Louis Metzger (dGenThera) talks about why astatine-211 may be the most scalable alpha emitter in radiopharma, and how stabilized halogen chemistry produces diagnostics that closely predict where the therapy will go.
What if the scan that finds a tumor could also show exactly where the treatment will go? That idea drives dGenThera, co-founded by CEO Louis Metzger. Louis joins Scott Larrivee to explain how his team is making it happen.
Louis trained as a biochemist at Duke and UCSF before leading discovery work at Novartis. He and his co-founders developed chemistry that keeps halogen emitters firmly attached to their targeting molecules, opening the door to imaging and therapeutic agents that are nearly identical.
Louis also makes the case for astatine-211, an isotope he believes is ready for a much bigger role in alpha therapy, and explains why its supply story may surprise listeners. Scott and Louis also discuss what’s ahead for dGenThera, how the company has moved forward in a difficult funding climate, and where Louis sees radiopharma heading over the next five years.
You’ll gain insights into:
Chapters:
(00:00) Introduction
(01:07) Founding dGenThera
(03:32) The Core Chemistry Advantage
(05:42) What Matched Theranostics Actually Means
(08:12) Crossing the Blood-Brain Barrier With Small Molecules
(10:52) Why Astatine-211?
(14:16) Scaling the At-211 Supply Chain
(20:16) How dGenThera Buckets Its Assets
(26:02) The Speed Advantage of the Tagging Platform
(27:57) Roadmap & Partnerships
(33:09) The Five-Year Radiopharma Future
(36:18) The Biggest Roadblock: Dosimetry
About Louis:
Louis Metzger, PhD, is co-founder and CEO of dGenThera, a biotechnology company developing next-generation targeted radiotherapeutics for cancer. He trained as a biochemist at Duke University and did his postdoctoral work at UCSF. He then spent several years at Novartis, where he led an antibacterial discovery team. Before co-founding dGenThera, he served as chief scientific officer at Tiara Biosciences. His expertise covers both small molecule and protein chemistry. At dGenThera, he brings that range together with his co-founders’ work in medicinal chemistry, halogen catalysis, and radiochemistry.
Guest Highlights:
“Our big vision is that anywhere that you can get an F-18 PET scan, you can then get a matched targeted alpha therapeutic.”
“More money by far has been invested in the infrastructure to produce At-211 at scale than has been invested in companies making molecules bearing At-211.”
“If you can make these molecules quickly cleared, you can get in, hit it hard, get out.”
Get Connected:
Our Sponsor:
‘Talk Radioisotopes: Going Nuclear on Cancer’ is brought to you by Nusano, a physics company whose breakthrough technologies are poised to help supply the fight against cancer and enable innovation across multiple industries. Find out more at Nusano.com.
Scott: [00:00:00] Hi, everybody. Welcome to Talk Radioisotopes. I'm your host, Scott Larrivee. We're excited to have you tune into the podcast. Our guest today is Louis Metzger, co-founder and CEO of dGen Thera. Louis, welcome to the show.
Louis: Thank you, Scott. Really appreciate the opportunity to talk with you today.
Scott: Well, we're excited to have you on.
For those who don't know you, you trained as a biochemist at Duke. You did your postdoctoral work at UCSF, and you spent time at Novartis, where you led an antibacterial discovery team, and you served as chief scientific officer at Tiara Biosciences. Do I have that right?
Louis: That is correct.
Scott: So you've got a great background, and now you are in this radiopharma space that we are covering on the podcast, and you're leading dGen Thera, a biotechnology company that's developing next-generation targeted [00:01:00] radiotherapeutics for cancer.
Tell us a little bit about your background and specifically what led you to found dGen Thera.
Louis: So it's actually a good story of founders and technology and chemistry really all converging. So I worked at Novartis for a number of years. Very dear colleague and an excellent collaborator, my co-founder Anthony Caseras, is CSO of dGen Thera, which in the rest of the conversation I'm just going to call dGT because we have too many syllables in our names.
So we're dGT. But Anthony was a fantastic colleague. We worked together on a number of small molecule discovery programs at Novartis Pharma. And then he had worked with our other co-founders, Dave Nicewicz, who's an expert at catalysis of halogen installation in molecules, and so that's really his background.
And then Zibo Li, the other co-founder, cyclotron director and radiochemist. And so for a number of years, [00:02:00] we've been talking about how to make a different class of targeted radiopharmaceuticals, and Anthony brought us together. So my biochemistry background connected to his medicinal chemistry background, and then the other co-founders' halogen installation catalysis design and expertise, and then radiochemistry.
And so the insights from all of those are what came together to allow us to build our molecular assets, and we have a couple of categories of those that were really informed by our past experiences. So I've worked with a lot of different modalities, so small molecules, a lot of small molecules at Novartis, but also have done a great deal of protein chemistry, both on the target side and on the ligand side.
And so in the radiopharmaceutical space, there's places for all of those different modalities. And then the question is: What sort of radioisotope payload do you choose to deliver with those [00:03:00] modalities? And I think dGT really allowed us to be creative, bringing together all of that knowledge.
Scott: Yeah. No, that sounds like a great approach that you guys have brought together, and the shared perspectives and backgrounds. For those that are either new to radiopharma or just new to getting to know dGT, as you like to put it, give me one or two sentences. What problem are you trying to solve? How are you guys different?
Louis: So we have chemistry that really stabilizes the attachment of certain emitters to tumor-targeting molecules, and those emitters are halogens, so F-18, various iodine isotopes, and then astatine-211, At-211, as the alpha emitter. And one of the things that have been limiting in using those therapeutic emitters, I-131 and At-211 [00:04:00] specifically, was in vivo dehalogenation, and this is mainly enzymatic.
So those At-carbon or iodine-carbon bonds are labile, and we have chemistry that stabilizes that attachment. And so that's a core piece of our IP. The other thing that we do that's, I think, very unique is that the way that our molecules are designed is that all of them have at least one fluorine in them.
And so that allows us to have exquisitely matched theranostic pairs or triplets, where there's an F-18 PET molecule, so an imaging molecule, that's then perfectly matched, or as closely matched as possible, to a therapeutic iodine-bearing or astatine-bearing molecule, because the diagnostic molecule has a cold iodine in it, and in the same position that one would put I-131 or At-211.
And so that is the best-matched theranostic pair or triplet that one could make [00:05:00] using available chemistry. And so that's really differentiating, because now you have single emitters where you have your PET emitter, you have a pure beta emitter in I-131 as a therapeutic emitter, and a pure alpha emitter in At-211, also as a potential therapeutic emitter.
And your biodistribution and all of the imaging data that you collect can then be used to predict exposure, and this is really powerful, and this is something that our chemistry enables that is unique.
Scott: So I've heard you use that term "exquisitely matched" before. I'm guessing it's a favorite phrase of [Louis: It is.] of yours. Just break it down really simply for me. What does that mean in practice for a clinician or patient? This means you're gonna get an image, and you're gonna have a much better idea of where the actual therapy is going to go in the body. Is that the right way of thinking about it?
Louis: Yes. So if you imagine matched [00:06:00] diagnostic and therapeutic molecules, the good thing about targeted radiotherapeutics is that it almost always involves a theranostic pair. Not always, but usually one can do imaging with the diagnostic and then therapy with therapeutic. The better matched those are, the more predictive the diagnostic is for patient stratification, for even de-risking a program, asking, what is the biodistribution?
Where does the diagnostic molecule go? And that can even tell you, is it even worth pursuing the therapeutic in human trials, right? Because [Scott: Right.] if the diagnostic [Scott: Yeah.] doesn't look promising in terms of its biodistribution or tumor uptake and retention, if the pharmacology doesn't look good in the diagnostic side, then you don't need to bother with the investment in clinical trial with the therapeutic.
But conversely, it's very predictive if you have a positive result, so you can go [00:07:00] forward with some confidence. Now, in the targeted radiopharmaceutical space, one's mileage may vary with the matching. So, for example [Scott: Okay.], with many of the chelated metal TRT theranostic pairs, the diagnostic emitter metal that's chelated isn't necessarily held in the chelation cage the same way as the therapeutic emitter.
And as the therapeutic emitter decays, its daughter atoms are held differently than the parent. And so what happens is that those emitters don't map as well, necessarily, from diagnostic to therapeutic, and that's, we think, very limiting, and our chemistry gets around that, because your therapeutic molecule is going to go where your diagnostic molecule goes.
And that's really powerful.
Scott: So this is really getting at, to my understanding, some of the current problems with radiopharmaceuticals, whether it's around stability, [00:08:00] dosimetry, toxicity. You think your chemistry and your approach is kind of solving some of those challenges. Is that a fair way of putting it?
Louis: Yes. And that's really why we did this. So there's this matter of making these isotopes, these halogen isotopes, attractive, especially iodine isotopes and then At-211, by reducing the possibility of dehalogenation, so those isotopes coming off the targeting molecule. And if you solve for that problem, now these look much more attractive for safety reasons, and then also, because they're covalently attached halogens, they don't have a big chelation cage.
Now you have this option of having small molecules that bear these isotopes, and molecules that can be designed to readily cross the BBB, the blood-brain barrier. And that's really powerful when you're looking [00:09:00] at neuro-oncology indications and, perhaps down the road, brain mets of primary tumors.
Being able to cross the BBB is quite useful, and being able to do that in a mechanistically driven way. So molecules that specifically get transported across the BBB instead of incidentally transported or incidentally crossed. And so that's another advantage to using these halogen emitters, is they can be [Scott: Yeah.] put on small molecules. And then in our case, the therapeutic is going to be very well matched to the diagnostic. And so if the diagnostic goes where you would like it to, the therapeutic is very likely to, relative to the other chemistries that are being used in the radiopharmaceutical space.
Scott: Yeah. So within this world of what broadly gets labeled as precision medicine, you're finding ways to be even more precise, it sounds like.
Louis: Yes. And [00:10:00] it's through very essentially clever chemistry. Yeah. Our strength is strong medicinal chemistry and really an expertise on SAR discovery and optimization.
And that comes down to optimizing bond strength, de-targeting various enzymes that dehalogenate some molecules physiologically. And though subtle, it's extremely powerful, and that's the foundation for the assets we've built.
Scott: Well, it's tremendously exciting. I've been following you guys for a little bit now and am really excited we can have you on the podcast to talk about this platform, because I think it is something that's a little different and is something that, if folks haven't taken a look at it, you should go to dGen Thera's website and check it out.
I wanna dig in with you a little bit more, 'cause I think we met at the World Astatine Community Conference about a year ago. [00:11:00] You've made a big bet on astatine-211. [Louis: Yes.] I think of you as one of the leaders in that space. What convinced you that astatine-211 is the right isotope for next-generation alpha therapies?
Louis: Good question. Well, there's a number of attributes that make it really attractive to the dGT team and why we've been interested in it from the very beginning, from when we were even considering founding this company. So, number one, unlike the other alpha emitters, which are really mixed emitters, At-211 is a pure alpha emitter.
So [Scott: Mm-hmm.] does a single alpha emission, soft gammas. This has a number of advantages in terms of dosimetry. It also perhaps has advantages in terms of next-generation strategies, like, for instance, pairing At-211-bearing targeted radiotherapeutics with, for instance, checkpoint blockade. [00:12:00] And then there's been some interesting work in the literature beginning to ask about how that might work in various tumor models, and I think that this is something that's exciting.
Why is At-211 very good for that? Because these alpha particles are doing double-stranded breaks. The host DNA that's been broken in that way actually looks foreign, so it is an innate immune system modulator, if you will. So TLR9 substrate, for those that really dig into the biology.
And that has the potential of turning immunologically cool tumors warm. And so at the same time, because it's a pure alpha emitter with the soft gammas, it's doing limited damage to A, surrounding tissues, and also surrounding immune-related cells, right? So there's a number of advantages there.
And I think from a safety standpoint, [00:13:00] the short half-life is really quite nice, because if one can exquisitely target At-211-bearing molecules, you can, in essence, get them in, do a high bombardment of alpha particles, because the short half-life means that the flux of alphas is going to be high. And I think that that high flux and that high density of double-stranded breaks is really going to drive efficacy in At-211-bearing radiotherapeutics.
So I see the short half-life and the purity of emission, just a bombardment or a barrage of alpha particles in the tumor environment, as being very likely to drive efficacy. But at the same time, that bombardment has a limited window, so that favors safety. And if you can make these molecules quickly cleared, you can get in, hit it hard, get out.
And so [Scott: Get out.] now you have the option of matching biological [00:14:00] half-life to radiological half-life. And with our small molecule assets, tuning those has been really important, having this At-211 half-life being well matched to the biological half-life of the molecules. So those are all the reasons we're really interested in At-211.
The other reason that I think shouldn't be underestimated is that we think At-211 is going to be very scalable, and we're not the only people who think that. You're starting with bismuth targets. That's the precursor. So unlike many of the chelated metal radiopharmaceutical payloads, there's really not a supply limitation of the precursor.
Not at all, actually. Now, they're made at cyclotrons, but there's now custom cyclotron build-out for this purpose. So At-211 is no longer just an academic cyclotron product. Obviously, Nusano [00:15:00] is standing up large capabilities of producing, I believe, enough At-211 to cover clinical needs for the continental US.
Scott: Yeah, we're going with the Oprah approach of you get At-211, you get At-211, everybody gets At-211. No.
Louis: Yeah. So Nusano's definitely sold on that. Ionetix is really moving forward, Ionetix in Lansing, Michigan. There's, globally, Alpha Nuclide, which is a really esteemed partner of dGT, is already showing, outside of Shanghai and then also with a second facility being constructed near Beijing, really how At-211 can be produced at scale in high quality, but at modest cost of goods, cost of production.
And so our big vision is that anywhere that you can get an F-18 PET scan, you can then get a matched [00:16:00] targeted alpha therapeutic that matches your PET diagnostic. And if you look at the distribution networks, we already can deal — we being the medical world, I suppose [Scott: Yeah.] — can already deal with installation of F-18 in various F-18 diagnostics, and so that's a pretty standard thing.
With At-211, because of the type of emitter it is, one could really piggyback on that infrastructure and have regional production of At-211 at a very modest cost compared to many other radiopharmaceutical strategies that are out there. And so cost of goods, cost of production is really important, because I think there's always going to be downward pressure on what healthcare systems are willing to reimburse for any type of drug, but especially expensive radiopharmaceuticals.
And so [Scott: Right.] if your floor of cost of goods and cost of [00:17:00] production is irreducible to an extent, now you're getting squeezed on both sides. And with At-211 as an alpha emitter, we think the scalability means that you can escape that squeeze. And that's also important so it democratizes the access to targeted alpha therapies and really would allow it in many geographies and healthcare systems for which it might be a struggle to get actinium-225, for instance.
Scott: Yeah. You and I last saw each other at the SNMMI conference in Los Angeles. And I think there was a lot more talk about astatine, at least in my conversations this year. It sounds like the supply chain bottleneck or the concern around the half-life is getting solved.
Is that reflected in what you experienced at that conference? That obviously we're not there yet, but there's a lot of work underway and there's a lot more options than, say, if we were talking about astatine two or three [00:18:00] years ago?
Louis: Yes, compared to two or three years ago, it's very different.
And I think that those plans for the scaled-up production were put in place much longer than two or three years ago. I forgot to mention IBA. IBA is doing fantastic work, and you saw their announcement of their At-211 production plans at SNMMI, and that was really promising and good to see.
So you've got Nusano, IBA, you have Ionetix, and then in Asia, you have Alpha Nuclide, you have Alpha Fusion and other collaborators in Japan. All of these different groups are really working, doing excellent work, and have been planning this for years to bring a steady and high-quality, high quantities supply of At-211 to patients ultimately.
And so [00:19:00] I think that it's no longer limiting the way it was. That has been a narrative, though, that's been difficult to disabuse people of that narrative, because they've been looking at limited academic production historically of At-211 and worried about scalability. And I would argue that this is an unusual situation where more money by far has been invested in the infrastructure to produce At-211 at scale than has been invested in companies making molecules bearing At-211.
So it's almost the opposite situation from what occurred with some of the other radiopharmaceuticals, where the molecules led the supply chain, if you will. Yeah. Here, At-211 production has been committed, and now we need good radiopharmaceuticals bearing At-211 to be advanced rapidly to the clinic to take [00:20:00] advantage of that supply.
Scott: Yeah. No, that's a very interesting thought. I hadn't thought of it that way, but you're right. It's going away, hopefully, is the argument of, "If only I could get my hands on it." It sounds like now it's here. What can you do with it? So that's an exciting place to be playing from.
I want to get back to talking about you guys a little bit, just in terms of: There's a lot of companies building targeted radiotherapies. What specifically is the gap that you think you're gonna fill with this astatine-based approach? Is it different tumor types you can go after?
I know you've spoken to it in our prior answers here, but I just want to put a pin on it for the listener who's tuning in of what do you guys see as the biggest opportunity ahead for your approach?
Louis: We have two broad buckets of assets, and each really bring unique things to the table here.
So I'm going to focus first on one and then the other. So our small molecule assets are transporters of [00:21:00] substrates that cross the BBB. They're transporters of small molecules that are overexpressed in a number of solid tumor types, and the other interesting part about it is there's substrate competition.
So the substrates of these transporters tend to be depleted in tumor environments versus healthy tissue. So you can really tune specificity by playing with the chemistry of these small molecule transporter substrates that inherently cross the BBB as a consequence of their biology. And so as I mentioned earlier, these are really exciting because they're small molecules, they bear these halogen emitters, they don't have a big chelation cage and linker on them.
They actually accumulate in the cells, so they go in the transporter, but they don't get exported very easily. They build up in the cells. You can really concentrate them that way. Why is this really special? In many solid tumor [00:22:00] types, depending on specific tumor and the structure of it, there's a problem with permeability and diffusion.
So better to have small molecules to get into those types of solid tumors. And so our small molecules have advantages both in terms of tumor diffusion, and then also they have this active uptake component. And so we think that that combination is differentiating and really powerful. And there's many other companies in the targeted radiopharmaceutical space that are increasingly understanding the importance of having molecules that really can diffuse into solid tumors.
And I think that that's why you're seeing really great work being done with cyclic peptides and peptoids and linear peptides even, also small folded proteins, which are really interesting, so sort of like 40- or 50-mer proteins. And as a protein chemist, I immediately look at [00:23:00] those and say, "Oh, look, they're very drug-like because they're very shapely."
This is, I think, the direction that the field is going, and that brings me to dGT's other bucket of assets. So I mentioned these small molecules, but when we looked at these small molecules — I'm a protein chemist, and I said, "Okay, lots of radiopharmaceutical companies are taking chelated metals and a linker and attaching it to some sort of biologic, whether it be a small peptide that targets tumors or a full-format antibody and anything in between."
I said, "Why don't we take our small molecules and all the features that I described, so the stabilization, the prevention of dehalogenation, the exquisite matchedness of the diagnostic to the therapeutic molecules, and make many different tagging chemistries that we can couple by many different coupling chemistries to peptides and proteins of any different sort?"
And so that's our other bucket. There's a [00:24:00] subtle but really key thing about that that you can't do as easily with the chelated metal therapeutics, and it's this. All those tags, they preserve the matchedness, diagnostic to therapeutic. They preserve the stabilization against in vivo dehalogenation. But they also were specifically designed to have diverse physicochemical properties.
If you're saying, "Okay, I have this peptide that targets a receptor on a tumor cell. I need to put a radioisotope-bearing moiety on it," I could choose a chelated metal, and because of the wandering daughters and the other drawbacks I mentioned, that wouldn't be what I would choose.
Or I could choose one of dGT's tags, but we have many families of tags. So we can look at the targeting bit, the targeting moiety — let's say it's a peptide — and then we can say, based on that peptide's physicochemical properties, what do we [00:25:00] want the physicochemical properties of the fusion molecule to be?
And then we can pick families of tags where the physicochemical properties are well matched to targeting and put them together. And that sort of tuning of physicochemical properties is something that is really unique and is something that you can do with our assets, but is much harder to do with chelated metals, because now you've got to build in all this linker chemistry, and there's been beautiful work and a whole cottage industry around linker chemistry for metal chelates attached to targeting moieties.
But why deal with that when you can have these systems of tags where you can a priori say, "We're going to start with these promising fusions and [Scott: Mm-hmm.] move on from there"? So that's subtle but key, matching of physicochemical properties and that flexibility, and we think that that's going to greatly expand and facilitate the type of chemical matter that can be produced in a [00:26:00] targeted radiopharmaceutical space.
Scott: I don't want to put words in your mouth, but not just expand, but is your hope it might also accelerate development because you're working with these known tags?
Louis: Yeah, that's actually a great point, and I really don't think I made that adequately. One of the really cool things about that tagging system is, again, the diagnostics are very predictive of the therapeutic because of the matchedness of the tags, just like the small molecules. So think about all the chemical matter out there that's been discovered that's very good for very specifically targeting tumor cells and not healthy tissues.
There's lots of it, right? [Scott: Mm-hmm.] But maybe upon that chemical matter binding to its target and internalization doesn't quite drive downstream cascade of biochemistry that results in efficacy mechanistically. Now, you can take that chemical matter, and you can say, [00:27:00] "Let me put the F-18-bearing dGT tag on and do in vivo PET, F-18 PET."
And you can quickly ask the question, in the relevant tumor models that you choose, how does this look? And so that allows you, as you point out, to very quickly ask the question, can we turn this chemical matter into a TRT or not? And I think that that makes the design-build-test cycle much faster and allows one to triage this chemical matter much more quickly.
And it's a special thing that you can do in the radiopharmaceutical space because we can do PET and SPECT, and that's one of the beauties of working in this whole field, regardless of what emitters one is using.
Scott: Yeah. No, that's really exciting. I think the ability to iterate and how folks are doing that is a fascinating part to watch in this space.
I don't want to get into things you can't [00:28:00] discuss or... But tell me a little bit about where dGen is at today, in terms of — you can talk about this from a business standpoint, or you can talk about this from a very pipeline, clinical type of standpoint. But what should we be watching to see from you guys over the next year or two years?
What are some exciting inflection points that you hope to have on the road ahead?
Louis: Well, with the caveat that there's many discussions in progress, I think that we have very rapid paths for some of our later-stage assets to have IND-enabling packages and to move to first-in-human in the coming next year or two.
There's some mechanisms with certain indications where that could be even faster. And in particular [Scott: Okay.], we have some potential collaborations on the table that would, if they [00:29:00] are finalized, really drive forward those timelines, or move forward those timelines. And so I think there's quite a bit of interest, both in the US and globally, in radiotherapeutics 2.0, so the next wave of the chemistry beyond the first wave of metal chelates.
And I think that we have a great deal of appetite to bring this to the clinic. So I've talked to many heads of nuke med programs, globally, and there's a great interest in doing IIT work with these types of molecules. So that's good. But where are we? We have a lot of options, and so the question is how to get these molecules to patients most efficiently and quickly.
And as I mentioned, we have a small molecule bucket of assets, and then we have this bioligand tagging platform. And the very interesting thing strategically is they're two [00:30:00] completely orthogonal shots on goal. They share many features, they share a lot of chemistry, they share advantages chemically, but the small molecules are one bucket, the bioligand tagging platform's another bucket, and the latter, properly funded, and if we turn the crank on that, is essentially a development candidate factory.
And so there's so much that can be done with that. And then the small molecules have many advantages of their own, and we kind of have a cottage industry with the small molecules around targeting this class of nutrient transporters and enabling crossing the BBB, enabling accumulation in cellulo.
So where are we going to pursue? Depends on which partnerships we ink with whom. But let's just say that we're in very advanced discussions with multiple publicly traded pharma companies and have some really interesting partnership possibilities. [00:31:00] So we're working out the details of those, and hopefully in the next year we'll have various announcements.
And so then it becomes deciding what do we partner and what do we take forward alone, and what mixtures of those do we do? So I can't really reveal too much more because of confidentiality, but there's a lot going on. And I think in this environment, for early-stage preclinical biopharma, startup funding has been very limited in the last few years.
And [Scott: Yep.] what we did is looked at that and said, "Okay, if that's the case, how can we turn that to our advantage? How can we make something good out of that ecosystem, or that — I guess funding weather would be the better term here?" And what it really led to was bootstrapping and a lot of creativity about how we move things forward.
And so we're very proud about [00:32:00] being able to bootstrap and being clever with limited resources, and now I think we're very close to being able to do some substantial deals and substantial collaborations that will allow us to keep our company independent, but at the same time move certain assets to the clinic very quickly, and then allow us time and resources and bandwidth to develop other assets that sit in our portfolio.
So many different shots on goal. [Scott: Yeah.] Hopefully we'll have announcements soon.
Scott: I think that was very diplomatically put and well put, but the takeaway I heard is you've got the pieces assembled, and our listeners should be keeping an eye on dGT, I think is maybe the key takeaway there.
[Louis: Yes.] So that's tremendous. Congratulations on your progress. I know you've got to get back to work, but before we let all of our guests go, we kind of have a little obligatory questionnaire that we do, if you will. We ask two major [00:33:00] questions, and it asks you to look into your crystal ball.
This is not specific to your company. This is looking at the industry as a whole. And so we like to start off by asking first: If all of this succeeds — and by that I mean radiopharma takes off, more drugs get to the clinic — what do you think this radiopharmaceutical world looks like in five years?
Louis: A few things. I think it looks like a Cambrian explosion of targeting modalities or targeting moieties, so the targeting piece of your radiotherapeutic. They're going to be different for different cancer types. There's going to be ones that have broad applicability, but I think that there's also going to be many very specific ones, and I think you're going to see differentiation.
You're gonna have to see different sorts of molecules that are looking promising in liquid versus solid tumors, for the reasons I mentioned, this accessibility, diffusion into the tumor. So I think you're [00:34:00] going to see still a diversity of chemical matter targeting the diversity of cancers.
And I think you're always going to see that in oncology, which is why I'm always amused when, for instance, politicians start talking about a silver bullet that's going to cure all cancer. It's such a diverse array of diseases that we're going to need many molecules. And then I think the other thing that one is going to see is really combination of targeted radiotherapies with other types of cancer therapeutics, but I think especially immuno-oncology strategies.
And so there's a vast amount of really good work, really accelerating work being done in the immuno-oncology space, and I see certain types of targeted radiopharmaceuticals as being excellent as either being potentiated by or potentiators of IO strategies. And I think that [00:35:00] we're going to see a lot more of that going forward.
I think radiopharmaceuticals as single agents are already and will continue to be very effective and, in some cases, extraordinarily effective. I also think that they're going to turn out to be potentiators or potentiated by other strategies, and I think that synergy is going to drive living with cancer, or even functional cures, but long-term options for patients and long-term quality of life for patients [Scott: Yeah.] that didn't have that option even a few years ago, or even right now. And so diversity of molecules, probably the exploration of combined therapies down the road after efficacy of single agents has been shown.
Scott: I couldn't agree with you more in the hope that hopefully we're moving toward a thing where a cancer [00:36:00] diagnosis, the meaning of it is a lot different, hopefully in a few years.
And so it's exciting to see the work that you and others are doing to make that happen. Last question. There's a lot between where we are today and success. There are roadblocks in the way for radiopharma. If you had a magic wand and you could make one challenge or roadblock disappear, what would it be?
Louis: That is a hard question. So many, so many different things. I would say — and this is already happening, because I think everyone understands the need for this — really a way to deal with dosimetry in a consistent manner, because a lot of dosimetry for targeted radiotherapeutics is really looked at through the lens of beam radiation, other types of radiotherapy, and it's a [00:37:00] bit different.
And so work is already being done to harmonize how we think of exposure, especially from a regulatory standpoint. But I think it's very different, obviously, in less targeted radiotherapy versus molecularly targeted radiotherapy. But there's a continuum, so it's complicated, and I think a lot of work needs to be done looking at how we regulatorily think about exposure limits and how we deal with safety.
The other thing inherent in that is looking at long-term tox and how we minimize long-term tox. And I would argue not having wandering daughters coming out of chelated metal radiopharmaceuticals is a way to mitigate long-term tox. But really thinking about that carefully, which is another thing that the regulatory agencies are already doing — I think [00:38:00] having a unified framework that's really specific to targeted radiopharmaceuticals is going to be key, and that's really going to help us design and execute clinical trials and understand more about how we optimize therapeutic index, quite frankly.
Scott: Yeah. I think that's well put. Well, Louis, this was a wonderful conversation. My takeaways are that we gotta keep in touch, because I think you're gonna need to come back on the show when you have some big news to share, and we'll be watching and cheering you guys on as that happens. And I just wanna thank you for taking your time to join the show.
Louis: Scott, thank you so much for hosting me. Thank you for giving the opportunity to talk about what my colleagues and I have been excited about for years now and are bringing forward. So really appreciate it.
Scott: You're welcome. Well, we'll be watching, and thank you all for tuning in to Talk Radioisotopes. [00:39:00]
Talk Radioisotopes is a production of Nusano in collaboration with our producers at Caspian. Thank you for joining.