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Oliver Sartor: Hi. I am Dr. Oliver Sartor here with UroToday, and it's really a pleasure for me to be able to have John Babich as a guest. I've known John for a long time, but you may not. John is the co-founder and chief scientific officer for Ratio and has a long history in the field of radiopharmaceuticals, including going all the way back to the initial small molecular therapeutics that have been developed for prostate cancer and PSMA. John, is there anything else you'd like to add to that brief introduction just so our listeners might get to know you better?

John Babich: No. That's fine. I spent my career both in academia and in industry, and this is, I call Ratio, the third company. Excited to be back on the industrial side of life one more time.

Oliver Sartor: The first question I'm going to toss at you is probably going to be pretty easy. We're living in an era of targeted therapies. We have antibody-drug conjugates. We have CAR-T cells. We have bispecifics. We have radiopharmaceuticals. Why radiopharmaceuticals from your perspective? What is it about this modality that makes it special?

John Babich: It's a great question, Oliver. I think one of the things that is unique about targeted radiotherapeutics is really the mechanism by which a therapeutic index can be achieved and how the therapy actually gets imported, right? Unlike a lot of things you just mentioned, where there's lots of second messenger activity, target engagement, downstream activation, this is an approach that really requires localization as its main function to yield a therapeutic benefit. It sounds very simple. It's not simple to achieve. So what we really require is for the... Again, all the therapeutic potential sits in a syringe that contains radioactivity, which is going to be administered to a patient. And it would be fantastic if every radioactive atom localized only in cancer tissue and stayed there for a long time. That would be your perfect therapeutic index, perfect drug, perfect targeting agent where nothing else goes anywhere else.

But we know that's not the case for any targeted agent, no matter how often we throw the word around. So I think what's unique about this is if you can achieve that, if you can achieve good targeting and you get good therapeutic indices, the targeting to the tumor versus other normal tissue, routes of excretion like the kidney, the bowel, and so on and so forth. So if you have these ratios, you have the potential of that therapeutic really to be able to deliver something beneficial to the patient, something that will be tumoricidal. And so I think... And it doesn't require activation of immune systems, it doesn't require downstream pharmacological activation, second messenger, G proteins. It really is a fundamental attachment in residence time that's important for the therapeutic benefit.

And then, of course, the therapeutic index is driven by what happens elsewhere. So it's quite unique in that regard. So the old saying, "close only counts in hand grenades and horseshoes," we need to get there and we need to stay there for a while and deposit the energy, and that's really the benefit. So while that's the simple part of it, the hard part is actually getting it there and finding the right targets that can achieve that.

Oliver Sartor: I love your use of the word "ratio," which is probably a play on your company, but I've explained to people that it's really about the ratio of the target to the non-target and then the susceptibility of the tumor and the non-target tissues to radiation-induced damage, and ratio really captures the essence of the argument very, very clearly.

John Babich: Yes. So "ratio" also is Latin for rationale. So there was a little bit of a play on words. You're always looking to name a company something profound, but it was pretty straightforward. The ratio is very obvious in this game, but we do have a little bit of a tip to the old Romans.

Oliver Sartor: Well, very nice. Now, there are a variety of isotopes that you might focus on, and you've worked with iodine. You've worked with lutetium. You're working with actinium. Just want to hear briefly about your view of isotopes and if you have a couple of favorites right now, why that might be the case?

John Babich: Yeah. So I would say Ratio generally is agnostic to the isotope. I think what we're trying to focus on is the development of ligands that have, just as we mentioned, good ratios. So the ratio here, we want to have good accumulation in the tumor versus other tissue, and that's the starting point. Then there's a temporal component to that, which is how long does the compound stay in the tissue and how long does it stay in the tumor tissue and the actual normal tissue? Because the area under the curve for those two things is really the difference in their therapeutic index.

And so if you have a compound that gets taken up into tumor tissue, washes out from normal tissue and stays there for a very long time, then having an isotope with a longer half-life, say a beta emitter or an alpha emitter, allows you to take advantage of all the energy that's going to come out of that radionuclide over time. So that's in the case of an alpha emitter for us, which makes actinium very attractive. If those ratios are good, but the temporal component of that is fast, so that maybe you only have good retention for 24 hours, even though you have a good ratio, then using something like actinium, which requires much more time to deposit all its energy, you may want to go to something shorter-lived. And that could be... And there's a lot of discussion in our field about the use of lead 212.

So if you still have a good ratio in terms of tumor to normal tissue ratios, but the temporal residence time is shorter, then lead becomes attractive. And you can calculate all this and model it mathematically as to how much energy gets deposited for any of these isotopes based on the residence time in normal tissue and tumor. So it becomes almost like a lookup table. If you have a certain amount of time in residence time, say if you get 50 hours of residence time in a tumor, which I would argue Progenics has generally, and Lutathera has generally, then actinium becomes very attractive. It doesn't mean other things can't be used, obviously, because Lutathera is successful. But actinium becomes very attractive in the amount of deposits of radiation that can occur over that period of time or 50+ hours. So we're very much looking at that.

I think the other complexity of our field is that you want to see what you're doing, and you can't really image actinium very well. There's a push to try to do that. A lot of very talented physicists are looking at this. The problem is that the physics of actinium, the [inaudible 00:07:16] decay physics, are not particularly attractive for generating images on a gamma camera. So we're going to get a lot of noisy data, and it's very difficult to have patients who have cancer throughout their body stay on gamma cameras for lengthy periods of time. So the practicality of doing that becomes, I think, a little onerous.

So we would like to have an isotope that maybe could be a surrogate for what we expect the therapeutic, whether it's lead or actinium or copper-67 or lutetium. So we want to have some kind of pairing of an isotope, and I think that becomes a little bit more complicated unless you have the same element, then you have to do crossover studies. You have to understand if I put actinium in this molecule, what's its bio-distribution versus if I put indium in that molecule or something else that we can image. So that complicates things a little bit from the point of view of translating one isotope to another and predicting dosimetry in a human. But lots of people are trying to figure that out, and I think we have a lot of good surrogates and we have a lot of biological models to test to bridge those gaps.

Oliver Sartor: Yeah, interesting. So I'm going to say target-heavy, retention-heavy, isotopic a little bit light, which is interesting. You're really emphasizing getting it onto the target, sticking it to the target, looking at the kinetics, and then matching the isotope to that particular compound, which is a little bit different from the way some of the other folks are thinking.

John Babich: Yeah, we're radioligand first, isotope second.

Oliver Sartor: Interesting. All right. Let's talk a little bit, and I'm not trying to get into proprietary information, but let's talk a little bit about targets. If you can, what targets do you have particular enthusiasm for, assuming that that doesn't violate any of your confidentiality issues?

John Babich: Yeah. So historically, and it's been out there in press releases, we did a deal with Bayer and the previous company, Neurotheranostics, was acquired by them to get technology, which came out of my lab at Cornell. That is really the platform technology, so the Trillium concept where we have LIM-binding domain, PSMA-binding domain plus the radionuclide component. And that was a first proof of concept of using our technology, which is really trying to modulate pharmacokinetics and maintain different specified PK. So from a target perspective, obviously PSMA is very attractive. It's not attractive to us anymore, because we've offshored that to our good friends at Bayer.

We are very interested in FAP, so fibroblast activation protein, alpha. This is something that has a history as being called other things like Seprase. There was some antibody work done by Andrew Scott, a group at MSKCC with antibodies against Seprase. That is now frequently referred to as FAP. There's a lot of small molecule work that the group in Antwerp had done, and then following that, Heidelberg, and then we've jumped into that as well. And we have, again, public knowledge. We've done a deal with Lantheus to develop and deliver to them a FAP diagnostic PET agent, and that's in the clinic now.

Under Lantheus, we did the phase one. We handed it off to them. They'll be taking that into further clinical development, but that's a target where we go back to the premise of what's important: residence time, uptake, clearance from normal tissue. FAP has been really quite exciting from the point of view of being able to visualize lots of cancers, because of the cancer fibroblasts. Lots of epithelial carcinomas express this. There was a lot of expression in sarcoma and other tumors, but the problem with the early ligands is that they didn't have the residence time, and so you'd have to give huge amounts of radioactivity to see any benefit from that. And people have tried that.

We spent a lot of time after we handed off our diagnostic program to Lantheus in trying to dig down into understanding how we can get these molecules to have the residence time we need them to have in order to really have a therapeutic opportunity. And I think we cracked that code, and we're now moving on with that, and we think it is the best option for sarcoma. We're moving on with an alpha-emitting version of our FAP therapeutic candidate, hopefully into clinical trials next year. So FAP is a big one. We also are looking at our technology, as I mentioned, our Trillium technology, which is really related to PK modulation. When you think about how poorly perfused tumors are, having something that rapidly clears from the blood doesn't give you a lot of opportunity for ultimately perfusing that and delivering it to the tumor.

So as Ian Tannock has published in many papers, we don't even know where our drugs go in cancer. So here we can see where they go and we can actually attempt to manipulate how often they pass through the tumor bed. So we're trying to take our technology, our Trillium technology, and apply it to, I would say, low-hanging fruit. So things that we know work but could work better without divulging the targets, and basically looking at them from the ability to say, here we know good models, we have good established models, good translational work. How do we improve upon what we already see as viable therapeutic potential compounds? And so we're truly trying to focus on, I would say, some better understood targets, without divulging anything, and applying our technology to them.

We've also acquired a very interesting suite of chelates. It turns out that everything we do other than the iodinated compounds, and we can talk about the other halogen acetylene in the space, the vast majority of everything we do is radio metals. And so having the ability to attach these metals to sensitive molecules in many cases, sensitive from the point of view of interacting with receptor and enzyme and engaging that target, that also gives us another series of building blocks in order for us to have a more expansive med chem approach to targeting. So I went around your question a little bit, but we're really trying to apply this to well-known targets and see how far we can optimize delivery.

Oliver Sartor: John, briefly, you mentioned Trillium, but I'm not sure that all our listeners are familiar. Could you briefly explain the Trillium concept just so our listeners can have a little better understanding?

John Babich: Yeah, sure. So the concept there, and I'm sorry if I jumped right into that. The idea really is that when you look at the development of a ligand, and this goes, I think, across most drug development, people focus on the affinity of the molecule for the target. And certainly that's important. But in the case of an injectable drug where you want to deliver the maximum amount of the injected radioactivity into the tumor, you know that if there's a very rapid first-pass clearance, whether it goes through the kidney, the liver, comes out of the blood pool, you're only going to get a small fraction of that injected activity basically brought into the tumor. Because again, tumors are typically poorly perfused.

We've seen this in early development in our early PSMA work where we took the same... We studied in the same patients, two different molecules that had high affinity for PSMA. And it became very apparent that the difference in tumor uptake, and this is over several days, the difference in tumor uptake had a lot to do with the PK and the plasma. And so we hadn't designed the molecules that way. We were designing more for affinity, but it was an observation. So then you think, "Well, how can I inject into the molecule a component piece where we can play with that particular PK characteristic?" And so it's very hard to do with very small molecules because you tend to want to put something on there that has nothing to do with the targeting domain. We wound up showing this, and we published this in 2016 maybe, 2017, showing that you could play with that concept in very small iodinated PSMA ligands, but that once you started manipulating that structure too much, you killed the PSMA affinity.

So the idea was just to break these component pieces open, spread them apart, physically spread them apart, and so we could have tethers connecting independent pieces. So the targeting domain in the first instance that we, again, it's all published, we had a PSMA-binding domain, which we optimized, which was single-digit nanomolar. We had a chelator for labeling with lutetium, whatever we like to label it with, typically DOTA. And then we had another piece of the molecule where we could change the structure to tailor the PK, or I'd say to tailor the albumin affinity.

So we're going after albumin. It's the most dominant protein in the blood. It's got lots of pockets on it for binding things like ibuprofen, fatty acids. There are a lot of things that bind albumin and get transported around the body via albumin. So if you have a reversible binding and you can tailor that affinity, you can actually change the plasma curve. So that technology became what we published on and what was the basis of Neurotheranostics, what went into the PSMA therapeutic that's in the clinic now in Canada and Europe, and is part of our technology platform here at Ratio.

Oliver Sartor: Interesting. John, I'm going to ask you to look into your crystal ball for a brief moment. Whether it's cloudy or clear, I'm not sure. But let's think about the next five years. What do you think the field of radioligand therapy will accomplish of significance in the next five years?

John Babich: Well, that's a great question, but we'll give it a shot. I think a couple of things are going to happen. One is we're going to understand the clinical utility of these molecules, and I think the PSMA space is just a great space to play this out, right? You have lots of men with prostate cancer at different stages of their disease. You'll be able to look at how early you can introduce a radioligand for treatment. Again, you have more experience maybe than most clinicians around the globe. These side effects from these therapies are quite minor, right? It's not that they're without side effects, but they're quite minor compared to, say, chemotherapy, castration, or whatever the other therapies might be.

So I think when we think about radioligand therapy, the clinical acceptance and the clinical expansion are going to be very important for the global appreciation. From a technological perspective, I think what we'll see is that we'll get a better handle on what's the value of doing radioligand therapy as an adjuvant, whether that's pre-surgery, whether that's pre-IO immunological treatments, and how that blends in the management of the patient. So I think there'll be a lot of, I would say, preclinical evaluation of things and then translation into the clinic on how we could use targeted radioligand therapy to aid in the management of disease in general.

I think there'll be another wave. I was just talking to a group yesterday. I think we still don't have a good handle on what the targets are out there. And having spent eight years at Cornell recently and attending a lot of RNA-Seq lectures and all the GWAS work. We're looking at genes, genes, genes. Very hard to understand whether or not it's going to translate into applicable targets. And so I think we need to get a handle on what's the real proteomic expression of targets on the cancer and cancer cells, and how do we get that information? How do we pursue it?

Because once we understand that there are targets there that we maybe have missed, or we were looking in the wrong direction because RNA-Seq was taking us in a particular place that didn't translate into those practical... I call them practical because we actually... There may be mutations that you have to go after because that's the driver for the cancer. But from the point of view of a targeted radioligand therapy, the driver is you want to have something that's highly expressed on the tumor cell so you can get as much of the radioactivity there as possible, a simpler concept maybe. And so I think that's going to be a big part of it.

And then the last thing I think is that we... And this is somewhat related, there are going to be targets that are getting expressed and multiple targets in the same tumor that we might be able to go after. Now people have talked about this using cocktails in neuroendocrine cancer. There's been a lot of discussion about using something like Lutathera plus MIBG. Tumors express the neuroendocrine transporter. Neuroendocrine tumors, they also express somatostatin receptors. What if you did both of those treatments in the same patients, non-overlapping toxicities, et cetera?

But then there's also the heterodimeric concept where you have a dumbbell molecule where one is attaching, let's say it's attaching SSTR-2, the other one's attaching GRPR or one's attaching FAP, the other one's attaching something else in this cellular milieu, in the tumor microenvironment. So I think it's not easy to figure those things out because you might actually have de-optimized everything by having something that's promiscuous. So the idea is how do you do that in a fashion that gets you a better targeting agent? So I think there's a lot of it.

There's also going to be a lot of chelate work that's going to come out, and we're going to see, I think, an expansion of that space, which has been pretty... Believe it or not, it's an old space, but not a lot has been done. And I think that expansion will open up some eyeballs when it comes to new compounds.

Oliver Sartor: John, that is absolutely fascinating, and I think we could think deeply about the last three minutes of our conversation and gain a lot, all the way from the dumbbells to the chelations to the PKs, the modulations. You've raised a lot of interesting concepts. We're just about to be closing out, but I wonder if there might be anything else you'd like to say before we finish up? Any particular final words?

John Babich: Well, it has been a pleasure, as always. I think having conversations and dialogue with clinicians and scientists—me being a scientist, you being a clinician scientist—I think these are some of the most fruitful opportunities that we have to actually listen to each other, have good dialogue, dig into the clinical problems, dig into the technical limitations, and how do we expand things. I think there's a lot of opportunity for dialogue in this space, and I think I would encourage that.

Oliver Sartor: Great. Well, thank you. A real pleasure today, John Babich, co-founder and chief scientific officer for Ratio. Thank you for being here today on UroToday.

John Babich: Thank you, Oliver. Good to see you.