Welcome to our Fireside Chat with Lantheus, and we're thrilled to have John Wiggins, VP of Isotope Strategy, with us today. John, I thought we could start with maybe an overview of Lantheus and what you are working on and what you are excited about. Obviously, radiopharma is a very hot area right now.
Yeah, absolutely. There, you know, there are a lot of new people in radiopharma now. Lantheus has been doing this for 65+ years. We've, we've been in this field for a long, long time. We know it well. We know what it takes to be successful in this field. In terms of the things we're excited about now, certainly number one is PYLARIFY. We love the success of PYLARIFY, on track to be the first blockbuster diagnostic. That's just a fantastic thing to see, to hear urologists say to us that this is the biggest change in how they practice medicine in their 30+ year careers. You know, what an impact that has had on patient care, that's just phenomenal. And we're excited to replicate that success with some other products.
I would say neurology is very interesting and exciting for us right now. Of course, we have two assets there, a Beta amyloid asset and a Tau asset, which many people consider to be the best in class in their respective fields, and you know, we see diagnosis, disease monitoring, potentially therapeutic selection as strong areas where we can play with those two agents and provide tremendous value to patients, to their families, to healthcare providers in terms of the information around that terrible disease, whether patients have that or some other condition, how that might progress for them, potentially therapeutic selection and disease monitoring after that, so you know, those are the big areas for late stage assets, late stage fields right now.
Of course, PNT2002 going along with PYLARIFY and prostate cancer. Looking forward to the 75% OS read on that in the very near future. I think, you know, going beyond that, we've got PNT2003 for neuroendocrine tumors, which is with the FDA now. And we'll be looking to the end of the thirty-month stay on that, spring of 2026 potential launch. And then having early-stage assets in the pipeline. You know, we've now got this GRPR bombesin targeted agent, RM2. That's a really interesting one to combine with something like a PNT2002 that targets PSMA.
We see in prostate cancer, there's some complementarity between GRPR expression and PSMA expression, so potentially a lot of patients who may have PSMA-negative lesions or may just broadly be PSMA negative or have low PSMA expression, often those patients have higher GRPR expression. So to be able to put a GRPR agent with a PSMA agent, whether that winds up being, you know, different patients or in the same patient, that's a very interesting area for us. We're really pleased with how Life Molecular has developed that agent to date and to be able to take that over now and progress that through clinical development, just a fantastic opportunity. And then some even earlier stage assets with LRRC15 and Trop-2, where we've got some really interesting targets. I think LRRC15 is...
In some ways, you might think of it as a FAPI-like target. It's on the stromal tissue of the tumor, not the tumor cells themselves, typically. And it gives us a way to go after a lot of solid tumors, including some interesting ones like osteosarcoma in pediatric patients, where there's a high unmet need, a really terrible disease for those kids who get that. And to be able to offer a treatment there is a fantastic thing, and then potentially expand into other disease areas beyond that.
So it has been wonderful for us to go from being so focused on commercial assets, late-stage assets a bit, and now to move up the pipeline into those earlier stages, where we have even more ability to shape exactly how those drugs are used. Think about what isotopes we're gonna use with them, both now and over the long term, what the dosing regimens are gonna look like, what diseases we're going into, what combination therapies we might look at. It's just a great way to continue to build our clinical development expertise there. So those are the things that are interesting to me.
There's a lot going on.
Indeed.
So I guess before we dive into some of the programs and, you know, the commercial products, I did want to ask you just from the strategic perspective, right? Obviously, John, you mentioned that you're doing really well commercially, so you're in a position, maybe to take advantage of that. And obviously, you have, you know, new CEO coming in. So just, I guess, from your seat, whether you can speak to any sort of shift in terms of what you guys are working on and focusing on.
Yeah, I think we've been tremendously fortunate with the CEOs that we've had for the past 10 years. Mary Anne's just incredible. And of course, Brian has been with the company for a long time as chairman of the board, so he has been there for that whole period and been very involved with what we do. So to have them switch places, and Brian be CEO now, and Mary Anne as chair of the board provides both continuity and a, you know, a new face and new approach in the CEO seat. Brian has been very focused on filling the pipeline, and you've seen all the deals that we've signed in the last six months or so since he took over, and that's been great.
So to see that focus on R&D, and that increased effort around drug development, is really wonderful. That's what we need. I think when you... You know, when you look at the last five or 10 years of our history, we've taken the success of DEFINITY and used that to fund the Progenics acquisition and the launch of PYLARIFY, and now PYLARIFY has been even more successful, and we've got a lot of cash from PYLARIFY, and we're starting to spend that on purchase of assets from other companies, and then development of those assets as well.
Okay, great. So maybe let's talk a little bit about, you know, isotope strategy. That's something that you are working on. So I guess, you know, it's such an important topic, and there are a lot of, you know, debates around, you know, which isotopes to use, and it's a very complicated issue. So maybe just give us a quick snapshot in terms of, you know, where we are with the isotopes and in terms of what are the key issues that we're working on.
Yeah, absolutely. Let me kind of split that answer in two, and I'm gonna talk about diagnostics and then therapeutics. So on the diagnostic side, of course, most of our agents are fluorine-18 based. Fluorine-18, as many people probably know, is made in a network of facilities around the U.S., that we call PET manufacturing facilities or PMFs. I don't know if that's a broadly used term, but that's what we use within Lantheus. So we have almost 60 PMFs today that are making PYLARIFY, and that gives us very broad geographic coverage and a lot of redundancy, within major metropolitan areas. So we're very proud of, and attribute a lot of the success of PYLARIFY to the robust supply network that we have for F-18, in order to support the supply of PYLARIFY.
I think important to note that the neurology agents especially, so the NAV-4694 and MK-6240 for amyloid and tau imaging, respectively, will also use F-18 supplied from those same sort of PMF networks. So we have that infrastructure, and that those kind of time slots, if you will, that capacity at those PMFs in order to supply future agents as well. So we're able, in a lot of ways, to capitalize on that, that kind of infrastructure capacity build-out from PYLARIFY and parlay that into capacity for NAV and MK as well. So that's, you know, that's good on the supply side. There are some particular, I think, more clinical aspects of F-18 that make it really attractive as well, kind of the physics of it.
One is a two-hour half-life versus a one-hour half-life for gallium-68. So the two-hour half-life means that it, you know, takes twice as long to decay by 50%, and that gives us a longer reach. So when we make a batch of PYLARIFY, we can then drive those doses further away, reach more patients. There's a bit more flexibility in the scheduling of those patients, in order to get a dose. It's also higher capacity because of the way it's made, because it's made on a cyclotron, and you can make many curies of this at once, whereas with gallium-68, you're typically doing it on a generator, and you get tens of millicuries. So you're getting a couple of doses versus tens of doses for PYLARIFY out of a batch.
The other thing is, this gets a little bit detailed, but I'll try and go through it, is what we call the positron range. So a PET-emitting isotope gives off this positron that travels a little bit away from the molecule. So the molecule's attached to a cancer cell, but when it decays, the positron moves a little bit away. If it moves a long way away, then you get a blurry image, and that's what happens with gallium-68. If it only moves a short distance, you get a lot crisper image, and that's what happens with F-18. So F-18 has a shorter positron range, a crisper image than gallium-68, and that's one of the things that we really like about F-18.
Now, I'll say that, you know, if you look further into our pipeline, we've got FAPI there, and FAPI is a, you know, a potentially, large, patient population, just looking at solid tumors. And we've selected copper-64 as the isotope for that. Copper-64 has similar positron range to F-18, so a nice, crisp image. It's got a much longer half-life. The half-life is in thirteen hours, ballpark, and that means that we may be able to centrally manufacture and distribute that across the country, and that would ease the manufacturing operations and make that a bit less complex for us. I don't think there's gonna be a huge difference on the on the patient caregiver side. They'll really have the same experience by and large, but it could ease the complexity of the manufacturing operations for us.
So that's why we decided to start looking at copper-64 and exploring that as a potential new diagnostic isotope. There are some other isotopes out there that people are using. Zirconium-89 comes up a good bit. Zirconium-89 has, like, a very long positron range. So again, poor sort of image resolution. We're not as big a fan of that one, but long half-life, so if you need... If you're gonna tag it to an antibody or something like that, that's very slow kinetics, it may be the best isotope for that. But by and large, I would say F-18 and copper-64 are the ones that we like most.
Now, that said, we've got some agents in the pipeline, RM two, where we'll probably use gallium-68 as the imaging isotope because that's what fits best with the molecule. So we're not tied to any specific isotope, but, you know, we try to pick the best one for the job in a particular situation. And now I'll switch over to therapy. Of course, most people are using lutetium-177. We have that with PNT2002 , PNT2003 . Great beta emitter. Has proven ability at this point. You know, a few things to note about it, it's got a seven-day half-life, which to us is a long time, and makes managing that supply chain relatively straightforward.
The isotope itself can be produced around the world and shipped to a finished product manufacturing facility. From the finished product manufacturing facility to the patient, you've got a few days potentially to get it there. So it really eases the logistics demand there compared to something with a two-hour half-life. There's also a, you know, question of patient release, so patients are administered a radioactive isotope, and they are, to some extent, radioactive. You have to limit how much they're around other people. Lutetium is great from that standpoint because it doesn't give off very much gamma radiation, which is what really escapes the body. So it's a much better isotope than, say, iodine-131 from that standpoint, and that's why people have switched from I-131 to lutetium-177.
And we're, you know, happy with those lutetium products. We may well use lutetium in additional products like RM2. There's some maybe subtlety in the lutetium supply chain, where there are a couple of different ways to make it. There's one that's a bit cheaper, that's called the direct route, where you put natural lutetium or maybe slightly enriched lutetium into a reactor, and some of that becomes Lutetium-177. The downside of that is that it then has a long-lived impurity with a half-life of ballpark two hundred days. It's not enough that that's an issue for the patient receiving the dose, but it does mean that waste disposal of that, what we call the direct route or that carrier-added Lutetium-177, is an issue for the healthcare providers.
So they typically have to pay to dispose of a radioactive waste after they've used a product like Lutathera that has that lutetium-177 impurity in it. For the point products, 2002 and 2003 , we are only using non-carrier-added or indirect route lutetium, which doesn't have that impurity. So that's a big advantage for the healthcare providers because they then don't have to worry about long-lived radioactive waste. They don't have the cost of disposing of that. It's a much cleaner product from that standpoint and easier for them to handle within their facilities. Other isotopes that we're looking at, certainly on the alpha emitter side, things like, you know, lead-212, actinium-225, maybe astatine-211.
I think there's a bit of a debate there, maybe a split between the longer half-life isotopes like actinium and the shorter half-life isotopes like lead and astatine. We're starting to see some evidence that the shorter half-life isotopes may have a better clinical effect than the longer half-life isotopes. Now it's early days on that, so that's not a firm conclusion, but I think we've got some interesting evidence to support that. Because of that, we're really excited about the, you know, lead-212 products, of course, the partnership we have with Perspective on some of those, and then astatine-211 and other shorter-lived half-lives are interesting because of that. I would say, you know, actinium is extraordinarily popular now.
My view of the reason for that is supply chain. If you have a ten-day half-life on an isotope, it's easy to get that isotope distributed again around the world, like lutetium, to get finished products distributed, and that makes it easy to work with, and it's easier for, you know, academics over the past several decades to have done investigations and studies with that isotope because they can order it, receive it in the mail, do their study, kind of, you know, over a few days or a week at their leisure, and they don't have to worry about producing and using that isotope right away. But commercially, what that winds up doing is putting more burden on the healthcare provider in order to make it easier for the manufacturers, and that's really the reverse of what we want.
We don't want healthcare providers having to deal with radioactive waste with a ten-day half-life, and potentially, lower clinical benefit, in order to make the supply chain easier on us. We're really good at managing complex supply chains with short-lived isotopes, so we are happy to take on the challenges of a, you know, lead-212 or an isotope like that with a ten, eleven-hour half-life. We know how to do that, and even at 11 hours, that's a long enough half-life for us to centrally manufacture and distribute that isotope, distribute that product around the country, very similarly to the way that, let's say, you know, iodine-123 diagnostics, which is a very similar half-life. That's been done for decades. We know that that can be done. We know how to do that.
It's a business that Lantheus, we're doing day in, day out. We are shipping SPECT nuclear products out of our facility that are, you know, made on a Monday and dosed into patients on a Tuesday. And we would much rather bear that burden and allow the healthcare providers the ease of radioactive waste disposal of a short-lived isotope, where they only have to hold it for, you know, four or five days, as opposed to months, in order for it to decay, and especially if there really is a clinical benefit to that shorter-lived isotope. So that, that's a big factor there. The other thing I would point to is, so clinically, is the difference in decay chains.
So actinium has a long decay chain, gives off four alpha emitters through a series of progeny, and of course, there's some concern about progeny migration. And once you have that first decay, the radioactive progeny escapes the molecule, and where it- where does it go now? Does it stay at the location of the tumor, or does it somehow redistribute through the body? And that's hard to tell, so there's some concern about off-target effects coming from that redistribution. Of course, supply chain is tremendously important there, so while I say we're willing to bear the burden of a complex supply chain, we have to know that the isotope's going to be there.
We've seen a lot of challenges, of course, with clinical development programs around actinium, where there wasn't enough supply, and that's caused pauses in clinical trials. I'm confident that we'll get there, just like with lutetium. There it was a rocky road for a while, but now there are a ton of people who make lutetium. There's a robust supply network out there. Actinium is probably headed in the same direction. You know, lead-212, when we look at that and the supply chain there, ultimately that goes back to an isotope called thorium-228, which has a two-year half-life, and that's almost unheard of for us in the radiopharmaceutical world, to be able to carry inventory of an isotope, and have that long-term supply.
So once we have that supply of Thorium-228, we can just continually get fresh Lead-212 off of that, and that's a big theoretical advantage for Lead-212. Now, that said, there's not yet the commercial scale supply of Thorium-228, so we need to be sure if we're gonna go into Lead-212 products, that we have that supply fully established, and that that's a robust network of suppliers as well.
That's great. So I think the debate around, you know, lead versus actinium, I mean, to your point, the clinical benefit that we've seen from some of the trials, it does suggest that you may get a little bit of maybe a, you know, better efficacy from lead. But I guess the pushback is sort of the distribution model, right?
Mm-hmm.
Because it's just hard to work with a short isotope. So is it your view that you can do it in a centralized manner, or you think perhaps we need to have maybe a dozen, you know, sites to really support the market?
Yeah, you know, I wouldn't say that's a finally decided thing for anyone, and maybe companies will take different approaches there. But I would point again to Iodine-123, which is, it's a diagnostic agent for thyroid cancer, and it's been around forever and ever. So it's, it's used in thousands, maybe millions of patients a year. And it has... That product is centrally manufactured by a couple of folks in the U.S.. I think there's a site in Denver and a site in St. Louis, and those are the sites that make it for the entire country, and it's got similar half-life to Lead-212. I think it's 13 hours instead of 11 hours. That is distributed overnight, dosed the next day, and we've been doing that forever and always.
So for folks who are new to radiopharma, looking at an eleven-hour half-life is intimidating, and that may sound like, "Oh, how do I possibly manage this overnight distribution to produce on a Monday, dose on a Tuesday," for example. But we do that day in, day out. We are making products in the Boston area. We are shipping them out the day of manufacture after full QC release, just like a therapy would, a therapeutic agent would go through, and they're being dosed to patients the next day. It's something that we know how to do. It's something that we have proven we can do time and time again, and we have incredibly high on-time and full delivery of those products to patients. So I don't see a fundamental challenge in replicating that with future products like a lead-212 therapy.
So I guess it goes back to your point that you made about waste management, just how big an issue that is. And so we heard that maybe in Europe, the regulations are a little bit, you know, strict versus the U.S., maybe less so.
Mm-hmm.
Maybe just talk a little bit about, you know, that, and is it truly an issue here?
Yeah. And there are two aspects to that. You know, one is the how the healthcare providers handle the waste that's left over from the administration. So when they do radiopharmaceutical administration to a patient, at the end of that, they have a syringe, some tubing associated with it, gloves, wipes, all sorts of different things that they've used in the administration of that agent, and the care of the patient during and after that administration, and they've got to dispose of all of that somehow. And typically, what you do is you hold a radioactive material for ten half-lives. So if your half-life is 10 days, like Actinium-225, that means you're holding that stuff for 100 days before you get rid of it.
If you're doing multiple administrations a week, maybe even multiple administrations a day, and you have to hold all that material for 100 days, you've got to have a waste management system, right? You've got to have some kind of maybe lead-lined room that goes into, and it's well-controlled and ventilated and all this sort of stuff in order to manage that waste while you wait for it to decay. If you have a twelve-hour half-life, you're holding that for five days, and then you're getting rid of it. So that's just tremendously simpler for the healthcare provider to get rid of that waste. The other aspect is the patient themselves. Now, the patient has that radioisotope in their body and is going to continue to kind of release that over the next several days or weeks.
And again, if the patient has a short-lived isotope, twelve hours, that's a very limited period of time that they're gonna deal with that. And if we think about things like municipal waste, it's a very limited period of time that it's gonna be in municipal waste streams. If it's a longer-lived isotope, that can be more challenging. Now, right now, there is general appreciation and acceptance by the Nuclear Regulatory Commission that the levels we're talking about are incredibly low and safe, and there's not a need for additional regulation around that. But there's always the chance that there will become more regulation, and that that'll be even more of a push to shorter-lived isotopes, because of the ease of releasing patients and waste and all those sort of things.
Okay, that makes sense. So I guess I wanna go back to sort of some of the competitors out there to PYLARIFY, right? Obviously, they're using alternative isotopes. I think, John, you touched on this topic, you know, earlier, but I wonder if you can just expand a little bit in terms of, you know, how with all the competitors coming in, how do you plan to sort of maintain your leadership?
For PYLARIFY specifically?
Yes, yes.
So, you know, I think the other folks coming on PYLARIFY, we see that PYLARIFY has the advantage of, one, being a fantastic agent, and we have, you know, a lot of evidence that we have from clinical trials that show superiority in terms of sensitivity and specificity for PYLARIFY over other agents, and, you know, higher positive predictive value, all these sort of things. The other is the distribution network that we have and the relationships that we have with customers. So having that...
Having that capacity established around the country, and that guarantee that the dose is going to be there on time, with an incredibly high on-time and full rate, just like all of our products, is a strong value for the customers in addition to the clinical value they're getting, just that confidence of knowing that it's gonna be there. And that's a difficult thing for other people to replicate. So, you know, other F-18 agents are coming in. They don't have nearly the coverage that we do geographically, especially if they're working with, say, a single manufacturing network, and they only have those locations around the U.S.. It's gonna be a lot more difficult for them to provide doses at the level of reliability and certainly the volume that we are.
But I also think on the, you know, on the commercial side, in terms of the relationship with the customers, because we have such a strong supply chain and a high level of customer satisfaction, customers don't see the need to go elsewhere. They are very happy with what they're getting in terms of PYLARIFY from a supply reliability, from clinical performance, and why deviate from that? So it, you know, it's good to be able to continue that momentum that we've got with that customer satisfaction.
I guess, on the therapeutic side, obviously, John, you mentioned that you guys brought in some maybe new assets with new targets. I did want to get your thoughts on how you guys evaluate what makes attractive targets, and how do you create that synergy, right, with your existing pipeline?
Yeah, you know, we are certainly looking at things that are complementary to the disease areas we're in now. So that's, you know, RM two as a complement to PSMA and prostate cancer, that makes that very attractive. And that we do a lot of scientific evaluation and commercial evaluation of these targets to be sure that they are scientifically sound, that we have confidence that they will work as we go through clinical development, and also that there is an unmet need that we can address in the market, and that we see a meaningful commercial opportunity there. And from a business standpoint, that they are reasonably priced assets, that we're not-
Mm
... you know, we're not giving away everything for a single asset in a crowded field. So, you know, those are all sort of the things that factor in there. I think what you've seen in a lot of the recent acquisitions is, you know, interest in diagnostics, where we see that Big Pharma is getting into radiopharmaceuticals, but they're really focused on therapy. And while we like therapy a lot, and we are pursuing therapeutic agents, we also see a lot of value in diagnostics, and it seems like Big Pharma is largely leaving that to us. So we're happy to take that and to continue to develop those agents.
And then from a, you know, from a therapy standpoint, again, that we're picking agents that are scientifically sound and reasonably priced.
Okay, maybe just last question from me, John. Anything you want to highlight from the isotope side, whether, you know, from Lantheus or, just in general from the field?
Yeah, you know, I'm continually excited about new evidence that we see on the up-and-coming isotopes. So, you know, I think on the alpha emitter side, the story has gone from everything being actinium-225 to now a lot of lead-212, and we're starting to see some interest in astatine-211,
Mm
which has some different chemical properties.
It's connected to the molecule in a different way that could give it some advantages. It actually attaches in the same sort of way that fluorine and iodine, so F-18 and I-131 do, and we have a lot of those type of molecules in our portfolio, so that may hold some interest for us. The other thing is that on the beta emitter side, we're seeing terbium-161 which maybe has a combination of beta and Auger electrons, which are an interesting type of very short range, like, you know, just a subcellular diameter range electrons that are emitted that could potentially have higher clinical effect than beta emission alone, so to see some comparisons there.
Otherwise, it's other than that, Auger electron, it's very similar to lutetium, so it seems like a natural step to say, "Okay, we're gonna take basically the same thing as lutetium and now add on this maybe extra little oomph behind it-
Mm
... and see if that does better, so interested to see how those sort of things play out. There are some companies looking at copper-67 as a slightly shorter-lived beta emitter, so you know, interesting to watch how that development goes. You know, I think those are the areas that are really interesting. With all of those, in addition to looking at clinical data, it's really keeping our finger on the pulse of supply chain, and what does infrastructure look like behind that? What would it take to have a robust commercial supply of isotope X? And often, that's the thing that holds up development of these isotopes.
You know, time and time again, we see, well, this is a neat isotope, but there's just not enough of it out there, and unless there's some evidence that it has clinical superiority by a significant margin, there's not gonna be the investment to develop that infrastructure.
Great. Thank you so much, John, for a wonderful discussion.
Thank you.