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Oliver Sartor: Hi, I am Dr. Oliver Sartor. I'm with UroToday with a very special guest, Andrew Cavey, well-known in the prostate world and beyond. Andrew was global lead of prostate cancer at Novartis, but now is CEO of ITM. Hello, Andrew, and welcome.

Andrew Cavey: Thank you very much. That was a glowing introduction. I'm not sure that was deserved, but thank you. It is really nice to be here.

Oliver Sartor: Well, the stakes are very high. This has got a huge global audience and they're all watching you.

Andrew Cavey: I'm waiting for my Emmy after this. Our Emmy.

Oliver Sartor: Our Emmy, we're going to do it together. Okay, so Andrew, you are very focused now on radiopharmaceuticals and it's a big world out there in cancer. We could be talking about CAR-T cells, we could talk about small molecules. We could be talking about antibody-drug conjugates, but we're going to be talking about radiopharmaceuticals. Why do you think that radiopharmaceuticals are the path forward in cancer treatment?

Andrew Cavey: Yeah, I've been lucky as well in my career to work across a variety of modalities in cancer care. So I do think it's wonderful, it's necessary for society that the academic, the clinical, the industry communities are all working on advances across all these modalities. You mentioned radiopharmaceuticals, but also ADCs, cancer vaccines, bispecifics, trispecifics, protein degradation, and so on. We need these, and I think in all worlds of future cancer care, each of these will have their own use cases. But among them, I am very bullish. I do see a lot of potential for radiopharmaceutical therapies beyond what we already see being used today.

And that's for a few reasons. I think firstly because actually it's not new. If you think about the arc of history of cancer care, radiation was one of the first tools used to treat cancer, radiation or X-rays. And then broader radiation was discovered in 1895, '96, and there's first case studies of it being used to treat various forms of masses already that same year, 1896, some report. So the use case goes back a long time.

And in general in cancer care, as the biology has been better understood, we've seen a move towards greater and greater precision, greater and greater balancing of benefit and risk. And that's exactly how radiopharmaceuticals have evolved to more precision and more balancing of benefit-risk. So it's just where we are today. I see it's a natural extension of using what we know, the power of the physics of radiation, but in a slightly less blunt way than with external beam radiation therapy and it works.

I think the excitement today that, and I see you see in our company and in the industry comes from maybe two or three things. One, the physics is the physics, it kind of works, the breakage use of radiation to address break double-stranded DNA, that works. There's an elegance with radiopharmaceuticals of the ability to image and treat, which reassures patients, reassures physicians, but also helps accelerate drug development. And finally, I guess there's a lot of excitement because this will change. But so far the major pivotal studies have largely been positive like we've seen with Lutetium PSMA and the Lutetium SSTR. That luxury I'm sure won't continue forever, but right now that helps generate excitement.

Oliver Sartor: It's interesting, there is a bubbling of enthusiasm I think of those positive studies and some of the small companies that have come into really important observations. And then takeouts, multi-billion dollars, I think that helps to fuel things.

If we think about the broad field of radiopharmaceuticals, some companies have a predilection towards certain isotopes and others do not. And I'd like to get your worldview, if you will, on any particular isotopes that you are particularly enamored with. Are you kind of an alpha guy, you're a beta guy? If you're a beta guy, do you have betas you like? If you're an alpha guy, do you have alphas you like? What's your kind of view of the isotopic therapies that are now available?

Andrew Cavey: Yeah, maybe I'll first talk about the therapeutics. I guess that the same discussion applies on the imaging side. Of course, I'm biased. As you mentioned, I'm very fortunate to lead the team at ITM. So as a disclaimer, ITM manufactures lutetium at global scale and also we're soon to manufacture actinium at global scale and moving into terbium, so there's that bias, but let me just try to do my best in an unbiased way to talk about the different ones.

Lutetium by far right now is the most developed in the sense that it's where there's the most use cases, where there's the most clinical data, where the manufacturing is the most advanced and the kind of distribution of lutetium and it's been used for a long time. So I think that will continue in my mind to be the working horse, the beta emitter course to be the working horse.

I know that so many now in academia, among investors, venture capitalists and young companies are looking for the next thing. And I often joke, I was at EANM last weekend, I was joking with someone, "It's like looking at what the iPhone 16 will look like," but the truth is the iPhone 12, the iPhone 10, they all work really well, lutetium is that. It works very well and it's very advanced and it's very widely used and we know what we have with it. So I think beta emission, especially for larger tumors, I think will continue to just be a gold standard for the foreseeable future.

And then if we think of what's next, the next most advanced is clearly among, there's a lot of excitement for the potential of alphas with a shorter firing range. And among those actinium-225 seems to be, there's a lot of excitement behind that. It was clear at EANM that many, many companies, including ITM, but many others are looking for new ways to manufacture this at scale. This has been one of the rate limiting steps for scientists to really move forward with clinical studies has been actinium supply. And you're seeing now an increasing number of assets in the pipelines moving forward.

So then beyond lutetium and actinium on the therapeutic side, I think there's lots out there. We at ITM are very excited about terbium-161 because it has the potential to combine the best of beta emission with these Auger electrons, which could sort of create an alpha-like approach. And at EANM, in fact, the Marie Curie award was awarded to an abstract using terbium-161. So we're excited about that.

But there's also many others out there looking at lead-212, astatine, copper, of course, astatine. So I think with all of these, really the proof in my mind will be in the clinical data. Lots of companies will move forward with different approaches, different supply chains, some more user-friendly than others, and then as the clinical data emerges, we'll see if there are clear standout winners. And you're much better placed as a clinician to say this to me, but my guess would be that the clinicians will gravitate towards those that have disproportionately good data. That's really where we'll end.

Oliver Sartor: And would certainly agree. Next question, Andrew, and I'm not trying to get into any proprietary issues, so please don't break any confidentiality, but are you able to discuss targets of interest? Obviously PSMA is a huge proof of principle. SSTR2, huge proof of principle. Are there targets beyond that you might be able to discuss and if that gets into confidentiality, then let's not talk about it.

Andrew Cavey: Look, I'm going to start again. I'm biased right from ITM, I'm quite excited about our pipeline, so I'll start with some of the targets we're looking at, but maybe I'll also just cheekily allow myself to comment a bit more broadly too. The way I look at the evolution of the targets is a few companies really took fantastic early bets in innovation around PSMA and SSTR, and there are several companies who've done this, largely based on the use of these in the homebrew setting by many nuclear medicine physicians around the world for decades.

I think that we see commercialized products targeting SSTR and PSMA today, and I think there still is an unmet need and I think you see more and more companies using different isotopes, different peptides to try and incrementally continue to improve on what we already have. That I think is gen one of the targets and we still have more work to continue advancing that.

In the ITM pipeline, we're looking at a few targets. We have one targeting carbonic anhydrase IX, which is overexpressed in clear cell renal cell carcinoma, as well as potentially a few others like pancreatic. In the clinic we have one looking at carbonic anhydrase XII in glioblastoma. That's an antibody fragment. Folate receptor alpha, which is alpha specific, not beta, which has uptake in the bone marrow as well. And I think all of these will continue to develop. I'm quite excited by those targets, but there's many others out there too.

To me, if I think more broadly then there's the low hanging... There's two things. One, there's the ADC modality. As a modality, antibody-drug conjugates is obviously many years ahead of where radiopharmaceuticals are and the scientists behind all the ADCs have really paved the way of understanding surface expression on cancer cells, and I think there's a lot there that we in radiopharmaceuticals can learn about where to go to next in terms of targets.

Then beyond that, of course the radiopharmaceutical approach doesn't need the biology to work. You kind of just need to bind and then you let the physics of the isotopes work. So I see a lot of potential there, just understanding surface receptors and ways of cleverly binding to them and not to non-tumor tissue as a way of having an even broader horizon of targets.

Oliver Sartor: Interesting and appreciate your insights there. And by the way, completely agree. Is it too early to talk about combinations? There's a lot of discussion about combinations of isotopes and immunotherapies, a lot of combinations discussed about isotopes and DNA repair inhibitors. Those are two that are kind of dominant in the combination discussion. Is it too early to talk about combinations or are you already thinking ahead toward the combination strategy?

Andrew Cavey: Yeah, I think it is not too early. It is early. I mean, first of all, already we are combining with standard of care. So if you look at the VISION study, others, the radioligand therapy was used in many of these studies in conjunction with standard of care. So that is a form of combination, not a particularly scientifically exciting one, but it's an important one.

Then as you look for the more scientifically exciting ones, I think yes, you're right. People have already started, mostly in the academic community, with PD-1 and with DNA damage repair inhibitors, especially the kind of first-generation PARP inhibitors. I think for PARP inhibitors, that makes a lot of mechanistic sense, having a DNA damage repair inhibitor used with radiation. I think it would be nice that what becomes tricky is the tolerability profiles, and so we'll have to see what that clinical data shows, but I think as new advances in synthetic lethality move on, I think there should be more and more promising molecules to combine.

Radiosensitizers is of course another big bucket of modalities to combine with, and then RLT-RLT combinations or isotope-isotope combinations are exciting and some companies have already started using a beta and an alpha or an alpha and a beta, different or alternating the sequences, and I think I'm very excited to see what those show. To me, one big challenge with these combinations is whilst they often make sense scientifically, the price tag starts to add up for society and for healthcare systems, and I really don't know how we solve that, but clearly we have to make sure that the science doesn't get ahead of the ability of society to afford this, and those things need to go hand in hand.

Oliver Sartor: Thank you for raising that, and that is often an unspoken issue. We won't delve into it further now, but that's a huge topic that you've just begun to broach.

When we're thinking about the future, we're always interested in the vision of our leaders and you're one of our leaders. I wonder if you might look into your crystal ball and imagine for a moment some of the things that we will know five years from now that we don't know today that you think are important. What's sort of the next level during a five-year scope of the knowledge gains we will have then that we do not have now? Not an easy one.

Andrew Cavey: I'm terrible at predicting. I always thought I'd have two children and now I have three children, so it just goes to show how well my crystal ball works. Let me give it a go, but then we will have to play this back in five years' time and see.

I'm going to mix a bit the science and some broader radiopharma and healthcare trends. Let me start with some good things that I think will happen that will be good. I think we will see a broader supply of radioisotopes, different isotopes from different partners and suppliers given in more user-friendly ways. I think we will see more treatment centers with more people with cancer receiving these medicines over time, and I hope that we'll also see an improvement in the logistics, coordination, management, the whole sort of digital back end so that all the logistics of you prescribing, the patient coming in on the right day, the drug, all that, I'm really hoping in five years, I think so many people are working on making that more user-friendly.

And I hope, but I also see good signs that we'll also see within the healthcare providers, more seamless coordination at the MDT level between, in your case, for example, the urologist, the oncologist, the nuclear meds, the radiation oncologist, and I know that you obviously work in very preeminent centers where this already works well, but in many smaller settings or community settings that today doesn't work so well.

I think scientifically we'll also understand a lot more. I think if you think of each component of a radioligand therapy, of a radiopharmaceutical, so many smart minds are working on so many of those components. We talked about the isotopes, the targets, the chelators, cancer surface, protein expression, how we modulate tumor to kidney ratios or other organs, bone marrow. I think all those things will have a much better, the use of dosimetry in clinical trials, all those things. I'm really hopeful that scientifically we'll have made big progress.

But there's a few things where I'm not seeing progress yet that concerns me. I see some people really making great efforts to start. The big one is around capacity, and I'm talking if you look across the world, first of all, there often are not enough beds to sustain the amount of innovation that's coming. There's not enough capacity to receive that at the other end.

Even where there are enough beds, there's often other limitations like imaging capacity in many countries. Even when that exists, there's a huge variability across countries of regulations. So you in Rochester, you might be able to get patients in and out very quickly. In some countries such as Japan, people have to stay in a week. So this really limits the flow of capacity and how many people can benefit from approved treatments. So I know some people are trying to think about this, and I really hope that more get involved and mobilized so that we build the treatment capacity and regulatory framework at the same time that we advance the science.

Oliver Sartor: That's a really important point, and thank you for raising that. Andrew, we just have a few moments left. I wonder if there might be any final words that you'd like to have before we say adieu.

Andrew Cavey: A few words to close. I've been fortunate to work with you for several years now. I think even in that short period of time, we've seen huge advances, progress with how radiopharmaceuticals are being discovered, developed and used by clinicians and prescribed. I think there's a lot more to come. I'm very excited about that.

I hope that ITM over the coming years as a company that's really been at the cornerstone of this industry, both on the isotope production side and with a growing clinical pipeline, I hope that we can continue to partner with all of the clinicians and scientists out there and centers out there to really make this field together with many other partners, to really make this field grow and be impactful.

Oliver Sartor: Thank you. A pleasure to have Andrew Cavey, CEO of ITM join us today. Thank you so much, Andrew.

Andrew Cavey: Thank you, Oliver.