Panel is the GI GU Oncology Panel. With us, we have six companies. I'm just gonna introduce them one by one in alphabetical order. We have Daniel O'Connor from Ambrx. We have Mark Erlander from Cardiff. We have Joseph Ferra from Elevation Oncology. We have Scott Koenig from MacroGenics, Joe McCann from POINT Biopharma, and Liz Barrett from UroGen. Thank you, everybody, for joining us. In terms of format, we're gonna ask maybe two general questions to the panelists, and then we're gonna go around Robin with specific company-focused questions. First question is, in GI GU Oncology includes, obviously, a wide range of tumor types, each of which has unique development considerations. However, there are some regulatory factors that broadly apply to all these tumors. I'll start with Project Optimus. How are you incorporating that in your clinical development? Maybe let's just start with, I guess, the left side of the table. My left. I think it was with you. Yeah. That's me. Okay. That's it. Right. Left. I think, you know, we're obviously in a dose-escalation study currently with our ADC targeting PSMA. We're obviously considering the Project Optimus, you know, guidelines from the FDA in terms of how we think about selection of those in RPTD. Great. I guess let's move on. Yeah, this is Mark Erlander here at Cardiff Oncology. We have a small molecule. It's a PLK1 inhibitor. We were coming off the heels of some really great data in our phase I-B/II trial, which is a single arm, and we did have three doses in that. As we move forward now into our randomized trial, we are incorporating Project Optimus. We're taking our recommended phase II dose out of our phase I-B/II + 1 dose below. That's how we're looking at two doses in our randomized trial that we just started in our flagship program, which is KRAS mutated metastatic colorectal cancer. Got it. Okay. Joseph Ferra, CEO of Elevation Oncology. you know, our spin with Project Optimus, we have our lead program as a EO-3021, an anti-claudin 18.2 antibody-drug conjugate. From an ADC approach, as we think about moving into phase I, which we said we're gonna do in the second half of this year, you know, especially historically with antibody-drug conjugates, you tend to see some of the talks not to come to fruition until later. When we think about Optimus, you know, of course, Optimus is about better options for patients and optimizing the dose for patients. We think, particularly as we think about our development, encouraging companies like us to looking at all various kinds of doses and optimizing doses and understanding the tox that can come to various doses early in the program is helpful for patients, but it's also helpful for the company so that you find something early that may come back to haunt you in the phase III that you didn't realize was there before. Great. I'm Scott Koenig. We are very fortunate to have multiple molecules in development for prostate cancer. We have an antibody B7-H3 ADC called vobramitamab duocarmazine. As we have announced, we're in a phase II development, looking at two doses with a very good interaction with the FDA on the selection of these doses based on the historical toxicology profile and the activity profile. As the name suggests, we've been trying to optimize this between a 2 mgs per kg Q4 dosing and a 2.7 mgs per kg Q4 dosing. We have a second molecule, Lorigerlimab, which is a PD-1 by CTLA-4 bispecific DART molecule that we've just recently presented data. We had done a dose escalation all the way up to 10 mgs per kg, decided based on activity and safety profile to advance on a 6 mg Q3 weekly basis. We are planning a next study where we will move forward with that dosing. We envision some side studies ultimately to look at optimization of the dose, which is obviously somewhat challenging in the checkpoint space. Finally, we have an older drug, an Fc-engineered molecule, enoblituzumab, also targeting B7-H3, which we're planning some additional studies. We have a long history of using this drug at 15 mgs per kg with a very good safety profile and intend to move forward with that dose. All right, Jessica, before we go to you, just to IT, can you guys start the clock? The countdown clock. The clock has not started. Great. Jessica. Okay. Hello, Jessica Je nsen. I'm here representing POINT Biopharma. I oversee our clinical development programs. POINT is a clinical stage precision oncology company, and we're developing radioligand therapies. The opportunity within the development of radioligand therapies is the use of dosimetry to guide dose selection. Dosimetry is the study of radiation to absorbed tissues. Those tissues can be normal organs or tumor cells. That really is a factor of our dose selection paradigm. Really just having to be nimble of using a nuclear medicine approach in marrying both the nuclear profile or the dosimetry profile with the clinical toxicity that we see. We are about to read out our phase III late stage program, and there's a strategy that we use for dose selection within that. Then our earlier phase programs will also be very wide-ranging, looking at dose selection with formal escalation in addition to dosimetry. Thank you. Liz. Finally. Hi, I'm Liz Barrett, UroGen Pharma. We're in a little bit of a different situation in the sense of our company is actually founded on a technology called reverse thermal gel, and it's a gel that's in combination with different products to deliver products actually locally to the urothelial for urothelial cancers. We have our dose in our pivotal study that we're studying today in our UGN-102. Earlier in phase I, we actually have the first ever CTLA-4 that will be delivered, you know, intravascularly. You know, it's a little bit different, but at the same time, we're actually looking at combination therapy. The saying that everyone's talked about as far as optimizing the dose and the balance between efficacy and safety as we start to, you know, build in the combinations. Definitely looking to move to combinations as quickly as possible, actually with a minimally effective dose, which we're doing with our CTLA-4. Locally delivering CTLA-4, hopefully to avoid some of the systemic side effects that you typically see with systemic chemotherapy and IO agents. Great. Sticking with the FDA, kind of regulatory process, there's a lot of question in community about accelerated approval and mostly timing of the confirmatory studies where the FDA wants the confirmatory studies to be largely enrolled at the time of filing of the accelerated approval. Maybe we'll go back to Daniel, to you, and continue in this direction. How are you thinking about that in terms of impacting your development timing and strategy? Well, programs that are a bit early, our PSMA targeting ADC, we call 517, is in the dose escalation phase I study, so thoughts are not necessarily going towards accelerated approval at this moment. You know, generally speaking, you know, I prefer randomized studies. I think they're much more dispositive. I think the regulatory path there is more clear-cut. You know, going for an accelerated approval on an ORR, I think is, it's challenging, because, you know, the FDA has already, you know, said that they wanna see more clear evidence, and they also wanna see the confirmatory study, you know, up and running. I think, on balance, when you think about creating certainty around your efficacy endpoint, I feel like, you know, pursuing randomized studies, is the better way to go than single-arm ORR-driven studies. Brent? Yeah. I mean, at Cardiff Oncology, we've just started our randomized trial, which is a 150-patient trial with, like I was saying earlier, two different doses plus a control arm. Of course, we're very mindful of the guidance as far as that trial is positioned, if successful, to go for accelerated approval. We are, of course, very mindful of the need to be able to have another, the confirmatory trial up and going. We are considering a couple different things right now, we're looking at how we would strategize that. I think that, you know, right now, we're very mindful of that, and we'll have much more news about how we're gonna end up doing the confirmatory trial as we progress. I'll probably lean into a word that you used, Liz, and you said, Daniel, it's about balance, right? accelerated approval is about getting needed treatments to patients sooner rather than later, but that doesn't really help patients if you can't get data to confirm it in a trial, and I think we've all seen some of the studies that suggested that may be the case. It's about balancing being able to prove that your drug is helping patients over the timeline, and it's part of the overall theme that all of our companies have to deal with, which is we're just forced to think further and further ahead about our overall development and commercial strategy. Earlier, it used to be like, you know, just get the good data, and you'll get there. It's not the case anymore, right? We have a lot of things we need to nail down well ahead of time. Even for a company like Elevation or a lead program, although our partner is under a phase I dose escalation or expansion, we haven't entered in the U.S. in phase I yet, and we're thinking about things like accelerated approval and timeline. Where it comes down to is timelines of potential approval and the investment needed to get there. It's just, you know, knowing that you have to have an accelerated, confirmatory trial largely enrolled just changed the calculation. Doesn't change the calculation for a drug that we believe is gonna help patients, but it does change the calculation. Our approach has been, I would say rather conservative on the following vantage point. We typically do our phase I studies, as a sort of a 1a/ 1b paradigm, where these are usually single-arm studies to do the dose escalation. We then do expansion into particular cohorts to see a appropriate safety signal. Our phase II development, is generally a controlled trial, we do not look at this as a pathway necessarily to accelerated approval. We'll let the data speak for itself. If we have an outsized response, we would then engage the regulatory agencies appropriately, to ask the question. You know, we let the data drive the conditions. As others have said, it is a much challenging environment in terms of the capital necessary to raise to have a, second trial ongoing before approval in the biotech space. Again, we hope to navigate this with data. Yeah, I would just mention that, you know, our late-stage program is not looking at an endpoint for accelerated approval. It would be a full approval with RPFS as the endpoint, supported by the totality of data. You know, looking, thinking about our earlier stage assets, you know, just really have to think about what's realistic for certain indications. You know, prostate to have an accelerated approval, you know, on an ORR endpoint, there isn't much precedent for that. You really have to. I think, though, if you're evaluating an indication, you know, which is something we're doing for our Fibroblast Activation Protein program that might be suited for an accelerated approval pathway, just as Joe mentioned, you know, really plan as far ahead as possible for the timeline that will take. You don't wanna rush data out, you know, if you know that could really backfire on you anyway. You know, you have to be convicted. You have to believe in your data, and you know, it sometimes it does take a little bit more, you know, exploration even after your pivotal trial should read out. You know, it really is a case-by-case basis, what is fit for accelerated approval. I mean, the post-marketing requirements alone, you know, for that development pathway, need to be planned, if you're really on an accelerated pathway. It's a lot of considerations, and I think it's really program by program from our team. Yeah. I think I'll sort of add something that's not necessarily relevant to UroGen, and I'll explain why in a moment. I do think the fact of what they're requiring from accelerated approval is not great for cancer patients, right? At the end of the day. At the end of the day, the whole purpose of accelerated approval is to allow for early access to medicines in areas where there's high unmet need. In our case, we actually don't have an accelerated approval pathway because our alternative is surgery. We actually go up, and there are no medicines approved in either of our first two products. Accelerated approval, even though we actually tried with our phase II study to ask for accelerated approval, didn't really meet the criteria for accelerated approval, even though now we have our phase III fully enrolled. We would actually meet that criteria. The problem is that there are no surrogate endpoints because, again, the alternative is surgery. As we move into our earlier program, though, you know, we would obviously think about that in our high-grade because there are a lot of products out there. The question is, you know, as we're looking at it now, it's obviously a much quicker, you know, drive to an approval if we go after patients who have already seen, you know, one, two, or three by the time we get there market. We are also doing the same thing is obviously considering, you know, the time and cost and, you know, associated with that. I do think that it's putting a heavy burden on companies, particularly smaller biotech companies. I'm not sure, you know, keeping in the integrity of what accelerated approval was meant to be for. Yeah. Great. Maybe one more general question also on the FDA is there's a lot of investor interest in this space. Another project they announced is Project FrontRunner, which is the initiative to develop oncology drugs in earlier lines of therapy instead of starting with end-stage disease. Just curious if that has factored into any of your consideration or if you have any opinion on this. Let's continue with the same sequence. Sure. I don't think there's been a lot of detail given on Project FrontRunner yet. At least I'm just generally familiar with it. I actually do wanna come back to the last question real quickly. One other idea that I've seen other companies do is build in an ORR endpoint in a phase III study. At a certain point per protocol, you can take a look at the response rate, and if you've achieved this, you know, a meaningful ORR, you can file on that basis while you're conducting the randomized study. It's building in that endpoint into a pivotal study, a randomized study. If you see ORR, you can take a look at that earlier than the phase III study readout and see if you can start the process by filing on a response rate-driven endpoint first and then have the phase III study readout. Anyway, just that thought came to me as we were going through the panel discussion. Yeah, on the other Project FrontRunner, I don't I guess I don't really know the specifics of the program yet. I felt that the concept was a good one. I think that the comment was made at the end, I agree with. You know, what we'd like to see versus what the regulators give us is sometimes different things. Certainly one thing we all know is cancer patients need options, and they need treatment options as quickly as possible. Any initiative that's looking to go earlier and create like an accelerated approval on the front end or, you know, kind of front, you know, this quote-unquote front-running idea, I think is a really good idea. Yeah. At Cardiff, we're currently in second line KRAS mutant CRC, we're following our data there, and we've actually have some quite exciting data that would suggest that we could go to first line potentially. I think I'll be asked a question about that later in this conference. Really, we're looking at Front Runner as a potential. Certainly, allowing us to leapfrog in with a trial in first line was very exciting for us and for our investigators, obviously for patients. Stay tuned, we certainly think that we might be able to be aligned in that situation. I mean, clearly, there's a few things that are pushing companies like us to consider going into earlier lines of therapy sooner rather than later. I know we're not talking about the IRA, but that's one of them that, you know, pushes us in that direction. FrontRunner is another way of shifting the balance towards companies like us, making sure that we're paying attention to all the patients. You're right, there hasn't been much detail. How exactly you translate that into a clinical development strategy on paper is probably less clear. Overall, I think all of us see the benefit, especially when you're talking about targeted therapy, giving that option to patients earlier in therapy. To have that as a choice earlier in their treatment rather than later, is beneficial for a lot of reasons. I'm answer this from a different perspective, which is the biology, and particularly when you're in a molecules that have immune modulating properties. A patient that's in a late line therapy and which has gone through multiple rounds of chemotherapy, where there's the immune system has been tarnished. There is a marrow has been reduced, is quite different in treating that patient versus someone who has early line and more intact immune system. The ability now to look at the use of immune modulating agents in early line makes a lot of sense. That's, you know, notwithstanding the history of what the patient has been treated with and tailoring that for where the appropriate biology will come out on that. Yeah, exactly. You know, you really have to start with the clinical or the scientific hypothesis and ask yourself, is it worth the, you know, the very large investment of such a large, very long study to pursue? Very often it is. You know, we are developing an actinium PSMA compound, and there's a lot of rationale for actinium to be administered, which is an alpha-emitter isotope, attached to PSMA, which is a validated target, you know, to invest in an earlier line that might be able to attack micrometastases or very small volume disease better than a beta-emitting isotope. The clinical hypothesis for that program is very strong. Again, there might not be a strong clinical hypothesis, you know, for other assets of ours. We are developing that program now and we are pursuing actually, we're making a big bet on the program by pursuing both populations in parallel. We have a cohort in BCR early line and oligometastatic as well as one in refractory mCRPC. Yeah. Just sort of, stepping a little bit back, but per Scott's message, if you stood and we don't have cell therapy, but, you know, I worked in Novartis and Pfizer in cell therapy. I mean, obviously, a patient earlier in their disease is a better, you know, better candidate for something like cell therapy. You know, personally, I would want cell therapy as quickly as possible. In our situation, because we are an alternative surgery, what's interesting is actually the FDA sort of pushed us to go after, and we actually had to push them to allow us to actually do it in the, in a front row, setting. That's kind of an interesting, you know, before that. You know, because we wanna be able to be used in both our upper tract urothelial cancer and then also our non-muscle invasive bladder cancer instead of and replacing surgery because these patients, there's a lot of comorbidities associated with multiple general anesthesia and an elderly patient population. These medicines able to be delivered up front, up front is actually better and these patients avoid it. The FDA initially really tried to push us to do adjuvant therapy. What we said, we're trying to bring a therapy to market that patients don't have to go through. Yeah. Because unfortunately, they tend to recur. It doesn't end up being one surgery. They end up having multiple surgeries. I'm all for it. I do think also it is very burdensome if you think about, you know, because where is the highest unmet need? If you go to the, you know, upfront setting, obviously the trials are longer, they're, you know, more, you know, more patients and you have a higher bar from an endpoint perspective. You kinda see sort of, you know, both sides of it. Great. With that, we'll turn to the company's specific question. I'll kick it off with Ambrx, with Dan. Can you describe Ambrx's platform for Engineered Precision Biologics? How does this produce differentiated ADCs? Sure. Our technology was envisioned at Scripps and spun out to Ambrx. At the heart of our technology is using synthetic amino acids to engineer protein. Really focusing on the engineering of the protein using a non-natural synthetic amino acid that enables us to precisely select on the site of the protein where we want to establish conjugation. We are an ADC company. Conjugation is, I think one of the main issues and potential problems with ADCs. We don't rely on nature to establish conjugation sites. Other companies need to do that because we have the IP. In that setting, they use cysteine or lysine conjugation techniques. Again, one of the main distinguishing features of our tech is being able to specifically select on the protein where we want to establish a conjugation. That decision is made by stability. We're looking for the most stable place to secure our toxic payload, our cell killing payload. Today, you know, as we're in the middle of a dose escalation phase I study, we have the only PSMA targeting ADC. When you look back historically at the other companies that tried to target PSMA with an ADC, you see that they ran into issues of not being able to establish a therapeutic window, premature release of toxic payload, and a lot of safety issues. So far on our program, we're now at a relatively high dose, 2.4 mgs per kg. We've not seen any DLTs, we've not seen any treatment-related grade threes. So far it looks like our thesis on using synthetic amino acids to establish a very stable homogeneous conjugation site is working. Thanks. Next we'll, you know, turn it to Mark about Cardiff. Can you provide an overview of the existing data set in the second-line KRAS positive CRC? Going back to Project FrontRunner, many investors have noted the difference in ORR between patients that were naive, or treatment experienced with bevacizumab. How do you interpret that sub-analysis? Yeah. Thank you. You know, at Cardiff, we are like I said earlier, we're in second line, we're in KRAS mutated CRC, huge unmet need. Just to kind of level set, standard of care today based on pivotal trials over the last 15 years have response rates that range between 5% and 13%. Now, in our phase I-B/II trial, which was a single-arm trial in combination with standard of care, our response rates were at 35%, so we were two to threefold greater than what was observed. Now, what was exciting about that, what Divya's asking me about, is the fact that we also saw within that trial a subset of patients that were eligible. They came in, they had not received Avastin or Bev in first line. It is approved for that, but some patients don't get it. Those patients did even more particularly good. Their response rates in our trial were between 70% to 80%, depending if it was all doses or the recommended phase II dose. Now, that was very exciting for us because we know that if a patient, based on historical data, if a patient was Bev, what we call Bev naive in second line, the response rates would bump up about 10% from standard of care, so they're between 20% to 25%. This was really a magnitude effect, was really unexpected. The question about that is obviously this exciting, but we also in talking with our investigators as well as our SAB, you know, one of the things that they've encouraged us to do is to really look at first line in exploratory trials, simply because all patients are Bev naive at that point. You know, at this point, we're still under consideration and looking at that, so we haven't made any announcements. This is something that's the reason why we're excited about this, is it has the potential for that, and that kind of falls into this front-runner concept as well. We've also done preclinical with those findings. We went on back into the lab and did more preclinical work to look at the mechanism and understanding between Bev and our small molecule inhibitor of PLK1. We're already seeing in vivo work showing that there is a significant increase in tumor growth inhibition with the combination versus either agent alone in CRC in vivo models. That's where we are today with the data. It's a, you know, really exciting finding and one that was unexpected. Next I'll turn it to you, Joe, on Elevation. Can you review the epidemiology and the market opportunity for the Claudin 18.2 driven tumors? You know, how prevalent are they? What tumors are they overexpressed in? Is there expression in healthy tissues as well? Yeah, sure. As I mentioned, our lead program is a anti-Claudin 18.2 antibody drug conjugate. Claudin 18.2 is definitely an emerging clinically validated target within oncology and somewhat of an ideal candidate for an ADC approach, a targeted approach, because in healthy tissue its expression is largely limited to the gastric mucosa. It's overexpressed in a range of solid tumors, the most prevalent of which is gastric, esophageal, and pancreatic, where expression has been shown to be as high as 80%, but then also in things like breast, lung, and ovarian, where expression can be as high as 20%. There's a lot of solid tumors that express Claudin 18.2 when cancer comes calling. Within that, I think the opportunity for Claudin 18.2 is that because the expression in healthy tissue is largely restricted to the gastric mucosa, that the toxicology associated with it can be somewhat very amenable in an ADC approach, where you're looking at an MMAE type payload that is a relatively known payload that has been part of approved, other approved agents where you can have a general picture of what to expect from the tox perspective. Just to follow up on that, what exact, maybe on-target effects could be associated with targeting Claudin 18.2? Yeah. You know, with it being largely expressed in the gastric mucosa, most of the on-target effects that have been seen for some of the other agents that are in clinical development, largely us, Astellas' zolbetuximab, which they had data late last year in ASCO GI earlier this year, as well as another ADC approach, keynote had data at ASCO GI. Most of the tox would be associated with nausea and vomiting, what you'd expect for a target that's largely expressed in the gut and healthy tissue. Great. Let's move on to MacroGenics. Scott, can you describe MGC018 molecule? How is it different from inotuzumab? What's the scientific rationale in general behind targeting B7-H3 in prostate cancer? Yeah. As you know, we've been focused on developing multiple molecules for B7-H3 for greater than a decade. Enoblituzumab is a Fc-engineered antibody, which was has five amino acid substitutions in the Fc region to enhance binding to activating versus inhibitory Fc receptors, which promotes better ADCC activity. That was one of the first molecules we moved forward targeting B7-H3. Vobramitamab duocarmazine is our ADC molecule that also targets B7-H3, which has a cleavable linker with a toxin called duocarmazine, which alkylates DNA and promotes immunogenic cell death and apoptosis. There are two distinct variable domains within these antibodies. The antibody was selected for enoblituzumab, the variable domain, recognizes an epitope and binds to the surface of B7-H3 expressing cells, the large part of that antibody remains on the surface to help enhance ADCC activity. The variable domain we selected for vobra duo, the ADC molecule, is much more efficient in incorporating into the cell, transfers the linker toxin into the lysosome to then get cleaved and moved to the nucleus. Those were selected quite specifically for the mechanisms of action. We love B7-H3 because it's a molecule that's highly overexpressed on most solid tumors. As you know, we're putting a high focus on targeting prostate cancer. If you look, for instance, by IHC and H scores, the majority of prostate cancer will have H scores that are in excess of 200. Many others between 100 and 200. The expression of B7-H3 occurs very early in newly diagnosed patients and all the way through late stage metastatic patients, and in fact, is more persistent than PSMA, where often PSMA will be reduced in very late stage patients. The other value of this target is that there's very modest expression on normal tissues, and you can even improve it with the selection of the particular epitopes that we have done to minimally bind to normal tissues. It's also been shown to be associated, B7-H3, with tumor progression metastasis and has immunological properties of inhibiting T-cell responses. From all those vantage points, in addition to the expression not only on dividing tumor cells, but on tumor vasculature and on T-regulatory cells, this seems to be an ideal target to pursue by multiple mechanisms. Great. Thanks for that. Let's move on to Jessica from POINT. You've mentioned your PSMA-targeting drug. Can you just summarize the study design for the SPLASH trial and also give us an overview of the efficacy reported so far from the leading cohort? Yeah, I'd be happy to. This is our lutetium labeled small molecule PSMA-I&T. This study started with a lead-in phase that was primarily to characterize the dose evaluation through the use of dosimetry as well as clinical toxicity, and evaluate the same endpoints that would be studied in the subsequent randomization phase. We had pre-specified criteria baked in with the same eligibility criteria in order to make some go, no-go decisions or changes to the randomization. All of our pre-specified criteria were met at time of completion of dosing for the lead-in phase. Just recently, this past fall at ESMO, we reported the efficacy data from that study. The study design of the pivotal program is looking at a PSMA PET-positive population who are mCRPC and not candidates for chemotherapy. These patients are being randomized, looking at lutetium PSMA at 4 cycles, 6.8 GBq against a second-line androgen receptor axis-targeted therapy. The efficacy that's been reported in the lead-in phase was an 11.5-month RPFS, which really did exceed our expectations based off of our protocol hypotheses of targeting only a 7.5-month RPFS. We're enthused by that data. We had an objective response rate in the evaluable population of 60%. We will see how the randomization reads out this year and look forward to reporting on that as well. Thank you. Great. Liz, now to you from UroGen. You have a unique technology as well. Maybe you could briefly describe the RTGel technology behind Jelmyto, and discuss the drug itself? What is it used? One of the key questions investors have is utilization of the drug via kidney catheter versus administration through the bladder. Yeah, sure. As I mentioned earlier, our technology is a proprietary technology that was developed that's actually called RTGel because it's a reverse thermal gel where it's actually liquid when it's cold. And as it hits the warmer temperature of the body, it turns to a gel and is able to deliver medicine, sustained release over a few hour time period. As I mentioned, one of the challenges with urothelial cancers is anytime you deliver medicine to the urothelial canal, obviously it gets voided out very quickly. You never really have time for the medicine to work. The technology was developed and founded in Israel based off of identification by urologists of a need to treat these patients. Actually the chemist went about, you know, developing this technology specifically for urothelial cancers. Actually, you know, unfortunately, I call these their forgotten tumors. They're low-grade tumors in the sense of they're not high-grade, they're not invasive tumors, considered to be more superficial tumors, but you have to treat them. Our first medicine, Jelmyto, that was approved in 2020, is for low-grade upper tract urothelial cancer. It's a rare disease. There's only about 6,000 to 7,000 patients. You know, as I mentioned, you know, it is, it's a procedure. I liken it to a drug device, you know, delivery, because you do have to, you know, manipulate the upper tract, get the medicine up to the upper tract, and then over a several hour time period, it disintegrates over time. The active in the gel for both our first two products is mitomycin. That's a very well-known chemotherapeutic agent, and we've seen very positive results. We had a 58% complete response rate, and we had over 80% of those patients still in response at 12 months. That was our pivotal study. For Jelmyto, we have since published data on real-world evidence, where some institutions on 132 patients that actually confirm that efficacy and that the safety is actually, you know, better than what was reported in our clinical study and in our label, you know, mainly because of the way the FDA sort of forces you to, you know, put AEs together. The comment about we have a retrograde and an antegrade, actually, you could deliver through a nephrostomy tube to the kidney in our study, no one did. Actually in use, whenever it was launched, patients actually said, "Is there another way to deliver besides retrograde?" You can have a interventional radiologist put a small tube in the back and deliver the medicine. It's a six weekly deliveries, and then, you know, and then you're done. We know that we can also retreat. We've seen some retreatment that's also considered part of our label. The exciting part about the technology is our next drug, which is UGN-102 for bladder cancer. You're actually looking at the same disease in a different location. The upper tract to the, you know, to the bladder area, a similar product, although the volume and ratio of the two mitomycin and the gel is different. It delivers the same. Actually, our phase II study was a 65% complete response and 70% durability. We're seeing some very consistent efficacy and, you know, of the medicine. Because it is locally delivered, while you do get your, some of your typical, chemotherapy adverse events, you don't see as much. When you do deliver it, you know, antegrade versus retrograde, because you're not manipulating the upper tract, you don't get the strictures and stenosis that was identified in our main clinical study. We've actually. It's easier to deliver in the clinic versus having to actually go to an operating room because you need baroscopy. Because of that, now it's over 50% of the administration has moved from, you know, the traditional administration to, you know, to really delivering it through a nephrostomy tube. We've seen now clinics be able to adopt it, you know, more in their clinic when we first launched, it was about 80% in the hospital. Now we're sort of moving to it's actually closer to 50/50. If you can do it that way, and the administration is much easier. We don't have that same complexity when you move to the bladder because obviously from a geography standpoint, the bladder is much easier to access. We just, you know, talked about home installation. We just sort of had a small feasibility study that shows it's just much easier, you know, to give when you give it in the bladder. Great. Now turning back to Dan at Ambrx. You've mentioned ARX517, which is the PSMA-directed ADC under development, advanced prostate cancer. Can you summarize the early dose escalation data that were recently disclosed? Sure. This is the first in human study with ARX517. This is an ADC targeting PSMA. We started at 0.32 mg/kg and have escalated to 2.4 or 2.2 mg/kg currently. Those cohorts are cohorts one through seven. Starting in cohort two, which was 0.64 mg/kg, we started to see PSMA levels decline or decrease. In every subsequent cohort, we've seen at least one patient have at least a 30% reduction. In cohort six we saw the first three patients experience a reduction of 50%, and then two of those patients went on to see a greater than 90% reduction in the PSA levels. Those were all confirmed PSA decreases, as well as one patient had measurable soft tissue disease, and we saw a RECIST response, confirmed RECIST response in that patient. I think importantly, and this relates back to the earlier topic I was describing about our conjugation technology. We've not seen any DLTs. We've not seen any grade three tox events. We think we do have an opportunity to go higher if we choose to do so. Right now we're looking to establish an RP2D. I think we're hopeful that we can do that relatively soon. We're looking to bring data forward at both AACR pre-clinically as well as at ESMO. We're targeting ESMO for another update on this program. Ultimately, we're the only ADC that's currently targeting PSMA. We like to target a lot, for some of the other comments about it being highly conserved in tumor targets, I think is really important consideration for ADCs. In our case, obviously, Pluvicto has established that it's a great target. It's also established as a good market. I think that how Pluvicto has been doing in the, at least in the first two quarters of their launch has been pretty impressive. I think their fourth quarter, just the second quarter launch, was $170 million. They do have, I guess, they've recently announced some issues vis-à-vis their ability to deliver the treatment to patients. However, I think what it does for PSMA as a program is it both establishes the target and establishes the market. Both of those things, we like. So far, vis-à-vis the dose escalation study, it's very encouraging to see no DLTs, no grade three tox, especially at these dose levels. Again, the companies that try to target PSMA with an ADC historically really have to tap out at these levels because they could not establish a therapeutic window. Thanks. It's our understanding that you had a meeting with the safety monitoring committee last month. What was the outcome of that meeting? Do you plan on dose escalating to the 2.9 megs/ kg dose, which is cohort eight? Yeah. I think we haven't described what the outcome of that meeting is yet, but I think based upon what we've seen, we do have the opportunity to go higher. It's gonna be up to us to decide whether or not we do wanna go higher. Project Optimus, obviously, is, you know, is something that we'd consider. I think, you know, from our point of view, it's again, it's very encouraging to see no DLTs, no grade threes at these dose levels, again, where other programs had to stop because of toxicity issues. I think we do have the opportunity to go higher. We'll provide an update at ESMO, you know, relative what other dose levels we may go to. The next one is cohort eight. Again, I think, we have the opportunity to do that based upon what we're seeing. Turning to you, Mark, the pivotal phase II ENSEMBLE trial is, you know, going on now. Can you talk about the design of the trial? You know, and I think a lot of the investor questions are around how the trial is powered to evaluate the ORR PFS and OS. If you could talk about that a little bit. Yeah, absolutely. The ENSEMBLE is a randomized trial. It has three arms. It has the control arm plus two different doses of Onvansertib in combination with standard of care, standard care being the control arm. The two doses that were chosen, one of them was the recommended phase II dose from our original phase I- B/II trial, and the other dose is the dose lower that was also in our phase I- B/II trial. That's kind of the general design of the trial. It is also 80% powered to be able to see a difference in ORR of 35% versus 15%. That also another very key factor in the trial Like I was talking to you earlier about this finding with the, with Bev and Bev-naive patients having a much greater response rate. What we're doing in this phase II randomized trial is we are stratifying across all three arms the same percent of Bev-naive patients. That will be 1/3 or greater of the patients in the trial will be Bev-naive across all three arms. This is really important because it allows us to really ask in a randomized fashion about our unexpected finding with Bev-naive patients. I think that's pretty much the essence of the trial. Yeah. To follow up on that, when can we expect initial data from the trial? What will the scope and the size of that data look like? We're projecting that the results of that readout top line will be in H2 of 2024. I didn't quite hear your last question. I'm sorry. The size and scope of that data readout. Well, we'll be looking at ORR, and of course, also we'll be putting out PFS. It may still be immature at that time, but we will be putting that out as well. Turning to you, Joe Ferra, for Elevation Oncology. You recently acquired EO-3021 through the licensing agreement with Megalith. Can you elaborate on the financing of the deal? Could you speak to what made this program specifically very attractive given all the other Claudin 18.2 antibodies being developed? Yeah, sure. A few things. It's, as you mentioned, for EO-3021, we licensed rights worldwide, ex-greater China, for EO-3021 from CSPC in July of last year. The terms of that would be over $27 million upfront, $148 million in clinical and regulatory milestones, and approximately $1 billion in commercial sales milestones. A few things there. I mean, certainly a attractive back-end-loaded deal that is, upon success with EO-3021 and Claudin 18.2 is when we owe the majority of the share of the milestones to CSPC. Another important thing to mention in terms of our agreement financially with CSPC is. They'll be manufacturing the drug for us, but also they'll be manufacturing the drug at no cost to Elevation Oncology up to and including phase II. As we all know, for companies like us, some of the early spend, meaningful spend for any program is in manufacturing, and CSPC is bearing that cost early on in our program. CSPC is currently running a phase I dose escalation and expansion in China, and we have said that we plan to move into our phase I in the U.S. in the H2 of this year. In terms of the landscape, as I mentioned before, Claudin 18, we think, is an emerging meaningful unmet need in oncology with a significant market opportunity. Of course, we all know with that comes a lot of competition. We honed in on an ADC approach early on because, as I mentioned earlier, with it being expressed largely in gastric, only in the gastric mucosa and healthy tissue, but really expressed significantly in oncology, it's a very amenable target for a targeted approach like an ADC. We thought an ADC approach was the right way to go. Amongst the landscape there, CSPC and their technology, we thought, was an opportunity to get meaningful differentiation from some of the other agents out there. Zolbetuximab done great. Astellas with Zolbetuximab done great data with their naked monoclonal antibody. There are certainly some CAR-T approaches. There are some ADC, and there's also some early bispecific approaches, which we think are all, of course, relevant. In any kind of treatment landscape, doctors always want multiple opportunities at their disposal. We think from an ADC approach, you know, we look at the range of expression. Astellas and Zolbetuximab, for example, are largely looking at the higher expressers of Claudin 18.2. We think an ADC approach is a way of looking at not just those that are higher expressers of Claudin 18.2, but also the medium and the low. You can provide an opportunity to help patients across the range of expression of Claudin 18.2. Just to follow up on that, when can we expect to see that differentiation become evident based on the clinical data? Yeah. We said, as a company in terms of public milestones, we're gonna present preclinical proof of concept data in the H1 of this year at a major medical meeting, As I mentioned, move into the clinic in the U.S. in the H2 of this year. As the year bears on between some of those events, we expect to have more details about 3021 and CSPC's technology that'll help understand further what this differentiation could bear as we move into the clinic. Great. Scott, over to you. You previously gave us some background on MGC018. Maybe can you summarize some of the latest dose expansion data and walk us through the study design of the phase II/III TAMARACK trial? Sure. As you note that we had initially dosed the drug up to 4 mg/ kg, we had been seeing some very significant objective responses, particularly in prostate cancer at the 3 mg Q3 weekly dosing. That led to multiple expansion cohorts of which we've been focused on the prostate, 40 additional patients. As we had reported at an earlier scientific meeting, we were seeing both significant PSA 50 responses as well, objective responses with patients both with measurable disease in their viscera, as well as responses in patients with bony disease. Based on those results, we designed the TAMARACK study. One of the aspects that we want to address in TAMARACK, as I commented on earlier, was identifying the optimal dose. What we were trying to determine is could we get the activity that we were seeing at a 3 mg/ kg Q3 weekly basis with a reduced side effect profile. In particular, the side effect that seemed to be most bothersome to patients was basically hand-foot syndrome, where they would be getting grade two pain associated with some of the side effects. We had done a very detailed analysis of the pharmacokinetics, and actually the majority of patients during the course of the study had their doses reduced or held to mitigate to some of these side effect profiles. When we modeled that, we sort of found that bookending the 2 to 2.7 mg per kg range was the appropriate one to go forward in a phase II dose. We also decided that we could give the drug a little less frequently instead of Q3, Q4. With that, we discussed that with the FDA and regulatory agencies, and that was agreed upon. The study was designed as a phase II/III design, where the phase II was enrolling patients that had progressed on taxane, most often docetaxel, and an androgen receptor axis targeting agent. The phase II portion of the trial is dosing 50 patients in each one of the experimental arms and 50 in a control arm. Based on the responses, we see the response rate and side effect profile, one of the experimental arms would be dropped and then would move on to phase III. Great. Fantastic. Let's move on to POINT Biopharma. Jessica, you're naturally gonna be compared to Pluvicto, and then I think that that seems very reasonable. One of the key differences is that you're using four doses instead of six doses as Pluvicto is being used. Can you comment on how you arrived at the four-dose regimen, and what data do you have to support that this dosing is better or more optimal than six doses? Yeah, absolutely. While we were initiating the design of this trial, we pursued a special protocol assessment dialogue with the FDA. We got some very deliberate and very meaningful feedback from them in regards to dose selection. Part of that was a recommendation for four doses. A lot of the literature on PSMA therapy to date has shown that specific radioligand therapy to date has shown that the biggest effect is after the first two is within the range of the first two cycles. There's been data published to show no difference in the total administered dose that we are studying versus Pluvicto's dose regimen. We, as I mentioned, had a lead-in phase that evaluated this dose, and we deliberately discussed whether we should modify the dose based off of the safety profile. We, at that point, did not evaluate the PFS other than just PSA itself. We elected to maintain the dosing regimen that was initiated within the design. We feel that, you know, the totality of both the dosimetry data, which shows potentially a nice differentiation of protection to the bone marrow, as well as other clinical toxicities such as to the salivary glands, you know, really might be better suited in an earlier line patient population as we're studying. You know, really will allow patients to reserve potential other myelosuppressive agents thereafter or at in combination, you know, such as with DNA repair mechanisms and that such. You know, overall, we feel it really may benefit patients. We were enthused when we saw the efficacy of PFS in the lead-in phase that really showed that we are not compromising on efficacy with the dose regimen that we selected. Great. Liz, moving on to you. We talked a bit about Jelmyto earlier. Let's switch gears to 102. First, can you comment what the difference is between Jelmyto and 102, and describe your pivotal development program? Sure. As I mentioned earlier, UGN-102 is our investigational medicine for the treatment of low-grade intermediate-risk non-muscle invasive bladder cancer. Actually, it's a very similar in the sense of it's our gel technology in combination with mitomycin, but it is a customized, you know, formulation because so the ratio of the gel versus the mitomycin is different and the volume is different because obviously the volume of the bladder is much bigger than the volume of the kidney, so they're not interchangeable. You know, they're both, you know, completely different, you know, different medicines. We actually are just finished enrolling our pivotal study, our phase III pivotal study. We gained agreement with the FDA in a 220 patient single-arm study for complete response rate being our primary endpoint and durability of response being the secondary endpoint. That was actually very important to the FDA. As I mentioned earlier, our phase II study had a 65% complete response rate and a 72% Kaplan-Meier analysis. Actually, we only had a handful of patients, but showed that the median duration when follow-up was about 24 months. That is in, you know, contrast to these patients that have what we call intermediate risk because they either have multifocal disease, they have larger tumors, they have a high risk of recurrence. They usually recur within 12 months. The fact that our long-term follow-up shows a 24-month duration of response was great news for us. We look forward to sharing some. We initially started with a phase III head-to-head study against a TURBT, transurethral resection of the bladder tumor, based off the feedback we got from the FDA. We didn't like that study because you're actually comparing a medicine to a surgery, and they have very different timing from an endpoint. Your complete response endpoint in a surgery is day zero, where your complete response rate in, you know, using UGN-102 is at three months. The statistics associated with it were very complicated, which is why the agency, you know, finally agreed that a single-arm study, you know, made more sense. The good news is we had enrolled over 200 patients in that study, and so we are going to read that study out mid-year this year. We expect to share that data soon. Again, our pivotal study will finish, has finished enrolling. We're following those patients and expect to submit to the FDA in 2024, and obviously, depending on whether we get priority review, whether we'll have an end of 2024 or, you know, first half of 2025, approval. Great. Turning back to Dan at Ambrx. Can you review the milestones for ARX517, perhaps nomination of an RP2D or further data update? You had mentioned ESMO, and maybe give us an idea of the scope and the type of data we're gonna get at ESMO. Sure. Thanks, Divya. I think the next milestones are establishing the RP2D will be an AACR with some preclinical data. We're targeting ESMO for clinical data. The scope will be PK/PD data, the durability of the responses, the PSA, the safety update, and you know, including all the cohorts, so the full demographics. I should mention that this is obviously a dose escalation, so patients are consented to receiving a subtherapeutic dose. These are patients that have approximately a year to live. They're metastatic Castration-Resistant cancer patients, so very sick, heavily pre-treated group. In the dose escalation, the average or the median prior lines was five, and some of those patients saw Pluvicto. We're really looking forward to kind of bringing the, you know, the full body of data that we have, and we're developing not only what we have currently, but also what we'll develop over the next couple of months. Turning to Mark. Outside of CRC, onvansertib is being looked at in a variety of different tumors, pancreatic, small cell. Can you give us some of the milestones that we can expect to see, or data that we can expect to see this year from those programs? Yes, Divya. We have also, as Divya mentioned, we have signal finding trials in three other cancers. We're looking at pancreatic, triple negative breast cancer as well as small cell lung cancer. You know, just to step back a little bit and talk about why we've gone into those things. First of all, our target PLK1 is overexpressed in many different cancer types. It's, it's unusual in the sense that it's not mutated itself, but it's overexpressed by tumors, and in essence, tumors hijack the PLK1 pathway. That's one consideration, is to look at where it is overexpressed. Even more important consideration is we do know a lot about synergies with inhibitors of PLK1, such as onvansertib, our drug, with other agents, and particularly two big classes, DNA-damaging agents. That's why we're in colorectal cancer, 'cause irinotecan is a DNA-damaging agent, and we're coupling it with. The other area is in essence, in microtubule destabilization and stabilization. For example, taxanes are microtubule stabilizers within the mitotic or the M phase of the cell cycle. That was kind of the drivers of why we got into those. To answer the question specifically for triple-negative breast cancer, for small cell lung cancer and for our pancreatic, Q2, Q3 of this year, we were putting out some more data on those signal finding trials. For the triple negative breast cancer, we're targeting Q4 of this year or to Q1 of next year to give data there. Those are our other really exciting trials that we're doing. Moving on to Joe from Elevation Oncology. You mentioned that you plan to initiate a phase I trial of 3021 in the second half of this year. I guess what can we expect, just in terms of any kind of updates from that trial this year or even early next year? Yeah. Yeah, sure. The only guidance we've given so far is the start of the trial, as you said, in the second half of this year. We look forward to giving more details about our clinical development plan as well as other things about our overall philosophy on developing EO-3021 goes from here. Keep in mind that our partner, CSPC, is currently conducting their phase I dose escalation and expansion in China, and we look forward to CSPC with time releasing their data. Great. Let's go to Scott. Scott, you have a lot of programs, and we realistically can't talk about all of them on this panel. Maybe can you summarize the key milestones that we anticipate to see over the next 12 to 18 months across the board? Sure. Just, of the drugs we discussed, obviously the enrollment in the TAMARACK study, the goal is to enroll this patient set in for the phase II in through 2023 into 2024, hopefully with the analysis at the end of the year of 2024. We will discuss very shortly the next study for lorigerlimab, the P-1 CTLA-4 molecule, a phase II study, which we will discuss very shortly, the design of that study. On the enoblituzumab study, there's the data on neoadjuvant treatment of prostate cancer from an IST with Hopkins that there's a publication in press which will come out very shortly and discussion of potential next steps of with that program. We have the outside of prostate cancer, we have a CD123 by CD3 in AML that we partnered with Gilead. That's a dose escalation moving quite nicely there. Again, we have also on the Vobra lorigerlimab. We have a combination study ongoing in six different tumor types, which includes prostate cancer. Timing of data late 2023 into 2024. We don't have the specific timing yet. Obviously we wanna be able to pick a dose and move into expansion cohorts there. Finally, we have a 50/50 partnership on a molecule IMGC936, which targets ADAM9. ImmunoGen is likely to present data later this year. Great. Jessica, let's move on to you. There's a lot of focus on later this year in terms of the Pluvicto data and your data. Can you just comment on the timeline for your data release? Specifically, what should we expect to actually see in that data release? Yeah. The current guidance is mid this year. It is an event-driven trial though. I'm monitoring that we have patient-specific models, you know, in order to refine that date as we get close to it, we'll provide updated guidance at that time. In terms of what to expect, we will be including results unlike some of the most recent results from Novartis. You know, we'll be including our RPFS results as well as safety. Other secondary endpoints we haven't provided guidance on yet. We'll ensure that it'll be as robust as possible. Great. Liz, over to you. You briefly described the design of the pivotal study. Can you comment on the timeline for the data release from both the pivotal study and actually your single-arm study? We have quite a few patients as well. Yeah. No. On the ATLAS study, as I mentioned, mid-year this year, we'll have all of our CR data and we'll have durability data, 15 months, post-initiation of study. We'll have some robust data not only on our arm, but we'll also have data on the control arm, which will be, you know, what happens after surgery, and we're particularly interested in safety. I think some of the misnomers from the FDA, but also even from physicians, is that a TURBT is a fairly benign surgery, but patients and, there are, you know, side effects associated with that. That data will come out this year. We also have our data on our ENVISION study, which is our pivotal study, and that will be 2024, the first half of 2024, with both DR and durability. Again, that will be the basis for our submission that will happen. In addition to that, on Jelmyto, we have a registry, we expect to continue to get ongoing data readout of the registry data in real use, you know, real-world experience of Jelmyto. Great. With that, we're pretty much out of time, so I'd like to thank the entire panel for your time.