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Oliver Sartor: Hi, I'm Dr. Oliver Sartor, and appearing on behalf of UroToday we have a special guest, Emanuele Ostuni, who's here, the CEO of ARTBIO. And Emanuele, I wonder if you might say a few words about yourself to introduce yourself to the audience that may not be aware of who you are and what you do.

Emanuele Ostuni: Thanks, Oliver, it's a real pleasure. It's an honor to be here. I'm an Italian-born and US-educated chemist through and through, from my bachelor all the way to a PhD. I spent time both on the bench running experiments, as well as slowly over time, developed myself career-wise, and spent time in consulting, as well as in small companies in biotech and nanotech before spending 10 years at Novartis, five in Generics, and five as the Head of Europe for the CAR-T business setting up all of that operation, including reimbursement. And then about two and a half years ago, after meeting Roy Larson and a group of investors, I was very taken with the technology and decided to leave the big company and jump into a very, very small ship as the first employee of what is ARTBIO today.

Oliver Sartor: Great, thank you. Now, obviously, radiopharmaceuticals are your focus, but tell me why. We have ADCs, we have CAR-Ts, we have bispecifics, why radiopharmaceuticals as a focus for you and ARTBIO?

Emanuele Ostuni: I think that the concept makes a lot of sense, first and foremost. We understand targeted oncology very well, we understand payloads very well. And, while ADCs have made a lot of progress, there's still a lot that is unknown about ADCs and a lot of potential issues around ADCs. And as a chemist, I looked at the constructs that we were working with in radiopharm and found them simpler to handle and manage, and therefore having a higher potential for efficacy overall. I think, as usually in these things, the first experiments are those that show you the way and that open up the mind to the possibilities.

And as we saw the initial data that the AAA team, after they were acquired by Novartis started to publish, it really showed an amazing potential. And as it was the first step in what is hopefully a 100-step journey and more of the technology, when thinking about the modality, thinking about what else we can do chemically to find better molecules, and what we can do by picking different payloads that have a different impact on the efficacy that these molecules can have, it really brought home to me the point that this is a potential to drive efficacy very well for patients. And given the nature of the interaction between radiation and cells, it has a much higher potential for being, using the big word, curative, the big word. And in that sense, we felt very encouraged that this has in some ways a higher potential for reaching curative stage than even other technologies, and that's what really sold me on it.

Oliver Sartor: Yeah, thank you. And by the way, I share your enthusiasm, but I'm glad to hear it in your own words. Now, going into the radiopharmaceuticals, we obviously know that there are a lot of potential therapeutic isotopes. And we had mentioned the AAA, which led with Lutetium-177. A lot of companies are enthusiastic today about Actinium-225, but ARTBIO is focused on lead-212. Why lead-212? What makes it unique in your mind and why the focus for ARTBIO on that particular isotope?

Emanuele Ostuni: Well, when we were starting the company, we had the benefit of looking at the space a bit from a distance. And myself as not having spent as long a time in the space as you have and many others, I had the ability to just ask a lot of why questions, to understand the whys of choices that were being made. And as we kept talking about isotopes, what jumped out at us was that the choice of long-lived isotopes seemed to have been driven first and foremost from manufacturing considerations, and secondly from the efficacy that it was shown to have delivered. And our view was to think about what we could do to increase efficacy first, and then worry about manufacturing. And as you look at the space that has evolved dramatically since the early days of Bexxar and Zevalin, and now moving over to small molecule therapeutics and low molecular weight agents coupled with isotopes, what we found was that there was a bit of a mismatch between the biological half-lives of the agents that we're all investigating, and the half-life of the isotopes that are more commonly used.

And so while some of those isotopes are working and are showing efficacy, our view was, could we get more efficacy by closer pairing of the biological half-life of the ligands with the half-life of the isotope? And as a result, lead stood out for being an alpha that has good predictable chemistry, one single alpha with fewer concerns about additional daughter isotopes doing strange things in the body, and a short half-life that would better match the biological half-lives of most ligands that we look at.

And as a result of that, we then said all right, well then if that is the isotope we believe in, and thanks in part also to some early clinical data that's been published from the groups of Del Pasan and Michael Schultz, it allowed us to say this is a good reason for us to focus on the technology for how we isolate lead, how we manufacture with lead, and start to build all of that infrastructure, while at the same time building the infrastructure for a new pipeline that would look at multiple agents and would try to really go after some of the more aggressive tumors for which there still is a lot of need today.

Oliver Sartor: Yeah, very interesting. Some of the naysayers about lead-212 focus on the short half-life, and then become a bit consumed about how are we going to deliver something with such a short half-life to so many patients who need it? And I just want to hear briefly your take on the manufacturing challenges and distribution challenges for this particular isotope.

Emanuele Ostuni: And those are very fair questions. And those are the questions that keep us up all day long and all night long. And those are the questions we're trying to address. If we step back for a second and look at the context of the industry, we do about 40 million PET procedures per year, globally. As you know, those PET procedures typically use isotopes that have anywhere from 68 to 110 minutes of half-life. So as an industry, we have figured out how to deliver 40 million doses per year of some very, very short-lived isotopes. So that's not to minimize the challenge ahead of us, but that is to say that it is doable and it requires a network of manufacturing hubs that doesn't look like the centralized network that all of Big Pharma loves to have. And as I was part of that too, at some point I realized the cost benefits and the efficiency benefits from having a single point of manufacturing.

But for lead, that just does not fit. And so we're building the supply chain and the manufacturing to fit the isotope. And so if you dimensionalize that and look at it in a country like the US, a network of about 10 hubs or so, 15 depending on the volumes and indications in our view will be more than sufficient to deliver to all of the populations that need the therapy, with sufficient redundancy to provide some safety nets. Now, it will be slightly less sufficient than doing it all in one place, but it's not possible in our view to produce tens of thousands of lead-based doses and ship them from one place to the whole country, it needs more hubs than that. So that's how we're planning to tackle it, and we're delighted to see early results and early indication that that is really working at the moment.

Oliver Sartor: Right, thank you. Excellent overview. Now, lead-212 is only part of the equation. The other part is, of course, the ligands and the targets. And, I'm not trying to get into any confidential data, but I wonder if you might discuss ARTBIO's perspective on targets and where you see enthusiasm if it's not something confidential. Again, we're just trying to get publicly-available information, but understand your approach and attitude toward target development.

Emanuele Ostuni: Yeah. So, the approach we took when we selected our targets was to look at a universe of about 400 targets. Typically, we focus on targets that were extracellular expressing the extracellular matrix, low soluble fractions to avoid having radioactive ligands targeting things in the soluble milieu of cells and tumors, and/or healthy organs. And we kept whittling down that list to also targets that are very much preserved in the tumor and not over-expressed anywhere else in the body, or at minimal levels in tissues that could take it.

As we whittled that down, we then looked at what is the level of biological validation that some of these targets have. And what we started discovering is that between efforts in CAR-T and ADC, and in even small molecule antagonists, there were a lot of targets where the biology was validated. We were clear on having targets of exquisite expression in tumors and not in healthy tissues. That allowed us to say the problem with those targets wasn't that the target wasn't good, was that there wasn't enough payload in those targeting agents. Meaning that once we knew that there wasn't a lot of on-target toxicity, that a good ligand with an exquisitely high payload such as one that an alpha can deliver, should allow us to deliver efficacy in those settings. And that was the spirit behind our target selection.

Now as I shared, we're not revealing our targets beyond the PSMA that is publicly on our website, but the next level of work that we did was to look at these targets and classify them in different buckets. Because not all chemistry fits all targets. There were some targets that had very specific binding pockets with known chemical matter to bind those binding pockets. That allowed a great point for chemistry to deliver a new therapeutic.

There were targets that had unknown binders but good pockets that lend themselves to peptide development. There were targets that had very large pockets that needed something bigger, like a macro-cycle, that would really fill that space. And then there were targets that don't have a pocket at all. And so hitting those targets requires conformational specificity that can be had with very specific platforms, such as the one with that FogPharma has, with whom we've partnered, to find ligands to targets that aren't classically druggable, as one would say.

So once we figured out that map, we then set out to find partners or technologies that we could use ourselves to hit all of those targets. And that's what we're doing at the moment, and we're looking at a universe of more than 10 targets in our own labs.

Oliver Sartor: That is very clear and very conceptual, thank you. I enjoyed listening to your answer. Now, this might be a little bit premature, but it's a common question that we encounter in the field. What about combinatorial therapies? What about combinations with immunotherapy or targeted therapy? Do you have enthusiasm for combinations at this point, or is it more about getting the targets, hitting it properly, and bringing the lead-212, bringing that alpha right to the cancer? Is it too early to talk about combinations, or what are your thoughts?

Emanuele Ostuni: I don't think it's too early. I think as you correctly say it, first you need a great ligand, and then you can talk about combination, but we have good confidence that we can get a few good ligands out of our efforts. But we do think that combination is very important. We are starting to learn so much more, and we're still in the early innings of the learnings of how radiobiology interacts with the immune system, and how creating a mini bomb of neoantigens by having an alpha-based therapeutic in a tumor creates a lot of opportunity to engage the immune system. I think that we are at the early stages, and yet a lot of preclinical work should still be done and can be done to understand that interplay.

To share something that we're very excited about is a poster that was published at E&M last year, where we showed that for the same total amount of dose given in animals, one dose was good enough to create a survival benefit, but taking that same dose and breaking it up into four distinct smaller doses, much smaller doses given once a week for four weeks, significantly extended the life of the animals. So there's an interplay there around the concept of little and more frequently, that is likely to play well with the immune system, which will keep getting stimulated by lower doses and more neoantigens being created, that we think has a lot of opportunity for development, both short and long-term. So absolutely excited about it.

Oliver Sartor: Interesting. Listen, I'm going to have one more question and then this will be wrapping us up. But, I'm going to ask for a brief moment to succinctly help share your view over the next five years. How do you see the next five years developing? We're five years from now, we're coming back in 2029, and tell us what you think the advances in the field are most significant from your perspective.

Emanuele Ostuni: I was going to tell you that I forgot my crystal ball at home, but I'm going to try to imagine what it will be like. It's a great question. I think from an ARTBIO perspective, we should be wrapping up our first program from the field perspective, and we should have a lot more programs coming to the clinic and in the clinic at that point. But from the field perspective, I think understanding exactly, or not exactly, but better understanding how different isotopes interplay with tumors. That difference between half-lives, how does that interplay with a molecule and the ultimate efficacy that those constructs will give to patients? The interplay between the immune system and radiation in a tumor, we will know so much more in five years. And to your point earlier, combination therapies with IO agents and radiopharma will probably be a lot more clearly understood.

But, I'm excited about what we both cannot even imagine today because there's a lot that can still happen in the field. It's still so early in terms of biology that we can still learn so much more to drive far more efficacy in patients long-term. So, I think there's a lot to be excited about in the field, especially as you look at it where in the next five years, isotope supply issues should be resolved. We should have much more clarity about how to regulate some of these agents. Even the regulators are still in the early innings of learning, and I think that it will bode very well for both patients first and companies second.

Oliver Sartor: Fabulous. Listen, this has really been a pleasure. Thank you so much, I know your time is valuable, but thank you for spending a few moments with us here at UroToday. Really appreciate your perspectives, and all the best with ARTBIO.

Emanuele Ostuni: Thanks so much, Oliver. Real pleasure. Thank you.