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Oliver Sartor: Hi, I am Dr. Oliver Sartor from UroToday. We have a very special guest today, Germo Gericke, CMO from Ariceum, and also very influential in Novartis' programmatic buildup of the radiopharmaceuticals. So welcome, Germo.

Germo Gericke: Thank you, Oliver. You're way too kind. Happy to be here.

Oliver Sartor: Well, delighted to have you. And I'm going to start out with a question that I think is provocative for many in the oncology field. We have antibody drug conjugates, we have CAR-T cells, we have bispecifics, chemotherapy, precision therapy, but you are focused on radiopharmaceuticals. Tell me why? Why are radiopharmaceuticals what you believe in now?

Germo Gericke: So first we haven't found a silver bullet. There are very few diseases that are monogenetic and easy to cure. So I think we have to use all the tools that we have in our arsenal, and radiopharmaceuticals have a unique combination of a targeted approach and radiation. Both of those concepts have proven very successful, both the targeting of tumor-specific epitopes or characteristics, and radiation. Why not combine them? In particular, for patients with advanced disease where external beam radiation is no longer efficacious, I think targeted radioligand therapies have great potential. We just have to lift it.

Oliver Sartor: Certainly agree. Now there are a variety of isotopes that are potentially available. Lutetium, of course, has had a big early run with Pluvicto and neuroendocrine tumors. But I'd like to hear you think about isotopes. Which one do you think, or Ariceum might think, will be brought to the clinic, and why?

Germo Gericke: So I don't believe in the one isotope curing them all. We'll probably see combinations of various isotopes with various tracers in specific indications. As you mentioned, Lutetium 177 has been the forerunner in terms of commercial applicability. There's definitely Terbium, very similar in the beta component, but then with an Auger component as a twist and potential booster, if you will, in certain applications. We've seen some very exciting data for the Somatostatin antagonist, different from the agonist that is the core of Lutathera in combination with Terbium, most likely due to the Auger effect.

And then we move from the betas to the alphas, where we have the short-lived alphas with lead, we have the longer-lived alphas with Actinium being the poster child. And I think the jury's out whether the short-lived alphas have a distinct advantage in the sense of kind of a hit-and-run approach, saving the immune system that invades the tumor after the radiation damage. For us at Ariceum right now, Actinium holds the biggest promise.

The preclinical data are exceptionally exciting. We have single-dose cure of all the animals with the dose that looks very well in the range of what we can achieve in human equivalent dosing, and therefore we are going to move ahead with Actinium. I know other companies are too. Also, I think we have to manage the supply chain, and as we've seen with Lutathera and Pluvicto, having a five to seven day supply chain window eases the delivery of the custom-made dose to the patients, relative to when you think of a lead, for instance, with less than 12 hours of half-life where it becomes more tricky from a supply chain perspective.

Oliver Sartor: Interesting. Next question, and I'm not trying to get any proprietary information, but I'd like to hear your take on targets. You mentioned SSTR2 with an antagonist, which is an interesting twist, but let's think a little more globally about targets and particularly those that Ariceum might be interested in. Again, nothing confidential, just trying to hear your thinking and what targets might be next.

Germo Gericke: Yeah, so I mean the ideal target is exclusively expressed on tumor cells, it is not shed, it is internalized and quickly recycled to get more activity into the tumor cells. It is genetically uniform, so you don't have a lot of variants that could get in the way of patient eligibility. It is not down-regulated as the tumor progresses.

So I think we all agree on what the perfect target is, and we all agree that it doesn't exist. When you look at the Somatostatin receptor, you wouldn't prioritize that in any of the routine analyses, because it is widely expressed throughout the body, and even in some critical organs like the pituitary gland. Yet history has shown that it's a quite good target as a receptor and was the first approved radioligand of the current generation of radioligands with Lutathera.

I think the pharmaceutical industry obviously eyes large indications with high unmet medical need. And I think we're going to see a number of targets, and I'm really waiting for the next generation of compounds to go beyond PSMA and Somatostatin receptor into the clinic. And only then will we see where the perfect target profile comes out.

I am hesitant to name any specific targets. At Ariceum, we have one totally new approach, which I think is very interesting, and that is to leave the outer cell membrane where most of the targets are currently explored, and go right to the nucleus, with the combination of PARP inhibitor and an Auger emitting isotope iodine one, two, three. The idea is that as long as the tracer is in the cytoplasm or in the blood or anywhere else, it doesn't cause any damage. It only really wrecks havoc on the DNA when it's very close to the DNA because of the short range of the Auger electrons.

And that I think is a really innovative approach and could be game-changing, if we can target intracellular components that are overexpressed in tumor cells, and can play a critical role in beating cancer. Whether it's DNA, whether it's tissue that has specific characteristics, we'll see. We're going into the clinic with this approach now, and we'll see how it pans out. So for me, that's kind of a whole new trajectory for radioligand therapies, if we can move away from the extracellular targets to intranuclear or intracellular targets.

Oliver Sartor: I saw that and thought it was fascinating. Now, one thing about PARP is that it's expressed pretty widely. And I'm just going to ask out of curiosity, how much tumor specificity is there, number one? And number two, given that PARP can be upregulated by damage to the DNA, would there be any type of synergy that you might get from targeting the tumor cell with the DNA damaging agent and then bringing in your PARP Auger on top of it? So I think it's a fascinating concept, but I want to hear your thoughts a little more, if you don't mind.

Germo Gericke: Yeah, no, absolutely. I think you're right on both points. So the underlying premise is that tumor cells have way more DNA priori, because of their rapid replication, and therefore more activated PARP. The PARP inhibitors only bind and accumulate where there is active PARP. So it only kind of happens on the DNA. The inactive PARP that is expressed and present in the cytosol and is not targeted by the tracer. So you have an accumulation where there is DNA damage.

And that obviously leads to your second point. Absolutely, combination with triggering DNA damage agents, whether it's radiation, whether it's chemo, whether it's targeted, makes a whole lot of sense. And I think in general what we will see, similar to other therapies, radioligand therapies are not going to be monotherapy five years from now. They will be used in combination, there will be sequencing. And we've seen some interesting experiments, for instance in combination with immune checkpoint blockers.

There is already the LuPARP study in Australia. Shanin Sandhu led the study or is leading the study, combination of PARP inhibitors, cold PARP inhibitors with radioligand therapy. So I think there's a lot more to learn in these combinations and sequencing approaches, and absolutely the radioactive PARP could be a very interesting combination partner for other therapies.

Oliver Sartor: Yeah, I think it's really interesting, and to my knowledge, you're the only group that's pursuing that strategy, which I think, again, it's quite provocative. You touched on combinations, but I might delve a little bit further. You had a brief checkpoint, you had a brief PARP, and then you had the idea of the DNA damage with PARP and an Auger to be able to take advantage. Are there any other combinations that you might find attractive? And just thinking broadly about combination therapy sequencing, are there principles that you might apply here?

Germo Gericke: Obviously the DNA damage repair is a natural combination partner, and we'll see what the ATM, ATR and kind of other family members can do in combination with radioligand. There is even a combination with other radiation sensitizers like Temozolomide that are in routine oncology practice that will be explored. And I'm looking forward to seeing those results.

The immune system, I think we're still kind of in the infancy of what we know, because the current generation of checkpoint inhibitors are more on the afferent immune system. I would see much more potential in the efferent immune system. So stimulating the antigen recognition and presentation, tumor infiltrating lymphocytes, understanding how we can leverage the damage that is done by radioligand therapy in the tumor and then combine it with immune activating concepts. That could be cytokines. We may even go back to old concepts of interleukins. I think there's really a big opportunity to explore more combinations.

Oliver Sartor: Interesting. We all have our crystal balls and some of them are clear and some of them are pretty cloudy, but imagine you're able to look into your crystal ball and look five years, hence. What do you imagine we might have accomplished during this next five years that'll really be changing for the field?

Germo Gericke: Yeah, I see two big obstacles that we hopefully will have cleared away in the next two to three, maybe even only in five years. But the two big obstacles I see are, one, the kidney, accumulation of peptides, and second, how to protect the bone marrow. Because those are the current dose-limiting organs for the radioligands. I do believe dose matters, especially in rapidly proliferating tumors.

We want to get as much activity into the tumor and metastasis as we can, and that is currently limited by dose and schedule. We're still driving the car, looking at the rearview mirror waiting for the peripheral cell counts to come back. So I really hope that we'll understand what happens in the precursor cells in the bone marrow and can potentially protect them, or again, manage by schedule and dose that we get around the bone marrow suppression.

And on the kidney side, I think there are very good early data available in preclinical models, and I hope they translate well into the human situation for small molecules to get through the kidney quickly and not be reabsorbed by the tubular structures. So that we don't have the long-term kidney damage risk that we currently have with the first-generation radioligands.

And in a similar vein, more specifically maybe to PSMA, I hope that we can find a PSMA tracer that spares the salivary gland. So I think we're going to work on specificity and general bio distribution. And then I would say the sky's the limit, because once we get those roadblocks removed, radioligands have many, many great opportunities in the field.

Oliver Sartor: Very interesting, thank you. Before we wrap up, are there any additional comments that you'd like to make, or concepts that you think our audience would enjoy hearing about?

Germo Gericke: Well first it's great to see how much interest there is in radioligands with now Lutetium and Pluvicto in the commercial realm. There's great interest from clinicians, there's great interest from investors. And I think with this massive capital inflow that we've seen over the past few years, both from big pharma and from venture capital, there are plenty of resources to do research and translate it into humans.

So I'm very optimistic and I hope that this excitement is maintained until we see great results. Because it will take time, there will be setbacks. But overall, I'm very optimistic that radioligands will have a bright future in the concert of anti-tumor therapies.

Oliver Sartor: Thank you. And I certainly agree. Germo Gericke, CMO for Ariceum, thank you for joining UroToday. Enjoyed the conversation.

Germo Gericke: Thank you, Oliver. Thanks for having me, and good luck with your series. I'm an avid listener. Thanks you.

Oliver Sartor: Great. Thank you.