Read the Full Video Transcript

Oliver Sartor: Hi, I'm Dr. Oliver Sartor, Medical Oncologist with Mayo Clinic, but here today with UroToday, the world's largest platform, I believe, when it comes to looking at urologic malignancies and beyond. We have a very, very special guest, Volker Wagner. I've known Volker for years, going back to his time at the Bayer Corporation, but now he's with Orano Med and is the CMO. So welcome, Volker.

Volker Wagner: Thank you very much, Oliver. Glad to be here and very much appreciate the opportunity.

Oliver Sartor: Good. Is there anything else you'd like to say in terms of the introduction? We have an audience who might be interested in more about you, so anything else you'd like to mention? I just gave something very brief.

Volker Wagner: Well, I'm a medical oncologist and a hematologist and have spent many years in the US working in various areas of clinical development. But as you mentioned, I have spent the last eight, nine years with Bayer, leading the clinical development of their radiopharmaceuticals, and I'm now the Chief Medical Officer of Orano Med since about nine months. Very excited to be here, and we'll talk more about that in this session.

Oliver Sartor: Terrific. And thank you for being here. So I'd like to start off with a simple question. Why radiopharmaceuticals? Right now, we're living in a time when antibody-drug conjugates, CAR T-cells, bispecifics, all variety of monoclonals are in vogue. Why radiopharmaceuticals? Why do you think they're important?

Volker Wagner: I think there are many reasons for that. In my view, radiopharmaceuticals have evolved and have proven to be yet a very new treatment modality. I think when you think back to the treatment options for cancer, there was always chemo, then there was external beam. Both have proven to be effective, but obviously we're still in a situation where most of the cancers cannot be cured. At best, we control their progression, and still even there, a lot of progress still has to be made. With the advent of biologic targeted therapy, be it biologics, be it peptides, we then entered a stage where we started to interfere with tumor biology, trying to switch off certain pathways and initially thought that is the answer to our needs. But then quickly realized that also the landscape of pathways is much more complicated. If you switch one of them off, others become active.

And so still, while we have made progress, it has opened even additional doors, additional needs. Radiopharmaceuticals basically take radiation systemically. EBRT only treats limited volumes of tumors, well-defined, and have shown to be very active, but we can't irradiate all disease in a patient with a metastatic solid malignancy. I think this is where radiopharmaceuticals close that gap as they take the radiation source to the tumor, wherever that is, be that larger metastatic volumes, be that circulating tumor cells, and different types of payloads may be able to do that differently well. We have also learned that radiopharmaceuticals, particularly the alpha emitters because they lead to DNA double-strand breaks, lead to immunogenic cell death. So here you have the connection to immunotherapy, which is one of the, I think, most interesting combinations for these kinds of new emerging drugs. And as we have learned to make targeting moieties for a variety of tumor types, the options, at least in theory, are endless. So I think that radiopharmaceuticals have allowed us to pass yet through another door in finding new treatment options for cancer.

Oliver Sartor: Thank you. And you mentioned the alpha particles, and now your focus is on a particular isotope, lead-212. I'd like to hear, in your own words, why lead-212 is particularly promising from your perspective.

Volker Wagner: Orano Med has always been focused on alpha emitters and was a strong believer that alpha therapy might have advantages over beta. I think in previous sessions that you moderated, that has probably come up a lot, that obviously there is that particular promise of alpha therapy, given that alpha particles have high linear energy transfer—that means they're super powerful. At the same time, their range is limited. So as they are powerful, the range is limited, which means that there is the chance to protect surrounding healthy tissues. And so alpha therapy, together with the double-strand breaks, where even a single alpha hit may lead to cell death, these are all reasons why alpha therapy is supposed to have advantages over beta, which has longer range, less power, single-strand breaks.

So amongst the alpha emitters possible, lead-212, I think, has emerged as a particularly interesting one because the different alpha emitters have different physicochemical properties, both in terms of half-life, for example, but also in terms of how many alpha particles they in theory can give off. So for some time, and when you look into the different players out there, many people are excited about Actinium-225, but Actinium-225 gives off up to four alpha hits. And so when you think about it a little bit more carefully, for a while people thought more is better—the more alpha hits you get, the more powerful against cancer. But in reality, particularly when you consider half-life of the isotope and half-life of the targeting moiety, many of those hits might actually not occur at the cancer site, but somewhere else.

So then all of a sudden, those hits become contributors to off-target tox. You don't have that with lead-212 because the half-life, first of all, is about 11 hours, and that goes very well with small molecule or peptide targeting moieties, which are known to also improve tumor uptake. And at the same time, lead-212 gives off one alpha hit that largely then stays with the tumor. So the potential for off-target toxicity is more limited. Another reason why Orano Med has basically built its portfolio around lead-212 is that we have particular access to the isotope. And we could talk a little bit about that further, maybe when we touch on the point why Orano Med might be different than some of the other players out there, even those that work with lead-212 as well.

Oliver Sartor: Well, let's go straight there because five years ago lead-212 was exotic, and probably very few people had heard of it. And today you have ARD Bio, you have Advanced Cell, you have Perspective, you have Radionetics, you have Orano Med. What gives Orano Med the leg up in this highly competitive space?

Volker Wagner: I think when you think about radiopharmaceuticals and what it takes to be successful in that space, then first of all obviously it's all about the science—to be able to pick targets that work very well with tumors and to build assets that carry the payload to the tumor. So there is that science part, and arguably every biotech might have great science in building those assets, but I think also very recently we have come to appreciate that besides the science, particularly with radiopharmaceuticals, as they decay, they need to be tailor-made and delivered to the patient in need—not like a chemo or a pill that a pharmacy can stockpile and pulls off the shelf whenever needed. So access to the payload, ability to produce, manufacture, and supply are critical success factors to really make a drug work. So you might have the best radiopharmaceutical in the world scientifically, but if you don't have access to the payload and if you cannot reliably supply to patients, you might have nothing.

And I think this is where Orano Med is set up in a very different and very promising way, in that, as you may know, Orano Med was founded in 2009 by the mother company Orano. And Orano is one of the world's leaders in uranium mining, enrichment, and nuclear fuel recycling. As part of that business, they built a stockpile of thorium-232, and that is the source material for lead-212. So we have a proprietary stock of thorium-232, which Orano got interested in because it is a fertile material, which means that through neutron capture, it can eventually lead to uranium-233, which at least at certain times was used as nuclear fuel. So with that huge stockpile of thorium-232, that is our source for lead-212 because thorium-232 decays eventually to thorium-228, which through radium-224 arrives at lead-212.

So we basically are in full control of an enormous stockpile of mother isotope from which we derive lead-212, which means we don't need a middleman or a third party to get it. We don't get it from any other country abroad. We basically have it. And the good news is that the mother material, thorium-232, has a half-life of 14 billion years, which means it's a primordial nuclide. That means probably it originated at the Big Bang or a little bit later, so it's much older than the earth. And with that material, we can reuse that every 15 years and derive lead-212 just through chemical processes. So it doesn't even involve a cyclotron. It doesn't involve a nuclear research facility. Just by having access to that mother material, we can basically, in an unlimited fashion, derive the asset. And that helps a lot.

So I think that makes Orano Med very different from some of the others that have to get their payload from someone else. And as we have recently seen, that's not that easy. Even if you might have supply contracts with three or four different vendors, that does not protect you from running out of it. And I think that makes us quite different and allows us to be very much focused on growing our manufacturing and supply base.

Oliver Sartor: Interesting. I'd not heard the 14 billion-year half-life before, so I'm becoming better educated. Thank you. Now, the next question, and I don't want to get into proprietary issues, I don't want you to divulge company secrets, but I wonder what you might be able to say about targets that are attractive to Orano Med at this time.

Volker Wagner: So we currently have two different assets in the clinic. One of them, the most advanced one, Alphamedix, targets somatostatin receptors, so it's in development for neuroendocrine tumors. The Phase 2 trial has already been completed, and that includes patients both Lutathera-naive as well as Lutathera-exposed. Earlier this year we received FDA breakthrough therapy designation for Alphamedix for treatment of the Lutathera-naive patients, and we are now preparing for Phase 3. The other asset that is already in the clinic targets GRPR, so basically the gastrin-releasing peptide receptor. It's a little bit similar to the NeoB program that, for example, Novartis has. And so this is a target expressed on many different tumor types. Obviously today, UroToday, we are also particularly interested in the GU space, so prostate cancer, for example, has GRPR expressed between 70 to 100%, but it's also expressed in non-small cell lung cancer, in colorectal cancer, in melanoma, cervical cancer, breast cancer as well.

So it's a very versatile target, and this asset is currently in first-in-human. We have already cleared the first dose level and continue dose escalation. We have a very interesting early portfolio with assets at the, I want to say, pre-IND stage where we hope to start clinical trials next year. So in the mix is also an asset targeting PSMA. For a while we were thinking, is it still worthwhile to do it? But along the lines of what was discussed, given that even if other assets may work well, we have seen issues in being able to provide those drugs to patients. I think with our unique situation and the power of alpha, we believe that doing a PSMA with lead-212 still makes a lot of sense. The targeting moiety is a dimer, so it should also allow for better tumor uptake, and we want to start that clinical development next year.

We have a couple of partnerships that we have already disclosed. One of them is with Molecular Partners, a biotech also based in Switzerland, close to Zurich, and they have portfolios built around DARPins. DARPin is an abbreviation that stands for Designed Ankyrin Repeat Protein. Those are artificial targeting moieties that are relatively small, about 15 kilodaltons, but that show deep tumor penetration, high affinity in the picomolar range. And we use those DARPins as targeting moieties to carry lead-212 to various tumor types. And the lead asset in this partnership targets DLL3, so yet again an asset that is relevant in the prostate cancer space.

For neuroendocrine prostate cancer—and obviously the primary incidence of, let's say, primary neuroendocrine prostate cancer is maybe somewhat limited, but we see more and more secondary neuroendocrine features emerging. And so this is supposed to be a very interesting asset for which we also want to start clinical development next year. We have a partnership with Roche about pre-targeting—a little bit of different concept. We have not disclosed the target yet. So quite a rich pipeline, which makes my life quite busy, but also interesting because I think with the payload that we have, we are very interested to pursue.

Oliver Sartor: Interesting. Very, very interesting. Now, you made an allusion earlier to immunotherapy, and I'm going to have a relatively brief response because I have one more question after this before we wrap up. Combination therapy. What type of combinations do you think are particularly attractive, and are there ones that are being pursued now, or is this a little bit more into the future?

Volker Wagner: I think when people consider combination therapies with radiopharmaceuticals, particularly with alpha emitters, then let's say two categories of assets always come to mind. First of all, combination with immunotherapies. And this is because, as I mentioned, through the DNA double-strand breaks, alpha emitters lead to immunogenic cell death. So here the concept might not be so much that the radiopharmaceutical has to control tumor growth. It's about creating enough, let's say, spark for immunotherapy to become much more potent. So that could be pursued in tumor types where immunotherapy—I think that's the easiest at least—to pursue that first in tumor types where immunotherapies are known to work already, so that you give them ideally, and you potentiate its activity. But you could also then, if that works, carry it forward into settings where you might have the hope that colder tumors could become hot and could become active for immunotherapy.

The other category of drugs that you would immediately think of are drugs that interfere with DNA damage repair, right? And so obviously for DNA double-strand breaks, maybe other assets would come to mind then when you think about single-strand breaks only. But for example, DNA-PK inhibitors, things like that, I think, are primarily interesting. But at the same time, depending on the tumor type that you plan to target, as you try to offer opportunities for patients in various stages of disease, you would always try to also combine with the standard of care available. And I think the safety profile of radiopharmaceuticals per se doesn't really exclude any combinations you could think of. So I would not shy away from combining with chemo or any other asset that is approved in a given setting.

Oliver Sartor: Interesting. Very interesting. Last question for you today, and this is not an easy one. If you can put on your imagination for a brief moment and look into your crystal ball, what do you think we'll know in five years that we do not know today? And so it's looking at the next five years, and where do you think we're going to be when we reach that five-year point? So that's an open-ended question. Any concepts or thoughts you'd like to share?

Volker Wagner: Yes. So I tend to think that as radiopharmaceuticals are still an emerging new treatment modality, when you think about it, it started off with isotope treatments that just because of their physicochemical behavior were active like radium-223 enriching in skeletal bone metastases. Now we use targeting moieties to carry isotopes to the tumor, and we usually still do that in more advanced metastatic disease. We don't do that yet in early, more limited disease. So in my view, a little bit like when we entered the biological space with targeting antibodies first, interfering with pathways, we have just opened that door, and so we will learn much more about how radiopharmaceuticals really behave. I'm sure that in years to come we will move towards earlier stages of disease, much more appreciate what those drugs can do even early on in the treatment of cancer. Maybe in a neoadjuvant or adjuvant setting where tumor load is more limited, where it's about eradicating circulating tumor cells or tumor cells that are hiding in sanctuary sites. I think that will be something quite important.

I'm also sure that the range of payloads we use might become a little bit more narrow unless, let's say, the providers of payloads find other ways to make them more easily. Given, for example, our setup, I'm sure that lead-212 is here to stay. At least for us, there will be no issue with it. But for other payloads, that becomes more difficult. And I think that we will also learn much more about the combinability and help also understand immunotherapy much better in the context of how those two modalities can work together.

Oliver Sartor: Great. Well, thank you. I really want to thank Volker Wagner, CMO for Orano Med and long-term enthusiast in the radiopharmaceutical field, for being with us today. Thank you very much, Volker.

Volker Wagner: Thank you so much, Oliver. Really appreciate it. As always, enjoyed the call and look forward to hopefully seeing you very soon.

Oliver Sartor: Thank you.