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Oliver Sartor: Hi, I am Dr. Oliver Sartor here with UroToday, and it's truly a pleasure to welcome Anna Karmann. Anna is the CMO for AdvanCell, and she joined AdvanCell from RayzeBio. She's a radiologist by training, so medical and business, and also had worked at McKinsey. So Anna, welcome. Anything else you'd like to add so our viewers may be introduced to you in a better way?

Anna Karmann: Thanks a lot, Oliver, first of all, for having me. It's great to be here. Maybe the only thing I'd add to my introduction is the common theme around my career or my past so far has always been that I've been drawn to innovation, really drawn to big transformative concepts and modalities that can really change treatment paradigms and deliver meaningful, lasting, positive impact to patients and their families.

Oliver Sartor: I share that passion, and that's a perfect segue to the first question. So you have really doubled down on radiopharmaceuticals. Obviously, you're passionate about their potential. Tell us a little bit why, and just for instance, we could talk about antibody-drug conjugates, we could talk about bispecifics, we could talk about CAR T cells, but we're not, we're going to talk about radiopharmaceuticals. Why?

Anna Karmann: Great question, Oliver. Maybe from a personal perspective, for me, the ambition has always been a cure, and if not being curative, at least achieve deep and durable responses that can really mean something for patients. Now, for solid tumors and most of the indications there, the only curative modalities are really surgery and radiation. We know radiation works. The payload is highly effective. Now bringing radiation internally and targeted to patients, that's to me just really exciting.

Now, you mentioned some of the other targeted modalities, and I think that RLTs, or radioligand therapies as we call them, have a real safety advantage over other targeted modalities. If we think about CAR Ts, ADCs, bispecifics, and so on, they often end up with black box label warnings on their label, think CRS, ocular toxicity, and so on. And we don't see that with RLTs yet. As long as we understand the biodistribution and the kinetics of the radiation delivered, then I think we have a huge safety advantage.

The other thing that excites me about RLTs is certainly I feel RLTs can deliver true precision medicine. We're not relying on a signature of a single lesion like some other biomarkers or tissue-based biomarkers, but we can really see tumor expression or target expression across multiple lesions and can also follow that over time, so I think it's a true targeted therapy that we have in our hands, and that, again, allows a lot of synergies now combining this with other therapies.

Oliver Sartor: I couldn't agree more in the ability to image what you treat and treat what you see. It's a little bit of a truism for the theranostics, but it really is an incredibly powerful concept and one that I think is transformative. And of course, I share with you the enthusiasm about the radiopharmaceuticals.

Now moving on for a brief moment, you've chosen to focus on Lead-212, and that's a little bit unusual. We've heard about lutetium for a long time and actinium for a long time, but Lead-212 is kind of the new kid on the block, and I wonder if you could explain why you think Lead-212 might lead the path forward?

Anna Karmann: Yeah, certainly throughout my career, starting as a diagnostic and interventional radiologist and then later at RayzeBio and now AdvanCell, I've worked with Yttrium-90, iodine, lutetium, actinium, and now Lead-212. AdvanCell is a company that focuses on lead-based therapies, and I'm personally excited for several reasons.

First of all, it's an alpha therapy. I think for most users, we understand that the beta emissions from lutetium or copper may just not be a big enough punch, so alpha is really key. The other thing that excites me about lead is its short half-life. That short half-life matches most closely to the kinetics of small molecules and most peptide binders. I think that's a huge advantage. But the short half-life also allows us to really innovate on dosing strategies, potentially dosing much more frequently, maybe lower doses more frequently. And certainly when we think about more aggressive tumors, tumors that replicate much more frequently, I think we need to match that biology with more frequent dosing strategies.

And then another important point I think that's sometimes overlooked still is the immune system. Even with highly expressed targets, I think we rely really on the immune system to go that last mile for us for really deep responses or even a cure. I don't think that we will, with any therapy, reach every single cancer cell, so we need that synergy with the immune system. Now the innate immune system comes in after approximately three days, and these dendritic cells, macrophages, they can be very powerful. And then after 7 to 14 days comes in the more adaptive immune system with the T-cells. Now at that time, lead has decayed, even after three days, the lead has decayed versus with other RLT therapies, these therapies kill as well the immune system that came into the tumor environment.

Oliver Sartor: Very interesting point. I've actually not heard that point made before, but I think just for our listeners, stop and pause for a minute. You allow the immune cells to thrive in a non-radioactive environment instead of radiating them as they rush into the tumor that's been damaged with the radionuclide. So that's a very interesting concept, and thank you for mentioning it.

Anna Karmann: Yeah, solely just from a radiobiology perspective, I think we just start to understand these synergies with the immune system better as we treat more with lead and explore more and also in our preclinical work, but if you were to design the ideal isotope from scratch, and from a radiobiology perspective, I think one would not design an isotope with a 7 or 10-day half-life. I think you want to be much closer to the dose rate that we see with external beam radiation where radiation is literally delivered within seconds.

Oliver Sartor: And you've raised a really interesting question when you start talking about the optimal dose delivery of the tumor, but you've got a short half-life, and that presents logistical issues. Let's talk a little bit about supply chain, number one, and number two, about delivery of a short-lived isotope to patients who need therapy. So let me hear your thoughts.

Anna Karmann: Yeah, absolutely. I think two important concepts that we need to understand when we think about the logistics of Lead-212, it's certainly not the centralized manufacturing that we know from actinium, so it's going to be a couple more hubs, and I think the OranoMed and Radiomedix collaboration has shown very well, as well as perspective, that the trials can be run with a non-centralized manufacturing.

Important for lead is that the half-life of lead doesn't mean the shelf life of the drug, and the same way the half-life of actinium does not mean the shelf life of an actinium-based drug. So for Lead-212, for example, the shelf life of our products will be more likely 24 hours rather than 10. And similar to other drugs like even lutetium-based drugs, they're still just-in-time drugs that will be delivered overnight, plugging in that last mile of RLT delivery that is well established and will be dosed the next day. So in many ways, it is different than the long-lived isotopes, but in other ways, it's not a barrier that isn't there that couldn't be overcome.

Oliver Sartor: Terrific. And thank you. You had alluded a little bit to the interaction between isotopes and the immune system and made the interesting point about you might have particular synergy with lead, but let's talk a little more explicitly about combination therapies. Bringing the isotope to the tumor is one thing, but how can you create synergy with combinations, and are there any combinations you feel particularly enthusiastic about?

Anna Karmann: Yeah, it's a great question, Oliver, and I think it's a very relevant question when we think about alpha therapies, especially in the shorter path lengths. But also when we aim for earlier lines of therapies and potentially being curative, I think combinations are key.

And as a field, the earlier we start combination therapies, I think, the earlier and more likely we will see drugs approved. Now, on the other side, I do think that we're just at the tip of the iceberg on understanding tumor biology drivers for target expression, understanding heterogeneity also over time and how treatments influence heterogeneity and so on. So also simply understanding why do some patients react and respond so very well, and why do other patients fail early or ultimately. I think we haven't figured that out. I'm hopeful that over the next year or so more rationale for combinations will emerge, but I think there will always be this concept of trial and error in combinations as well.

Now, when picking from the menu for combinations with RLT, one important factor considered is always overlapping tox. Now, luckily with targeted alpha therapies, we have very limited tox, and tox is mainly on target, so that's an advantage. But especially with a lead-based targeted alpha therapy, I expect less overlapping tox due to the short half-life. So potentially the menu of combinations is potentially bigger with a lead-based targeted alpha therapy. But also if you think about how to sequence and combine these different therapies, when to give them, dosing schedules, and so on, I think the short half-life opens more opportunities to really dose optimize even combination therapies.

Oliver Sartor: Interesting. One of the things that has attracted the field, and you've talked about the RLTs, is the diversity of potential targets. Now, I'm not trying to get any information that is not shareable at this point, no proprietary information, but can you talk a little bit about targets that AdvanCell thinks are important?

Anna Karmann: Yeah. When I think about targets, first comes to mind, KLK or HK2, you and Mike Morris really made me excited about this target with your ASCO presentation. I think by now we can consider KLK2 a validated target. Now we've also learned that a combination of an antibody plus actinium has its considerable downsides.

Other targets that I'm generally excited about are the oncofetal proteins such as GPC3. That profile, target expression profile, lends itself very well for RLTs. Further, I'm interested to see data emerging at some point on DLL3 to see how targeted alpha therapy performs in targets that are expressed at very low levels, and I think there it will really come down to optimizing the specificity of the therapy.

But if we think a bit even beyond prostate, I'm excited about MC1R and the melanoma space. I'm excited about what we can learn from that. Melanoma is a cancer that does extremely well with IO. IO actually even started in melanoma, but still we don't see the level of cures that we were hoping to see, so I'm excited when bringing an RLT or targeted orthotherapy into the mix, what that really does on response and survival rates for patients.

Now, Oliver, big, big picture. I think I'm also quite interested to see where CAR-T is heading, going to targets in the autoimmune space. I think we have also with external beam indications beyond oncology, even going down the history lane, I'd say on RLTs, there's indications in synovitis. Even RLT has been used in cardiology back in the days in Germany, so it's a bit of a far road, but as we venture there, I think you may want an isotope to pair with that, that has a very clean profile, that is widely available, that is scalable and has minimal waste, and such an isotope is lead.

Oliver Sartor: I haven't heard anyone mention the possibility of non-oncologic disease, but for those who may not be aware, there's some really exciting data emerging with CAR-Ts and things like autoimmune disease, SLE, in particular, with some pretty stunning responses that have occurred. But CAR-Ts are cumbersome and not easy in a lot of ways.

Anna, I'm going to ask you to look in your crystal ball, and perhaps it's a little cloudy, perhaps it's clear, and to think about the next five years. And I'm just sort of wondering, in your mind, five years from now, what do you think we will have accomplished that is important in this space? So five years from now, where are we, and what's the path forward?

Anna Karmann: That's a great question. I love it. I mean, in general, I'm extremely excited about this field. I think we're really at a phase of exponential growth of data that come in and how we can move this field forward. I think as a community we can achieve a lot if we push it all in the right directions.

First comes to mind I think in five years from now the field, but also regulators, have a much better understanding of the long-term safety of RLTs, but also specially targeted alpha therapies. I think I am very hopeful that we may have leveled the playing field in five years and really treat RLTs like any other drug. If we had held the bar of 5% or no more than 5% risk of late complications at five years accountable to any other modality, I think we would not have any oncology drug approved by now, so I'm very hopeful and optimistic that we will have moved on from the external beam dose limit concept based on data.

I also think we will see RLTs moving to earlier lines. We will see more combination trials. I think we will have changed how we dose. We will have moved on from the more traditional dosing concept that we see currently to more adaptive and to more innovative dosing strategies by having done more phase one trials and more dose optimization, but also having learned from post-market approval data.

And then generally as a field, I do think RLT will continue to lead and change the paradigm of drug development. I think RLT will continue to lead in times to approval in acceleration. I think we will see more phase one compassionate use, fast into human, fast fail, fast proof of concept studies. I think ultimately this mechanism will divide the successful from the not so successful companies in the field.

And I think this will be ingrained in probably more of our drug development process overall. Now for AdvanCell, or maybe one more to mention actually, I think in five years from now, I would expect that at least one targeted alpha therapy will be approved by now, so it will be interesting to see who wins the race, if it's a lead-based or actinium-based therapy. For AdvanCell, I predict that in five years from now, we will be deep in a registrational trial in metastatic castration-resistant prostate cancer in a trial that hopefully will be no less than practice-changing.

Oliver Sartor: Terrific. I really enjoy that. Anna, we're going to be wrapping up here in a moment, but I wonder if there might be any additional comments that covered items I did not bring up as questions or anything else you'd like to bring up before we close out?

Anna Karmann: No, thank you. I just want to end on this very positive note. I think we're in the most exciting times in the field of RLT, and I'm just very excited where we all move this field together forward.

Oliver Sartor: Thank you, Anna. Anna Karmann, CMO for AdvanCell, exciting new company, lots of new concepts. Thank you so much, Anna, for being here today.

Anna Karmann: Thank you, Oliver. It's been an utmost pleasure.