Welcome, everyone, to our second fireside chat of the day with Lantheus. Now, the company is a leader in diagnostics and imaging. It's also building a very interesting therapeutic pipeline in radiopharma. We're very pleased to have John Wiggins, VP of Isotope Strategy, with us for the discussion. And John, maybe just for our audience, maybe you can talk a little bit about your role within Lantheus, and what does Isotope Strategy entail? Yeah, absolutely, Li. Thank you. Isotope strategy is certainly, maybe not entirely unique, but not everyone has a role like that. And it really is at the intersection of all of the different functions of the company. And I have a background in manufacturing and commercial as well, so I have that experience across the company to bring to it. But when we think about picking the right isotope for new products and ensuring that we have the right supply and support and understanding of regulatory environment, that sort of thing, for both new and current isotopes, there are a tremendous number of factors that come into that. I know we'll get into some of that later today, but you can imagine that there are regulatory issues, commercial issues, supply chain issues, and then certainly a tremendous amount of R&D issues, whether that be clinical performance or the chemistry pharmaceutical development side of it. All those things come together to inform isotope decision, and that's why we have a central or a specialized area to look at isotope strategy. Okay, great. I think isotope selection is probably one of the biggest debates right now in this space, and we're all trying to figure out, is there a best isotope, or is there sort of an oversimplification of the question? I just want to take a step back. John, you mentioned there are a lot of considerations here, right? There are many radioisotopes out there. Just from the perspective of nuclear medicine, what are sort of the main buckets of radioisotopes, and why is the field only focused on a select few? Yeah, it's a great question, and obviously one that I spend a lot of time wrestling with. I'll list a few factors out there that I think that influence our decision and maybe also explain why the field is focused on a select few. I'll start with clinical performance, and this is sort of the expected efficacy and offsetting that maybe the toxicity from different isotopes, and this is really focused on the therapeutic side. So if we think about the energy that's delivered, the type of radiation, type of particle that's emitted, and how that's expected to behave together with a molecule in treating a disease, that's a big piece that goes into this. And then on the toxicity side, whether the element that's involved is drawn to any particular organs in the body, where organ toxicity might be a risk, or if it tends to dissociate from a molecule, if it has progeny that are longer lived and might redistribute through the body, all those sort of factors. From a physics standpoint and matching the half-life of the isotope with or ensuring you have a compatible half-life for the isotope with the kinetics of the molecule so that you don't have an isotope that's decayed away before it reaches the target. Or conversely, that is so long-lived that the molecule has time to bind and dissociate, and then redistribute through the body before a significant number of decays occur. From a chemistry standpoint, being sure that you can connect the isotope to the molecule in a stable manner, that's gonna—it's gonna remain attached as it distributes through the body. Thinking about handling, so all the way from production of the isotope through production of the finished product, and then ultimately administration to the patient and release of the patient back to their family, what are the hazards associated with that isotope, and what constraints does that put on ability to use the drug, and on the patient's willingness to undergo that therapy? And then, of course, availability. And availability is a tremendous factor there, and I think is the real reason that there are so few isotopes being studied because people don't have this... If you're sitting in a lab somewhere and you wanna get a radioisotope to do studies with, you can't just get anything that's on the chart of nuclides behind me. You have to get what's available. And conversely, people aren't going to make new isotopes available until there is some demand for them. So that bootstrapping problem of not having supply before demand or demand before supply is really what pigeonholes us a bit. But it's understandable because unless there is some demonstrated advantage of a new isotope, there's no reason to shift production resources away from the existing isotopes. But we do see, you know, more and more interest in less studied isotopes. And of course, Actinium-225 has seen a tremendous amount of investment in production and in research effort over the past several years. Lead-212 is now coming up behind that, and maybe Astatine-211 behind that. So we are seeing some breadth on the alpha emitters. And on the beta side, people move from Iodine-131 to Lutetium-177. Now, there's a little bit more discussion of things like Ytterbium-176 and, sorry, Terbium-161, and whether that isotope is gonna be maybe a competitor to Lutetium-177. Great. And John, you mentioned there are a lot of considerations here, right? You mentioned, you know, the clinical perspective, physical, half-life, chemistry, logistics, and availability of isotope. I guess, how would you rank these factors? It sounds like availability sits very high on top. It absolutely. We know that if we can't get the isotope and ensure that it's in reliable supply, in time for that demand, so it doesn't have to be there today, but it needs to be able to get there in time for late-stage clinical and certainly for commercial studies, then it's not worth putting a tremendous amount of effort behind it. Now, you have to have the other pieces as well. You have to pick something that's going to be or expected to be clinically effective, that's gonna be safe, for administration and release of patients and those sort of things. But really, supply chain is a tremendously important factor there. You know, I think what we've seen in isotope production generally, but I would especially say in Actinium-225, if you look at the dollars that have been put into manufacturing there, and the fact that still today there is not a robust supply of GMP Actinium-225, that shows you what the lead times can be like, and the inevitable delays and those sort of startup of new manufacturing capabilities. So we wanna have a really good understanding of what the supply chain is gonna look like, how it's gonna be made, where the raw materials for isotope production are gonna come from, if they have to be enriched, if we need enriched stable isotopes behind that, where are those being produced and enriched? What does that whole supply chain look like, before we go all in on a new isotope? Yeah, so that makes a lot of sense. So I guess from your due diligence of the supply chain of various isotopes, how would you rank them? I mean, you mentioned there may be some challenges with actinium, right? I know the field is putting a lot of efforts into, you know, ramping up the production. But I guess in terms of, you know, supply chain, isotope production, what are sort of the isotopes that you think are in the best position here? Is it lutetium, actinium, like lead? How would you rank them? Yeah, lutetium, I think, is a great example of what happens when an isotope is successful, and we've seen a lot of people get into the lutetium business. They all need enriched Ytterbium-176 in order to make their lutetium, and we're seeing more and more people enriching that Ytterbium-176. That's not maybe not a fully solved problem, but I think when you look at the ecosystem of lutetium suppliers out there, that's a real success story to me. That's not to say that it's a done and dusted problem, and there never will be a lutetium supply issue, but there is now a robust supply chain of that where there wasn't just a couple of years ago. And I think actinium will get there. There will be multiple suppliers of actinium through a variety of routes even, but it's not there today, and it's taking a lot of investment to get there. We'll see who gets there first and with the most reliable, highest capacity, most efficient supply of it, but it's on the way. The thing that we like about Lead-212, and one of the reasons that we have this partnership with Perspective, and the investment in Perspective, is that Lead-212 is produced in large quantities today. And more importantly than Lead-212 itself is the Thorium-228 parent isotope with a 2-year half-life. And because that Thorium-228 parent has such a long half-life, you can build inventory, and that's an unheard of thing in the radiopharmaceutical world. We are a just-in-time supply chain for almost everything out there. But suddenly there's this isotope with a 2-year half-life that we could actually stockpile and have that ultimate source material of Lead-212. Now, there's still plenty of challenges associated with getting the Lead-212 out of that, making finished product, distributing it, so it's not a trivial thing. But it is very comforting from an availability supply chain standpoint to have that long-lived parent out there being produced in honestly commercially meaningful quantities today. That's not to say that the radiopharmaceutical companies have it stockpiled in those quantities already, but there it is being produced at that level. And that gives us a lot more comfort about the future of Lead-212. I would point out that that's really coming from the US Department of Energy, primarily, and with a single production route of irradiating a source of material in a reactor. There are alternative ways to get Lead-212 or Thorium-228. Thorium-228 actually is a naturally occurring isotope. Its parent isotope, Thorium-232, has a tremendously long half-life. It's a big part of, well, it's really natural thorium, so you can separate out Thorium-228 from natural thorium that you dig out of the ground, that you have to process a lot of natural thorium to get there, but it's another important way that we could get that Thorium-228 parent. Having those two shots on goal there between the reactor production and the natural extraction separation gives us an added layer of confidence in the supply chain behind Lead-212. I assume that's not the case for actinium. So, I guess, is that sort of the bottleneck for actinium there? I know they're- Yeah ... trying different production methods as well. Maybe talk a little bit about that. Yeah, actinium does have more of a challenge. There's not such a long-lived parent isotope behind it, but there are a number of ways to get there. There are folks who are. Well, I shouldn't say there's not a long-lived parent, because I'll turn around and say TerraPower is using Thorium-229 for separation of it. That's maybe a fixed quantity. So you can't go dig Thorium-229 out of the ground, unlike the other isotopes I just mentioned. So TerraPower has access to that through a waste stream, and that's promising, and I know they've been shipping Actinium-225 recently. That's great to see. But I think there's concern about the capacity there and how much they can ramp up. Questions that are better for the TerraPower folks to comment on their ultimate capacities, but I know there's some concern there. The production routes for it use, you know, a number of different methods. Probably the two that you see most commonly are proton irradiation of a radium-226 target. So in a sort of normal cyclotron, and then using a different type of cyclotron-type machine, a particle accelerator, in order to also irradiate radium-226, but have a little bit different route to get there, to the actinium-225, going through a different parent isotope. Ultimately, both of those routes use radium-226, and radium-226 is hard to come by. It's radioactive in and of itself. It's extraordinarily expensive, and that makes it a bit more challenging. A lot of those companies that produce actinium have built up a meaningful inventory of it, and that gives them an advantage there, in that supply chain. I think it's really about proving the capacity, reliability, and efficiency of those different production routes, to see who can do that, in a manner that's gonna be the most commercially successful. But I think, as I said earlier, I'm confident that as an industry, we'll get there, on actinium production. It's just a matter of time. Yeah, great. So John, you talked about the clinical perspective, right, for isotopes, and I think the field has this big trend is moving from beta to alpha emitters. And the perception is very much alpha emitters are more potent than beta emitters. So I guess assuming that we solve the supply chain for alphas, do you think there'll be a role for beta emitters like lutetium? I do, and I think that while there's this great theoretical advantage behind alpha emitters in terms of the delivery of much more energy over a shorter distance to the tumor and hopefully a corresponding increased efficacy there, I think that there's a lot that beta emitters still have to offer. First, just in the demonstrated success, so to see the number of beta emitter-based therapies out there that work, that are providing survival benefit, or in the case of very old things like thyroid cancer, that are curing disease, it's, you know, it's really a strong base to stand on for the beta emitters, going forward. The alpha emitters do seem to have a lot of promise, and I'm extraordinarily interested in them. But I think there are a lot of questions out there about how well they're going to be tolerated. And ultimately, if we haven't changed the therapeutic index, the ratio of dose to the tumor versus dose to a healthy organ, then it's not intuitively obvious that an alpha emitter is gonna be able to do better than a beta emitter. Now, I think there are reasons to be optimistic about the alpha emitters and the mechanisms of cell death there are less susceptible to recovery by the cell. In other words, they create such a large number of double strand breaks in the DNA that just a few transits of a cell by an alpha particle would kill that cell. And you know, regardless of needing some sort of BRCA1, BRCA2 mutation or something to make it radiosensitive, it seems like there's good evidence that alpha emitters can overcome that radio resistance and still kill cells. So that's great reason to be excited about them. I think also when you look at involvement of the immune system and the level of immunogenicity from alpha radiation versus beta radiation, there's more reason to think that alpha particles may elicit a stronger immune response. And that could be beneficial either standalone or potentially in combination therapy. So I do think that there's a lot of good reason to be excited about alpha emitters, but the beta emitters with, you know, with their different mechanisms of action probably better tolerability on the whole because they're also doing less damage to healthy tissue. And things like longer range could certainly have a continuing role there. And, you know, a lot of people discuss combination of alpha and beta therapy together, and perhaps having the mix of the two different types of radiation could address some issues of how well different cells within a lesion get targeted. And I think there is a notion because, as you mentioned, lutetium has a little bit longer travel path versus some of the, the alpha emitters. So there is a notion that maybe for bulky tumors, you can use lutetium versus actinium or lead. I mean, what is your view on that? Yeah, I know there was a lot of people felt that way, I think, particularly a few years ago, and then we saw some evidence where actinium-225 was used in bulky tumors and was effective. So clearly, it's not a surface-level answer of bulky tumors are gonna be better treated with betas and micrometastases with alphas. There may be some truth behind that, but it may depend on how well vascularized the different lesions are. And there may just be more factors to it. Inevitably, there are more factors to it than just the size of the lesions. But that could ultimately be a factor in selection of when we use a beta therapy versus an alpha therapy. Okay, so I want to maybe dig a little bit deeper into lutetium, actinium, and lead. I think those are sort of the three isotopes a lot of investors are very focused on. And we have programs in this space, you know, targeting PSMA or somatostatin, basically just swap out lutetium with actinium and lead. So John, I wonder if you can talk a little bit about pros and cons of handling these isotopes, especially for the same target. Yes. How do we choose which one is the best, and how do we sequence them? How do we use them? Yeah, absolutely, Li. And I love the fact that you said handling in there, because handling and the safety aspects of it are tremendously important. So I'll jump first to the clinical efficacy piece. And, you know, NETTER- 1, NETTER- 2 results with lutetium dotatate, those have been promising. lutetium dotatate is in many ways standard of care now. The early results, especially with Lead, seem extraordinarily promising, and maybe that SSTR-targeted Lead molecules are going to show even higher efficacy. That would be a wonderful thing. Actinium, the data aren't quite as clear to me yet. That's one of the things that I, that I'm most looking forward to seeing for the alpha emitters is those clinical results, especially, as we get them likely first within the SSTR area. I think that from a. We talked about supply chain earlier, so I, I'll kind of, I'll skip over that for now. But from a handling standpoint, one of the big differences there is in half-life, and Actinium-225 has about a 10-day half-life. Lutetium-177 has a 7-day half-life, and then Lead-212 with an 11-hour half-life. So you've got quite a range there. That's likely going to have an effect on the clinical performance because even if you deliver equivalent dose to the tumor with all three of those isotopes, just the fact that you're delivering it within a different time frame is likely to have some sort of difference in response. And a higher dose rate, delivering the same dose but over a shorter period of time, depending on disease state, the rate of cell proliferation, all those sort of things, may have a stronger effect. So one of the things that we're interested in about Lead-212 is that short half-life, high dose rate, and for certain diseases and disease states, does that have a higher efficacy, in terms of the same dose, eliciting a stronger response, against the tumor? But that also then plays into waste handling, and in administration. So when you administer an isotope with a shorter half-life, in order to get an equivalent amount of activity to the tumor, you generally need a much higher dose at first, and it's roughly proportional or inversely proportional to the half-lives there. So if it's a 20x shorter half-life, you need about 20x the dose, in order to have the same number of decays over time. So you have a higher starting activity to deal with, and maybe that presents a little bit more radiation exposure for the healthcare providers. Although, with alpha emitters especially, we're talking such small quantities, that's not likely significant. Then, when you look at the other end of it, of waste handling, we as a rule of thumb, we say you have to hold on to waste for 10 half-lives. So if you have 10 half-lives of an 11-hour half-life isotope, you know, now you're talking just a few days, 4 days-ish, and that waste is fully decayed, and at that point is essentially non-radioactive. 10 half-lives of a 10-day isotope, you have to hold on to that waste for 3 months, and that's a much more difficult thing for healthcare providers to manage. And when you think about patients and the waste that the patients have to deal with themselves, that's that can also be a challenge or an issue there. So, the waste handling aspect of it is not insignificant and definitely favors short half-life isotopes in terms of making that easier. Lutetium has an interesting wrinkle to it because there are a couple different ways to make it, and one of the routes by which it's made gives it a long half-life impurity, Lutetium-177m. M means metastable, and that has a 100-day-plus half-life. And that can be a problem for waste handling as well. There's not enough of that in the dose that it really would be expected to affect clinical performance or how it behaves within the patient, the radiation that the patients receive. But it does mean that the waste remains radioactive for a long time, and we've heard a lot of concern from healthcare providers about their ability to handle lutetium products with that lutetium-177m impurity. And as we've worked with POINT on their products, and importantly, those two products, PNT2002 and PNT2003, use only the non-carrier-added version of lutetium, which does not have that impurity. Okay. So John, you mentioned, right, you want to match the half-life of the binder and the isotope. Maybe expand on that concept a little bit. Why does it matter from a clinical standpoint? Sure. So, you know, and when you think about how these molecules distribute within the body, if you inject something like a full-sized antibody, and there are a lot of radiopharmaceutical companies out there who are working with full-sized antibodies, those take a couple of days, maybe even more, maybe 3 or 4 days, to really reach the peak binding and concentration at the tumor lesion. And if you put an isotope on that that has a half-life of, say, 11 hours, like lead, the lead would all be decayed away by the time that it reached that peak concentration of the tumor. Now, it may be okay to have a short half-life isotope with some antibodies if they, if they're faster, if they have faster kinetics and enough of it gets there on time. But you have to be careful about matching that up in order to not have too much of the decay occur in the blood or while the product is still circulating through the body. Conversely, if you have a very fast molecule, most of the small molecule PSMA agents out there have pretty quick kinetics. Then you can put a short half-life isotope like Lead-212 on there, and it's likely that you'll deliver most of the dose to the tumor and not while it's circulating in the blood. But if you were to use a long half-life isotope, say Actinium-225, then you have to worry not only about how quickly it gets there, but also about how much it comes off, and whether there's redistribution through the body, and where it's gonna go over the full half-life of the isotope, and how much time it's gonna spend as it's cleared from the body in different areas. And so it doesn't necessarily mean that a fast half-life or a fast kinetics molecule has to have a short half-life isotope, but there's just a little bit more work to be done to understand what happens if you put a long half-life isotope on there, after a couple of days. Is it, is it redistributing through the body now, or does it stay bound? Does it get internalized at the tumor? So I guess it's another question about the binder modality, right? So it sounds like the field is looking at the smaller modality. We're talking about small molecules, we're talking about peptides. So, just based on what you've said, John, I mean, do you think the optimal isotope for these smaller modalities may be lead because it has shorter half-life? Versus if you're using antibody-based binders, maybe actinium could be a better match. I mean, what is your view on that? Right. I think it's easier for me to say that if you're gonna use a full-sized antibody, you need to have a longer half-life, almost inevitably, a longer half-life isotope. If you use a small molecule, then it opens up the world of isotopes that you can use, and now you have the ability to use the shorter half-life isotopes, like Lead-212. And that's where there are some interesting aspects there that we like early on. We still need more clinical data on this to understand that these things really are significant, but the corresponding higher dose rate of a short half-life isotope, and the easier waste handling. Of course, the logistics are more challenging. Now you have to get this thing that's decaying so quickly all the way from manufacturing to the patient within a short period of time. So there are trade-offs in all of those things, but to me, it's using small molecules opens up the world of isotopes that you can pair with. And then with actinium and lead, I wanted to talk a little bit about the distribution models here. I mean, of course, you know, from the clinical standpoint, it makes a lot of sense to use lead, but also from the distribution perspective, like, we're really talking about centralized versus regional distribution here. So maybe tell us a little bit about, you know, manufacturing and distribution side of these two isotopes, and just because the lead is so, half-life is so short, I mean, how do you solve the logistics here? Yeah, great, great question. Let me start with actinium. So actinium, 10-day half-life, that's, that's one of the longer half-life isotopes, out there in the radiopharmaceutical world. So that, that is kind of the luxury of time that, that many products don't have. And, I think, you know, importantly, what, what that enables, for actinium is production of the radiochemical, just the Actinium-225 itself, not the, not the finished drug product, at centralized, specialized, companies. And those companies can then distribute that around the world. So that, that's a great thing, that's a great advantage for actinium, from a radiochemical infrastructure standpoint. Then, when you match that up with the drug molecule, make the finished pharmaceutical product, you do have time from a half-life standpoint, and as you pointed out, can enable centralized distribution and perhaps even international distribution for Actinium-225 finished products. But with any radiopharmaceutical, really with any drug product, you have to be worried about stability, all the more so with alpha emitters. Alpha emitters give off so much energy as they're decaying in solution, that stability of those drug products, even over, you know, a matter of a couple of days, can be pretty challenging. So, it's an important challenge for us as drug manufacturers to solve, to ensure that we have a formulation of these alpha emitter based drugs that can remain stable long enough to take advantage of that half-life. And it may not mean the full 10 days, but maybe it means that the drug product is stable for 5 days or 7 days, so that we can have that ease of distribution, and the healthcare providers can receive the drug product one day and administer it the next, or maybe even the day after. And those are all advantages for a longer half-life isotope that the short half-life isotopes certainly don't have. For Lead-212, there are a lot of folks who view a Lead-212 distribution chain as a distributed manufacturing approach and maybe even kit products, that there are these generators sitting in radiopharmacies, as we've done for decades for SPECT products, and the radiopharmacies mix up generator eluate with a kit product and prepare a dose just for people who are within a short drive radius of their site. That may be a possibility. I would say personally, I would have some concern about that level of distributed manufacturing for a therapy, where we have to be absolutely certain, because this is a potent enough product that it is going to do damage to cells in the body. We want those to be the cancer cells, not the healthy cells. To do that final step of manufacturing in a radiopharmacy environment, as opposed to a GMP manufacturing environment, would give me pause. So for a Lead-212 product, what I would envision is, while there might be a more distributed version of manufacturing than you know, just one or two sites around the country. Those do need to be full GMP, FDA-regulated facilities, and not under the PET drug regulations, but the normal drug regulations, for therapeutic pharmaceutical products. We need that level of quality of manufacturing behind the Lead-212 therapies. It could be that we need several of those around the country, and probably in the early stages, in clinical stages, it's more distributed because you have smaller scale manufacturing, and the requirements aren't quite as strenuous as for full-scale commercial manufacturing. But quite honestly, an 11-hour half-life isn't that bad. There are plenty of products out there on the diagnostic side, like Iodine-123, that we've been using for a long, long time, that have similar half-lives, and that we centrally manufacture and distribute around the country. At Lantheus, we do this day in, day out. We make products routinely. In fact, we're making them right now, where we will manufacture the products started at 6:00 A.M. this morning. We're gonna manufacture them over the course of today. They're gonna ship out tonight, and patients will be injected with material from those products or with those products themselves tomorrow morning. So we can, we can do that with Lead-212 as well. We can centrally manufacture products and distribute them across at least the U.S., maybe North America, from 1 to 3 sites within the U.S. We'd wanna have more than one site just for redundancy, but I think in terms of, of the need and the ability, in principle, it can be done from a centralized site. Now, we're not gonna ship to Europe, or it's unlikely that we would ship to Europe from the U.S. or vice versa, for a Lead-212 product. There does need to be some level of, you know, regional, continental, manufacturing, most likely, but I wouldn't discount the possibility of a relatively centralized approach, even for something like Lead-212, with an 11-hour half-life. Okay, so I wanted to talk a little bit about quality control here. I mean, radiopharmacy sounds like some of the QC work is done in parallel to when drug products are being shipped to customers. So maybe just talk a little bit about that process and what happens in the event that it's not up to standard. Yeah, that's a great question, and it gets into the details of how do you do same-day manufacturing and release? And I'll tell you from my experience in the pharma world outside of nuclear medicine, normally from the time you make a product until the time you release it to patients is at least a couple of weeks, usually more like a month, and that's when things are going well, and that's when you've got a robust system that's working smoothly. So to be able to do all of that in one day requires you to have an extraordinarily efficient and robust manufacturing, testing, and release process, and the QC there then needs to start as early as you can have it start. So when we're making drug products, as the very first vials or form whatever format they're in, product is coming off the line, we wanna immediately start the QC tests on those so they can be running while the things like inspection, labeling, secondary packaging, are still happening for the rest of the batch, and then we're doing those in parallel. And having a quality control laboratory that is set up, staffed, has the equipment, the processes, the redundancies, to be able to perform those tests in a quick, reliable, efficient manner so that you get as many results as you can before you release that product from your control is the way to do it. Now, there are some areas where people take different approaches there, and release from your control could mean you don't let it leave the factory, or it could mean you don't let it leave the possession of your own courier, or those sort of things. So there are some ways to stretch that and to ensure that you still get the most efficient delivery and the longest delivery range out of those things. There are a couple of important tests that can't be done for almost all products within the required time frame for normal pharmaceuticals and the shelf life of radiopharmaceuticals. And when we do some of the microbiological tests that require incubation for a couple of weeks, those are things that we have to do on risk, and that's allowed within the USP within the pharmacopeia. So for radiopharmaceuticals, you're allowed to do that test in parallel with its distribution and use in the patient population. Of course, you have to notify customers, FDA, if there was an issue with those tests. But by and large, the tests are done before the product is released and administered to patients. As with any drug product, if there's a failure to meet specifications, then you would hold that product until you can investigate that failure, and immediately have to extend that investigation and at least assess potential impact to other lots, and ensure that the other products and other batches of that same product that you made at other times are not affected. Okay, I know we only have a couple of minutes left, so I wanted to touch on diagnostics. So, I guess what makes one radioisotope better than the other in the context of PET imaging? Yeah. There are a few things that I can talk about there. And, you know, the easiest to compare, I think, are Fluorine-18 and Gallium-68, because those are the two that are most commonly used today. Copper-64 is another interesting one, and as you know, we're using that in our FAPI clinical program. So that's maybe a third to throw in the mix. Some folks are using Zirconium-89. And its half-life is certainly an issue there. Supply chain is an issue. When you think about PET technology, so positron emission tomography, there's an interesting sort of intermediate step in how those products work. For a PET isotope, a molecule gets to a certain spot in the body, and then the thing that it gives off is not-... Photons that can be immediately imaged by a camera, the thing it gives off is a positron, and that positron is going to go some distance from the site where the molecule was bound before it collides with an electron. So positron is an antimatter electron, and when that positron collides with a normal electron, they annihilate one another, and they give off two photons. And those are the photons that are imaged by the cameras and turned into a diagnostic image. The distance that that positron travels then gives kind of a fuzziness to the picture, and if the positron travels a longer distance, then you're gonna have a blurrier image. If it travels a shorter distance, you're gonna have a crisper image because it's the annihilation, the source of the photons, is closer to the actual site that the molecule was attached, which is likely the tumor lesion. So looking for a short positron range is important. Fluorine-18 has just about the shortest range, positron range of any of the PET isotopes out there. Copper-64 is pretty close. Copper-64 is just a little bit longer than F-18. When you get out to the things like Zirconium-89 and Gallium-68 especially, that's a pretty long range that those positrons are traveling, and that degrades the image quality a bit. Now, still, obviously very usable. There are approved products out there, so that's not to say that you can't have a diagnostic image off of those things, but it's not as crisp as we would like, all other things being equal. Another aspect is half-life. Fluorine-18 has roughly a two-hour half-life, gallium-68, roughly one hour. So that can create differences in how they're distributed. F-18 is relatively more centralized, although we still have, you know, over 50 sites around the country making fluorine. Whereas gallium-68 has to be more distributed, but gallium-68 has generators, so it can be more distributed. That works reasonably well. It also... Half-life also affects the imaging procedure, so from the time it's administered to the patient, it's, of course, continuing to decay, and the longer the half-life, the later out that you can perform imaging. So things like Copper-64 or Zirconium-89 add some interesting capabilities to image on subsequent days, whereas F-18 and Gallium-68, of course, have to be same day and even within a couple of hours of administration. All right, maybe just the last question from the audience. I guess, how do you see radiopharmaceuticals fit in terms of line of therapy? I think right now, most current radiopharmaceuticals are utilized after other lines of therapy have been exhausted. So I guess, what is your view on, you know, moving this modality earlier in, the treatment, algorithm? And what needs- Yeah, absolutely. What needs to be seen? So, you know, inevitably, new therapies, new modalities start this way, right? You start last line, and you move up. I am so excited about radiopharmaceuticals and the benefit they can provide patients. And I think what we've seen in so many of these trials is that they've demonstrated good efficacy, they've demonstrated great safety and quality of life compared to chemo is just night and day in so many of these studies. And when you think about the effect on a patient, not only being able to treat the disease, but of limiting the change to how they live their life, I think that's a great benefit of radiopharmaceuticals, and I'm excited to see them move further up in the lines of treatment. Okay, great. So I wish we had more time, but unfortunately, we have to wrap up. I want to thank John again for the terrific discussions and really appreciate your insights. Thanks, Li.