Anna Karmann: Thank you, Oliver, for having me.
Oliver Sartor: And secondly, I'd like to start by talking about targeted alpha therapy and Lead-212. Not everybody might be familiar. So I wonder if you could explain a little bit about the Lead-212 isotope and what makes it attractive for the AdvanCell company.
Anna Karmann: Yeah. Oliver, Lead-212 is an alpha-emitting payload that is characterized by a very high physical energy that is delivered over a very short range in tissue. And that translates into potent tumor cell kill, but delivered precisely at a cellular level. And sparing surrounding tissues and potentially minimizing offtarget toxicity. The other characteristic of Lead-212 is that it has a half-life of 10.6 hours. So that is different compared to the long-lived isotopes that have traditionally been in development or so far in approved drugs such as Lutetium and Actinium. And when we develop our lead-based product, we try to evaluate and assess and characterize all these different elements and characteristics of Lead-212 in our first-in-human trial.
Oliver Sartor: Interesting. Now, at ESMO 2025, you presented very provocative data on the phase one. And it's had a little bit of complexity to phase one. It's forward both dose and schedule a bit. I wonder if you might help our audience understand a little bit about that initial phase one experience presented at ESMO and any other data that you feel is not confidential. I'm not trying to ask confidential data, of course.
Anna Karmann: Yeah. Thanks for highlighting that, Oliver. Yeah, our phase one in contrast to traditional radioligand therapy development, we have early invested in dose optimization and adopted strategies from other therapeutic modalities. And a key element of our first-in-human dose escalation was that we escalated activity levels, but also escalated dose intensities by exploring different dose schedules. And we've learned a lot from doing that. And it was all in the spirit of learning, characterizing the isotope. And I think some of the key learnings of this phase one trial translated now how we think further about the development of this asset.
Oliver Sartor: Let me drill down a little bit further on that. So when you talk about kind of dosing schedule, are you talking about weekly, monthly, biweekly? What kind of doses, just to kind of help familiarize our audience with some of your experience?
Anna Karmann: Yeah. In our phase one trial, we explored doses between every six weeks to every week, so up to weekly. That is certainly somewhat provocative. And it was an open-label trial, and we have not seen any dose-limiting toxicities even at the weekly schedule. That was a key learning, and that helps us a lot when we think about how do we dose optimize? When is the best timing along the treatment journey of when we administer these dosing? So not only optimizing or developing novel therapies, but also thinking carefully about, how do we best dose these therapies? And some of that was driven by the characteristics of lead and exploring that. But also, I feel in radiopharmaceuticals, we've traditionally never been dose optimized.
So schedules of current approved therapies were largely derived by isotope supply availability. What was available at the time in compassionate use or IITs. And then some specifically in the prostate Lutetium PSMA dose schedules that were also adopted from neuroendocrine tumors. So if you will, a dose schedule that worked in a very indolent disease was adopted to metastatic prostate cancer that has a very different radiobiology. So I do think there is a lot to learn and a lot to improve in terms of how we best treat with radioligand therapies. And that was one of the key elements that we explored in phase one, but also now move forward with this program.
Oliver Sartor: And we give a little editorial comment, your dose and schedule optimization is absolutely key. And I think particularly with Lead-212 and short isotopic half-life, you're going to come out with something perhaps very different than you might with the Lutetium or the Actinium. And I'm going to congratulate you for early exploration on dosing schedule, which I think is really critically important. Now, you have a poster here of a new trial, phase two. And there's some unusual design elements to that. And I wonder if you might kind of briefly take us through some of the phase two thinking, planning, and how you see this sort of playing out.
Anna Karmann: So the phase two design we present here is the benefit-risk evaluation of ADVC001 across three distinct prostate cancer populations, each with a high unmet need. And I think some of the key design elements that we implemented are the dose regimen consisting of induction and maintenance, and the other one is adaptive dosing. In addition, we are exploring two dose levels in a randomized fashion that is in accordance with FDA guidance. All of these design elements are based on the learnings from our phase one data. What we have observed in phase one is that we saw the deepest and most rapid responses in dose schedule cohorts that were very accelerated. So in the dose-intense cohorts, we saw rapid control over the tumor. And that observation together with adopting treatment regimen from other therapies, I think an idea of an induction therapy designed to overcome resistance that sometimes happens due to cell repopulation, simply outpacing a low-frequency schedule.
So I do think this idea of gaining rapid tumor control with an induction is a key element, substantiated and supported by our phase one data. What we know though from radioligand therapy, but also other therapies is for maintaining durable responses, it is critical keeping time on active therapy, keeping the foot on the pedal, if you will, with cancer. That is where the maintenance therapy comes in. The maintenance therapy is designed to prolong PFS while also maintaining tolerability. So we do that maintenance at a less frequent schedule. And with that regimen, we hope to solve for rapid tumor control, deep responses, prolonged responses. But also maintaining a tolerable profile.
Oliver Sartor: No, very clever thinking. And I'll simply say that it is provocative to be able to hear you speak, and think through these problems. Now you mentioned three different disease states. Why don't you cover those just so people can understand what you're thinking might be on the disease state approach?
Anna Karmann: Yeah. We're evaluating across the disease continuum in three indications that we see there's a substantial unmet need and there may be a true potential for patient impact. So one is the hormone-sensitive space. But not the same population as PSMAddition enrolled. It's a described population of so called suboptimal responders. We know these patients have rapid endpoints, have a progressive trajectory. And in those patients, we think adding a PSMA-directed therapy on top of the hormonal therapies could drive response and maybe bring the patients on a different trajectory than they otherwise would be. So that is a indication where the median overall survival is less than two and a half years, and there is a substantial unmet need. And I do think an alpha therapy may fit there very well treating maybe also some more low-volume potential micrometastatic disease that we may see there. But the alpha therapy needs to have a safety profile that you can position in this hormone-sensitive space where patients are often living their daily life and feel quite well on the hormones. So now you add an intensification that needs to come with an acceptable quality-of-life profile.
The other two indications are in the metastatic castrate-resistant prostate cancer space. So one is the pre-chemotherapy. We're exploring the monotherapy as well as the addition plus ARPI. And then there's also an escalation post Lutetium PSMA, so an experienced patient as an escalation strategy in a later-line.
Oliver Sartor: Terrific. I think we're going to need to wrap up, but I wanted to say thank you for being here with UroToday. Thank you for explaining that 212, some of the phase one, extending onto the phase two. I think there's really provocative data that you've been able to present so far. We look very much to the next presentation whenever that may be.