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Oliver Sartor: Hi, I'm Dr. Oliver Sartor here, I'm with UroToday and a very special guest, Chris Behrenbruch. I've known Chris for a long time, but I'm simply going to say he is the founder and CEO of Telix, which is having a very successful run. Thank you, Chris, for being here tonight.

Chris Behrenbruch: Thank you, Dr. Sartor. It's great to see you.

Oliver Sartor: So one of the things I'm going to probe initially is your fascination with radiopharmaceuticals. You've actually been involved with this field for a long time and I know you're passionate. I'd love for our listeners to understand why you have that passion.

Chris Behrenbruch: Well, I got into nuclear medicine through MRI, which is, if you are a student of nuclear medicine, is not such an unusual concept because they're so closely entwined with each other, particularly in the neuro space, which is one of the areas that I was mostly interested in in early days.

The person that got me really excited about PET was Sam Gambhir. I met him when I was a grad student and I was doing my PhD in biomedical engineering and with an imaging focus, and I had a chance to interact with Sam, and just infected me with what you could do with PET and SPECT. And I think that if you're a scientific generalist, nuclear medicine is an amazing field because it touches on every aspect of science that you can imagine, from chemistry, biology, physics, material science. And then if you're a little bit more of an engineering type like me, the logistics and supply chain and manufacturing has some of the most unique challenges in medical science. It's a fascinating area.

So I'm a problem solver, and so nuclear medicine is just one enormous sandpit of problems to solve, and that's why it's exciting. And then you layer on top of that the patient impact, which is, I think, why we all get out of bed, and certainly it's why I get out of bed every day, because honestly there are easier jobs than running a nuclear medicine company. It's the opportunity to have profound patient impact and nuclear medicine is about to hit its stride in that respect.

Oliver Sartor: I certainly agree with you and pace of progress has been amazing. Of course, PSMA-PET has just revolutionized the way we approach prostate cancer, and I think there are many more to come. You're focused on both the diagnostics and the therapeutics. And just for a moment, I'm going to leave the diagnostics and ask you to focus on therapeutics. Some isotopes that you're developing, I know you're working on both Lutetium-177 and Actinium-225. Let me hear a little bit more about why these particular isotopes, and are there other isotopes that you think hold promise as well?

Chris Behrenbruch: We have a pretty isotope-agnostic view of the world. I actually don't like platform technologies. I think that you want to solve a particular pharmacology problem, you want to think about the target, you want to make sure that your choice of isotope and the radiation biology effector function that you're looking to utilize is appropriately matched to the biological problem that you're trying to solve. And so if you look at our pipeline, we work with a whole variety of different isotopes because we think that a certain isotope is going to have a certain utility.

I'm excited about alphas. My main worry with alphas is that I think the major opportunity is in treating perhaps curatively, early-stage patients, early metastatic patients. But the challenge is that you're going to irradiate a patient that may have a very long lifespan after that and you need to be able to deal with the consequences of a very potent radiation profile. The reason why we don't put alphas on renally excreted agents is because I think that you're going to see a lot of long-term latent nephrotoxicity.

So I think as a general rule, we don't treat patients aggressively enough in nuclear medicine, so I think that we shouldn't be afraid. These are serious cancers, serious disease, but I think on the other hand, we need to think about, okay, as we move into earlier lines of therapy, what are the real consequences?

Oliver Sartor: Yeah, Chris, I've read, I hear you raise that there was an SNMMI FDA meeting not so long ago in May, and that particular topic was a significant part of the agenda of that meeting. And we all understand that patients with cancer need to be treated aggressively. And quite frankly, I don't think we've been adequately dosing the radiopharmaceuticals to date and we need to change that. But, as you pointed out, as you move earlier, you assume more risk, and particularly the alphas where we really don't have any long-term follow-up. So I appreciate what you said and believe it's a very important point.

I'd like to move on to targets, and I'm not trying to get proprietary information, but I'd love to hear your take on targets you think are particularly important and where Telix is concentrating today.

Chris Behrenbruch: Yeah, most of the things that are next-generation targets, we're not talking too openly about. Although, spoiler alert, I think that there's a lot of targets that have been attempted to be drugged in the ADC space that could be really well applied to nuclear medicine. And since we are interested in biologics, we're one of the few companies that's really committed to biologics. So there are some lessons to be learned from other fields. We always have to remember that nuclear medicine, until the last decade or so, was not funded as a commercial space, as a well-funded research space. And so we're a little behind in terms of the range of targeting agents that we can use. And for some of the really interesting targets that we might want to go after in nuclear medicine, small molecules may in fact not cut it in terms of their internalization and residualization characteristics.

I think that in nuclear medicine we've typically focused on targets that are more pan-cancer or more prevalent in a particular cancer type. We haven't started to slice and dice disease areas. So you said you wanted to focus on therapeutics and, as the host of this podcast, I want to honor that request, but I do think that the imaging piece is still super important because that will enable us to select patients for some of these targets where a subtype of a particular patient population may be really accessible and really suitable for targeted radiation.

Oliver Sartor: Couldn't agree more, and I'm actually waiting for the ADC field to wake up, and the CAR-T and the bi-specific field to wake up. The molecular imaging will help their targeting selection—

Chris Behrenbruch: Definitely.

Oliver Sartor: ... improve their therapeutic index. Why would we give a drug to somebody who doesn't express the target? And they continue to work on things like immunohistochemistry on biopsies we've done a decade ago, it really doesn't make sense.

Chris Behrenbruch: Totally agree. So I think all the immune cell targets are really exciting both diagnostically and therapeutically in nuclear medicine. One of the things that I am personally excited about are some of the hematologic targets, some of the leukocyte and neutrophil targets as well in nuclear medicine. Because if you look at, sometimes in nuclear medicine, we get focused on what's exciting in nuclear medicine and we forget about the rest of oncology. But if you look at the tsunami of cell and gene therapies that are coming down the pathway, they're going to need to have very robust, safe bone marrow conditioning, and nuclear medicine can deliver that hands down. If you look at high-intensity bone marrow conditioning regimes for hematopoietic stem cell transplants, they have a high mortality and high morbidity rate associated with them. And nuclear medicine can pave the way. We know how to do that, we can pave the way for safe preparation of those patients for all kinds of next-generation cell and gene therapy, so I think that's an exciting target space.

But that's also, by the way, not a space where being hypothetical about your choice of isotope is going to play out very well. We are going to have to go and deal with old-school betas like Lutetium and Yttrium-90. Yttrium-90 is a fabulous isotope in that application, Samarium, which is, I know, one of your old stomping grounds, is a fabulous isotope for that application. And so again, to come back to the original question, I think you have to really choose your isotope on the basis of the clinical problem that you want to solve.

Oliver Sartor: Yeah. Thank you, Chris, you made that abundantly clear. Combinations. We're in the very infancy of looking at radiopharmaceuticals in combinations with other therapies, and I wonder if you might have any thoughts to share on that topic.

Chris Behrenbruch: So I think we'll look back 10 years from now and we'll realize that we are at the cusp of the moment where targeted radiation and immune oncology really came together for next-level patient responses. And we're seeing some of this in our own clinical research today where patients that are progressing rapidly on immunotherapy can be brought back to immunotherapy with radiation. That's why when I said before, it may not be that double-strand DNA damage is the most important mechanism of action, actually relatively low doses of radiation to certain types of targets, which may in fact not even be tumor targets, but rather more stromal targets, could be really interesting for moving the needle on the field.

And then of course, we've got to work out how to layer those therapies, but we also need the biomarkers of response to know how we're layering these therapies. So I think we're going to see a whole next generation of PET agents play a role in imaging that immune function and that immune response to make sure that we're tiering these, we're layer-caking these therapies in an appropriate way.

Oliver Sartor: I am very aware of imaging the immune system, I think it's in its infancy, but I think we're going to learn a great deal along the way, and that'll be part of the biology that we appreciate, that then we can then exploit therapeutically, I hope for patient benefit.

Chris, I have a crystal ball that I'd like you to look into, and in a brief way, think about moving forward about five years. What will we know in five years that we don't know today that you think is going to be really important?

Chris Behrenbruch: Wow, that's an amazing... Well, like I said, I think the IO space is really big. Can I tell you what I think is going to be the biggest transformation? And I'm already starting to see it. It's not the products, but it's the services. It's the medical practice that is going to undergo a massive change in the next five years. And as I said before, and I didn't mean it to sound snide, it wasn't an accusatory comment, that historically nuclear medicine hasn't run a clinic per se, but that is changing.

And also as these therapies become more refined, and I really hope as an industry that we do run the combo therapies, that we do integrate nuclear medicine into standard of care. Historically, we've had a tendency to go head-to-head with standard of care, to go, "Well, we're nuclear medicine. We're special. We can do things differently." I really think that we should run integrated trials where we're showing that targeted radiation is additive to standard of care when patients are selected appropriately. And what that's going to mean is that medical oncology is going to become a much bigger stakeholder in the success of nuclear medicine, and that will lead to a change in the clinical practice of nuclear medicine. It will become a much more clinical specialty.

And then that will also adjust the risk appetite of managing patients. Because you'll say, "Yeah, I'll tolerate certain AE profiles, because I'm working with a care team that's better equipped to manage those kinds of AE profiles." Now, you're a multi-trained professional so you know exactly what I'm talking about. I think that for all of these great things that we're talking about to transpire, we actually have to also change the practice of medicine. And that's going to happen really quick. You're seeing specialty theranostic centers popping up. You're a part of one. You're seeing private nuclear medicine departments, or private nuclear medicine groups, appearing, that are cross-disciplinary teams. You're seeing urology take charge of imaging, much like what we saw cardiology do some time back, some decades ago. So I think that whole practice of medicine is going to shift, and I think that's actually the most interesting thing that's going to happen in the next five years.

Oliver Sartor: Interesting. Appreciate your perspective. Chris, Telix is a little bit unusual in the use of biologics in addition to small molecules. Some people have criticized that approach. I'd like to hear your rationale for why the biologics as opposed to the small molecules for therapy.

Chris Behrenbruch: Yeah, this is a question I get asked a lot, particularly by investors, and I just want to say upfront, we do both. We're commercializing small molecules today. Typically with biologics, and we know this from many decades of research, that you tend to have fewer off-target effects. You can direct the payload much more straightforwardly. That's why we don't have a lot of small molecule drug conjugates in, say, the cytotoxic space. You can control your clearance organ much more carefully. I think that to have more hepatically excreted radiopharmaceuticals is actually really interesting, particularly as we go into alpha, your liver is a much more radiation-resistant organ, and so if we're going to treat patients more aggressively.

But I think it's really the selectivity and the fact that you can rapidly develop new targeting agents against all kinds of targets. But truthfully, if you want to get something across the blood-brain barrier, unless you use a novel transporter or something, a small molecule is probably going to be better. If you have something that's a target where tissue penetration is an issue, doesn't tend to be with things like PSMA, which is essentially a neovascular target. But with some of these other targets where you want to get deeper into a tumor, maybe a smaller format or a small molecule is better.

So again, I think it comes back to my earlier comment where you should choose the platform that delivers the pharmacology that you need to solve a particular radiation biology problem. And we just happen to have an open mind that sometimes you'll achieve that with a biologic and sometimes you'll achieve it with a small molecule. And I think that's just good risk management, to be quite honest.

Oliver Sartor: Another question for clarification. Antibodies are typically large and monoclonal. What about fragments? What about camelids? What about some of the variants that we've seen with heavy-chain-only engineering?

Chris Behrenbruch: Oh, I love some of these formats. I love some of them. And that, again, comes down to choice of isotope. Let's just say for discussion purposes, why would you put Lead-212 on a full-length IgG? Makes no sense whatsoever. And similarly, why would you put Lead-212 on a small molecule? Makes no sense either. You're going to have all of those decay events happening in your kidney cortices rather than in your tumor. So I think that a half-life-extended small fragment with Lead-212 is an example of where the pharmacology really fits beautifully onto the half-life. So I think those small formats are really great. I hope that if we can keep an open mind in the field about biologics and, let's call it, engineered constructs, that we're going to see a whole explosion of medicines that will be really in the sweet spot of efficacy and patient safety. That's what I think.

Oliver Sartor: Terrific. Chris, we're going to be wrapping up here in just a moment. Are there any final remarks you'd like for our audience to hear?

Chris Behrenbruch: I don't really think I said anything particularly intelligent, and I don't think I said anything that most people don't already know. Look, I really hope that this field continues to be open-minded about where the potential next blockbusters are going to come from and how they're going to be achieved. And the only thing that matters at the end of the day is the clinical data. We shouldn't wed ourselves to a particular platform or a particular isotope.

Obviously, we can't concentrate our efforts in everything, so there are going to be some winners and there are going to be some losers. I think there are some clear signs that there are certain platforms and certain isotopes that are going to be more successful because there's more momentum or there's more raw material availability or whatever. So I think that by Darwinian selection, there'll be some concentration that appears. But we've had now almost two decades, prior to Lutathera and Pluvicto and other things that are coming up, we had two decades where there was no therapeutic innovation in nuclear medicine, okay? And so we have to be open-minded about what are the technologies that are going to be successful in nuclear medicine now that we're in a position to invest.

Oliver Sartor: Chris, I really appreciate your perspectives. Thank you for being here today. I know your time is valuable. I've enjoyed the conversation and I'll suspect the UroToday audience will have enjoyed it as well. Thank you.

Chris Behrenbruch: Well, thank you. Thanks for the opportunity and nice to see you, as always.