and my physics people will present this at this year's as an SMMI Annual Meeting that the dosimetry we can do with Lead-203 precisely predicts the dose we really get with the Lead-212. So this is very important for this theranostic pair, Lead-203 and 212. And therefore, I'm very happy that we are part into this compassionate use program, and I come to my conclusion. So I think with this data we have done in Germany, we really can show that Lead-212 VMT-Alpha-NET can safely apply to patients even after Lutathera and after actinium-DOTATATE. And we have still a very good response of these patients. All patients were stable after 3 months and some of these patients even have a stabilization after 21 or up to 21 months. Even the rechallenge with another 2 cycles of VMT-Alpha-NET was tolerated well by 2 patients meanwhile, and we didn't find any grade 4 or 5 toxicities in these cases. Thank you very much. And of course, I'm also -- I also thank my team. Without this, this wouldn't be possible. So we have the physics group, the radiochemistry group and of course, all the physicians who deal with the patient and the technicians and nurses. Thank you.

Thank you, Dr. Bundschuh for that. It's really great to see that in both the U.S. and Europe, there is hope for patients post the Lutathera, so great to see is how things are safe. What we show here a lot is images. And I think to any person treating patients, would you like to know in advance if the patient will respond and how. And would you like to know in advance what some of the side effects could be. It feels like almost a rhetorical question but there's so much that's embedded in these images. We thought we'd just do a little bit of a kind of imaging buyer distribution to [ 101 ] and show pretty quickly where they build up to. I'd like to introduce Dr. Elcin Zan, Chair of Nuclear Medicine at Cleveland Clinic.

Good morning, everyone. I'm here with my prop. And with due respect to scientists and PhDs in the audience and online, please let me take this opportunity to start with MOA. What are we talking about here? This is a neuroendocrine tumor -- sorry, this one is a neuroendocrine tumor and that one is a prostate cancer. These are real representations, 3D models. Unfortunately, TSA broke my tentacles. They want to -- as I was going through the security, they compress it because they were not heavy enough. So sorry about that. But -- so cancer, let's talk about cancer, right? At a cellular level, cancer is an identity crisis, it's cellular level. A cell decides to dissociate itself from the multicellular healthy organism, humans and decides to overexpress some fake identity. What do they overexpress in neuroendocrine tumors? So what does receptor type 2? What is it in prostate, the PSMA. They are all receptors. The definition of receptor receiving something, right? So why -- how are we different than the chemotherapy or non-targeted therapy drugs? There are multiple holes. I know it's difficult to see from our side. But when we give chemotherapy, there is no specific targeting. They go into the intracellular compartment. They create some -- they disrupt some metabolism, like folic acid metabolism, right? It's not specific. They go into the cancer cell, which is de-identified itself and also to the bone marrow, also to the kidney, which is in a healthy identified state. So we are looking into -- yes, we kill the tumor cells, but at the same time, create a lot of toxicity. How is theranostics different? So receptor, right, and receptors and receptors. So talking about SSTR2. The receptors can be recognized by the man-made molecules, ligands that we go and find and at the same time, we'll be carrying some sort of radiation like this one or other type of radiation like that one. What's the difference? This is a positron emitter, which means it's non-ionizing. It doesn't induce damage after -- in the SSTR2 setting, after it binds, it gets internalized, stays there. We put the patient under a camera, and we can see the bio-distribution of this de-identified state of the cancer cell. And once we know that, we can do highly targeted therapies simply switching the radioactive component receptor put it in. It's simply -- this is this time, this is particle radiation is ionizing. It's going to kill the tumor cell. Once it gets binds, internalizes, from this -- most of the time from this effect, there is really no going back because we nuke the cells and we kill the cells at a very targeted manner. So theranostics, combination, right, contracted word, diagnostics with positron-emitters, gallium-68, F18 and therapy with particle emitters, beta particle, lutetium-177, Lead-212 beta plus alpha, actinium-225 alpha. So one final thing to discuss here. Once this is in the field, do we want the longest tumor residence time possible? Yes. But because the receptors are also expressed by the physiologic sites like bone marrow, your longest residence time needs to be very carefully optimized to control your toxicity. So I'm going to be talking about -- that's me my disclosures but nothing really unique to this topic. There is no Kaplan-Meier curves in my talk. There is no formal analysis. These are all real-world data from my own patients so that we all can understand MOA because you're investing in your finances, we are investing our time. I really want to create some meaningful change in the patient care, and we will need to all cooperate. This is an estrogen receptor, biodistribution, gallium PSMA, prostate cancer, FDG, which is our workforce for the -- in any cancer setting. And the other one is a gallium-DOTATATE PET. So at the bottom, these are physiologic distribution sites, which means that if we go really powerful, right, with the alpha versus beta tools, you're going to definitely in the estrogen receptor setting, you're going to see some uptake in the liver, maybe elevated liver enzymes. PSMA, not that much, but the hottest organs in PSMA are -- I'm going to walk for a second. Hottest organs are the salivary gland. This is why we see a lot of toxicity side effect in salivary glands. FDG for diagnostic purposes, we are there not using and the DOTATATE, we still have some hypothesis uptake, pituitary gland, some salivary gland uptake, liver, spleen. But when we do SSTR2 target therapy, we don't really see that much toxicity in the DOTATATE setting. We don't see a lot of salivary gland toxicity, not pituitary mildly thyroid. We always keep an eye on. We do thyroid function test and all. But when you get to the PSMA, which we're not going to talk today but salivary gland, as you can see, is hot. And for unknown reasons, the uptake somehow indicates that the patient's side effect profile will include salivary glands. So lucky enough, I showed you a neuroendocrine tumor cancer cell and a prostate cancer cell. And that is my only patient where he came to us for post- prostatectomy for PSMA with rising PSA, and we found nothing. But we found a couple of lymph nodes in the abdomen, and it's very unlikely for a lymph node to show no PSMA uptake and be prostatic cancer nodal presence. What do we do? We know how neuroendocrine tumor because we are looking at this on a day-to-day basis, how it looks under the CT. These are calcified mesenteric lymph nodes. If I was reading this case without knowing prostate cancer history, I would have immediately called it this is neuroendocrine tumor metastases next case. And what we did, DOTATATE PET scan. So it proved it. On DOTATATE, you see all these spots. This was a neuroendocrine tumor metastasis and coexisting cancer states in this patient's body. And that is when we talk about precision oncology, when we talk about directed therapy. If you were to treat this guy without imaging with rising PSA just because we have PSMA targeting agents, it wouldn't work. It wouldn't have worked because there's an uptake here. And that's why the biodistribution is the best information, best data collection state that we have for identifying, which patient has -- should be treated with [indiscernible]. But at the same time, bio-distribution also tells us that what are the natural sink sites, right, physiologic. And as you can see here, PSMA targeting therapies create toxicity in the fibroblasts as opposed to neuroendocrine tumor targeting therapies. We don't really see a lot of thyroid or pituitary neurotoxicity for, again, unknown reasons yet. Real-time patient journey. PSA is elevated. He's 80-plus and then we do MRI, first thing you do. And from there, you do -- if you see some typical MRI presence, diffusion resting lesion. And the prostate is huge. It's 300 grams. It's very difficult to see where the tumor is. This is the beauty of targeted understanding of the disease bio-distribution. PSMA only in one spot, total body imaging only in one spot and MIP image only. So that tells you that this patient has localized disease. We can treat this patient with localized radiotherapy, external beam or at the age of 80, right, we can just follow now very confidently with PSMA PET scan. And our mod for [indiscernible] is treat what you see. I twist it a little bit, treat if you see it. So for all of us, we're going to have a collective hand raise, please. Different phases of PSMA, and different types of patients, PSA levels, let's suppress it for now. A couple of uptake here, a lot of uptake there in the bone, more uptake, heavier disease. So all these patients come to our clinic for rising PSA, right? And we have the lutetium-based therapy available. Who would treat this patient? There's no target. There's nothing to treat. Who would treat that patient? Not me, because there are only 2 small targets there in the bone, they can be treated with external beam radiation. Who would treat that patient, right? Raise your hands, beautiful and this one, right? So this is what we talk about target expression. Of course, there's a little bit more science behind that. The target needs to be expressed more than the liver because the FDA-approved trial tells us that it should be expressed more than the liver. We always pay attention that it should be expressed more than liver. But if that's the last resort, then it becomes a case one-o-one discussion. These are -- since now you are a part of our group, you start -- you decide to treat some patients. bottom, pretreatment, top, posttreatment. And I combine it with the PSA. The only way you're going to see in any patient PSA from this side that drops to that level is prostatectomy. So in their past, all these patients had prostatectomy. So the second thing that you will see, which will take down the PSA in one cycle is radiopharmaceutical therapy. It's not ADT, it's not docetaxel. It is radiopharmaceutical therapy. They work fast over a period of weeks. It still takes some time to see the final treatment response or response. But whenever you see a PSA, right, if you see this, that's what we do because it's highly targeted. So we treated this patient, beautiful treatment response. Most of the bone lesions disappeared. PSA is talking the same language that it's working in this patient. This was interesting. Entire bone marrow is infiltrated and it really cleared most of the lesions, left a couple of ones, large ones, conglomerating ones for us to treat with targeted radiation, collaboration, multidisciplinary in this patient, very difficult to treat maybe a type of soft tissue mass. It's very unlikely for prostate to come with soft tissue mass only in that sense. But look what it did. It's really working. So these are all -- I'm showing PSA, PSMA-based therapies. I know we're in a neuroendocrine tumor conference mostly. But this is to show you that for theranostics, MOA is irrespective of the receptor. If you know how your receptor pharmacokinetics work, your biodistribution works, it's going to work in a cancer-agnostic way. Cancer agnostic, finally, neuroendocrine tumor real time. This patient, who would treat that patient. We have only 2 spots. Would you treat this patient with DOTATATE targeting lutetium-177 was the only available drug to us. Who will treat this patient? What if the patient model setting tells you that. She's gone through tons of chemotherapy, long-acting [indiscernible] drugs and these are the only 2 bone needles with excruciating pain. She's on sleep medicine, medical pills and she cannot sleep. That was our only indication after really having a very extensive discussion. We treat the patient. She was progression-free for 46 months. When I say progression-free, of course, the picture did not change, but her symptoms pain-free for 46 months. After 46 months, unfortunately, this is what we saw. What you're seeing here is from bone dominant disease to liver plus bone disease. We attempted to rechallenge, it's a technical term in this patient but her liver really got very unhappy, let's say, and her enzymes were elevated. We were only able to give her tumor cycles. And this is when you see the cancer becomes so dedifferentiated, right? You still have the lutetium targeting. But for some reason, right, it's not only one receptor. There are other receptors. Maybe we were creating some receptor occupancy, some saturation, we don't know. But the liver got probably really unexpectedly high level of radiation and caused all the elevated liver enzymes. So we had to just stop treating her. And unfortunately, she passed away soon after. That is one of the most interesting patients I've ever treated, which are not one of the longest people in the field but pancreatic primary and 2 liver 3 -- sorry, 1 -- 2 spots, pancreatic primary, inoperable. So the surgeons cannot touch the patient, medical oncology doesn't really want to do more chemotherapy. She's frail and comes to us cycles of lutetium-177 delivering somatostatin receptor type 2 therapy took it from 10 centimeter to 3 tiny spots, 2 cycles. So we stopped at that because with this, we know we won't be able to cure the patient. The liver metastases have cleared. The mass shrunk massively, and we -- we gave the patient a [indiscernible] from giving 2 cycles. So there is definitely a lot of discussions at our tumor boards. But right now, this is how theranostics science progresses by Max Planck . This is one of my favorite quotes. Science advances one funeral at a time. So it means both, right? Medical oncology, never believed in us. Now they are our biggest champions. So -- and at the same time, the patients, unfortunately, in the past, who should have been treated earlier in their treatment journey that this therapy is at last. When we -- right now, all this Phase I clinical trial design, hopefully will change sometime in the future, not that very far because Phase Is are when you take the patients little one step off the grave and try to treat them, nothing works. And in that sense, if something works, it's really a miraculous response. This is why what we try to get them treated a bit earlier. So patients, another one, delivering DOTATOC, these are all very comparable images but this is agonist. DOTATATE, you're delivering lutetium 177, two years later, it doesn't really do that well. So now you're delivering 177 with a different peptide. So when I say different peptide, let's do it this way. This part, this key part is different, which what we see with alpha -- VMT-Alpha-NET, the key part is different. The peptides are being designed differently. So a different peptides, not internalizes, doesn't do really that well because, again, lutetium, which is beta particle emitter. Look at this actinium, different peptide from this to this on a couple of cycles. This is really great treatment response. And don't forget, if you want to create that treatment response with chemotherapy, you need to knock out the bone marrow most of the time. So CAR T cells, different story. We can't talk about differently. But -- so what we do here is in theranostics, you have the beauty of changing your radioactive treatment molecule, changing your peptide and creating different combination of therapies. This is why not every peptide, right, combined with lutetium versus alpha should be 101 compared to each other because you're talking about really 2 different drugs. And FAP. FAP is an emerging target and Perspective has a promising FAP agent. We look forward to looking -- seeing it in the clinical trials. Why FAP is important because until now, we've been trying to kill the tumor cells, right, doing this image and kill. But if your drug cannot access the tumor cell because of the tumor microenvironment being full of some desmoplastic, some scar tissue around it, right? You will never know your drug has never made it, you will think that your drug has failed. This is why FAP is an emerging target where it image the tumor microenvironment, but at the same time, in sarcoma like cells, it image the tumor cell as well. So you can get what is it, 2 birds with 1 shot. So if you can create good FAP imaging that would translate into good FAP therapy, you're looking into a vast opportunity of creating FAP plus standard of care therapies. In pancreatic Dr. [indiscernible], biggest -- let me see if there's one here. Yes, here we go. Pancreas. Beautiful. Background is 0 because healthy tissue should express no FAP, uptake, uptake, uptake. Perfect. It's a great candidate. In pancreas, what we do in most of the cells we use FAP, you are targeting the tumor microenvironment so that it's kind of like cracking the code, right, degrading the enzymes, the collagen, the deposited nasty stuff so that you can access the cancer cells and do your job. But in sarcoma, it targets both tumor microenvironment and the tumor cells themselves. And as you can see here, representation, FAP by the tumor cell, all these FAP by the stroma. So the stroma component, yes, metalloprotein inhibitors, right, protein degraders. This is a great opportunity to use FAP as an imaging agent because none of these -- none of the clinical trials outside Theranostics looks into biodistribution under the PET scan. And not every FAP is identical. That takes us to the same. This is same patients published FAP molecule 1 is being compared to FAP molecule 2. This is why not every FAP is the same. It's very important to understand that fact because since every FAP is not the same, if you think you are treating [indiscernible] this is a sarcoma tumor cell, right? If you are sending that FAP for imaging perfect. And then if you think that you are treating that perfect. But if you are going to treat this with a discordance not fitting FAP molecule, you're not going to get the same result, but you will think that the drug has failed. In actuality, the drug was never meant to work in that environment. So theranostics, short half-lives for full -- long full lives. This is the title of the talk I gave a few weeks ago at a Nuclear Energy Summit because the nuclear energy, right now, everybody keeps talking about fission versus fusion. I think the nuclear energy's future, the progress, the progress is our progress because there is a vast opportunity where we can look into new medical isotopes like Lead-212. And precise targeting of tumors don't forget, leads to improved efficacy and minimize toxicity know-how first. Thank you so much.

Thank you, Elcin, for that. So I mean, we like to really talk about one of the differences, and she alluded to some of those differences as well with the FAP and how things sort of go to the body, what does an image tell you and what does overall retention tell you? We've brought up this image here and normally, I just show this as an abstract image, but this image is courtesy of Dr. Bundschuh. What he's done has shown that at 24 hours and 41 hours post injection, really long tumor retention. So it's not just a question, will it go to the tumor and then wash out? or will it go to the tumor and stay there? And with FAP, that's actually been a really differentiator because initial imaging agents with FAP that Dr. Zan showed, those were agents designs that they went to other tissue, went to tumor and then washed out. That doesn't work for therapy. For therapy, you have to have it go to the tumor and stay there over time, ideally at least to half-lives. So any radiopharmaceutical that you're looking at development, you really want to say, what does the image look like? Where is it going? Can I predict side effects or not? We actually have this amazing ability here to look at this patient, where this is a patient with FAP scan and so Dr. Bundschuh, if you can tell us about this patient.

Yes. So this -- so I'm also very happy that we can take in the compassionate use program for the FAP and all. And this is a very special patient. It was the first patient to be treated within this compassionate use program in Dresden. It's a young patient. She is 59, I think, and he is still working completely as his own company. And he has the sarcoma. It's a pleomorphic sarcoma, which was diagnosed around 3, 4 years ago. He got first a chemotherapy, and then he was set on a tyrosine kinase inhibitor. And there he was stable for approximately 2.5 years and then he got slightly progression. And then we decided to set him into a disrupt program. And first, we started with a FAP with lutetium 177. He got 2 cycles of the 177 lutetium FAP, and he was merely stable and soon, he showed progression under the lutetium. And then we gave him the chance to go into the Lead-212 program. And we could imaging him as well with the Lead-203, which you see here. So this is the pre-therapeutic imaging, and we see already that he has a very, very intense uptake. The uptake was much higher than with the other FAP ligand we used for the lutetium 177. So in this case, it really fits very well with these 2 tumor cells. And the peptide really connected very well to the tumor, which you see in the 30-minute image already. So the peptide goes to the tumor, binds very fast. But you also see that in most of the tumors, it stays there. And this is what was important, what was mentioned by the previous presentation that it's really important for the treatment that the molecule stays at the tumor and it doesn't go away anymore because then you do not get a radiation dose to the tumor. And this you see here over 3 hours, 9 hours and 24 hours. And with the given half-life of the Lead-212, this is the more or less the 2 half-lives of the Lead-212. So you really have the full tumor dose of your alpha emitter at the tumor itself. And the patient is meanwhile, I just mentioned this. While we are speaking here this week, the patient was referred now for the third treatment with Lead-212 to our department and we'll probably get it tomorrow.

So what's also important here is what you don't see. So you don't see salivary, you don't see thyroid, you don't see lacrimal, you don't see kidney. These are all things that help predict or help you guess what's going to happen later with this patient, where will those alphas go. And if you inject the patient with alphas, you want them only going to tumor and staying in tumor over time. That's absolutely critical. The nice thing is Dr. Bundschuh's group has also showed direct imaging of the therapy real time in progress. So here, you're seeing the Lead-203 in this patient on the top, and you're seeing direct imaging of the Lead-212 in the bottom. So there's no other case in cancer where you can actually give a medicine and watch it work and prove yourself as it's working, where is it and where is it delivering the energy. And that's pretty extraordinary for -- in terms of our ability to feel comfortable what we can tell the patients to expect what we give them and what side effects to expect as well. So incredibly powerful. The scanner technology is vastly improving to actually enable more and more sites to be able to do this and be able to image. And we started from first in the world ever that Dr. Bundschuh's group published 2 years ago to now more and more sites are trying to replicate this and some regulators are asking for this as well because it is so compelling. So now for something completely different. So I'm really excited to show this patient here. So this is our latest drug that we're bringing the clinic. It targets CCK2R. I thought Dr. Zan, if you don't mind just explaining what's happening in this patient, what should people see on the scan here?

[indiscernible] Distribution. This is what a patient is imaged with F18 FDG. It's just radioactive glucose that we give in a nonspecific manner. It goes still through some receptors GLUT1, but it's not specific because you can see even heart muscle shows FDG uptake. This is nonspecific. -- still receptor based but it's not unique to any cancer, colorectal, pancreas, anything, right, lung cancer. They will all show this high glucose metabolism because of the Warburg shift effect. We're talking about precision oncology. We see some uptake in the thyroid on the right side. And we know the pathology, it's medullary thyroid cancer. In the United States, it's FDA approved but not available yet in everywhere. We can look into the F-dopa. Imaging of medullary thyroid cancer because we know there is increased in a more targeted way of F-dopa uptake. Does it tell that there is increased F-dopa uptake in that lesion despite it being an MTC? No, we don't see. FDG performs even the same plane, FDG outperforms F-dopa. So what do we know about the cancer cell now? It's not showing uptake on F-dopa. We need something better, something more unique. As I said, cancer is an identity crisis at a cellular level. But they do have some receptors, they do overexpress them, and that is the CCK2. It's another novel receptor-based imaging. Hopefully, that will be converted translated into therapy. This is precision oncology. You know your target, you know your biodistribution, very minimal. There is no heart uptake, right? There is no -- compared to this one, kidney uptake is very minimal and probably a little bit gallbladder, which right now we're seeing in a couple of different traces, which tells you the story, right? When we look into overexpression of receptors at the cancer level, there is some uptake at the normal organ level. This is where your toxicity versus efficacy optimization kicks in. This is why working with true scientists, doesn't matter in academics versus in a company really is the way to go because when you look into that, it is going to be very optimized because you want your tracer to be sitting here, it's the analogy that we use for our like this is stop by. We know it's going to be there for maybe a couple of hours a day or so and the next, it will dissociate. This needs to be a sleep over because we want the tracer to be sitting there to do its job because right now, it's carrying gallium-68 imaging, positron emitter, next time, you stick it different amount of radiation, it's going to carry more potent radiation. We wanted to sit there and to start blasting the tumor cells but not here and not there. So this is very exciting. I haven't seen this before, by the way. That's really cool. Congrats.

So we're really excited about this as a target. We have this relentless focus to following biodistribution. And in order to do that, we'll start on the animal side. And so if you look at the bottom left here, we implanted a tumor, and we could see under the animal scan that this is a positive tumor and nothing else lit up. It's really important for us that we don't see anything early, medium or late. Because we know that's going to follow the decay profile for Lead-212 over a 24-hour period, what will get damaged and what will not get damaged. And so if the kidneys let up here, we know there's risk of kidney damage. If the salivary lit up, there's risk of salivary damage. And so any image you want to look at in nuclear medicine, look at the biodistribution, look early, look medium, look late, and that's going to tell you what you should expect. And so it's pretty amazing here that as work our way through, we do the work in animals, we do work actually imaging humans. If we don't like the human images, we'll go back. If we do like the images in this case, we love this image, will go forward. And so CCK2R is actually really interesting. This helps really open up the field beyond what we've seen previously with NETs and prostate. We actually see an awful lot in small cell lung. We see in hepatocellular carcinoma. We see it in colorectal, PDAC, GIST, medullary thyroid cancer, some really interesting approaches. CCK2R is a target we've been trying to follow in the scientific community for about 20 years now. And nothing has really been able to give us sort of really, really good indications. So the fact that we actually can get great human biodistribution, it really opens up a whole new frontier of tumor types for us and we're actually pretty excited about what this can do. So having programs in our portfolio that target all kinds of different tumor types. I actually really like the phrase that cancer is a healthy cell from an identity crisis. Well, we don't care what the identity is. We'll figure it out. We'll bind to it and then ultimately deliver a payload to it that can actually cause a lot of damage. So as we go across the field, what do we see? We think these markets are extraordinary. We know the MC1R targeting melanoma, SSTR2 tumors. We're expanding those indications out now. We're starting to look at other indications for that post-Lutathera meningioma. There's applications that people are studying in breast and lung. FAP is a pan-tumor agent. If any solid tumor gets large enough, it's thought it's probably going to develop stroma. And so can we target that? Can we go after some really clear unmet medical needs with CCK2R? Are there other targets we can pursue as well on spoil alert, Yes, we're going after a lot of other ones. But we only want to really show if we like it or not, once we actually show a good human biodistribution because the human biodistribution tells you everything you need to know, almost everything you need to know about what you can expect from a safety and efficacy assessment. I want to reiterate here that we're one of the only companies radiopharmaceuticals that are extending the supply chain. We're integrated. We can deliver products anywhere across the U.S. right now, and we're doing it actively. We have a stockpile of the precursor. We optimized our biodistribution. We're several years ahead of anyone else trying to build out our Lead-212 network, which means we can actually do higher and higher volumes of patient quantities, and we're building commercial-ready facilities as well. We have a commercial-ready facility already in New Jersey, our flagship site in Chicago will finish completion this year, and we'll also be looking into next year for our L.A. site to come online. And across the board, this is incredibly valued. We have end-to-end engineering on everything we do. What does that mean? We now have 107 issued allowed and pending patent applications. We have patents covering the chelator. We have patents covering the composition matter of the ligands. We have patents covering methods of treating and imaging patients. We have patents that cover how do you actually scale up that lead 212 production. And so if you have thorium, radium and Lead at all in different sites, how do you do that in the most efficient, safest way. And we have all the patents -- we have a lot of patents issued about how to scale that up. So it's not a matter of sort of talking about it, we're actually doing it, and we couldn't be prouder of our team in terms of what they do. Over the decade, what has this given us? We think Lead currently is the isotope of choice for all the tumors that we go after with how we do it with peptides. There are other approaches that are very, very interesting. At this point, with peptides and cyclic peptides, lead has been absolutely fantastic. We've set up commercial scale manufacturing. We have our proprietary chelator. Our networks are building up. Everything we do keeps building and building and building. And it's an incredible foundation with a decade of engineering work, and I'm really proud to have some of the people that have made it possible in this room. We've actually been able to go and really deliver an awful lot for patients. So I'd like to thank you for today and open up the panel for Q&A. If the panelists can come up and Dr. Puhlmann can come up too.

So great. So I think there's microphones being passed around the room. Annie, are you moderating questions? So I think there's microphones being passed around the room. Okay. Are you monitoring questions?

Biren Amin, Piper Sandler. Thanks for the presentation. For the company, I guess, given the differentiating efficacy and safety profile for the VMT-Alpha-NET program that's been generated to date, what are your design plans and timelines for the pivotal trial? So that's your first question. And then second question for Dr. Maluccio. You mentioned that the objective response is not the only variable and you would not necessarily choose a PRRT with a 60% response versus one that delivers a 48% response. I believe you may be referencing AlphaMedix and comparing it to the VMT-Alpha-NET program. Could you maybe elaborate on that statement? And what other variables would you consider for prescribing PRRT to your patients with a particular focus on differentiating the differences of VMT-Alpha-NET to AlphaMedix? So a 2-part question.

Why don't you take the second question first because she's asked to remember it all.

No worries, I get asked that question a lot. So you have heterogeneity of tumors. I think we will know that. You've got heterogeneity of patients. I think that we probably didn't go over as much. And so neuroendocrine is often very specific about a unique patient experience and what it is you think they can tolerate. So what was also alluded to, but is important is that we define objective response, meaning that something has to shrink by at least 30% in order for it to fall into that category. And PRRT in general, beta PRRT has really been less about objective response, and it's been more about stability of disease. And we have good long-term data to suggest that the durability of that stable disease is going to be in the years of time. But that you have a patient where you got to put your money down on getting an objective response, you're not going to choose a beta particle that is all about stability of disease. You're going to put your money down on that objective response. And yes, you're going to do that knowing that maybe some of the side effect profile is going to be worse, but that you're going to be willing to do that. It's just a conscious decision informed consent, everything that we do. If you have someone that has aging, not necessarily aged kidneys, but aging kidneys where you know that if they were to do a 24-hour urine, their creatinine clearance is not going to be the same as a 40-year-old. So are you going to put all your money down on a 60% response when you get a 48% response without having some of that side effect profile, you just wouldn't do it. And so I think that those are the nuances of what all of us do when we're making decisions that are very patient-specific. But that I do believe, I think that the -- also alluded to is that the promise of the future particles and platforms, whether or not that be the chelator or the delivery itself is seemingly addressing the -- at least the renal type stuff that may ultimately make that answer very different. But there are a lot of people. It's not like lung cancer where you're going to put all your money down on KEYTRUDA because it gives you that highest objective response rate compared to something else. Here, it's really about getting a response rate that's now clearly better than chemo right now with a less side effect profile. And then the nuances of the way we're studying PRRT now, people in your position want to be able to compare those as if it's apples-to-apples comparisons, and it is not. The patients that are included in those trials is actually not even identical. So that looking at even that 60% response rate from the AlphaMedix trial, those patients would potentially be different than the patients that were included in the VMT-Alpha.

And the first question was, I'll answer 2 parts. I'll take the first bit, which is I just want to be really clear. Our organization is all in and getting ready to be ready to initiate patients in the registrational trial at the end. So we are moving forward at full speed and doing everything we can on the interaction side. Dr. Puhlmann, do you want to comment on the design and what you're doing with Cohort III and IV? And does that slow down Cohort II?

So very good question. Cohort III is fully enrolled. So we are obviously following up the data. Cohort IV is a new cohort that we put in, and we are very excited about this front-loading approach. We do not expect safety-wise to see any differences. If at all, then it would only be an even more safe picture because of the overall administered dose, you expect that even more will actually bind and deliver the alpha particle to the tumor. And no, we do not expect that there will be a delay. This is just for us to better understand this approach. And we -- as I said, there are 2 promises. One might be a better safety profile. The other one is that maybe we can increase and speed up the kinetic of the response.

Let's go over to Yuan.

This is Yuan Zhi from B. Riley Securities. Thank you for the insightful sharing from all the KOLs. Maybe first question to Dr. Bundschuh. When you started this trial, why did you only give the dose -- the patients 1 to 2 cycles of the alpha radioligand therapy. And then the dose, I think, is around 2 to 3 millicuries versus 5 millicuries. Maybe elaborate on that. And then the second question to Thijs, on this new target, CCK2R, I think there have been some clinical evidence from the lutetium version of it from another company. I'm just wondering maybe this target is validated. What will be your main cancer indication that you will target versus between small cell lung cancer, colorectal cancer and liver cancer, which one do you think will have the most promising opportunities out there?

Okay. So I'll start with the first question. At the moment, we started in March 2023. There were not yet these elaborated safety data we have now. So -- and it was a compassionate use program. So we were careful and starting with the lowest possible dose. And after we have seen that even with this dosage, we can achieve quite good stabilization of the patients, there was at this moment, no need to increase the dose. And even when we did rechallenge now in these 2 patients I showed you at the end, we still stick to the lower dose increase a little bit, but we are now with the 3 millicuries. So -- and we found quite good results for our neuroendocrine tumors, which we included in our compassionate use program.

Yes. I'll touch on CCK2R a bit. I think let's do 1 question first and then we'll go on. So, Alec.

Great event so far. Alec Stranahan from Bank of America. Just thinking about Cohort IV, I guess, what's driving the higher upfront sensitivity to radiation in the tumor? Is it may be like a debulking effect or something else? Maybe if the experts on the panel would like to opine on that. And I appreciate this cohort might enroll in tandem with conversations you could potentially be having with the FDA around Cohort 3 data over the coming months. So if you do reach alignment on a pivotal design for Cohort 3, would you want to wait for Cohort 4 to read out before initiating that study? Just thinking about the timing of when these events could happen.

So we have no intention of waiting for a registrational study. We're pretty keen to move forward, and our team will be ready. I don't know, Elcin or Yusuf, you want to tackle the concept of front loading.

The Lutathera data also shows that the receptor expression actually starts to go down after each cycle. So that is why we really want to hit the tumor with the first dose because the receptor expression or the uptake appears to be the highest. This has been shown in several studies that the dose of the tumor goes down with each cycle. So you may have a better chance of targeting the tumor with the first dose.

Is that a selectivity like you're essentially reducing the high expressing population? Or is it kind of a cancer evolution within the tumor?

I think the -- one of the initial responses to tumor is actually changing the receptor sensitive receptor status.

Thanks, everyone, for taking the time for a great presentation today. Maybe to Dr. Maluccio, looking at Lutathera and how it's used today and talking about its presence on the NCCN guidelines. As we move to alpha therapies, how do you see that evolving the sort of paradigm for treatment with SSAs and other options?

Yes, I think that's a great question. That's probably what is most debated at our conferences is, is how will -- as the landscape changes, how will we make those decisions. And another thing I should have brought up with this question is that you also have a patient population that will have other drivers of mortality. So you're trying to balance then your cancer treatment, potential life expectancy and then putting your odds down on something else ultimately taking their life. So I am one of the people that I just don't think that beta particle -- particle therapy is going to disappear. It is incredibly well tolerated. And I mean, I've treated a 92-year-old with symptomatic bone mets with beta PRRT and had her do extremely well. And she will ultimately succumb to some other medical condition, but she -- we did it with really payload of intent, and it works even if it's just stability of disease. And then as we're bringing beta particle PRRT upfront line, all of a sudden, they're starting to say, "Hey, wait a second, we're starting to see higher response rates once we're allowed to give it earlier on." I think that's what Dr. Munro was trying to say about receptor density maybe earlier on. So where I think that alpha particle is, it's more potent. I mean it clearly is -- and I think that what you can't express without going over hundreds of patient data is regression versus objective response and the durability of that response where you would need a treatment. What you find with beta PRRT is that on average, those patients will ultimately progress. And yes, we have found in alpha particle trials that we can safely give 4 doses of alpha particle PRRT even in patients that have 800 millicuries of beta PRRT and without having substantial significant end organ side effects. So I think we all thought it was going to be as that second line, meaning that you would give your beta PRRT and then you come in with your alpha PRRT in those patients who progressed 2 years later. And I think that the conversation now is really with the safety profiles coming out in these trials maturing is that we will likely doing a patient-specific and alpha particle PRRT is going to be on the table in the same way the beta particle PRRT is. And I think we might be doing less beta PRRT in younger patients.

Comment about this is, we all know, MER-2 has been approved. FDA updated the indications. When you sit at the tumor boards, medical oncologist still is very resistant to view the [indiscernible] first line. And there is no cognitive -- other than cognitive bias, there is no cognitive reasoning why it should be. And then we sit at the tumor boards, it's always, yes, I want to try this first, this one and that one. So from our end, we are right now having a very open conversation then what would it take medical oncology to accept the fact that there is a first-line PRRT available. So then this takes us to the overall -- the response rates because neuroendocrine tumor is a very slowly progressive disease, thankfully, most of the time. And when you do biopsy, it could be G1, you do a second biopsy, it could be G2. So first one tells the patient is a good candidate for different types of therapy. Second one, yes, first-line PRRT is available. So right now, the medical field still has not really found the answer to which patient should be sequenced to go to PRRT first despite [indiscernible] is available and the trial is over. So I think getting tumor versus more aggressive squamous cell cancer of the lung, the outcomes are -- the measurable outcomes are very different than each other. This is why right now, looking into frontline, yes, receptor density matters, receptor expression matters. But at the same time, you want to give your radioactive therapies to a very healthy or to the bone marrow that is in a healthy state, liver in its healthy state before trying to give states out every 6 weeks, 8 weeks, fixed doses because you are over time, as [indiscernible] has shown in her publication, I suggest you all take a look at it. When you give 4 cycles of PRRT, your dose exposure to the kidney doesn't change, but your dose exposure to the tumor size keeps decreasing over time. And you don't see shrinkage in the tumor mass which tells you that, okay, we're not creating shrinkage. We're not -- it's not overall the objective response is not out there and the receptors are shutting down. So I think this is why fronting is a concept that we should be a bit more aggressive about, not only in this company APC setting as a concept that we should be more aggressive about that because you want your response to toxicity data as early as possible. This is radiation. This is not chemo that's going to work over time over 2 years.

This is Justin Walsh with Jones Trading. I have a question for Dr. Bundschuh. I'm just curious how your experience using actinium-225 DOTATATE compares with Lead-212 VMT-Alpha-NET?

Yes. So as I said before we do much more actinium-225 treatments in our department and also doing it sometimes the standard therapy, so lutetium and actinium in one treatment cycle. And one big difference I have experienced so far in this patient is the bone marrow toxicity. Actinium often shows very, very high toxicity for the bone marrow, which is at least for the patients we have done so far with the VMT-Alpha-NET less. As I showed, we have no serious side effects, no Grade 4 or 5 and I think just one grade, Grade 3 in one case. So this is much less. And it seems to be at least for the NET patients, the same effectivity. So yes, it may be advantages. But of course, there's a different number of patients. We have treated probably 150 patients with actinium and just this presented 12 with the let up so far. But I would guess that especially the bone marrow toxicity should be more easy to deal with.

It's Leo with RBC Capital Markets here. I wanted to touch on something that both -- a couple of the KOLs mentioned both Dr. Maluccio and Dr. Zan, is, I guess, other therapies and how there can be complementary effects rather than necessarily needing to sequence. So I guess as you think about [indiscernible] Lead approach. And are there other treatments? There's many things coming down the pipeline of TKIs, DL3 ADCs that you think would be good combinations with some of the alpha emitters? Or conversely, maybe would it make sense to combine and you already have a clear idea of how you'd want to stage them?

Yes. If I would say how the landscape is potentially going to change, and clearly, there are going to be patients with higher-grade tumors where the TKIs are going to be completely appropriate. So those are going to be people that may not have the same somatostatin receptor avidity that would make us confident that a PRRT strategy is going to target those cells. Do I think they're going to be complementary? [indiscernible] when they first initially did their trial, I think almost half the people that had been treated in that trial have been treated with 4 doses of beta PRRT. So we know that, that was safe without having some of the significant myelosuppression that we were seeing in patients that have previously been treated with beta PRRT and then had capecitabine and temozolomide where they were struggling with more profound myelosuppressive consequences to that. And so I do -- when I say complementary and we went into biodistribution, not to the extent that I think I look at it as the simple surgeon approach is that if you look at the extent of disease and the degree of receptor density or somatostatin receptor avidity and you look -- you're infusing this and the only biodistribution we're going to know about is going to be, oh, yes, this is going to go all over the place. But is the liver going to be a hungry hippo and therefore, you will not then biodistribute evenly to some sites where we don't have as good targeted therapies like the bone or some of the retroperitoneal lymph nodes. So when I say complementary, probably one of the most common complementary methods we're using is really not a chemo plus PRRT, but a cyto reduction or a liver-directed therapy where we're trying to bring down the total disease burden, whereby the PRRT or chemotherapy or whatever is trying to deal with a lower total disease burden. But that I do believe that PRRT has been studied in heavily treated patients and still come out as being safe and effective under those circumstances. And what we're really debating now, and I completely agree with medical oncologists, so I'm just happy that, that happens to be me in my program is medical oncologists being somewhat more resistant about giving up on the chemotherapy. But the reality is that the chemotherapy has a higher side effect profile for a lower objective response rate than almost any of the PRRT platforms that are coming down the pipe. Did that answer your question?

Perhaps I can add, for example, we did preclinical studies combining TKIs and radioligand treatment on net tumor cells, and we found even synergistic effects if you do a combination treatment, which was also published by our former group. And so combination treatments will also be a very important topic in the future.

Can I ask a question? Since you have been serving the field for -- I mean, every company, every new IDR, who believes that monotherapy will be the future?

So right now, we are really looking into the true effects of PRRT because ultimately, what defines the dose, the poison, the difference between poison and the medicine really is the dose. And we are hopefully, one day, we'll be having a discussion about dose de-escalation. And that's really inspiring to see that they found efficacy, it's really [indiscernible] care level. This is pretty inspiring so that it gives you the flexibility to combine the drug with standard of care because toxicity, yes, if the patients live long enough, we are facing toxicities. And we want to minimize it from the beginning, Dose de-escalate on your TKI, dose de-escalate on your PRRT, I think that will be a better future for the patients. But that's a brilliant question. And I'm so glad that no one really believes in the future in the monotherapy because right now, TKI, as you know, T-cell engagers, CAR-T cells, they are all coming down the pipeline with true toxicity profile that are -- if you give it long enough, high enough, there is -- all the thyroiditis, hepatitis despite the fact we do have uptake, as I showed in the P2 treatment in the thyroid gland, we don't see enough itis with the neuroendocrine tumors. So we don't know why. Hopefully, when they will understand in preclinical models. But I think this sets the stage, if you can find a hep medium with radionuclide that is given the highest but minimal amount that is just efficacious that really then becomes a game changer for combination therapies.

Greg Renza from Truist Securities. [indiscernible] perspective and to the excellent panel on the event today. if I may, when it comes to the registrational plan, you have commented on the, call it, the necessity of Cohorts 3 and 4 before the FDA and just getting registrational buy-in. Just curious if you could maybe elaborate a little more as we look to Cohort 2 and the 5 millicuries, what role will the 3 and 4 play as you engage FDA over the year in order to stay on track? And then secondarily, maybe just a broader question to you and to the panel perhaps with the FDA dialogue about real-time tracking and the use of AI, what role could those capabilities potentially play in this field in radiopharma as well as for perspective?

So I'll take the second part, and then I'll ask Dr. Puhlmann to comment on the first one. So I think in terms of how things are evolving in AI, no one really knows right? I know how to spell AI, but that's about it. But I think we're investing in these tools. There's a lot of data out there that people want to explore. We've been approached with ideas of how to actually look at real-time sort of surrogate patients, taking all the placebo patients that the FDA has in their database. There's so many things to explore, but I think more data faster earlier at the end of the day, especially with open-label trials should allow things to become more adaptive and more flexible. Markus, do you want to...

So regarding the first question, what will Cohort 3 and 4 contribute with the discussions. So first of all, I think we all agree that Cohort 2 shows a wonderful benefit risk proposition. And when you have a good drug, you want to understand also you want to push it a little bit and try to understand what is actually the slight -- the upper limit. We are not interested in understanding the [indiscernible]. I just want to point this out. But in animal experiments, we've seen that moderate increases can actually lead to a dramatic benefit in regard to increased objective responses. So we feel we need to understand and characterize what would we or will we see with a slight 20% increase. We expect to see something more of either responses or some toxicity or maybe a combination of thereof. But it will really get us additional information about the drug itself that I think is very viable. Also, if we want to go into more aggressive indications such as neuroendocrine carcinoma, we may want to have a dosing schedule that is a little bit more aggressive. In regard to Cohort 3, we always think about can we actually optimize the total administered dose. So this is a simple optimization that is relatively risk-free. And we have this 5x 4 dosing schedule that is -- we have plenty of data that is very well characterized. But again, is there something that where we can very simple get additional bang for our buck, so to speak.

This is David Dai from UBS, and thanks for the great present. I actually want to switch gears and talk a little more about EU's perspective here. So Dr. Bundschuh, you're [indiscernible] for VMT-Alpha-NET and you have a lot of experience with EU. So I'm just curious in terms of how are you using PRRT therapies in EU and how is it different in the U.S.? And also given the fact that you have used actinium-based therapies, just talk a little more about the supply changes in EU for actinium.

Yes. So it's probably a little bit -- one of the differences is that we have the Lutathera more or less quite early stage in Germany. So we are allowed to do Lutathera as soon as we have progression to octreotide, which means that we have a lot of neuroendocrine tumor patients at a second line or even in some cases, we skip the octreotide if there is a high tumor load, then we can directly start with both of them, so we can do radioligand treatment in first-line treatment in the G1, G2 NETs. What we also do, for example, if you have peritoneal carcinosis, then we directly start with the PRLT together with the octreotide in combination. Yes, supply chain, this is a very interesting point. And especially recently since we have the problems with the Middle East, we have -- we had several weeks where we didn't get actinium. So actinium is a problem in Europe. Also, there are now some more vendors coming up on the European market. So we -- I talked to some of them and several offers, I mean, new options to get actinium, but still we have to change patient schedules very often due to lack of actinium delivery. It's a problem. One of our actinium changes via Israel, the other one is since the Ukraine crisis with Russia is very difficult. So we would have -- I would have more patients, which I would like to put into alpha treatment, and I cannot do and I have to stick to lutetium.

Great. Li Wang Watsek from Cantor. Nice presentation on dosimetry. I wonder if the panel can expand a little bit on the feasibility of using dosimetry sort of guided treatment paradigm. And in practice, how do you balance the value of dosimetry for patient care with care burden and potential reimbursement hurdles here? And then what's the FDA's view on this issue?

So thank you for that question. I think there's a lot of opportunity for dosimetry to be incorporated into the treatment planning. I was actually going to mentioned, I think there are opportunity for AI tools to actually help with dosimetry in terms of post painting, doing tumor and normal organ assessments that actually will help. The feasibility also depends on having sufficient experts for the dosimetry. So I think I'm expecting that there will be AI tools that will actually make the process simpler, more robust and reproducible. In terms of the early phase clinical trials, my understanding is that in most studies, FDA actually is requiring that dosimetry data is included, how it will be ultimately used on a larger scale in clinical practice will depend on the development of tools, which is an active area that is explored -- that it will become more -- it will come into a more widespread use with the development of more automated tools I'm expecting.

I just can add that also the EMA, the European Medical Association that also insists on doing dosimetry on all clinical trials on therapeutic radiopharmaceuticals at the moment. Even on the actinium trials, which is, in this case, sometimes a little bit silly because doing good actinium imaging is difficult, but they insist on doing dosimetry in all clinical trials with radiopharmaceuticals.

And there are companies that are working. There are quite a few vendors that are working on some of these tools that are in different phases of development.

Chris from Lucid Capital Markets. Thanks for the great event. I'm curious about the post-PRRT expansion potential for VMT-Alpha-NET. Just kind of curious what that setting looks like in terms of patient numbers, benchmarks and any plan going forward?

I'll take that quickly before actually going for an indication. So we know the number of patients post lutetium is increasing, right? And you can track Novartis' sales and probably see how the numbers of those patients are. We'll need to be very thoughtful about how we approach, what makes the most sense for us to go towards an indication and registration. I think the initial safety and efficacy data we've seen so far is quite compelling. And again, we want to look at all possible engagements with the agency to figure out what makes the most sense to bring the medicine forward.

Great. Jeet Mukherjee, BTIG. On the topic of FAP alpha, certainly high potential for it as a target given it targets the tumor stroma. Are there any standard of care agents that you feel would ultimately synergize well with it once the tumor microenvironment is opened up? And maybe a question for Dr. Zan. Are you aware of any other tumor types outside of sarcoma where there's a high degree of expression on both tumor cells as well as stromal cells?

Thank you. Yes. Right now, the target is pancreas adenocarcinoma. If you can combine this because FOLFIRI and FOLFOX, all these regimens are [indiscernible] toxic and not very tolerable. So we are looking into this as an inoperable patient, pancreas primary presence and can we combine FAP with standard of care to APs, crack, reduce and make the patient -- hand off the patient to the surgeon. That's a great idea. But at the same time, there are different developments of indicating CAR-T cells where you have a CAR-T that targets the FAP cracks and then targets the PDAC, and deploys the toxicity. And from there, T cell engagers for -- I forgot but from there, create a T cell engagement. So in this complementary pancreas-specific for now, [indiscernible] right approach, where does the radiopharmaceuticals fall into that paradigm, imaging. If you can show it, then they know what the biodistribution looks like, then they know if it's a localized disease that they are treating. And at the same time, the toxicity of radionuclide, which is known as tumor kill effect, right, is very well established in -- when you deploy alpha, there's really no rescue from that. But when you deploy other toxicities, it will take some time for the metabolic intracellular compartment metabolism to be affected. But from the other end, FDA still is -- I'm not sure how open they are in orphan disease, difficult disease, yes. But in other diseases, let's say, breast cancer, right, how open they are to the combination therapy. So I think these are all very important concepts that we will need to stress probably with starting with proof-of-concept IIT in Germany really has been a great help in that sense. But at the same time, what other targets are out there, I think breast cancer, while the breast cancer probably will be a promising one, PDAC itself, right? And on the tumor, when we get into the stroma -- sarcoma-like cells, probably you have a better answer to that question. But from my perspective, any mesenchymal tumor cell becomes an FAP target because those are very difficult to treat cells at the same time. Even in [indiscernible], I think it's very new and has the greatest potential is it's a cancer-agnostic target. Even sarcoma itself becomes cancer agnostic because it's expressed in the microenvironment as well the tumor cells.

Time for one more question because our KOLs have to get to the airport. Oliver, do you have a question?

I know we touched on this a bit before, but I'm curious on the interest level in taking VMT forward for pre-SSA or SSA naive neuroendocrine patients or perhaps whether you could perhaps take an agnostic approach to that trial design? And then Dr. Maluccio, you -- it seems to have some experience with alphametics, certainly with Lutathera. You've seen some of the safety data with VMT. I'm curious between these 3 different products, how you think of the relative safety profiles.

Okay. Yes. So we treated a number of patients on the alphametics trial, obviously, getting a lot of attention because of delayed renal impairment that became more and more clinically significant and then some of the dysphagia issues that they're still trying to assess out exactly what that was and whether or not it's because of targeting myenteric plexus. And then you look at that, but the alphametics trial is different than the current VMT alpha setup in that the alphametics was targeting patients where the majority, if not all, of the measurable disease had to be somatostatin receptor added up to a certain point, clinic score of 3 or above. Whereas VMT alpha was allowing something that if we looked at those images in the context of what the other panelists were talking about biodistribution and avidity, you have a little bit more of what we would assume is mixed grade. If you went and [indiscernible] tumor cells out of every single site of disease, they would not necessarily be identical and therefore, not necessarily quite as responsive or able to get your target there and the concentrations that you want. That's when I say that it is impossible to actually look at those as apples-to-apples comparisons. So if you were to look at that in the whole context, that's when I say don't get so enamored by the 60% objective response rate because the 48% or whatever response rate is a perfectly respectable response rate, especially in a mixed grade type atmosphere. But I think the most promising thing is that the way that the data for alphametics is being presented, I don't think is necessarily quite as telling as what we are experiencing in the clinic, which is that those have been trade-offs for a lot of people, and that delayed renal impairment has been substantial. And then you guys are going to say, oh, but we don't have enough follow-up in VMT alpha to suggest that it is. Well, you have enough -- you have enough follow-up at the point at which we saw the delayed renal impairment to know that I think that those 2 platforms when it comes to the most consequential, the VMT alpha is looking like it's just got a better safety profile. And so yes, therefore, I think that if you're going to look at those 2 agents, as I think I told you before, and you're looking at a patient with potential baseline renal impairment where we could feasibly squeeze 4 doses of Lutathera in and not ultimately box their kidneys, you are not going to be nearly as comfortable giving someone a platform where you are unable to identify because you got to remember all those patients were treated on trial and met every single eligibility for treatment at the time the treatment was given, right? And so if you couldn't identify who is going to be at risk, then you're going to have a lot of confidence issues in delivering a platform where you may not see it for 3, 6, 9 and sometimes 12 months after the delivery of the dose, whereas the more this data matures, the more comfortable you're going to be that, that consequential side effect and the dysphagia side effect are really seemingly irrelevant.

So just looking at the clock here, I'd like to thank everyone for coming, our physicians for giving their insights, you all for your attention. You give a warm round of applause to our panelists that would be terrific. And thank you for coming.