To the Piper Sandler Healthcare Conference, my name is Biren Amin. I'd like to introduce our next company. We have Perspective Therapeutics and their CEO, Thijs Spoor. Thanks, Thijs, for coming and attending and sharing their Perspective story. So maybe you could tell us about you are clearly focused in the radiopharmaceutical area. If you could tell us about the platform, the radioisotope that you are focused on, as well as the chelator technology, and then the target that you are pursuing across your three clinical stage programs. Terrific. No, Biren, thanks for having me and hosting us here. The radiopharmaceutical space has been a fascinating field for the past 30 years. I got in the field 30 years ago as a nuclear pharmacist. And back then, Iodine-131 was the only really viable therapy that was there. Iodine-131 is a beta emitter. It goes to the thyroid. No matter what kind of drug you conjugate it to, it's still going to go to the thyroid when it dissociates. And that led the scientific community to say, is there anything that's better than Iodine-131? Thankfully, there is. So they could take Lutetium-177, which was chelatable. If you chelate it, which is better than a covalent bond, you're going to then bring that isotope to wherever you want it to go if you can attach the right targeting vector. That led to some real innovation in the space with Lutathera and Pluvicto. You've got sort of blockbuster drugs now in the radiopharmaceutical space that are generating billions of revenues and formed a really strong beachhead for the industry to really keep innovating and inventing. Lutetium has its trade-offs, in my opinion. It has limited potency. The beta particles on their own, it takes about 1,500 beta particles to kill a cancer cell. It takes a single alpha particle to kill a cancer cell. The next innovation was to say, can you get more of a punch than lutetium by going to Actinium-225? And the chemistry is very similar, but not identical. There's an interesting paper that was just published in ScienceDirect two weeks ago that shows that whenever you try and change metals, you have a lot of issues in trying to identify what's what. How do you find surrogates? How do you track things through? And Actinium-225 sparked a great wave of interest to get a lot more energy onto a tumor. But Actinium-225 has four radioactive daughters in the decay chain that act very similar to toxic metabolites. And so to the degree that everyone in the room knows about toxic metabolites, you get the same issue with toxic daughters or off-target daughters that can show up with Actinium-225. And that's really led us into the whole field of lead. There's a big push right now in some other isotopes like astatine and terbium that are all developing a lot of interest. Lead-212, we think, is very impressive as a potent alpha emitter. The lead itself emits a beta, but its first daughter emits an alpha particle. And so if you can hold the parent and daughter together onto a tumor, you can then actually destroy the tumor cells. And that's very important in what we're trying to do. So there's a lot of things that start with the isotope, but then it goes down to you can't just give a free isotope. There are a few drugs that were approved where just the isotope on its own was a drug. So iodine, strontium, samarium worked that way, and certainly the Zofigo drug from Bayer. But in order to get more precision, you actually want to have the right targeting vector. And so then you have a choice. Do you target it using a peptide, or do you target the tumor using the antibody or small protein? And the issues there are going to be biodistribution. As anyone knows, biodistribution, you talk about it, what does that mean? In the radiopharmaceutical field, we can see it. We can see it real time. We can see it in advance of a patient being treated. We can also see it as the patient's being treated. And the first-in-human images ever on Lead-212 are starting to be published where you can actually see real time as the patient's being dosed, literally what dose is going to every tumor and every organ in the body over time. And that's a big breakthrough, and that adds a lot to the commercial potential and the ability for doctors to drive revenue off of their procedures. So when we sort of look at that whole cascade, we thought we need a safe way to chelate it. And so chelate the Lead-212. So our scientists invented one. So we have a proprietary composition of matter protected chelator that holds Lead there and holds the Bismuth daughter. And if you hold both those things in place, you get a lot of power at the tumor. And if you can design it properly, it washes out from all other organs. So then you actually don't get accumulation off-target. And that's that trade-off between on-target, off-target that's really going to make the difference between what's a winner and what's not. For the chelator, it's a net zero charge, correct? Yeah. What are the implications of that? Whenever you're doing things to a molecule and you're swapping out metals with different charges and you're doing things with the protein fragments, a charge on a protein fragment will mean that automatically the kidney will try and harvest it. The kidney's job is to pull charged proteinaceous fragments out and filter them and hold on to them and try and process them. If you put a charge onto your peptide or your protein, you're going to get kidney accumulation and retention. We prefer kidney clearance. If the drug goes through the kidneys, it will go through. As long as it doesn't stick, then you have a better chance for a therapeutic window. The kidneys are also important because you want to be mindful of a bismuth daughter in either an actinium decay chain or a lead decay chain, that the bismuth is also retained so you don't get kidney toxicity there. So what we like is that that net-zero-charge chelator makes our drug design that much simpler. Got it. And then the lead program, VMT-α-NET, it's clearly targeting SSTR2 positive tumors. There's currently one radiopharmaceutical that's approved by Novartis, Lutathera. How does VMT-α-NET compare? What's the value proposition, I guess, compared to Lutathera? It's a great question because we always think about unmet medical need. Everyone throws that term around a lot. What does this mean for these patients? These patients, when they start to get neuroendocrine tumor, their tumors are highly secretory, which means the patients feel terrible. So the first thing that clinicians want to do is treat them symptomatically. You can treat symptomatically with a somatostatin analog, and the person can be on that for quite a while with stable disease until they're not. When they start to progress, they need some kind of intervention. Neuroendocrine tumors specifically, and that covers a broader segment that's not just GAP-NETs, the gastroenteropancreatic neuroendocrine tumors. It also covers neuroblastoma, pheochromocytoma, paraganglioma, HER2 positive negative breast cancer, some lung tumors as well that all start to express SSTR2. If they express SSTR2, we can bind to them and then cause damage. And so Lutathera got approval in the package insert with a 13% ORR, which is better than the somatostatin analog of 3%. So patients have a standard care that can cause they can give them a PFS of about two years with about a 13% overall response rate. However, there is some risk of some side effects kicking in. So what the VMT-α-NET program offers is, so far, a higher degree of efficacy with a lower impact on the safety signals. So if we can deliver a more effective and safer medicine, we think that's really transformational for these patients. And what we've seen with our latest data that's come out, a huge surge of physicians trying to get patients into our studies now. And so the data we had that came out a few weeks ago at ESMO showed that there was actually a very, very strong therapeutic profile, very solid clinical profile, strong tumor activity, incredibly clean safety profile. And we always care about safety in patients, but there's a huge push to really care about safety in patients who are going to live more than a year. And a lot of cancer patients don't have a good prognosis once it's metastatic. The neuroendocrine tumor patients, though, should be able to get decades of life. And the big risk is you don't want to give them a therapy that's going to induce a chronic disease or chronic condition. And we've seen is that with some of the competitor programs, you run that risk in either bone marrow, kidney, or something called dysphagia. We want to make sure that we have a safe drug. So far, our medicine looks incredibly safe with this profile. You mentioned the ESMO data. I think the overall response rate that was reported from the ongoing trial is about 44%. Can you just contextualize the efficacy compared to Lutathera patient populations that you've looked at in this trial and how that compares? Yeah. So if we look at the patients with GAP-NETs that are SSTR2 positive and all tumors being positive with that target, if you look at that scenario of patients where all tumors are positive with GAP-NETs, the package insert for Lutathera shows a 13% overall response rate. And with that same condition, we showed a 44% response rate and with still responses that can be seen. So that's our best response to date. However, we're so early in our program and the tumors appear to keep shrinking, there are opportunities for more patients to show up as responders, even those that have already been treated. So for a patient that has the disease, if the choice is 13% with a known safety profile or going up to 44% with a better safety profile, that's pretty compelling and shows why the physicians and patients are really surging into our study right now. When do we get more data from the trial? Will that be next year at some point with additional follow-up, additional patients? So we've shown from our first cohort of patients at 2.5 mCis, we've now got survival data out to two years that looks very, very strong. We have been dosing patients at 5 mCis. We showed 23 of those patients and their clinical response. All the safety data is bundled together. And so those extra 23 patients we'll be talking about next year. And we've also got permission from the FDA to dose even higher. The first company to really break through this theoretical limit for kidney exposure, we've blown through with very, very good safety data. And those patients dosed at 6 mCis, we expect to comment on next year as well. Got it. Got it. And I guess in the safety profiles right out, so no dysphagia. Yeah. It's so fun when we read our safety profile slide. No one says it's fun to read these slides. But what's great for us is all things we can say no to. And we can say no dysphagia, no long-term renal tox, no grade four or five adverse events, no discontinuations from the study, no DLTs. And so as we go through the list of all things that we don't talk about because we don't have them, that feels very good as a developer of a new medicine to be able to have that kind of a good safety profile. And in these patients especially, the lack of kidney tox signal and the lack of dysphagia are pretty meaningful for these patients' quality of life. Got it. And then I guess as it relates to the ESMO data, there was, I think, some investor confusion around your data relative to competitor data from Sanofi, Orano Med, AlphaMedix. Can you talk about the data that they presented and how that compares to the VMT-α-NET program? Sure. And the chain of ownership is interesting with that program. Sanofi has the rights to commercialize it. Oranimed owns the CMC rights to that program. And Radiomedics had previously held the clinical rights to it. So the three names are used interchangeably. There's some very interesting data presented at ESMO in patients post Lutathera and in Lutathera naive patients. And in both those cases, what they showed was that you can actually deliver Lead-212 in a very safe fashion, that you can actually run a study, deliver the medicine, and get some kind of disease control. In the patients that were radiopharmaceutical naive, so their first newly progressing patients that had never seen any kind of radiopharmaceutical before, those patients with the Sanofi compound, they actually showed that if they adjudicated the results, they had a 60% overall response rate, and if it was independently reviewed, it was more in the mid-50s, and that was after two years' follow-up. All responses had been seen. However, there's a particular focus on the safety, especially dysphagia and the potential for renal toxicity in those patients, and that was a particular focus for the presenters of that data. Our data that still newly emerging patients are still showing up, we're seeing on the spider plot that the tumors are still shrinking, so our best response to date has been it was 44% in a like-for-like comparison, and we did not see those safety issues showing up. And any safety signal you're going to look at, our metrics were much lower on a percentage basis and an absolute basis as well. There's always the chance for late-term toxicity to show up across any program. And so we track everything. We get accused of being very transparent, which I'll take all day long. We present our creatinine values for our patients. We present spider plots. We present everything that we're seeing because we want to make sure that the medical community is informed. And we're being rewarded by that with a surge of patient interest and physician interest. And so sites that previously we had thought were going to be in the competitive program are now coming to us and saying they'd like to be involved with our program. And so how are you able to accommodate these sites and these new patients? And I did want to talk about timelines on the ongoing phase one, two. So you've gone to dose level three. At what point do you say, "Okay, we've got enough data that we go to the FDA to discuss what the pivotal strategy looks like? So we think our 5 mCi dose is actually in the zone for being what we want to drive towards a registrational trial. And when I say in the zone, meaning we're getting sort of a 3x- 4x increase of the ORR versus standard care with so far a better safety profile. And so the ability to actually get meaningful tumor reduction in patients is an important metric. But what was missing from the discussion at ESMO is really what's the approval endpoint? And the approval endpoint is disease control. So the clinical need for these patients is they were stable and they're starting to progress. And so the first thing that clinically that the doctors want to do is bring them back to disease control again. And that durability of response is so important. We think that our data that's emerging so far gives a fantastic durability of response profile. We want to see how that tracks through. We think we have enough data to go to the FDA and discuss what a registrational trial would look like. The current FDA has a really strong focus on safety, which we think plays very well to how we're developing our medicines. We also know we need to have some sort of comparator, and we need to have those negotiations. But our team is working quite actively to get all the patient data that we have and to figure out what a registrational trial looks like. The questions we get from investors are really, is it the 5 mCi dose or the 6 mCi dose? And which way do we go forward? And what we need to learn with the patients that are currently being dosed with 6 mCi is what do we get more of with more dose? Do we get more safety issues, or do we get more tumor reduction, or do we get earlier responses? And how does that translate through to clinical benefit? So the default setting here is that we've got a fantastically effective medicine that's very safe. If by going 20% higher, we can make it even more potent without a safety spend, fantastic. That's the one we would swap in for registrational dose. If we find that all we see is an increase in safety, we've still got a fantastic medicine. If we have both, then we'll look at those trade-offs. But one thing we know for sure is we've got a very broad therapeutic window, which means we can actually really do a lot more on dosing. And then the FDA issued some draft guidance on dose optimization of radiopharmaceuticals. To date, have you kind of aligned to those draft guidance guidelines that the FDA has issued? So the interesting thing about that guidelines is that they've been very helpful for the industry. And they came out of a joint workshop that the FDA had last year with the Society of Nuclear Medicine. And we were in attendance at that workshop. We took notes, and we followed what we heard at the workshop last year. And so when the draft guidance came out to the industry in September this year, I asked my team and said, "How does this translate with what we did?" And they said, "Thijs, you could basically have written at the bottom of every page just like Perspective Therapeutics did." Right? And so we've been following through. We listened to what they wanted to see. We've given that to them. And the draft guidance to industry very much tracks the process that we followed, which is generate the data, show the safety profile, test it carefully, and go and meter it in increments. And so as the first company to ever go through that perceived grade 2-3 of exposure to the kidneys limit, we feel quite validated that we're following the data, presenting the data, and the agency listens to that. Great. And then we've got about seven minutes. I did want to touch upon some of your other programs, the VMED 01, 02 program. This is targeting MC1R. What's the rationale with targeting MC1R in patients with metastatic melanoma? So if we just zoom out a bit on the field, radiopharmaceuticals we think are going to be the third pillar in oncology. Right? So if you're looking at how you're going to treat cancer patients, you can always treat with chemo, or you can treat with targeted chemo like an ADC. You can have the body's immune system try and fight the disease, or you can boost it with a checkpoint inhibitor. And then lastly, on the radiation side, you can give it externally, or you can give it internally. And if we think through the evolution from chemo to ADCs as a targeted version, that targeted radiopharm has huge benefits. One, you can cause physical destruction of the tumor itself if you can target it. But also, if you have the right degree of particle, in this case, if you have an alpha with a short half-life, you get this colossal new antigenic storm at the tumor site. And that really allows all the other things that your body may try and throw at the tumor to be engaged and to kick in. So MC1R is a very interesting receptor that shows up in patients with melanoma. Only half of the patients have it or express it that we can tell. It gets upregulated with the BRAF inhibitor. And so we can actually screen a patient in advance. If they are MC1R positive, then we can treat them with an MC1R targeting medicine that our preclinical data shows gets a huge potentiation if you actually give a checkpoint inhibitor simultaneously. In patients with a post-second-line plus melanoma, that's a really tricky field to be in. We've helped quite a few of those patients with our three mCi drug. We're testing the combination with Opdivo at the same time. If we can go into first-line therapies so that any patient is receiving the checkpoint inhibitor gets this boost to the immune system by presenting all these new antigens, we think that's transformational for cancer care. The radiopharmaceutical business isn't just a last chance effort across tumors. It really drives in the front line. Any tumor that expresses things can be physically destroyed, and all those fragments play a role in letting your body fight the disease. We think it's pretty transformational. We also have our FAP program, which is targeting FAP alpha that shows up in either the stroma of some tumors or on some tumor cells. And in that case, any solid tumor when it's big enough appears like it starts to actually form stroma, this infrastructure that protects the tumor from the body. So if you knock out what the tumor is building to protect itself, you then allow the tumors to shrink on their own and allow the body then to fight the tumor directly. So anything that protects the tumor we think is bad, and we want to sort of take that out. And we've shown fantastic biodistribution studies with our FAP program. We're enrolling patients in the US right now with our dose finding and the dose ranging work. And so we dosed 2.5 mCi, very quickly moved up to 5 mCi, and are actively enrolling patients now at that level with solid tumors that have sort of metastasized throughout the body that express FAP. FAP has been targeted by other programs without success. I think with your program, you've got a novel peptide that's targeting FAP. Can you talk a little bit about that? It's both a peptide and the mechanism of action. So I think previous attempts to address FAP have lacked an ability to figure what does FAP do. And it's neither a passenger nor a driver in a lot of processes. It's one of these almost undruggable targets because, yes, you can bind to it, but it doesn't do anything. In that case, that's a perfect radiopharmaceutical target, something that exists. You can target it and then destroy it. And so we think that other approaches haven't put enough energy into the stroma, haven't put enough energy onto FAP expressing tumors, and then been able to release damage. An ADC construct targeting FAP would have to bind and then release the toxophore and have the toxophore do something at that site. Whereas with the radiopharm, you bind to it, its presence there is what's destructive and then damages all the tissue. So we think there's a novel way of approaching it. Like most approaches, we've done fantastically well in animals, but we want to see the human experience now. When will we start to see some data from the program? So we've been enrolling now actively in the study. We expect to comment on that data next year, certainly on the first tranches on safety and efficacy. We like to present at medical conferences. At various medical meetings that seem reasonable, we'll usually submit an abstract and see if that can be presented. Good, good. And then I guess with the VMED 01, 02 data as well next year? Same thing, yes. Is there, I mean, are you sequencing the checkpoint relative to the, or are they being dosed in parallel? No, we give the checkpoint inhibitor usually three or four days afterwards, and that seems to be better for what the impact you've had to the body so that the checkpoint inhibitor can come into an activated system. In the combination, are you enrolling patients with a certain PD-L1 status at baseline? So not necessarily. If they are allergic to or sensitive to PD-L1, then we won't include them, but we're not putting those as a gating criteria. Great. And then with all three programs, clearly you have to manage resources and make sure that they're adequately funded. What's the cash runway as it relates to the three programs? Yeah, so our cash runway extends till the end of 2026 through all these programs we're actively enrolling. From our last filing, it's $172 million on the balance sheet. Our burn has historically been about $20 million a quarter. And we're making reasonable investments or healthy investments into infrastructure as well. And so our current runway assumes that our programs are going at a very good speed, very active enrollment, as well as scaling up our infrastructure at the same time. We've secured a strategic thorium stockpile, which gives us several years' window into our supply chain. So if we don't receive any more isotope in-house, we have enough to handle our capacity or our demand for the next several years. And so we're making strong investments across the board. Some of our cash moves around the balance sheet. It goes from cash into PP&E, and that PP&E can be marked up at a much higher value. Got it, got it. And then I guess on the manufacturing facilities, currently how many facilities are in operation? So we have an operational site in Iowa right now. We have an operational site in New Jersey. We've purchased buildings in Chicago, Houston, and L.A., and those are in the various stages of being developed to produce product. Each manufacturing facility is broken down into manufacturing suites. And so you think of it as one drug per suite. So we have multiple suites in each of those locations that we're scaling up. And we've actually been very excited to hear other people in the industry approaching us, asking us to access our capacity. So we've invested the time and energy to do best-in-class manufacturing sites. We can go up and down the isotope hierarchies. We can use any isotope we want in our facilities, pretty much. We've engineered them to handle everything. And we're excited to have those facilities come online. Great. I think we're about out of time. Thanks, Thijs, for sharing the story and looking forward to all of the data updates next year. Absolutely. Thanks, Biren, for having me.