Good morning, everybody. So my name is Andy Shea. I'm a research analyst here at William Blair. I cover Lantheus. I'm required to inform you that for a complete list of research disclosures and potential conflicts of interest, please visit our website at williamblair.com. So we're pleased to have John Wiggins, the VP, head of asset leadership, with us today. And we're going to do this a little bit differently. We're not going to have a presentation, but we're going to have a fireside chat about company operations with a specific focus on isotopes so and then after our fireside chat our breakout is going to be burnham b on the second floor so john thank you for uh joining us today maybe for the first you know kind of part you can talk about lantheist strategy kind of the operations and why isotope is such central to your you know company strategy and positioning Yeah, absolutely.

So I'm John Wiggins, head of asset leadership at Lantheus, and for those of you who don't know, Lantheus is the leading radiopharmaceutical-focused company, and radiopharmaceuticals may be unfamiliar to some people, so I'll just give a quick background on that. When we think about radiopharmaceuticals, they're often called molecularly targeted agents because we administer a drug that binds to very specific molecules within the body. If I take prostate cancer as an example, there's a protein that sits on the surface of prostate cancer cells called PSMA, the prostate-specific membrane antigen, and our drugs can find that protein, bind to that, and then in the case of our drugs, which are diagnostics, essentially light up those tumor cells. So they give off a particular type of radiation that's detectable by what's called a positron emission tomography scanner, a PET scanner, and then physicians can see an image of what where in the body that drug is gone which generally indicates where in the body there's prostate cancer so if there's a question of whether a patient has metastatic disease or not you can administer a dose of polarify and it will light up anywhere in the body that there's prostate cancer and then the physician can tell if there is metastatic disease if it's gone beyond the prostate itself there are also companies that make therapeutics and we have some therapeutic agents in our own pipeline those use a different type of radiation and can kill off cancer cells for example and treat disease that way in addition to being able to see it we think about isotope strategy the the different radioactive isotopes that you attach to that pharmaceutical molecule have different effects so I talked already about the difference between imaging and therapy in the type of radiation that's given off by those isotopes but even within diagnostics of the different types of isotopes that we can use all have different properties and there are things like half-life which is how quickly they they decay away and that affects how how close to the patient they have to be made how long the physicians have to administer the drug and then take an image there are there are properties like the the range of the radiation that they give off which end up affecting the resolution of the image whether we can get a nice crisp image with very high resolution or whether there's a little bit of blur to the image and then how often those isotopes give off a particular type of radiation and that can affect things like scan time so how long it takes uh for the for the image to be acquired how long the patient has to be in that scanner and therefore ultimately the throughput of the imaging center so a lot of different properties here that we have to take into account when we're developing our agents and picking what which isotope we want to use yeah maybe we can talk a little bit about how they're produced because it's fundamentally different from what we know you know bioreactors small molecules right it's basically chemical synthesis so so how do you think about you know upstream ways to produce these short half-life isotopes yeah the supply chain for radiopharmaceuticals is an integral part of this whole ecosystem because these these things are radioactive and are decaying all the time we can't make a product that sits on the shelf we have to be able to make it essentially in real time. And that could mean anything as close to a couple hours before it's administered to maybe out to a week or so before it's administered for the relatively long half-life isotopes. The way that those isotopes are made generally starts with some sort of enriched stable isotope. So in the case of, for example, fluorine-18, which is the isotope that we use with Polarify, that starts with oxygen-18. So there's a particular type of water that our contract manufacturers use that's called oxygen 18 enriched water so if you think about water as h2o it means the o in that case is oxygen 18 specifically and when you put that on a cyclotron which is a particle accelerator and strike it with a proton it absorbs that proton and it kicks out a neutron and that becomes fluorine 18 so this is uh this is basically particle physics but it's being put to use for medical imaging there are other Other types of isotopes, like gallium-68, which we use in a number of products in our pipeline that are produced from a generator. So in that case, you might use that same kind of particle-accelerator approach to produce what's called a parent isotope, and the parent isotope in this case is germanium-68. And germanium-68 has a much longer half-life, a couple hundred days, and it sits in a little unit about the size of a paint can, and it is constantly decaying to gallium-68. and by eluding that generator by by rinsing a special solution through it you can collect the gallium-68 that's been produced gallium-68 has a short half-life about an hour so you need essentially a new batch of it every couple of hours to be able to produce imaging agent and that generator gives you an item that can sit I'll say on the shelf it's really inside of a clean room hood and you can continually produce fresh gallium-68 off of that generator so those are those are very different supply chains one of them requires a cyclotron to be sitting relatively close to the patient and then it produces a large number of doses for use in that immediate area the other one requires just that little pink hand-sized thing but you also only get a couple of doses off of it at a time so maybe you can also talk a little bit about some of the therapeutic isotope lutetium 177 things like that yeah how How would that different from the generator-based and the cyclotron-based production methodologies? Yeah, lutetium-177 is the isotope that we use for the therapies that we have in our pipeline, and it's the most widely used isotope in therapy today, at least in new molecularly targeted therapies, and that's produced in a nuclear reactor. So it starts with an enriched isotope again, in this case it's called uterbium-176. That's put into a nuclear reactor. nuclear reactors give off lots of neutrons that uterbium target captures one of those neutrons turns into uterbium-177 which decays into lutetium-177 and then that can be separated out extracted and attached to these molecules and then that that gives off a different type of radiation that can be used to kill off cancer cells but that that supply chain because lutetium is a bit longer half-life about a week that can be done in reactors all around the world shipped to processing centers and then to pharmaceutical manufacturing facilities and used to make patient doses. Those patient doses still typically have to be administered within a few days of production. So it's still a very short supply chain. You can't make the product and put it on a shelf.

Yeah. Well, I appreciate your 101 on alchemy, but I also wanted to talk about these complex supply chains. there's been historically a lot of you know different disruptions right you know Bristol Myers after the acquisition raised bio they did have some some hiccups there also the kind of the OG of the radiopharma space Novartis you know after launching Pluvicto there were two major supply disruptions so talk a little bit about some of the remediation strategies that you have at Lampia's to really you know mitigate potential supply disruptions and maybe identify where in that supply chain you see major problems yeah I think the two

different so Victor disruptions that you read things are really really enlightening because they were for two different reasons one of them was that lutetium shortage and and the fact that there wasn't enough lutetium 177 being produced in the world that it wasn't reliable enough that that the production was concentrated in a small group of nuclear reactors in Europe and it happened that all of those essentially went offline at the same time and because there were there were no reactors available to make more lutetium it we very quickly run out of supply within a week or two and therefore there there wasn't enough the lutetium supply chain has since become much more robust and it's a relatively commoditized product now there are a lot of people who make it in a lot of different reactors around the world including in nuclear power reactors in the U.S. and because nuclear power reactors run a very high percentage of the time that means that it's much more routinely available now. The actinium-225 shortage that you referenced with Ray's Bio, I think it's really just that actinium is in that same point in its life cycle that lutetium was several years ago. And I'm sure that actinium will go through that same growth curve and will ultimately be robustly available, but it's not there yet. The second Flavicto outage wasn't because of the isotope shortage. It was because of finished pharmaceutical manufacturing. And as you might imagine, making a radioactive drug takes a whole different set of sort of safety requirements and manufacturing capabilities than a typical pharmaceutical. And because Pluvicto was the first really large scale lutetium product, radiopharmaceutical therapy, that didn't exist in the way that it needed to. and we had to also build out or in this case Novartis had to build out the manufacturing infrastructure for the for the finished pharmaceutical drug and that has to meet these these two competing requirements on the one hand it has to meet the FDA requirements which are basically separate make the make the drug safe from contamination and people are the biggest source of contamination so keep the keep the drug in the safe spot the kind of I don't know, insulated, isolated area of manufacturing. And usually what that means is, if you think about that from an airflow standpoint, it means all the fresh air goes right to where the drug is being made, and then it flows outward to the people. But for radiation safety, you want exactly the opposite. For radiation safety, you want the airflow to go away from the people and into where the radioactivity is. And you can't have both those things. So that's a tough thing to do to to build that manufacturing environment that can meet both the FDA requirements as well as the Nuclear Regulatory Commission requirements. At Lantheus, on the diagnostic side, we have the advantage of working with this infrastructure of fluorine-18 manufacturers that have been around for a few decades at this point. We've been making fluteoxyglucose, FDG, and there are over 2 million scans a year done with FDG because it's been around for so long, it's well-established, and Polarify fit right into that manufacturing infrastructure. So unlike the therapeutic developers who are going through this kind of learning curve and growth curve of a brand new type of product out there, we're plugging into an existing manufacturing infrastructure, and that has certainly made it an easier path to get Polarify to where it is today. And similarly, when we look ahead at our pipeline of diagnostic agents, by and large, they fall into that same sort of thing. They're either fluorine 18, fitting into what we call the PET manufacturing facility infrastructure, or they're gallium 68, or they fit into a radiopharmacy infrastructure, and that's using those kind of paint can type things that I described earlier. I would say there's a notable exception there in copper 64. We have one agent in our pipeline that uses copper 64. This is a fibroblast activation protein, or FAP-targeted agent. FAP is broadly expressed across a lot of solid tumors. it's also expressed in fibrotic diseases like mash liver disease like cardiac fibrosis pulmonary fibrosis so we see ultimately that the potential for a very large market there and one of the things that we like about copper 64 is it has a little bit longer half-life 12 hours versus the two hours for fluorine 18 or one hour for gallium 68 and therefore might be able to be centrally manufactured but that copper 64 infrastructure doesn't exist today so that's one that's going to have to go through that growth curve and we're going to have to build up much more robust supply of that. We think we've timed this right to have a phase one agent because by the time it's ready for commercialization, that infrastructure will be in place, but it's certainly not there today.

Yeah, yeah, it's very interesting in terms of the fluorine 18 gallium 60A comparison. I'm curious if you can quantify that for us in terms of the volume, right? I mean, And that's a very important question in terms of the scalability of psychotron-produced versus generator-produced gallium-68.

Yeah, that's a great question for PET, for positron emission tomography in general. We've just seen such dramatic growth of things like Polarify and PSMA PET in prostate cancer. Of course, we're excited now about the amyloid agents. We're doing Alzheimer's imaging for those, and that's a very quickly growing market. So there has been a fantastic growth, but we're starting from that base of FDG that I mentioned of 2 million plus doses a year. So it's not from zero to 500,000 doses a year. It's a little bit more modest growth overall. As we look at the availability of F18 capacity, of production capacity on those cyclotrons, we're seeing robust investment in new cyclotrons, in new pet manufacturing facilities, in upgrades of existing pet manufacturing facilities. And we're confident that we're going to be able to keep up, at least on a national level, with the demand for F-18. Because F-18 is still a short half-life, that two-hour half-life, production, like all politics is local, all F-18 production is local, and there may be some kind of bumpy spots throughout the U.S. in terms of, hey, this city is going to be behind on F-18 manufacture. But at a large scale, at least, we believe that there's going to be robust capacity there. Gallium-68 is a different ecosystem because it's now these generators instead of cyclotrons. We again see a good growth in the production of those generators and the kind of capacity of those generators. But they take up a lot of clean room floor space in radiopharmacies, and that's expensive floor space. So we see that radiopharmacies are going to have to add more space to put these generators and to use them in production of radiopharmaceuticals. Again, we think that's going to keep pace with the demand that we and others are bringing to it. But it does take the investment that's going on. And then copper 64, as I mentioned, that has a lot further to go. But we do see the investment there that we think is necessary to make that happen. If I look beyond the isotope production and the radiopharmaceutical production, and the next piece we need, of course, is scanning. We need the PET imaging machines. And we are seeing a lot of investment in those. That's probably more of the bottleneck than the isotope, than the pharmaceutical production. And what we're seeing there is that these imaging centers are starting to open on weekends, extend their hours, and do what they can to make more slots available during the week. The other piece of that that's important that I mentioned earlier is throughput. And with an F18 agent like Polarify, what we see is that these centers can get a faster patient throughput. They can shorten their scan time per patient in comparison to some other agents like Gallium-based agents that require a little bit longer scan time to get the same amount of information out of the scan. And that may be an advantage for our customers in using Polarify versus other agents to be able to make better use, more efficient use of the existing infrastructure that they have. Along with increasing the number of scanners and the times those scanners run though, we have to have staffing to do that. We see that staffing can be a real challenge there.

We're working closely with not only industry associations, but also associations of physicians and technologists, including the Society of Nuclear Medicine, to train up more and more of these technologists and make them available to operate these scanners at extended hours and more days of the week. yeah I wanted to ask you about the patient flow so a patient comes in get the infusion plurified you know what can you describe what happens afterwards and then finally to the image acquisition and then the results I've heard also new machines you know one at Peter Mac down in Australia they basically have low single-digit you know image acquisition time so talk a little bit about some of the newer technologies from you know scanner manufacturers and potentially how can that squeeze in the patient, you know, inpatient time, and therefore allowing a more robust number of patients getting scanned too. Absolutely.

So that just to go through that whole patient process, that patient flow, the patient comes in, ideally, the dose is already there waiting for them. But these doses are delivered, you know, with within an hour, maybe in many cases of the time that they're going to be injected into the patient. So this is a very, a very real sort of thing and and things can go wrong there you know you can have a driver stuck in traffic or the patient stuck in traffic and things aren't there at exactly the right time so it's very careful it's takes very careful planning to get those doses there right when they need to be there and make them available for the patient typically and this is the case for a prostate cancer imaging after the patient's injected they'll go through an uptake time it takes some time for the drug to circulate in the body and bind to the tumor and clear out of the bloodstream and and away from healthy tissue and that's about an hour so usually the patient will be sitting in a holding room for about an hour and that can be a limiting limiting factor on capacity for a lot of these imaging centers is that they don't have enough rooms to hold these patients in and as they add another scanner for example they need to add a suite of holding rooms along with that so that's another area of investment for these imaging centers is to be sure that they have the capacity to do that. After that hour, the patient's going to go lie on the scanner, and you talked about the different types of scanners, and in many cases, it's the different age of scanners. Newer scanners have more sensitive detectors, and those may therefore allow shorter imaging times. They also have things called time-of-flight imaging, which can tell more precisely where the radiation emission occurred within the patient and give you a more high-resolution CRISPR image, potentially with less data and therefore with less time on the scanner. The other thing that we've seen a lot recently is just the size of the scanner. So originally these scanners might only image a slice of the patient that's maybe a foot at a time, or maybe not even that much, and the patient has to wait a minute or two at that position, maybe four or five minutes at that position, then advance to the next slice and kind of move all the way through, and that could take a half hour or more to acquire a full image you talk about Peter Mac and some of these other places that have whole body scanners where the scanner is the full length of the patient and therefore you're requiring all of this information at once and that gives you a much shorter scan time and it can also do some really cool stuff in the clinical phase or you can dynamically watch the agent being injected and see where it goes in the body as it's as it's going through that uptake pattern and that can actually be useful in a lot of cases not only for that clinical stage drug development, but then in developing what you want the imaging protocol to look like. And as an example, one of our agents that's actually, it's commercially available today is NeuroSeq, and we're developing it in cardiac amyloidosis as well. So today it's used for Alzheimer's imaging and the future potentially also for cardiac amyloidosis. There are two different types of cardiac amyloidosis, light chain and ATTR. And we see the potential with this agent using either dynamic imaging, so where you actually watch the uptake over the first you know 15 minutes or so after injection or maybe it's just two time point imaging so you look five minutes after injection then again 15 minutes after injection that we can diagnose cardiac hemoidosis and then potentially distinguish between the two types and they have two different therapeutic approaches so that's useful information to get out of it and it's certainly easier to do on one of those whole body scanners now in the case of cardiac imaging you're only imaging a small slice of the body anyway so that can also be done on one of those older scanners as well but the type of scanner that you're using is certainly important after the scan it's important to realize you know this this patient's been injected with radioactivity and to some extent they're giving off radiation after that so we need to be careful about where that patient goes what they do when they can be released for agents like gallium 68 isotopes like gallium 68 and fluorine 18 that have short half lives it's really not an issue there the patient is giving off low levels of radiation to begin with and they're only giving them off in meaningful levels for a few hours afterwards so that's not enough time to do to be of any danger to the public when we think about longer half-life isotopes and this can be the case for the therapeutic isotopes where there are large quantities administered or potentially for agents like zirconium 89 for example that patient is going to be giving off more radiation and giving it off for a longer time period and in some cases there have to be restrictions on when those patients can be released from the hospital and what they can do afterwards for example they may be given instruction to isolate from their family for a day or two and that can be a limit on how much of these isotopes we can give to a patient and therefore the therapeutic efficacy so we have to have this kind of careful balance of giving enough to treat the disease but not so much that there's a danger from radiation and as therapeutic companies are developing their products that's an important factor for them to take into consideration yeah i think i think this is a good time to kind of wrap summarize all the isotopes that you have talked about just in the pet imaging area basically

gallium-68 fluorine-18 zirconium right and then and then and then copper just because there's so many things out there there there are you know kind of things that's in regulatory review there are things that's in phase three that could come online in two years so just do a quick summary for us pros and cons you know some of the you know physical properties biological properties for us for those four pet imaging isotopes yeah absolutely let me let me try doing it by uh by property so if i if i start with half-life i'll go from shortest to longest here so gallium 68 is about a one hour half-life fluorine 18 is about two hours copper 64 is 12 and then zirconium 89 is about three days and that that makes a difference in a few ways one is the supply chain

So the shorter the half-life, the closer the production it has to be to the patient, the more real-time it all is. So things like once you get to copper, to 12 hours, you can conceivably do centralized production. And we have isotopes today like iodine-123 with a similar half-life that are centrally produced in the U.S., distributed, and used in relatively high volume. So we've seen proof that centralized manufacturing with that 12-hour half-life can work once there's enough supply infrastructure. And centralized manufacturing gives some advantages from a kind of a manufacturing efficiency standpoint. It's relatively transparent to the customers and to the patients what that supply chain looks like kind of behind the scenes. The other area where half-life can be interesting and useful is in the imaging protocol and what type of pharmaceuticals you can use there. So with zirconium-89, for instance, with that three-day half-life, if you have an antibody, like a full-sized antibody as opposed to a small molecule, the kinetics there are just much slower. And typically it takes a day or maybe a few days for an antibody to fully bind to the target and to clear out from the blood pool. And therefore you need a longer half-life isotope like zirconium to be able to do that imaging. What we see in the general direction of our imaging development is an antibody may have advantages for therapeutic uses. We don't see as much advantage for diagnostics. And our preference is to have a small molecule that binds quickly so it can be a single session. The patient goes in, they're administered the drug, and then within a relatively short time, they're imaged, and they don't have to worry about coming back at some later time. And then if I go over to another property of radiation safety that I mentioned earlier, you have this fundamentally PET isotopes emit positrons, which give off a certain energy of gamma ray photon. And they all give off that same energy. They may also give off other types of radiation. So when we look at gallium-68 and fluorine-18, those are pretty clean. They don't give off a lot of other radiation, gallium-68 more so than F-18 does. Copper-64 and zirconium-89 do give off more other types of radiation, and zirconium-89 especially. So a big downside for zirconium-89 is that it's giving off this potentially more dangerous radiation, and because it's got a longer half-life, it's giving it off for a longer period of time. So that's another reason that we would lean away from zirconium-89 and away from that full-size antibody body as the pharmaceutical molecule that we want to use, and again, prefer the shorter half-life isotopes and the smaller molecules. Another aspect that I would look at is the scan time associated with these, and I mentioned this earlier in comparison of F18 and Polarify to gallium products. It's all the more so the case for copper 64. copper 64 gives off the positron which is a diagnostically useful type of radiation to us less than 20 percent of the time that it decays so if you want to get the the same amount of information with a scan using copper 64 you need about five times as much of it to be equivalent to gallium 68 and even more than that to to reach f18 levels and and that just may not be doable The half-life makes up for a little bit of that, but not a ton. So when we look at copper 64 and where that's useful, there has to be a clear advantage in terms of that longer half-life, and there has to be enough of it administered. And I think that the challenge that we've seen with a lot of the copper products, both the one that's commercial now and the ones that are in development, is that they've... I don't think they've done their dose development work correctly, I'll say. They're not administering enough activity to get a high quality image in a reasonable scan time and therefore a lot of these centers, especially a lot of the community centers that don't have the brand new state of the art full body scanners, which is the vast majority of them, are going to have to put patients on the scanner for a lot longer and then you go back to our capacity discussion earlier. That's just tough to do when you're in an environment where you've got more and more demand for PET scans and you really want to be sure that you've got efficient patient workflows and throughput maybe for the last question I want to ask about the true view you know it's version 2.0 you know supply chain perspective how do you kind of slot these two across your manufacturing you know infrastructure yeah absolutely that's a that's a great question so for those not familiar with polarify and maybe the radiopharmaceutical diagnostic market more broadly Polarify has been around for five plus years now and when when a new radiopharmaceuticals approved it can apply for what's called pass-through payment it's reimbursed at a higher level then that only lasts for three years so pass-through on Polarify has expired already what we see is that some of our competitors still have pass-through payment that only that only applies to traditional Medicare patients so fee-for-service Medicare patients in in the hospital outpatient setting. So it's a relatively, it's a minority of patients, but it can have implications beyond that as a lot of these hospital institutions want to use a single agent. We've come out with a new formulation of the PSMA molecule behind Polarify. So this is called Polarify TrueView. It's based off the same clinical studies that supported the original Polarify application. So the same initial diagnosis, initial staging, and biochemical recurrence. the difference is on the manufacturing side we've added a radio stabilizer which allows us to put more activity into each batch make a bigger batch of polarify and we can get out of that some combination of more doses or doses that are delivered further or have a later expiry time and that helps us with reaching more patients and especially we talked about the expanding hours of a lot of these imaging centers it helps us with reaching patients at more times of day in a more efficient way so you know we're excited to see that come to market and and bring that increased availability to patients because of that we also expect that it will bring with it pass-through payment through CMS so we've applied for that pass-through payment now we'll find out in mid September I think whether we whether we get it but that's expected as it's it's really just kind of a checklist of things that we have to go through to to get that payment and the biggest of those is FDA approval which has already When we think about how we roll that out, while we expect the coding for it to be effective on October 1st and the pass-through payment, that doesn't mean that that's loaded into all of the payer systems right away. So we want to give some time to be sure that there's really no friction for our customers and that they're able to get prior authorization where necessary, that they're able to get reimbursement smoothly, that they have it loaded into all of their systems. So we're not going to launch immediately on October 1st. So we're going to look later into Q4 to start our launch. And it's going to be a rollout geographically across the US. So we'll make TrueView available in one region first. And that's going to be one of our lower volume regions to be sure that everything goes smoothly, and that we have some time period after that before we continue the rollout to be sure that the manufacturing and the payment and everything is occurring as expected, and that we can address any issues that come up there. And then we'll continue to roll out that availability across the US.

Great, I think this is a great stopping point. So we'll continue our discussion up on second floor Burnham B. Thank you for your attention. Thanks John. Thanks Andy.