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Oliver Sartor: Hi, I'm Dr. Oliver Sartor, Mayo Clinic, here on behalf of UroToday, and we have a very special guest, Jessica Jensen. And I was trying to figure out how to introduce Jessica because I've known Jessica for years, and I've known her with Progenics. I've known her with POINT. Now, she's with Lilly. And she just kind of does it all when it comes to radiopharmaceuticals. So Jessica, what would you like the listeners to know about you that you think they may not know?

Jessica Jensen: Thank you, Oliver, and thanks for this opportunity. In terms of me personally, I think the real gut of what I'm driven for is just helping teams execute great things for patients and have seen that transpire with some drug approvals over the years. And there's nothing more rewarding than that.ac

Specifically, I have been in drug development for over 20 years. Started within the statistical programming and statistics of clinical trials, and then over the years have evolved into development and managing clinical operations and all of the many different intricacies of clinical development. So it's been a very rewarding time and have been in the radiopharmaceutical space for about 10 years now.

Oliver Sartor: And we're here to talk about radiopharmaceuticals. And first of all, this has just been an amazing journey over the last decade in radiopharmaceuticals, but let me hear from your perspective: why radiopharmaceuticals? What fuels your passion for that field?

Jessica Jensen: I remember when I transitioned from developing immunotherapies to radiopharmaceuticals, and I was at first quite overwhelmed and honestly tempted to flee. And I think that was because I had such an overwhelming desire to master the complexities of these operational workflows and the radiation science. But specifically, that burning urgency to get a promised dose to a patient.

And then when you accomplish that in such a patient-centric way, it just became such a passionate endeavor. And you have your physicians relying on you, you have the physician teams. Everyone is so hardworking. And when I was first in this field, I was working with a rare disease, so patients were flying from all over the world to the centers of excellence to receive these products. And so it became very personal, I would say.

But then next, the adaptive learning that can occur with the immediate data analysis being at your fingertips, specifically with molecular imaging, just became very powerful. And what I mean by that is you spend a lot of time just shadowing these imaging scientists and medical physicists to understand those complexities and power how imaging can guide on therapy.

And that was such a unique offering to this field that was immediate, and I just couldn't get over how rewarding that was to understand on a patient-by-patient basis how this patient could potentially benefit, and then to learn from that and adapt your development plans associated with that.

So overall, it's just been a really rewarding duration. I remember when I started, it was with—I don't know if you know this, Oliver, about my history, because we didn't work together on this program, I don't think—but I started with very high dose and a very complex manufacturing process with a bit of a quite toxic regimen of I-131 MIBG.

And I remember patients being in isolation in a hospital for almost a week. And this was really quite an endeavor. We had to manage release criteria. We had to work through so many logistics to ensure that these products moved forward. But the support from the agency during that time, the patient advocacy groups, the knowledge of dosimetry, and really the efficacy that we were seeing was just so intriguing and kept us motivated to keep going.

So I think once I embraced all of those challenges and understood that there was a way to maybe simplify it, to understand it and overcome it, it just became very exciting for me. So I would say I now feel very driven, especially at a company like Eli Lilly where there are some expert, expert developers and larger gloves that can really move the throughput of these products. That just gets me very, very excited to see where it's going to go next.

Oliver Sartor: I couldn't agree more. And there's nothing more motivating for me—and I hear from you—to make a patient better.

Jessica Jensen: Right.

Oliver Sartor: And particularly the patient who has a limited number of options, that is trying their best to participate in their own care and to make things better, and to be able to do it is just an amazing reward. And I hear that passion in you. Let's back up from some of the logistical issues and let's talk about some isotopes.

And we could talk a lot about isotopes. We could talk about what isotopes you might have a particular affinity for. We might talk about supply chain issues, but are there isotopes that you feel like are particularly promising in the field that you'd like to tell us about? And then I'll give a little follow-up on that when we hear your perspective.

Jessica Jensen: Sure. Yeah. I think what I've learned over the duration of my time is that you really need to first understand the heterogeneity of your target and then think about what is the right isotope for that target, for that tumor. And these are actually now the new complex issues that I still feel I need to master next with the amazing team. I'm a firm believer that it's not one isotope or another or the use of a beta versus an alpha or an alpha versus a beta.

You really have to remain agnostic and unbiased in your approach. So I appreciate, for instance, that actinium decay can be complex and the incredible work that our colleague George, who I know you know well, and others have now helped us further characterize this. I personally worry less about short-term constraints in supply. I think as long as you don't start a trial by over-promising to patients and physicians, I think that if you start seeing efficacy, I think the field has overcome incredible hurdles and can continue to do that.

And maybe that's because I've worked with such great manufacturing and supply chain teams. But overall, there's radiation science that really has to be understood in this field to answer that question because it's not one over the other. I mean, I know there's a lot of excitement for new isotopes and there's limitations to them being provided today.

But overall—and this is something I've really learned from my preclinical colleagues as well as Tom Hope and others—is that you can't forego understanding how these different isotopes distribute at a cellular level. The target expression is homogeneous in some cases, it's heterogeneous in others, and then the pairing of that isotope is really important to consider. We've seen betas have higher therapeutic index than alphas in certain circumstances and vice versa.

So I know that's kind of vague, but it's really how I am learning and understanding the field, that you have to really think about your target. That's very complex. And what we've seen is that target expression when it's more spatially sparse across a tumor can benefit more from potentially a beta.

But other tumor cells such as sarcomas or mesothelioma may benefit more from an alpha, where Lutetium could cause more damage to other types of cells. So there's so many complexities and considerations within, I think, the answer to that question. I don't know if you feel the same or different.

Oliver Sartor: Oh, I do. And really what you're talking about is the individualization of therapy. We're talking about precision medicine. And it's certainly not a one-size-fits-all, and that patient in front of us—

Jessica Jensen: It's not.

Oliver Sartor: —has a heterogeneous disease. Oftentimes there's complexity related to their past therapies, their bone marrow suppression or lack thereof, their liver function, kidney function.

Jessica Jensen: Exactly.

Oliver Sartor: We're trying to figure it all out. Now, let me move into briefly, because I don't want to get totally sidetracked on this, but I do want to talk a little bit about supply chains. You've been involved with moving the isotope from the manufacturing actually into the patient. Now, we've seen real trouble with this even by huge companies like Novartis that have failed to deliver on some of their supply chains. So I wonder if you could just tell me briefly your sort of view of supply chains and how much confidence you have going forward in this radioisotopic delivery.

Jessica Jensen: Yeah. No, I really do believe that early investment in this is something that's critical, and I think that's something that POINT has done very well and why we might be poised to really capitalize on an abundant supply of once-rare isotopes in the future. So I think it takes time. It's taken time with other isotopes and it's going to continue to take time, whether it's generator-based or cyclotron-based.

Again, there's so much variability in how we think about supply chain. And we try not to rely on what we're comfortable with, but think about the future and what's going to impact the patients the most. So I think this is a very fluid question and answer. And you really need somebody who's not binary in thinking about it, but visionary, innovative. And that's what I'm really proud of to have been part of at POINT, is it was manufacturing-led in terms of thinking about supply chain, and it's really—it's just been an incredible team to work with.

So I think that we do need to understand the rarity of raw materials, but it's experts that can help us navigate that. And I do feel that there's ways to overcome complexities. We've seen that happen. But again, I think where the field gets into trouble is maybe when you launch too soon and you're not ready, or maybe when you over-promise by starting a phase three trial without being ready.

So I think it's a delicate balance and I understand the complexities of those decisions. But I also think that we have an obligation to patients to make sure we're thinking so far in advance of when the market's needing these products that we're prepared when they are relying on us. I hope that answers the question, but it's very broad. I mean, we're excited now about lead. I would love to think about astatine.

There's so many really cool isotopes. And now we're seeing great supply from Lutetium. That's really a great isotope to work with. But again, if you really focus on the science of these products, you want to not be so biased of what you are used to and have access today and think about the future. Because development is a long road. And so thinking eight years ahead of time, sometimes you need that investment. Right? And that's also the nice part of being part of a company that has more financial ability to support the future if they're committed to this modality.

Oliver Sartor: Yeah. And just maybe an offhand remark, but I was fascinated to see Lilly jump in. And Lilly has enormous resources and has really been a long-term strategic thinker. So it'll be extremely interesting for me to see how Lilly adapts to this rapidly evolving space with a long-term vision.

Now, I don't know if this is really your sweet spot, but I'll ask anyway. What about any targets that you might have particular enthusiasm for? Of course, you've worked on PSMA, but I was wondering if you might have any additional targets—not seeking proprietary information—that you have an enthusiasm for?

Jessica Jensen: Yeah. I think that I'm not really in a position where I can specify targets. There's a really exciting future, I think, at Lilly and within the field right now. But this is really the elegance of RLTs. So you can quickly, meaning a handful of patients, understand biodistribution, normal organ liabilities, and then followed by the quick understanding of retention and tumor deposition.

So these bases of the science of what we're doing in development can really support high throughput of screening. And I think that's the beauty of RLT compared to ADCs, for instance. You don't need to consider specific receptors and antibody stimulation and a lot of biology that needs to be hijacked. I mean, there's biology, very important biology that I think the field has moved so fast they still need to step back and understand in terms of radiation science.

But we just want overexpression of cancer cells and limited expression in normal tissue. And sorry to be so simplistic about it, but I try to think simplistically every time I make a decision or think or communicate, and this is really the response I think of how we think about it. We are invested in this and are invested in the future, and there's a lot of screening to do to get there.

But now we have partners. We have partners like Radionetics and Aktis, and we are working with some incredible discovery folks that have developed amazing medicines. And I think that there's really an optimistic future as it relates to understanding: can these other broad targets be a foundation for the next opportunity to impact patients' lives?

So it's an exciting time overall. And I don't know if there's a specific target that I would mention at this point, but there's been a lot published on new targets being addressed in radiopharmaceuticals. Those are some that are very interesting to me, but also I would say there's a lot of undisclosed targets that also may have potential we still have to learn.

Oliver Sartor: Absolutely. I think that's probably the theme of the day. We have a lot to learn. Jessica, we're going to be wrapping up here in just a moment, but I wonder if you might share any final thoughts just about radiopharmaceuticals in general or your personal perspective. And then after that, we will be concluding, but any final thoughts to share?

Jessica Jensen: Final thoughts? I think that I am an eternal optimist. My family is constantly giving me a hard time for being an optimist. But I think that I'm also a pragmatist. And so we have so many new companies that are in this field, and that's very exciting, that we have a lot of larger investment in developing these drugs. But they really can be very complex, and I don't want to see wasted efforts necessarily in failures just because we aren't cautious and humble in the process.

So I would say with the expert developers and discovery groups that I've mentioned, it's extremely exciting to see where we could go next with these products. And I think we have to continue to be courageous in the process. I think something I've learned carefully is in order to reap benefits of that, sometimes you need to really help the agency through the learnings of these products early on.

And that's very often when you're on the frontier of developing new drugs. And I'm feeling optimistic that we will overcome some dose limitations based on very strict EBRT thresholds that have been applied to this field in the past in a vacuum. And we're going to start thinking very holistically about dose delivery.

I think we've learned a lot about dose delivery, thinking about the target expression and how can we deliver the highest dose density to the target, and how can we supplement that with combinations because it's not necessarily such a binary process. So I think just in closing, it's an exciting time. I have spent the majority of my time in the field in prostate and neuroendocrine tumors as most.

And so now that we have potentially the opportunity to educate many more broad medical oncologists, patients, and have that impact broadly, I think there's just a really exciting road ahead. But I do believe that nothing is easy in development, and so we have to continue to tread carefully.

Oliver Sartor: Great. Well, thank you very much, Jessica Jensen from Lilly, and a real pleasure to have you on UroToday. Thank you for joining us.

Jessica Jensen: Thanks, Oliver. Always good to see you. Thanks again. Bye-bye.