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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm with UroToday, and we have a very special guest today, Andreas Goutopoulos, who is the founder and CEO of a company called Actithera, and we're going to explore Actithera and some of the very novel approaches that he's taken to radiopharmaceuticals. So welcome, Andreas.

Andreas Goutopoulos: Thank you, Dr. Sartor. It's great to be here.

Oliver Sartor: Let's start off by having, in your words, an introduction to Actithera and what makes it different from the 43 other companies that have come on now focusing on radioligands. Why are you distinct?

Andreas Goutopoulos: Yes, again, thanks for the opportunity. We started Actithera a couple of years ago with some novel ideas about the design of radiotherapeutics. We looked, for example, at Pluvicto. Pluvicto, really, it's a remarkable molecule. It has a very short half-life in circulation, which is important for avoiding toxicities. But then, on the other hand, it has a remarkably long retention in tumors—a week or longer. Actually, it's ideal because more or less the half-life in tumor matches the half-life of lutetium.

However, it's been very difficult, actually, to replicate this PK profile on many other targets. So, for example, if you look at FAP, a target that many, many companies are working on, it's been very, very difficult to achieve this prolonged tumor retention. So what we thought at Actithera was to maybe bring some new ideas that were specifically designed for improving properties that we thought that most likely will also prolong tumor retention. So we kind of focused on this property, and one of those ideas was covalency. We thought that leveraging the concept of forming a covalent permanent bond between the target and the molecule will, in turn, also prolong tumor retention. This was one of the key questions we started the company with, and basically now we have data, especially on the FAP program, which, as I said, is notoriously difficult in regards to achieving this tumor retention property that are very, very promising.

Oliver Sartor: Well, I love the idea of covalency. There was an interesting article published in Nature very recently that talked about covalent binding of FAP in this retention. I wonder if you might be able to help our listeners understand the relationship or the lack of relationship between that article in Nature and your own work.

Andreas Goutopoulos: Yeah, absolutely. This was a very good paper. It came out in May. We actually welcome this paper because, basically, it's external validation of our approach. We have now a second group using a very similar approach and that, also in their case, also results in molecules that have promising long retention preclinically, and we'll see also in the clinic how that translates. So remarkably similar strategies targeting FAP.

Our compounds are different. We use different chemotypes, we use different design on our linkers to the chelator, we have a different approach to forming that covalent bond between our molecules and FAP. Also, our IP is definitely a very different IP position than the Chinese paper. But I think, as I said, at the end, this has been a very helpful paper for us because by being external validation of the covalent concept, it has been helpful for us in fundraising and attracting interest from KOLs.

Oliver Sartor: Interesting. Now, you know a lot about covalency and I don't, and I think most of our listeners don't know very much. Could you briefly talk about covalency in small molecules as a precedent in terms of hitting druggable targets? Is this a totally new concept or is this something where there's already some precedent?

Andreas Goutopoulos: Oh, absolutely. This is one of my favorite topics. I came into the field from outside. My background is in oral drug discovery. I've been in the pharma industry for more than 25 years, but I spent most of that designing small molecule drugs, commercial small molecule drugs, not radiotherapeutics. And in that space, we had a very important debate about covalency about 15 years ago. That was when ibrutinib, one of the first covalent inhibitors, came to light, and there was a debate about whether covalency is a good idea. And that's because we were trained to avoid covalency, because experience with covalent drugs was primarily drugs that are forming reactive species during metabolism, and those reactive species, of course, by being too reactive, bind indiscriminately to proteins other than their own target. And of course, that results in toxicities.

But what we learned now about leveraging covalency for targeting specific proteins is that if you really attenuate the reactivity of those groups that are designed to react with certain amino acids on the target that we intend to bind with, we can have a very selective, very—as we call it—contact-specific adduct formation. And that results in a very selective mode of action, especially if that is paired with selecting amino acids that are non-conserved; similar proteins from the same family don't have the same amino acid in that same position. So if you have those two principles, you can achieve exquisite levels of selectivity.

Once we understood that this is the case, and we had several examples, this whole concept really flourished in the oral drug space. So we have many other compounds that now are approved. Actually, I'm not sure about the number, but some people say 5-10% of drugs that are approved these days, in the last five years or so, are covalent. So at the moment, by this time now, 15 years later, this is a very well-established concept in the oral drug discovery world, so I thought that it was very fitting also in the case of radiotherapeutics, and I was surprised that the concept was not really already being explored in radiotherapeutics. Because, as I said, in this case, keeping the compound in the tumor is very important. And maybe, again, as I said, forming a covalent bond, permanent bond between the molecule and the target, one can reasonably expect by that, that we'll also have better tumor retention.

And then another good argument about using covalency in the space of RLT was the fact that in RLT we have imaging, and preclinical imaging in each optimization cycle allows us to really detect the compounds that are really indiscriminate, they're not selective enough, they bind to other targets, to other organs than ones we intend to. And that, by having that ability to, by imaging, exclude compounds that are unselective, make this drug discovery process a lot more efficient and safer at the end.

Oliver Sartor: Yeah, that's one of the beautiful things about the diagnostic field is you can image your target. By the way, I don't even know why we're not using imaging for the development of a variety of targets, whether they be antibody-drug conjugates or bispecifics or CAR Ts. We could benefit from being able to see that target for all of oncology, not just the theranostic and radioisotopes.

Let me ask you a little bit if you can, and I don't want you to divulge anything that'd be proprietary, are there any targets that you might be willing to discuss as of being potential interest with the covalency approach? Or is that a little bit off-limits right now?

Andreas Goutopoulos: No, I can discuss at least in broad terms. When we first started, we were looking at the cysteines as the main amino acid that is suitable for covalency. I think most of the experience we have so far in the oral drug space is targeting cysteines. Unfortunately, cysteine is the rarest amino acid in proteins, so that actually reduces the number of targets that are eligible. The other point is that in RLT we're mostly extracellular proteins, and in the extracellular space, by having a more oxidative environment, a lot of the cysteines are either oxidized or in disulfide bonds. So that actually limits the number of targets to an even further degree.

However, what has happened the last few years is that the covalent drug space is actually moving now beyond cysteine. So there is now a lot of experience with targeting tyrosine, lysines, and more recently the aspartic acids, glutamic acids, histidines, and so on. So by expanding that scope, I would say that pretty much more or less any target that is considered as RLT target more or less will be suitable for the approach.

Oliver Sartor: There's been a rather remarkable recent Nobel Prize given for protein structure. I'm just curious, in the thinking that you bring forth to targets, are you using artificial intelligence to be able to look at conformation? How do you go from a protein to a binding pocket to the presence of a tyrosine or another potential covalent target? How do you kind of go from point A to point B to point C in your development?

Andreas Goutopoulos: Yeah, great question. The way we design covalent drugs is one of the challenges is that you have to position this weak electrophile that I mentioned earlier in an exact position in respect to the targeting amino acid. So you have to be very, very close to it; you have to approach the amino acid and that nucleophilic center with the right geometry, the right distance. That means that you need to have very, very accurate information about the structure of your protein; you have to generate often co-crystal structures between your molecule and the protein to understand exactly how to optimally position those electrophilic groups.

So of course, yes, absolutely, having some information from AlphaFold is useful, is maybe the first step. But we actually go more into details and actually generate co-crystal structures or cryo-EM structures to understand with a lot more accuracy and confidence the relationship between the protein and the ligand and the exact positioning of those two groups. And that allows us to have a much better, much faster design of proper ligands that way.

Oliver Sartor: Interesting. Very interesting. Thank you for clarifying that. One of the things that I had worried about when I first thought about your approach, which is incredibly elegant and it will work if you get a retention in the same way that you can have retention with another molecule, depending, of course, on the turnover of that target, which is another issue probably not going to talk about. But with the radioligands, you often have to have a chelate that is attached, and I would have a great deal of concern that the chelation would actually carry your beautiful molecule designed to interact with the target in the binding pocket, but that the chelation would interfere with access to that pocket in a very real way. I'm curious how you might approach the idea that chelated small molecules might be different than just the small molecules that would be optimal for covalent binding on a target.

Andreas Goutopoulos: Yeah. Again, I think this is a matter of design, and this is exactly why we employ actual structural information about the target and the way the molecule binds to the target. Because that information is critical for designing the proper linkers that will allow the presence of the chelator in a position that doesn't affect binding, doesn't affect the covalent binding, the covalent adduct formation, and everything works fine. So it's just a matter of design, and there's not any reason as to why a chelator, if it's properly positioned, will affect with the covalent binding.

Oliver Sartor: Well, I love your approach, Andreas. In the radiopharmaceuticals, it's all about retention at the target. You mentioned the PSMA, the rather remarkable fact that even a week later you are fully able to retain the lutetium within the target because of the remarkable properties of PSMA. And by the way, you get beautiful retention with SSTR2, but we're trying to find these other proteins on the cell surface. It might have similar effects. And of course, they're not so easy. There are others, and that's a whole broad topic in and of itself.

But we're going to need to wrap up here in just a moment. I'm curious if you might have any final thoughts for our audience who might be listening and understanding covalency maybe for the first time, but now I think they can see the possibility that your tiny little company might be able to bring to the table. Any final thoughts or concepts for our listeners?

Andreas Goutopoulos: No, I think, as discussed already with the paper in Nature, we're contributing to this idea of using covalency as a way to design better therapeutics. It's not going to work all the time in every case. I think there will definitely be cases where covalency will not make a difference. And that's why we have developing in Actithera other approaches as well. We have, actually, three pillars in our chemistry platform. One of them, the first one, the original idea was around covalency, but we have two additional ways that we can increase tumor retention. And we use them according to the target, according to the needs of the target, according to what we know about the target and the starting points that we use for ligands. We use them all three, or in some cases we'll only use one or two.

So it's not going to be only covalency. But I think it's an important concept that I'm sure now that it's more out there, I think a lot of other companies will also try. There's a lot to discover here. As I said, especially with new amino acids beyond cysteine, I think there's a lot of new chemistries to explore and finding new groups that can form those covalent bonds in a very, very specific manner, and at the same time, they're very stable in blood, in circulation, they're very stable in respect to radiolysis, for example—that's another concern. So I think fine-tuning the chemistry that will enable covalent drug discovery in theranostics is just starting now. I think it's just at the beginning, and it will keep going.

Oliver Sartor: Well, thank you. And by the way, Andreas, I wanted to thank you personally for meeting with me at Hamburg at the EANM meeting. I know you're a very busy guy and the many demands on your time, but you took the time to sit down and explain some of your concepts to me, which, quite frankly, I found fascinating. Thank you for being on UroToday. I wish you the very best as you develop your company, your concepts. Always try to remember the patient. We have many patients out there who can benefit from the concepts that you're proposing. Thank you for your good work. Keep going.

Andreas Goutopoulos: Such a pleasure, Dr. Sartor. Thank you for the opportunity.

Oliver Sartor: Thank you.