Good morning. Welcome, and thank you all for taking time to spend part of your morning with us. My name is Mark Schoenberg. I'm the Chief Medical Officer for UroGen Pharma, and we have a very exciting program for you today, so I'm glad you're here. This might be the only time anybody says in a venue like this, "If you're not looking at your phone, please do so now." Two important press releases have just come out, so don't turn off your phones. Anyway, these are our forward-looking statements. I won't read them to you. This is our agenda for the morning. Our CEO, Elizabeth Barrett, will come up to the podium in just a moment. We're gonna have presentations by some scholars in the field, as well as a very important data discussion and release, finally, a panel discussion, and a Q&A. We look forward to having a very interesting and robust conversation this morning about some very exciting data. With that, let me welcome Liz Barrett, CEO of UroGen, to the podium. Thanks, Mark. Thank you for being here, as Mark said, I just wanna give my thanks as well. Also want to acknowledge we have a couple of our board members, our Executive Chairman, Arie, and I can't find you here. Where are you? There he is, Arie Belldegrun and Dr. Leana Wen also. The rest of our board members are online, happy to have you all here. You know, I've been trying to teach Mark to get out of his doctor tone, he can't do that, I'm gonna do it for him. You know, I get often asked often about highlight of your career. What's the, you know, what's the thing you're most proud of? Let me be very clear: it's today. I mean, it really is. I've been in this industry for a long time. I actually was on the consumer side and decided I really wanted to be part of pharmaceuticals when I was at Johnson & Johnson because I felt like really making a difference in people's lives. I know you hear that a lot, and you think, "Well, is it really true?" Trust me, it's really true. I'm really proud. At the time, you know, I started in oncology, you know, the survival rate for cancer patients across all therapy, all different types of cancers was pretty dismal. We've made so many advances over the years to be where we are today. When I got the call from a recruiter saying, "You know, Arie Belldegrun," whom I had never met at the time, "you know, wants to talk to you about UroGen." I was sort of like, "I don't know. I've never heard of UroGen. I've been around a long time, you know, probably not a good time." They said, "Just talk to him for a few minutes." I don't know how many of you guys know Arie, but, you know, saying no to Arie is almost impossible. What he said to me was, "Just talk to the team. Just talk to the team." I did. I said: Okay, okay, I'll go into New York, and I'll talk to the team. It was actually Mark Schoenberg, our Chief Medical Officer, who's still a practicing urologist, when I sat down with him, and after all the advances that we had made in oncology over the years for all the different tumor types, and he started describing what happens to patients with urothelial cancers. I have to tell you, I was shocked. I was like, "Wow, we actually really do still treat patients." There really aren't any medicines for these patients that have low-grade UTUC or low-grade intermediate-risk non-muscle invasive bladder cancer, so I was actually really surprised. The other thing that I was surprised about was the fact that he showed me the data on UGN-101 at the time, which became JELMYTO, with a 58% complete response rate. I was like, Wow! I mean, that also, in my 25 years in being in oncology, doesn't happen very often. That sort of brings us to today, and we thought that was very compelling, and we were very excited about what we were able to do for patients with upper tract disease. Now what we're going to be able to do, hopefully, assuming we get approval in bladder cancer, is just amazing. I hope that you find today as compelling and as exciting as we find it, and we really are looking forward to sharing the data with you today. With that, I wanna just talk a little bit about. For some reason, it's not moving. Sorry, the slides aren't moving. Try it again one more time. Okay, there we go. You know, with that, I do believe that UroGen, of all companies, is uniquely positioned in this space, and I'm gonna talk to you about why. You know, we aspire to change the treatment paradigm. I just talked to you about when I first heard about these patients and how patients were being treated, and you know, urologists are doing a great job with them, with, with what they have, and, but for us to be able to actually change the paradigm for these patients. We all, we sort of took a step back and said, "Why?" We said, "We believe that patients deserve better." We have a portfolio, specifically in urothelial cancers, and it's really driven by the technology that was developed by a small team in Israel, and the, called RTGel. Actually, there's some around the back if you have an opportunity. If you haven't, then there's actually some also in front of you. What was unique about it is it was a gel technology. It's called RTGel, and it's called RTGel because it's a reverse thermal gel. It's actually liquid when it's cold, that hits the warm temperature of the body, turns to gel, delivers medicine, and what that does is increases the dwell time, allows for local delivery of these medicines, so you don't have the systemic side effects you do with some chemotherapeutic agents, and hopefully improves the therapeutic response. We've seen that both our data on gemcitabine and now our data on UGN-102. Because of that, it's it disintegrates naturally in urine flow and then is exited from the body. Bladder cancer is actually one of the most common cancers, and you didn't hear a whole lot about it, but you don't hear a whole lot about it. There's over 700,000 people in the US alone living with bladder cancer. It's also one of the most recurrent cancers. These patients, they come in, they get their treatment, and the tumors tend to come back. Of the 82,000 patients that are what we call low-grade intermediate-risk non-muscle invasive bladder cancer, which means they have larger tumors. It's a multifocal disease. They tend to recur more often. 68% of those will have two or more recurrences, and 23% will have five or more recurrences. The nice thing about UGN-102 is we get to leverage the similarities with our marketed product, JELMYTO, which we often talk about JELMYTO being a proof of concept for UGN-102. Because the area, the urothelium, is whether the tumors in the upper tract or the bladder, genetically and then mutationally, are very similar. The products are very similar. They're not the same. We often get that question. It's not the same, they both use the technology or RTGel technology in combination with Mitomycin. For that, you see a lot, you know, there are many of us who expected we will see positive results in bladder cancer because we feel like the disease is very similar. There's distinct advantages to UGN-102. One of the things with upper tract is you have to manipulate the upper tract. You've got to get the medicine up the upper tract. You have to do it under fluoroscopy so that you do it in the right way. The market is very small, so you really have 6,000-7,000 patients for JELMYTO, so it's hard to find them. Any one urologist might only have one or two patients. Not the case with UGN-102, a much larger patient population. You're going to hear from the physician panel very shortly, you know, every physician, every urologist sees these patients. The administration is much simpler because you don't have to get up to the upper tract. It's bladder, it's a really simple procedure that can be done in the office, it really fits in the way urologists treat, you don't need the special equipment. We have the potential at UroGen to unlock a significant opportunity, most importantly, as I said, really drive advance for patients with these diseases. What you see here is $5 billion plus in total is for non-muscle invasive bladder cancer, both the low grade as well as high-grade disease, in which we actually have medicines in our portfolio to address. We're very excited about our opportunity. As I said, we believe that UroGen is the only company who's really solely focused on urothelial cancers. We will be, if UGN gets approved, we'll be the first medicine ever approved for this patient population. As I said, we can leverage our, the infrastructure that we have in place. It's a $3 billion market just for this one alone. I also would be remiss if I didn't thank some very important people that are here today that allowed us to successfully have a $120 million private placement. Thank you very much to those of you who are here. This was very telling for us because we had partners coming to us saying, "We want to work with you. We believe in what you're doing." I think that the diligence that they did around our company, around the product, around the opportunity, is testament to the true opportunity that we have here. I think, again, we're in a very, very unique position. I'm going to come back after you hear from... about the data, to talk about the package that we have and the compelling package we have on UGN-102, and why we are so confident as you see the data today and compare it across our clinical studies, why we have the confidence in getting an FDA appro as soon as possible. With that, I'm going to turn it over to Mark to introduce our panel, physicians. Thank you. Thank you very much. Thank you, Liz. Imagine what I sound like when I'm not excited. But in my defense, I will say the last thing you want is an excited surgeon. We're very lucky today, to have a group of experts, who are here to help us present the data. I'd like to welcome Dr. Karim Chamie to the podium to talk about low-grade intermediate-risk non-muscle invasive bladder cancer, to place it in context, and to talk a little bit about the unmet medical need that we are addressing with UGN-102. Without further ado, Dr. Chamie. Thank you, Mark. Thank you, Liz. You guys can hear me okay in the back? Great. You know, I was talking to Arie a little earlier. You know, I first, you know, my first encounter with UroGen was about 13 years ago. I was a fellow at UCLA, Arie, came to me, and he says, "Look, I got this Israeli company, they've got this gel. They want to mix it with chemotherapy. They want to use it in the bladder." At the time I said, "Bladder? We've got aqueous chemotherapy we can put in there. Let's use it for the upper tract." Obviously, 13 years later, I'm still working, you know, as a doctor, Arie Belldegrun, obviously, is Arie Belldegrun, he's truly a visionary, I did not ENVISION the data to be this strong many years later. Congrats to the UroGen team. As the director of the bladder cancer program at UCLA, I see a significant number of patients with bladder cancer. On my typical clinic day, I do, you know, 15, 16 cystoscopies. I see about 60 patients. I'm instilling chemotherapy. This is a population that suffers a significant amount from this disease. We did a research paper many years ago that looked at the burden of bladder cancer. We were looking at high-grade non-muscle invasive, we followed those patients out for five years and found that only one out of seven patients was alive five years later without a recurrence or progression. This is a cohort that suffers from significant comorbidities, and they have co-competing risks. Taking these patients to the operating room puts these patients at risk. Slide won't go forward. There we go. Bladder cancer is highly heterogeneous, right? When we talk about bladder cancer, we tend to talk about grade and stage. Those are the two important criteria in how we classify the disease. We go from Ta, Tis, which are non-invasive tumors, to T1, which is superficially invasive, to muscle invasive, which is T2, T3, and T4. We also look at grade, we look at tumor size, location, multifocality, and that's how we develop risk of disease. More importantly, as physicians, we have to look at the age of the patient and their competing risks to determine whether this is someone we want to operate on or not. The AUA has developed some nice stratification tools, and we use those to stratify patients as either low risk, intermediate risk, and high risk. 50% of patients that get diagnosed with bladder, well, 70% of patients get diagnosed with bladder cancer tend to have non-muscle invasive disease, but the vast majority of those are low grade, and many of those low-grade patients recur, and they tend to fall into this intermediate risk. This intermediate risk cohort that undergoes surgeries, you know, as surgeons, we think we can go in there, and we can completely resect these tumors, and we feel confident in our resection, but we oftentimes don't realize the implications of what we do. This is a study that we published using real-world data from Kaiser. Kaiser is a closed network where patients who receive Kaiser must go to a Kaiser emergency room, they must go see their Kaiser doctor, they must receive Kaiser medications. It's hard to do that in, you know, using SEER-Medicare data, because sometimes patients get care outside of their vicinity, and it goes unrecognized. In the Kaiser system and in a closed system like that, you're able to capture the universe of that patient's care. What we found was that the adverse events within 90 days of a TURBT is 33%. TURBT is the most complicated outpatient surgery we do in medicine. If you actually look, in addition to the readmissions due to the fact that you're mixing urine with blood, with bacteria, and instrumentation, that's basically a nidus for infections and recurrences that oftentimes, you know, pains these patients. The recurrence rate and the progression rate. While the vast majority of these patients don't go on to develop muscle-invasive disease, they too oftentimes progress to high-grade disease or they end up progressing to a higher stage. There was a Scandinavian study that actually looked at the patients who undergo multiple TURBTs, and what they found is that those who undergo two to four TURBTs have a significantly increased risk of dying overall. You're putting these patients... You have to stop their blood thinners. You have to wean them off any other medications they're on. You have to put them under an anesthetic. It's not surprising to see a higher mortality rate from it. We think it's due to the fact that these patients getting anesthesia, the risk of the complications, and the lifelong surveillance and treatment monitoring for these patients. What we need is an option that offers patients something that can reduce their rate of recurrence and not necessarily need to take them to the operating room. That's where UGN-102 falls in. What they're targeting is patients that have non-muscle invasive disease, and they want to go after this intermediate risk, which makes up a significant portion of patients with bladder cancer. Obviously, we talked about OPTIMA, the Phase II study, that showed that the complete response rate was 65% amongst all those with intermediate-risk disease, and the durability was quite good. It was 72.5% after a year. We then looked at a cohort of patients who were followed for a longer period of time, and what we found was that the median duration of that response was over two years, so 24.4 months. This is a significant number here. We're dealing with patients who have a really good response rate, and once they get that response, they're able to maintain it. This is the extent of my presentation, and I think what you're going to hear today is some really exciting new data that is paradigm-shifting here. Mark, thank you. Karim, thank you very much. Great setup. Now, for a very exciting presentation by Dr. Sandip Prasad, who is Director of Urologic Oncology at Atlantic Health and who is actually the principal investigator for the trials that he will now present to give you a sense of where we are in the development of UGN-102. Dr. Prasad. It's really just a real privilege and honor to be able to present the data that I know we're all here to talk about today. We're going to review the top-line data results for the two P hase 3 clinical trials, ATLAS and ENVISION. We'll do them separately, but again, both of them are sampling the use of UGN-102 in the management of intermediate-risk non-muscle invasive bladder cancer. Just to talk a bit about the study drug, UGN-102, overall, as Dr. Chamie described, the initial study with this agent was the OPTIMA II study. That was a single-arm study where all patients received the study drug. The study launched in 2018, with the results published in 2022, which demonstrated a 65% complete response rate at three months and really quite significant durability of response data. The ATLAS study, which is a Phase 3 randomized trial between the study drug, UGN-102, and TURBT, which is our standard of care, the resection of tumors in the bladder. That study launched in 2021 and has enrolled 282 patients. We then launched an additional study, which is a single-arm study with the study drug, the ENVISION trial, that launched in March of this past year, has enrolled 240 patients. We're gonna present top-line results for both of these studies today. For ATLAS, we'll present both complete response rate data, durability of response, and for ENVISION, we'll present that first 3-month complete response rate. We'll have both of those available to share today. We'll begin with the ATLAS study. The study endpoints for ATLAS, and again, remember, this is the study that randomizes patients to surgical resection or topical treatment with the study drug. The primary endpoint with an intention-to-treat analysis was disease-free survival. This was defined as from the time of randomization until the time of any event deemed to be clinically significant. That would include residual disease, recurrent disease, progressive disease, and death. Importantly, there were two key secondary endpoints as well. The first was a complete response rate at three months. This is for patients who received topical chemo ablation alone, comparing those patients to surgical resection, how do they do at the first evaluation that we do at three months? That's traditionally the timeline in which we reexamine the bladder with a camera called cystoscopy and sample the urine, called cytology. That's really our first evaluation across the board for urothelial cancer when we're looking to see if there's a complete response. For those patients that were complete responders, we want to determine how long did they have a durable response with this agent. We look at those patients who are complete responders at three months and then follow those patients forward until they have one of those events we described earlier, either recurrence, progression, or death. We'll present both of these, both primary and secondary endpoints for ATLAS. Just to walk you through the trial schema. Patients were enrolled here with any suspicious intermediate-risk disease. As Dr. Chamie described, this is actually a fairly heterogeneous group. These are some patients who have large de novo tumors, greater than 3 centimeters. These are patients who may have new multifocal tumors, and these are patients who may have recurrent tumors. All of those are grouped together in intermediate-risk patients because those patients have a higher degree of recurrence subsequently, but they may be different biologies, and that's sort of our study cohort. The treatment is really assigned to any of those disease types in this study. Patients undergo screening to ensure there is no high-grade disease. That involves cystoscopy, which is our visual check of the bladder. A biopsy is performed to confirm low-grade disease. A urine cytology samples the urine to ensure there is no high-grade cells or cells coming from the upper portion of the urinary system, and we just use radiographic testing as well to confirm that the disease is only in the bladder. Patients were randomized one to one to the study drug, UGN-102, or to a TURBT to resect out the tumor. The UGN-102 drug is administered in sort of the traditional way in which most intravesical therapy studies are done, and most of our intravesical therapies are performed, which is that patients come in once a week, have a catheter placed, have the study drug instilled, which takes about a minute or so, and the catheter is then removed, and the drug is administered. Patients come once a week for six weeks. It's the same way we've been using BCG for four decades, and really how we do almost every intravesical therapy that's been approved or on study, really mimics the BCG schedule. Once patients have completed either their resection or their 6 chemoablative treatments, patients were then assessed at three months, and that's a standard timeline to assess for recurrence in urothelial cancer. These patients then went to the operating room. Every patient received a cystoscopy. If a lesion was seen, the patient would receive a four-cause biopsy, and all patients had urinary cytology. At that point, patients were deemed to either be complete responders or non-complete responders. For patients who are non-complete responders in the UGN-102 arm, they received a TURBT, which is the standard of care, to clear their disease, and then patients were followed. For patients in the TURBT-alone arm, they were then followed again to observe for recurrence, progression, or death. These data for demographics and safety are available in your appendices. I won't cover the data, but in general, based on randomization, as you'd expect, the demographics and baseline characteristics were equivalent between the two groups. Treatment-emergent adverse events were mild to moderate. These, again, are patients that have received a cystoscopy, 6 catheterizations, and another cystoscopy at a minimum, to be on study. The types of things that we see are the types of things that urologists see, difficulty with urination, burning, blood in the urine. These are things that are well within our wheelhouse to manage. The safety profile is very similar to other studies with this study drug. In terms of serious treatment-emergent adverse events, these rates are really quite low across both arms. In the group that received study drug plus or minus a TURBT, the rate was 1.4% for a serious treatment-emergent AE, and in the TURBT-alone group, that was 0.8. Again, exceedingly low, significant, serious adverse events. This is the primary outcome, which is disease-free survival. I think the takeaway here is that we see a significantly higher rate of patients with some event. Again, this is either recurrence, progression, or death. In the right column, the TURBT-alone group, where 39% of patients had an event, compared to the study group, which was the infusion plus or minus a resection, if needed, in 26% of patients. That results in a hazard ratio of 0.45. There's a 55% reduction of experiencing a recurrence or progression in the study drug arm. I'm going to show you a Kaplan-Meier curve here, which again, illustrates this difference, which I think the magnitude is fairly obvious in terms of study effect, I'm sorry, of treatment effect on study. Again, these patients experience a durable, consistent reduction of risk across all three parameters of recurrence, progression, or death in this intention-to-treat population. We look at complete response rate at three months, recall, all patients are gonna undergo a three-month cystoscopy with a biopsy, if needed, and this is the initial response to just the chemoablation alone versus a surgical resection. On the left, you'll see that for patients who had UGN-102 alone, the complete response rate was 65% with a fairly narrow confidence interval. If you look on the right with patients who have received just a surgical resection, the number is almost identical. It's 64% with, again, a very similar complete response rate. There were a small percentage of patients who did progress to high-grade disease. There's a small amount of missing data, but again, from the confidence intervals, I think we can surmise that these rates are likely to be very similar to one another in terms of complete response. I think it's important to notice that this is really the natural history of recurrent intermediate-risk non-muscle-invasive bladder cancer. It recurs. Even in three months, we'll see lesions in patients, which is why they come so often for their cystoscopies. When we look at the duration of response in these complete responders, we see again that the rates of disease-free survival are improved in the study drug alone group in those patients who are complete responders from the very beginning. Here, the hazard ratio is 0.46, there's a 54% reduction in risk of recurrence, progression, or death in patients who receive study drug alone with no surgical treatment, compared to those patients who had to go to the operating room, be put to sleep, and had a resection. The nonsurgical option here is superior in terms of the duration of response. The Kaplan-Meier curve illustrates, the natural history and the magnitude of this change between the two study groups. The light blue here is the UGN study drug alone without resection, in the blue, is the TURBT group alone. These are for patients who had a complete response. Those patients we knew did well initially. We see a persistent benefit across time for patients who received the field treatment with the study drug, rather than the focal treatment, the surgical resection. ENVISION is our Phase 3 single-arm study, same study protocol. The primary endpoint here is that three-month complete response rate. Again, the cystoscopy at three months with a visual assessment to see if there's any tumors that are left behind. The secondary endpoint, which will not be presented today because the data are immature for this, would be that duration of response, which is very important in this disease state, and again, was very favorable in the ATLAS study. They'll be looking again for recurrence, progression, or death, but again, those data are not available today. It's a little bit of a different patient population for ENVISION. For ATLAS, those patients that were allowed could be de novo tumors, patients who had no prior history of a tumor but had either multifocal tumors or a large initial tumor. For ENVISION, the patient population are specifically patients who've had a prior diagnosed low-grade tumor. By definition, every patient in ENVISION is a recurrent patient. This study cohort really saturates that element of the cohort a bit more. It's a single-arm study, so the demographics and baseline characteristics are typically what we see in patients with low-grade, intermediate-risk, non-muscle invasive bladder cancer. Again, just to remind you, the mean age is 75. Most of these patients are former smokers. There's pre-existing cardiopulmonary disease. Many of these patients are on blood thinners. This is a sick patient cohort of elderly patients who go to the operating room every three months, potentially, for their disease. Again, a very important study population for us to try to minimize surgical risk. Treatment AEs and safety profile, very similar to seen in other studies. Really, the takeaway slide is that for this patient population of recurrent patients at months, who had a treatment with UGN-102 alone, and this is 240 patients, we see a complete response rate with no surgical resection of 79%. That really is something that is truly paradigm-shifting in surgical management. We, as urologists, use intravesical therapy all the time to minimize future surgery. We give BCG to all of our patients. We give intravesical chemotherapy to patients after a resection in the office, in our cancer centers. To have someone who undergoes no surgical resection and almost four out of five patients will have a complete response at three months, and with pre-existing durability data, that seems quite excellent. This is extremely exciting data. We're obviously going to speak as a group together about this today, but I think this is really the fundamental takeaway slide of what we're seeing, which I think is going to be a shift in the way in which we manage surgical patients. Thanks, Mark. Oh, I'm sorry. Last thing I would just say for ENVISION, because it's important, the durability is going to be important. Those data will result in 2024 with a planned NDA submission to follow. To quote another deadpan member of our company, our Head of Statistics, Brad Berger, "Remarkable. Remarkable data." Really, Sandip, thank you very much. We're going to have a panel discussion now. You have met two of our panelists. I don't know if I can get this to advance. Thank you. Somebody more talented. It's not advancing. While we're trying to get the slides to advance, let me make a couple of statements regarding the panel discussion. Obviously, we're talking about an investigational drug, it is the FDA that determines safety and efficacy. Obviously, we are talking about the use of this drug in the context of clinical practice, but it is not approved, obviously, the conversation has to be considered within that context. That said, we think it's very important for you to hear from experts in the field about how this drug might be used if it is approved. To that end, we will have what I hope is a vigorous panel discussion about the data that you've just seen presented. Remember, also, that things can change in medicine. We're talking about what we know today. With that, let me introduce you to panel members you've not met. I want everybody to come on up. You've already met Dr. Prasad and Dr. Chamie, but we are also lucky to have Dr. Katie Murray join us today, who's Associate Professor of Urology at NYU Grossman School of Medicine in New York. Dr. Trinity Bivalacqua, who is a Professor and Director of Genitourinary Oncology in the Department of Urology at the University of Pennsylvania. Without further ado, where did the clicker go? Oh, okay. Well, since I know what the first slide says, let me start with that. Katie, What? Oh, that one's working? Okay, thanks. What'd you think of the data? Yeah. I think, you know, this is exciting. As a practicing urologist, you know, it's. You know, to find something that could potentially change our practice if we're talking, you know, FDA approval, I think the data is very compelling. I think that we gave a great description of. We see these patients in our offices. They're seeing us, we are trying to find something more. We do TURBT. Yeah, it's one of the most common procedures that a urologist does, urologic oncology does. It's probably not good enough, right? We need something else because these patients are recurring. I think it's very exciting. Trinity. I was sitting in the back, and I was thinking, when we were looking at this data, is that you realize we are gonna have to train a whole generation of urologists differently if this gets FDA approval. Well- I mean, it is gonna change everything, potentially. I was thinking to myself, could you imagine telling your residents, "We're actually not gonna do surgery? We're just gonna put some, you know... Okay, so. -spritz some stuff in the bladder, and we're gonna potentially, change this disease course. Well, as you anticipate, something that Sandip said to me as we were getting ready for the program: Is this gonna take surgery away from urologists? Does that matter? I mean. It's interesting. I, you know, I was in academics, and I'm now a community-based practitioner. This is disease we see throughout the community. This is generally gonna be seen by every urologist. There's people who are concerned that, "Oh, you're taking away a surgeon's bread and butter. They're not gonna do as many resections." We have been practicing to minimize reduction in resections for 40 years. Every patient who gets BCG is to reduce recurrence and surgery. Every patient who gets intravesical chemotherapy is to reduce recurrence and surgeries. Nothing has numbers like this in terms of doing it. I think urologists, like we have been doing for many decades, will be enthusiastic to have things that reduce future surgeries for our patients. One of my jobs is to try to get you to fight with each other. Yeah. I'm not sure that's gonna be possible. Yeah. Let me, let me try. Karim, do you agree, paradigm changing? Isn't that too far? Is that, is that a reach? I think the UGN-101, the gemcitabine was paradigm changing, and we didn't realize it. We, as urologists, don't really think of these drugs as chemoablative and chemoresection. That's a term that was passed on to us, and I think UroGen was really innovative in bringing the idea of chemoresection or chemoablative therapies. obviously, the idea of chemoablative maybe is not novel in this study, but obviously, the data is pretty significant. I think the data speaks for itself, and I think it's gonna be able to change how we practice. Speaking of the data, let's talk about some of the data. Here are some complete response rates across UroGen's trials of UGN-102, the Phase II OPTIMA that you all know about, as well as what Sandip presented this morning in ATLAS and ENVISION. This is, as Katie was pointing out, you know, the use of this in recurrent patients seems very obvious. Here are the complete response rates in patients with recurrent disease. Trinity, what does this tell you about how you have to think about bladder cancer? I think it was sort of where you were going when you were thinking about training residents. What does this say to you? I think one of the things as urologists, we're. Intermediate-risk non-muscle-invasive bladder cancer is sort of, has never really gotten much attention, and despite the fact that that's the majority of the patients that we're taking care of. There's plenty of high-risk and high-grade cancers for us to resect, you know. This is actually what, what patients are suffering from, which is intermediate-risk low-grade papillary. What this data says to me is that we now may potentially have a new agent that will be able to reduce recurrence, if the durability, obviously, is sustainable in the ENVISION trial. would take give us an opportunity to prevent patients from going to the operating room, where, unfortunately, we, as urologists, cause significant morbidity. I think it's all due to the, essentially, the innovative formulation of this drug in delivering chemotherapy, in this case, Mitomycin- C. You opened the door. I gotta ask Karim because he was thinking about this, and we were talking about it last night. Mitomycin in water. How come we don't just use Mitomycin in water here? I mean, we've talked about it, right? I mean, we use Mitomycin after TURBT, not often, right? I mean, we've shown that the acceptance of Mitomycin around the time of a TURBT is low. It's about 5%. Urologists tend to be very fragmented in the way they practice, right? When you're operating in the operating room, we tend to do surgeries. When you're seeing patients in clinic, you tend to want to give intravesical therapies, and we're very compartmentalized that way, and I think our practices are kind of compartmentalized that way. There was a Danish study that was published about a year ago that actually used aqueous Mitomycin- C versus TURBT. What they found was that those patients who get aqueous Mitomycin- C plus or minus TURBT, they did no better than those who got TURBT alone. I think what you're seeing with the ATLAS trial is really a change in that thought process. Here, you're clearly seeing a difference between those who get UGN-102 + TURBT compared to TURBT alone. I know you're comparing apples to oranges here with two different trials, but those that got aqueous Mitomycin- C ± TURBT did very similar to the TURBT alone arm in this trial. The takeaway is there is something special about UGN-102. There's definitely some special sauce in UGN-102 ± TURBT. Here's a special sauce, at least a part of the response rate, and this is the Kaplan-Meier for duration of response, in patients with recurrent disease in the ATLAS trial. These are patients who received either only drug or only surgery. Sandip, what do you think? Yeah. Again, I think this really illustrates the dark blue line of TURBT alone, really illustrates the natural history of this disease. Again, these are patients who are complete responders, and you can see the decline in rapid recurrence within the first 12 months in the majority of patients, which is why we do so much surveillance cystoscopy. You're seeing here that the majority of patients in the study drug alone arm will never reach a 50% recurrence rate at the time of follow-up, at least for this Kaplan-Meier analysis. You know, a 66% reduction in risk of recurrence and progression is significant. That alone is something that I think can compel you to talk to patients and say, "Not only will we avoid potentially the first resection, we're looking at downstream cystoscopies, resections, lessening the surveillance regimen, potentially for patients who receive this because they don't need to be examined every three months, because they don't recur quite as frequently as with TURBT alone." Again, it's really exciting because it's going to sort of upend some of our management strategies. Again, all this is predicated on receiving appropriate reimbursement and all the other things that are going to be part of a drug, hopefully once approved, to get into the hands of urologists. It's going to not just change how we treat upfront, it's going to change how we do surveillance going forward. Trinity, does this tell you anything different or confirm any suspicions you might have about the biology of this disease? What, what does this say to you? Yeah, this is one of the few trials, we heard about one previously, but that looks at, you know, TURBT alone and following them in a rigorous way. This tells me that if you've got a papillary low-grade disease with all of the genetic mutations that are present there, you recur. Thankfully, these are recurrences, not necessarily progression. What this also tells me is that if you use an agent, a therapeutic agent, that is able to coat the bladder, treat the bladder entirely, because remember, this bladder urothelium is genetically predisposed to development of a tumor. We're actually able to potentially reverse that process, which is, you know, you hear it from us over and over again, that is going to have a direct impact on patients, patient care, but more importantly, their quality of life. The people that we suffer from taking care of and they suffer, they're suffering, and we're actually suffering with them, people that we're just having to go back and go to the OR, TURs, and then get. Have to look them in the eye and say, "You know what? I know you've got hematuria. I know you've got dysuria, pain with urination. You're going to the bathroom often, but don't worry, in a month from now, you'll be better." You know, that gets old. This could potentially directly impact- You just told me that he's going back to Penn today to go back and to look in someone's bladder to wash out blood clot. I mean, this is something we see... Yeah in patients, so. Katie, have we been, excuse me, overstating to patients for years, the benefits of TURBT? Does this tell you something about our assumptions about TURBT that might not be true? I think it probably absolutely does. I think, you know, at the gut of us, we've probably thought this for some period of time, like, you know, Trinity mentioned that we've never really followed these patients to see, you know, how direct those recurrences are. The patients are also out there asking for this, right? The patient that I scoped yesterday, right, she says, "Oh, we just did this three months ago, and now these tumors are here again. Isn't there anything else that you can do?" I don't mind, right? It's, you know, it can have complications with TURBTs and do, you know, to go to surgery, she takes off work for the whole entire day. It impacts, you know, her economics. It impacts their whole entire family, her life, right? A vacation day from work, so many other things. She says, "Okay, and then I'll come back, and then what? I see you in 3 months, and we probably do this again?" Right? Because she has gone down that route. I think from our perspective, we're excited for this risk reduction, but the patients are excited, too. They've been asking. Let's go back to the hazard ratios for a second, for slightly different ways of looking at the ATLAS population. The top line is what Sandip presented earlier, the intent to treat population. That's everybody. Remember, ATLAS had patients who were newly diagnosed as well as those who were recurrent and had had a prior history of tumor. You know, it's pretty obvious that this is something that everybody on the panel has already, in one way or another, mentioned would be useful in patients with recurrent disease. Does this say there's also a use for patients who have a new presentation of tumor? Sandip, what do you think about that? Yeah. You know, it's really interesting. When we think about how we're going to practice clinically, I don't think we're going to say: Oh, it's a patient that has this recurrence pattern at this rate, and we're going to select that way. The study was done in intermediate risk patients. I mean, that is the study cohort. I can tell you, I put a patient on a study, which I knew probably had no chance of being successful, but the patient, he's a military veteran, he's in his 60s. He's had recurrent tumors for five or six years. He probably has 40 to 50 tumors in the bladder. To give you a sense, that would take us two to three hours and maybe multiple different operations to try to clear this patient, and even ergonomically, we can't reach it. I have never cleared the patient in five or six years. I'm basically triaging his bladder, coming back three months later, doing it again, trying to avoid bleeding episodes. I put this patient on study, and I looked back into three months, and he went from probably 50 to 55 tumors down to about four. Technically, the patient was not a complete responder. I resected that patient, and he has since been disease-free for the first time ever. Again, I'm not a believer in anecdotal-based medicine, but for that patient, we have completely changed the natural history of his bladder cancer. Because this treatment, it reaches places that we can't reach surgically. It doesn't cause the collateral damage of 50 resections, hoping one of them doesn't bleed and bring you back to the operating room. Again, I look at that patient population as the entirety of the cohort may potentially benefit, even if they're not three-month complete responders. I think that's how we're gonna use it in practice. I think we're gonna find a way to keep patients out of the operating room or to minimize what we have to do in the operating room. Yeah. Thank you. Katie? I, you know, you made me think of something, how, you know, there's all these technologies, so much research has gone into enhancing our eyes for doing cystoscopies, right? Enhancing the way that we do that so that we're not missing tumors or leaving tumors behind. Yet, despite all of those, things come back, and they recur, right? This really does touch that field defect of urothelial cell carcinoma, right? It's touching all those unseen places that no matter how we enhance our eyes with cystoscopy or whatever else, it just hasn't been good enough. Yeah, I was gonna say that, what's most impressive about this is that this is a clinical trial that was done at places where we have specialists that treat bladder cancer, right? If you actually, you know, I'm not gonna try to say this, but if you're gonna extrapolate this out into the community where the average urologist treats maybe one bladder cancer or two bladder cancer patients a month, I think these hazard ratios would even be smaller. I think you'd be looking at even a more profound effect. Here, you're, you know, you're dealing with a control arm of a really good surgeon thinking that they can resect everything, and I think if you extrapolate, you'd find even a greater difference there. Good point. I'd like Obviously, the data is what it is, and it shows that this is an effective agent. You know, I think it also tells us that when you think about intermediate-risk non-muscle-invasive bladder cancer, the de novo patient that meets that criteria is probably gonna appear to do potentially better than those that are recurrent. However, if you've got that high-risk recurrent patient with intermediate-risk non-muscle-invasive bladder cancer, they're still responding, and they still have a good durability response. I think when I think about intermediate-risk non-muscle-invasive bladder cancer, it gets restratified, right, into very high risk of recurrence. Once again, these are not people that progress and those that, that, you know, you may be able to do things like surveillance, for example, or maybe, I mean, I'll throw this out there, maybe you won't need six intravesical installations. You may need less. You know, what is the role of maintenance? You know, I mean, there's so many things that I'm thinking about as I, as I look at data like this and how we would use it in clinical practice. More importantly, really novel clinical trial designs for the next trial to look at. Thank you. Speaking of clinical practice, this is in contrast to JELMYTO, which does take some technical finesse no matter how you deliver it. This is a different administration. How does that impact how do you think this will get used, Katie? I think that's a great question, right? I think, you know, Sandip's mentioned it several times. This intravesical installation is not new to urologists. We're extremely familiar, right? We love six weeks. This is what we do in our routine practices, and it's already part of our practice, and it doesn't require the physician to instill that, right? It's a catheter into the patient that can be done by an APP easily. What does that do? That frees us up as the surgeons to see another patient who has a different disease or a higher-risk disease or something else, and taking more patients that need to be going to the operating room for other things. I definitely think in comparison to even JELMYTO, the adoption in just routine practice seems much simpler. You're working in an academic center. Sandip, tell us about how this might fit into community practice from your perspective. Yeah, we're a group of 26 urologists, which is a very large practice, probably larger than most academic practices. We consolidate all of our intravesical therapy centrally. It's given by a single nurse in a single center. That's whether it's BCG, gemcitabine, docetaxel, Mitomycin. Implementing these types of practices into large group practices like mine, it's very easy to sort of integrate this agent in, just like when the physician orders BCG or gemcitabine or docetaxel or whatever they order, the process and pathways for weekly installation is extremely straightforward. Again, to me, this in our practice, is just a grow-the-pie opportunity. This just allows me to do something else and see a new patient, though I might have had to wait another week or two to see. You know, again, reimbursement's gonna be important, right? That's gonna be important for any treatment that we give. But again, this has got a very easy and nimble way of giving it. I think as long as those are sort of a reasonable commensurate reimbursement for the time, I think this is not gonna have much in the way of obstacles for implementation. Interesting. Urologists won't be pining away for these patients. They won't be missing the surgery, so they'll find something else to do? Well, I think that, you know, I treat primarily bladder cancer, so this is what I do for a living. If I had patients who didn't go on to TURBT for their intermediate-risk, obviously, I wouldn't skip a beat with regards to those patients. I think the perception that this is going to take away, you know, part of their income, I think it's a misconception. I think when a patient comes in. When we, you know, in surgery, we kind of value our time in the operating room or in the clinic based on work RVUs. A typical TURBT gives you anywhere from two to seven RVUs. Most of the patients are in the intermediate risk group, tend to be around the two to five range. Installations in the clinic over a six-week period gives you about 12 RVUs, which is about two and a half times what you would get from just doing the surgery alone. The economics makes sense for the urologist, and I think in the long term, it's going to benefit the patients more. Yeah, I can tell you from... If you are, if you advertise, if this gets approved and UroGen and your institution advertise that you've got this new novel agent, you're going to see a lot of patients with high-risk non-muscle invasive bladder cancer, people with muscle invasive bladder cancer, because you have the new and improved and what's new? This kind of stuff just doesn't happen. People always talk about it, but in reality, you know, use prostate cancer. active surveillance is going to take away radical prostatectomy. Did it? Absolutely not. You know, you have more people that are showing up and, you know, ultimately, those people in active surveillance, guess what? They need surgery or radiation. These things are, we see it every decade, something like this comes up. Speculate about what impact patient interest in this type of therapy, if it's approved, might have on practice. Will patients be drivers of adoption? I think so. I think I mentioned earlier that, you know, we're excited about this. Patients are going to be excited, right? We talked about in one of those first slides, how recurrent this is. People are undergoing five, 10 TURBTs over the last 10 plus years of their lives, every three months, coming to see us in clinic and go through these things. The first inkling that they hear something, their ears are going to perk up, right? Because they're asking us every three months, "So now what?" Right? I say, "Well, I'll see you in three months. Have a nice vacation." You know, or you know, whatever it is. I definitely think that patients have their ear to the ground, kind of waiting for something. There is a new percolated interest in non-muscle invasive bladder cancer in general. You know, the exciting thing here is this is really an area that's not been studied, intermediate risk, low-grade bladder cancer, and it's a chunk of our patients. We're going to still be doing cystoscopies. We still have to do surveillance of the bladder, right? This is not eliminating cystoscopy. What this eliminates is TURBT, right? That eliminates anesthesia, eliminates taking you off a blood thinner. It eliminates, you know, all the things that are involved in a more intensive operation. Flexible cystoscopy in the office, which takes each of us, you know, a handful of minutes to do, is still going to be part of the paradigm for urologists. We're still going to be practicing bladder cystoscopic care, but with a much less intensive regimen that's much less burdensome for the patient. Urologists have a somewhat checkered record with regard to adopting level one evidence and data in general into practice. Any advice for UroGen regarding how to talk to urologists about the value of this new-. Get on the guidelines. Pardon me? Get on the guidelines, on the AUA guidelines. It will be utilized. Yeah. Any other thoughts? ways to talk about this. Yeah, yeah. I think, you know, the important thing, and we've kind of touched on this, is that these patients come in lots of shapes and forms, meaning they're recurrent, their initial diagnosis with very multifocal tumors. It's a reminder that these patients have had TURBTs. It's just another tool and a very compelling and exciting tool to add to our armamentarium of what we already do, right? These patients, many of them are recurrent. They are going to have had TURBTs. You can still, based on the ATLAS data, if you get, you know, a very multifocal tumor and it decreases in, you know, amount, like, in Sandip's patient, then you know, that patient then went on to a TURBT and had a complete response thereafter. It's a very mixed bag, and I think that we very much have to approach it that way, with the surgeons, and urologists out there. I mean, there was a paper that we, you know, we wrote about maybe 10 years ago that looked compliance with guidelines. We found that the compliance was terrible, right? You know, Ed Messing, who ran the SWOG trial, where they gave perioperative gemcitabine compared to TURBT alone, he was able to accrue, like, gangbusters in the clinical trial. Once the trial was done, you know, patients getting perioperative gemcitabine tanked. The reason why is that sometimes, as physicians or as researchers, we tend to design trials that provide patients with the most efficacy. I think we sometimes fail to understand the importance of feasibility. I think doing a trial like, you know, the ATLAS and the VISION trial is truly a study that's feasible, that urologists will adopt and provide for the patients. I think the most important factor here is feasibility. Yeah, I mean, Karim, I hate to push back, but, you know what? I'll push back. I mean, using perioperative chemotherapy after TURBT, that's variable, right? I mean, the patient may have hematuria, the body, bladder is thin, you know, you name it. This is a therapeutic agent for a disease state that is safe. Yeah. It is easy to do because urologists are used to doing it. Nowadays, you know, unfortunately, I shouldn't say that. There are other oncologists besides urologic oncologists that are managing non-muscle invasive bladder cancer. What they're doing is looking at the NCCN guideline, looking at the AUA guidelines as to what are our recommendations. A study from 10 years ago, I don't know necessarily may relate to what's going on today. In the waning minutes of this, because we got to finish up, I'm going to ask you one other thing, and then we, we've touched on a little bit, but just to get a concrete statement from you. The neoadjuvant paradigm, we, you know, we talk about it all the time in muscle-invasive disease. What do you think it, how do you think it will play in non-muscle invasive disease? Trinity, you want to start off with that? Yeah, I think that, it will be a lot of education and being able to educate and impart knowledge to urologists, that this is a concept that will work. I think urologists are very much early adopters. I mean, look at the surgical robot. I mean, we have adapted the robot quicker than any other profession. I think if you show them the data, or, you know, I keep saying this, if the durability is good and, you know, from the Phase 3 trial and you show the data, I think urologists are going to very much embrace this for many reasons. Katie? I was going to say, I think it has to do with, you know, really targeting those patients with that very multifocal disease, because oftentimes, these aren't patients. You don't look in and see a single solitary tumor. They have them kind of scattered around the bladder. I can't tell you how many times, you know, in my practice that I get referrals in from, you know, a community urologist who says, "I could do that resection, but it's way up at the top of the bladder, and I can't get my scope up there, and I can't do that." It does, you know, come into play in that situation, that you could really downstage or decrease volume of patients and make them, you know, more resectable at TURBT at that point in time. I think that that is the perfect patient for neoadjuvant therapy. I think the reality is that 80% of patients are complete responders. I mean, we don't have to really ask this question. I mean, the vast majority of patients are going to be completely free of disease at that cystoscopy. I think, as I mentioned, the patient I told you about anecdotally, if they're partial responders, thank you. Right? I wouldn't look at anything as a neoadjuvant paradigm. This is a treatment that has incredibly high rates of complete response. You take what you get, but you're probably going to get a complete response. The definition of neoadjuvant is that you're going to give them something and then later on, do the more definitive surgery. Here, like Sandip Prasad was saying, is 79% of patients never go on to that definitive surgery because the treatment was able to chemoablate. I think this is different. I think, you know, when you look at the hazard ratio for the muscle-invasive bladder trials, I mean, you're looking at a hazard ratio of 0.7, 0.8. Here, you're looking at hazard ratios of 0.3, 0.4, which is significantly more profound, you're avoiding a more extensive operation down the line. I think that's important. Let me ask the panel to stay here for just a sec, because we're going to move into a question and answer session. In a moment, I want to invite Liz back up for that. Let me just close, as if this is not obvious to you already, we've all had the privilege as surgeons to participate in the development of this therapy. Actually, Sandip and I were talking before the session began, and he said something to me that actually is the whole point for us as doctors. This is probably the first time we've ever done something that changes the actual practice of urology. Everything else is kind of incremental improvement, interesting scientific observations. With these data, we actually are looking forward to a different way of caring for patients. UGN-102 is not just a drug. It is, as Karim, I think, said earlier, it is a different way of looking at cancer. That is incredibly profound. The only historical paradigm or sort of comparison I can think of that would be relevant is Bernard Fisher's move to take us away from radical mastectomy to lumpectomy and radiation therapy in breast cancer. This is that big a change in the way we think about this disease. I hope that's come through clearly. With that, let me invite Liz Barrett back up so we can do a Q&A. Let me ask the panel to stay here in case there are questions for panel members. Yeah. Thank you. Thank you, Mark. What we're going to do is, we're going to just moderate the panel with the physicians, so in case you guys have some direct questions, and then we'll relieve them of their duties, and Mark and I and, yeah, we'll join you for a management Q&A, and hopefully, maybe we could talk Arie into coming up and joining us as well. Any questions you have for the physicians for us? Sure. Thanks for joining us today. Boris Peaker from Cowen. The focus has been on intermediate risk. Right now, obviously, the data looks fantastic. We just want to get a sense of how much do you think spillover is going to go into lower risk or spillover to high risk, particularly now that there is a BCG shortage as well. Sandip, you want to- Yeah. I think there's probably. Again, for a de novo tumor, all right, we visually can assess a tumor as papillary or sessile, meaning papillary, generally a bit more favorable, less likely to be invasive, sessile being a little more likely to be invasive. I think for de novo papillary tumors, if you're looking and you think a patient's a candidate, I think you're probably going to give it. Sometimes you may do that in the absence of getting the actual tissue pathology, 'cause I would say visually, we're generally pretty good at assessing low, low-grade and high-grade tumors. For patients where there might be a high operative risk to taking them in the operating room, you might treat initially. There's no question that the BCG shortage changes kind of the paradigm for much of the things that we do. These are just, these are patients which we previously might have treated with BCG. You just can't use it in this patient population. You have to reserve it for those high-risk patients, and I think it's going to bleed into that cohort as we begin to see more time on these types of treatments. Trinity? I think we use Mitomycin- C for high-grade non-muscle invasive bladder cancer. As you heard, it's in a different aqueous solution. We can do things to help optimize that. This is something that this is a chemoablative where we're treating, whereas things like BCG and other agents we use in the adjuvant setting, it is a little bit different. This I would suspect that this is going to have activity in high-grade disease as well, because we know that in the adjuvant setting, it works to treat high-grade papillary disease. I suspect that there'll be a great spillover into the high-grade disease. I think as urologists, as you heard, we're good at understanding what's a papillary tumor. We start to see broad-based, you know, more invasive cancers. You know, those are the people that are undergoing major surgery, like bladder removal. I suspect that this will be utilized in throughout the low risk, all the way to the high risk, potentially. I'm not saying that the FDA is going to approve that. That's not the indication here. If you're asking me about clinical practice. Potentially, yeah. Great, thanks. Anything? Paul? Thanks, Liz. For the doctors, obviously, the three-month data is very strong here, but could you maybe comment first on, you know, what you'd like to see in terms of durability, either at 12 months or the sort of median duration that would be more, you know, absolutely convincing for you to integrate one or two into your practice? My second question is just how you're thinking about maybe elaborating on utilization in newly diagnosed. We touched on that briefly, but maybe if you could just comment on what population or subpopulations, large or small tumors, that would be ideal for that. My third question is just, you've touched on this as well, which is just, with patients presumably coming in less frequently, your revenue would, you know, profitability per patient would go down. I guess, can you maybe elaborate a little bit more on how you're thinking about this and just what sort of, how you or your practices or institutions might approach that challenge? Thank you. Great. You wanna start off? Sure. Why don't you take one, and then we'll just work our way across. Sure. I'm, With regards to the question as far as, profitability- Durability. Durability? Well, I mean, I think if you look at, if you look at the Optima trial, you look at the OLYMPUS trial, I think we tend to see that about 70%-75% or up to 80% durability at a year. It wouldn't be. You know, for me, I'm expecting something within that range. That's based on historic data. I'd expect to be about a 70%-80% durability at a year. Would it be clinically meaningful? I think at least 50% would be clinically meaningful. What I expect to see is somewhere between 70%-80%. I was gonna mention, you know, when I, when I think of this, it takes me to that initial Kaplan-Meier, where us doing TURBT alone, the recurrence rate within a year is very high. I think anything that we're preventing recurrences that's better than what we're already doing is a win. If we get a patient, and we give them UGN-102, if it were approved, and they go a year without a recurrence, that is a win all day long because those patients in our standard of care as of today, they're recurring. Do you wanna talk a little bit about the use in new patients? I think Paul would have wanted to know about as opposed to recurrent. Yes. Yes, the newly diagnosed. Newly diagnosed. Yeah. The newly diagnosed patients, you know, I think, you know, We've already mentioned us, as urologists, you know, try, you know, getting that idea of a really papillary tumor and how that is, and what it is. I think what this offers is that those patients, you can take them to a TURBT, and then if they have a recurrence, you can use UGN-102, or you can use it upfront, in the upfront setting. I think that that leaves the option, and I said this earlier, it really just puts something extra in the urologist's armamentarium, right? Because if that patient gets a TURBT on their initial one, the chances are that they're going to recur, and they're going to be a candidate when their recurrence occurs. You wanna talk about the money? About the- Yeah, no, I think I would agree with that. I think that, again, there's some gestalt you're gonna have as a urologist that we're pretty good at in terms of determining whether a newly visualized tumor is gonna be something that's invasive, non-invasive, even low grade and high grade. I think there's a quite a number of studies that say urologists do a pretty good job of that. You can do an office-based biopsy under local anesthesia. If you wanna just take a little pinch of a tumor, make sure it's low grade, you could do that in the office in a little cautery. That's a very well-tolerated procedure where patients are under no anesthesia, find out it's low grade. Again, if the data are, turn out to be as robust as they appear to be, at least a three-month realization, four out of those five patients can probably be treated without a TURBT. I think that's probably enough for me to offer that to patients. Worse comes to worse, if you're in that 20% that doesn't respond, you get a TURBT. You know, we remove the tumor, but, you know, four out of five patients, you're taking away from them. For me, at least, it seems to be very straightforward. In terms of the revenue cycle, I mean, Karim alluded to a little bit, you're gonna have to have reimbursement for this. If it can be done by an APP who's sitting in another office setting, doing other intravesical therapies and sort of adding on to that, this is a five-minute installation. I mean, there's really no burden on the practice for adding an additional patient. I think as we learn to use these therapies, we're still gonna be doing cystoscopy, right? We're going to be looking in to make sure these patients are being treated and aren't recurring and don't require TURBT. This is not going to make absent cystoscopy. The hope is it will minimize TURBT. There's revenue from both of those, and it's actually quite incrementally different, as Karim said. It's not a big leap between the two, surprisingly. I think, you know, we won't be taking that procedure out of urologist's hands. We'll just be taking, again, holding blood thinners, general anesthesias, those sorts of things. Karim, you had a comment? Yeah, I think, Let me say it like this: the FDA has not provided us with an exact number, at least I'm not aware, maybe. That's correct. They have not provided us with an exact number as to what is a, a clinically meaningful CR at 12 months. We know what that is for BCG unresponsive disease, 'cause we actually came up with that number at a table about like this at GU ASCO in 2015, but they haven't. The good news is, is that if you just show that there is a response which is better than the historical other trials, it is going to get approved, and urologists will use it. It's a disease state that is very much, under study. I mean, with regards to the question as far as newly diagnosed, I think the big 800-pound gorilla in the room is that the prevalent patients are about 10 times the newly diagnosed patients. You got 726,000 patients walking around with bladder cancer versus 72,000 that are newly diagnosed. When I see patients in clinic, I do 15, 16 cystoscopies in my typical clinical day. Only one of them is a patient that I'm newly diagnosing with bladder cancer. The other 15 are patients that I've already been treating, that's where the burden is. It's not in the new diagnosis. It's really the prevalent diagnosis, where they're using a lot of hospital resources, I think there's significant benefit here in helping those patients. Great. Thank you. Next. Thank you. Then just grab it when you're done, just give the mic a little bit ahead in front of you. Thank you. Charles Zhu from Guggenheim Securities. I think the answer to this question will be pretty apparent just based on the commentary so far. How are you guys thinking about the potential for re-challenge with the UGN asset after a potential recurrence? Does this kind of thinking change based on how the patient had previously responded, whether it was a partial or a complete response? You know, how are you thinking about durability response and impacting that decision point? Thank you. Trinity, you want to take that one? Yeah, I, I think the way, and as bladder cancer specialists talk about induction course, which is the first treatment, and then you can do a second induction course. I would suspect that that's exactly what's going to happen if this gets approved. We're going to be looking at a second induction course to see if there is a response, and especially for those that had an initial response, and then we would reintroduce as a second induction course. You know, unfortunately, this is a disease of recurrence, so the patients are still going to recur. If they have a durable response, for example, 12, 18, 2 years, I would have no problem going back and giving them a second induction course. Somebody mentioned this earlier. I can't resist asking, what about the use of maintenance? There's no maintenance data. We have no idea. Yeah, I said that. I mean, do you think maintenance will actually arise out of this experience? Well. It's definitely going to be a discussion, you know, for that, because it's such a recurrent, but I really think that's where we have to really see out what this duration of response is going to be and ENVISION, that's really going to guide us, right? 'Cause as of now, that initial complete response, we're talking about 20% of patients that didn't respond. You know, and so the 80%, what's that durability? And if it's really good with just the induction course, maybe you don't need it. We know that intravesical maintenance therapy with chemotherapy, with the chemotherapeutic agents, more recently, what we use is a combination of two chemotherapeutic agents on a monthly basis. We know, at least from retrospective data, that it does reduce recurrence. There are now some new trials that have been designed to look at maintenance therapy in comparison to things like intravesical BCG, so we'll have a much better idea. Once again, that has now become almost standard of care, especially at large academic institutions, that use maintenance, monthly maintenance. This is the curse of having a good durability response, is that you may not need it. I mean, that's really the remarkable thing is if you can just do this once every three years, when a patient presents with a nova tumor on cystoscopy, you know, you kind of have that back in your armamentarium. I think you got to study maintenance. I mean, clearly, what it would do is just treat microscopic disease that you haven't seen yet, right? Mm-hmm. That would have eventually become visible three months or six months later. You're basically treating it, and I think that's how, you know. It works. the combination, sequential treatment works. It's basically treating, you know, occult disease before it's visualized. Again, you could make that argument here. If the durability is very strong, I'm not sure. You may or may not need to do that and just retreat when appropriate. Well, we think that's great. Yeah. It's great for patients, right? I think at the end of the day, you want to do what's in the best interest of the patients. If the patients can have some treatment-free intervals, great. You know, and when they do recur, if they're, you know, they'll be able, hopefully, to get UGN-102, just like we do with gemcitabine. We're starting to see that now, and we, you know, we will definitely need to study, and we'll study that. Great question. Sandip. Hi, thank you all for being here. I'm Mitchell Kapoor from H.C. Wainwright. I just wanted to ask, obviously, you guys have a lot of positive sentiments on UGN-102 and the data we've seen. Amongst your colleagues, could you just talk about what some of those barriers to uptake might be? What might be something that someone might say, "Hey, this might not be right for a patient, or some of my patients, or all of my patients? I think that's a great question, right? We're all bladder cancer surgeons. This is what we do all day, every day, and think about, but a majority of urologists are not that that see this. You know, it is a very mixed bag, right? Oftentimes, surgeons and physicians are very narrow-minded, and they want to know exactly: Do I do a TURBT and then give it? Do I give it and then give a TURBT? It's going to be very important for us to design that and lay that out as how do you. You know, I say it's in our armamentarium now, but where does it fall in the sequential, you know, treatment of these patients in our armamentarium? Obviously, we've talked about the finances and the reimbursement. I, you know, that can definitely be something initially that urologists come off with, right? "This is a routine surgery that I do. Don't take it away from me." The other thing that we mentioned is training, right? We've been taught, historically, now that is changing paradigm, but, you know, for years, we've taught residents, and I was taught as a resident when I was in training, that, you know, you can't see a tumor in the bladder and just throw some chemo or throw some BCG on it and expect it to go away. You have to do surgery on those patients. It is an educational thing that's going to be, and that's the exciting part, is that this actually truly flips around what we've been taught, and I think that that is exciting, but it does pose a complexity in how that goes forward. There's going to be logistical issues as well. I treated the first patient after commercial approval of gemcitabine in the United States. There was no codes. We didn't know what the reimbursements were going to be. UroGen was really worked well with us to be able to ensure that that was under the surgical center, we had the additional aspect of an ambulatory surgical center involvement for that care, which won't be relevant here because this can be done in the office under local anesthesia. You know, how will we get the drug? Will it be at a dispensary, a third-party pharmacy that has... Yeah ... to deliver it on the day of? Are we going to be able to somehow constitute this ourselves in the office, like that we do BCG? There are practical implications that on study we don't have to worry about because everything is streamlined for you from a process standpoint. I think those are going to be really important for the UroGen team to help us with. I think the Gemcitabine experience is going to help that. I mean, again, the 95% crossover between pathways, some of this has been worked out a bit with a very similar agent, of course. I think that's important, especially when you're talking about the breadth of practices this has to reach. Yeah. That's important. Very, very good point. I mean, the, I think we all know, you know, the logistics and very challenging for Gemcitabine. Everything we've learned, we've implemented for UGN-102. It will be much easier for so many different reasons, you know, and we won't have the eight hours. There'll be so many things that will be so much easier and, you know, that's our goal, right? To make this easy as possible for urologists. Still, you still are talking about a drug that's in, you know, with our technology, with our gel. It has to be mixed, we're going to do everything pre-mix. We've learned and doing everything we can to make it as simple as possible. In reimbursement, look, I think we're very pleased with where we ended up with reimbursement with Gemcitabine. We have over 99% reimbursement. We'll do the same things we did with Gemcitabine for UGN-102. To your point, the fact that we've launched and we've learned, and the fact that a lot of the physicians who have used Gemcitabine, as, you know, you know, Dr. Chamie said earlier, will be the candidates, they'll want to use UGN-102. A good question, Trinity. I'll be very quick. Two barriers. One, community practice, solo practitioners, three to four practitioners, don't have a specialty pharmacy to be able to mix it, to get it to them. That will be a barrier for a lot of like, community-based urologists. At least that's my opinion, okay? Second is, telling a urologist that this is that you don't do surgery and then do adjuvant. That is going to be a situation where we're going to have to teach people that this is, the trial design was the following, and this was given in the presence of a tumor. That is going to take. I think there's going to be a generation gap, where you're going to have people that just are like, "I don't get it. I'm not doing that." Others where you'll have those early adopters, so. Yeah. I think that there's two things that are happening that are kind of helping to obviate some of those concerns and challenges, right? One of them is the fact that I think with gemcitabine, it was a little bit of an issue because you have to have the specialty pharmacy to mix it for you that day. Nowadays, when you have 96 hours worth of formulation, I think it's going to help reduce that burden. I think it's going to be easier to make it four days prior and provide it. The second issue is that we, as urologists, are becoming increasingly more comfortable watching these tumors. I mean, when you actually look at the original bladder cancer trials, that we're looking at BCG, at three months, a significant number of patients still had positive cytologies, we were patient, and we gave them BCG, and they responded. If you look at a lot of BCG unresponsive trials, a lot of patients recur, but the vast majority don't get the need to get their bladder out. we, as urologists, are becoming a little more comfortable in our skin, giving these drugs and just being a little more patient before we become radical and do our resections. I think that's, that's permeating through the field. Can I just say one more thing? I just thought of it as we were kind of talking about implementation. We can't forget that, you know, gel, volume, right? Volume of patients. Yes. Right? Gemcitabine, there's not as many nowhere near the number of patients that are going to be, you know, eligible for if this were approved for intermediate-risk non-muscle invasive bladder cancer. Just the fact of doing things more streamlines the ability to have that in place for a pharmacy and to get that up and rolling, right? The community urologist, who doesn't see very much upper tract urothelial carcinoma, to go through all of those hoops to get Gemcitabine up and going on their formulary, it's way easier to say: "Oh, I'll just refer them into Katie or to Trinity or whoever else," you know. The volume that they're going to have of intermediate-risk non-muscle invasive bladder cancer is going to be worth it to them to go through those steps and do that. No, it's absolutely, and we talked about that a lot, right? When you only see one or two patients, to change the way you practice is very different than when you see the number of patients that you see with this patient population. We will have actually over a week, so even 96 hours, where stability will be even longer for UGN-102, and we'll be providing it mixed already. All of those things that, you know, the challenges, some of the challenges we faced, we won't have even from the, from the get-go. Any other questions? I think Leland. Yeah. Leland Gershell with Oppenheimer. thank you. Great to finally see this data- Yeah. thanks for the discussion. My first question actually is a lead in from this discussion about the preparation for the premixing. To what extent will, you know, UroGen need to? I mean, a lot more patients, a lot more physicians practices will be treating these patients. What's your approach there? How much will you have to deploy to get, you know, physicians in position to be able to give this who don't have the facilities? My second question, as we learn further about the data from ATLAS and ENVISION, you know, we'll learn about baseline characteristics and so forth. I mean, LGIR is still a fairly broad and variegated population. Are there any particular factors that these patients may show at entry into the trial that may, when the data come out, about how they perform, drive decision making with respect to UGN-102 versus surgery? Because the data are so strong, it may be other factors, you know, reimbursement, access, and so forth. I think the study populations are. Yeah. representative of the patient population we see. I don't think you're seeing a pretty. The ages are in the means, are in the 70 years of age. Cardiopulmonary baseline is similar to what we see in clinical practice. I don't think it's a selected population in any particular way or enriched with any particular characteristic. I don't think we'll see a significant difference in the patients that we then apply to in clinical practice. At least that would be my opinion. Yeah, I agree. Absolutely. I think also, you know, it's not gonna be that we just wanna use it on the patients, that we have to stop anticoagulation, that we don't wanna take to surgery. It's gonna be an option for those patients, but also an option for the patients that are younger, healthy, that we could easily take to surgery, right? They would potentially do well with it. A general anesthetic isn't gonna hurt them. It does cross that gamut. Okay. Yeah. What I would like to see is a breakdown of size of tumor, how many tumors, and recurrence. If they had a recurrence, how soon was their recurrence? Like, the ENVISION trial was enriched for patients that had a history of low-grade papillary disease. Was that 10 years ago? Was that six months ago? Was that five years ago? You know, yeah, there's a lot of factors that I think would, would help us be able to understand, really a lot of things about the therapeutic efficacy. Just a note about this. This trial, as you can imagine, the ATLAS trial produced an enormous amount of data. We will be looking at analyzing and then reporting on these data, you know, in the months to come. This is the first tranche, obviously, very exciting, but there's lots of other exciting information in the study that we will be talking about as, as time permits. Yeah. There are several publications coming out of this. Arie, did you wanna- Let me make Arie Belldegrun. I would like to just to make a few comments. This is a great day for many of us, specifically for Mark and myself, who for the past almost 10 years, tried to convince urologists that it's time to change. Number one, is that I really enjoyed the panel. To see a group of experts, all around the country, East Coast, West Coast, all agree with one another. I can tell you, I've been over three decades at the AUA, I have very rarely seen a panel of experts all agree with one each other. Absolutely doesn't happen much. There's always some naysayers: "However, the study was not designed well. I don't see the control group. I don't. There are some issues." That's why they are called experts in bladder cancer. To see all of you agree that it's time to change the practice of urology is really special, and number one, thank you very much. Urologists are going with the habit of what they trained. I can tell you that I'm sure that Mark at Johns Hopkins, where he trained, and I at Harvard, at the Brigham and Women's Hospital, years ago, practicing urology, 10% of what we were trained. One of the 10% is TURBTs. We were trained that you see a tumor, what's, what you see, you get, you do a TURBT, you cut it out. What would happen later? Let's wait three months. We'll see what happens. This is wrong education. I'm sure that we will start changing it, because just as an example, when somebody is smoking for years and has a carcinogen in his urine, it's very clear that over the years, something is changing in his DNA, and it doesn't change in a specific site. It changes wherever urine is touching the urothelium. It's a field defect, so everything is diseased. When somebody comes with bleeding and you look inside and you see a bladder tumor, you don't tell him, "You know, in three months, you might have four or five tumors. Maybe we'll wait three months, and at that time, we'll do a TURBT, and we'll cut all the tumors. Then three months later, maybe wait six months because there will be more tumors." Every tumor has a different... The DNA changes not equally, therefore, there will be multiple tumors. We were trained that way, and that's how we continue for so many years. I don't think that anything has changed. That's why I trained Karim Chamie years ago. Now he's the professor and the head of the bladder cancer, and he's tried to change, and I hope he will teach the residents in a different way. I think I view it not much as the UroGen or UGN-102 or UGN-103. This is a new concept, the disease in the entire urothelium, and we need to treat not what you see, but what the, and what is diseased. That's, for me, a big paradigm shift that will take it to the next levels. I can tell you, as a company, as UroGen, you have to focus and not do what you can do. We have immunotherapy in the company, a agent that you can put into the gel, and it will stimulate the immune system. Very exciting, but we had to focus financially, specifically these days in the, in the biotech. There is no reason why not to combine now this chemotherapy with the agent that we have in immunotherapy and change the milieu inside the urothelium and the bladder or the upper tract. I think that that will come next, but first, we need to educate the urologists to understand about the change in the practice, and from there on, all the new technologies that are coming. ... immunotherapy of renal, of kidney cancer and other tumors will be applied to bladder cancer as well. Thank you all much. It was a really great panel. Right. Thank you. Any other questions for the panel before we let them go? Mark and I will stay up in case you have any other company questions. Thank you. Thank you, guys, very much. Really, really, really, really appreciate it. It was awesome. Thank you. Thank you. Thank you very much. It was really great. Thanks so much. Really appreciate it. Thanks. You're rock, man. Thank you. Thank you. Yep. Oops. Anything else? Yeah, just a few questions for me. I guess two questions. First of all, with ATLAS being so strong, do you think you could just file on ATLAS and not necessarily have to wait for ENVISION to mature? Second question is, how are you thinking about pricing, in this broader indication? Okay. Of course, our next step is to engage with the FDA. We agree this is very compelling data. When you look at, as I mentioned this earlier, when you look at the three studies, OPTIMA, ATLAS, and ENVISION, very, very consistent, you know, very consistent responses, very consistent durability. We're demonstrating for the first time. You know, we stopped enrollment of ATLAS, and we did not expect that we would demonstrate superiority to TURBT with the 280 patients, which we did. Definitely, we will be having those discussions with the FDA. Right now, what our plan is, is that we continue for ENVISION, we continue to follow them for durability. As you've heard before, once we get to 12-month durability, our plan is to file with the FDA. This data gives us a lot of confidence in what the ENVISION study is gonna be like. It's just so consistent that we believe it. Yes, we will be engaging with the FDA. We will be aggressive with them about talking about this data. The ATLAS study was, you know, something that had never been done. You heard it from the panelist. There was really not a lot of data out on the natural history of using TURBT, that's what this study does in addition to that. We will engage the FDA as soon as we can, and we will ask all of those questions about how much durability do they need to see in ENVISION, what type and how quickly, because our goal would be as quickly as possible to get an FDA submission and approval. We're gonna give it our shot, right? You know what they say, I mean, what we know today is they've told us that ENVISION can be a pivotal study and that durability is important. I think durability, you know, or durability in ATLAS and the similarities between them will be very key. On the pricing, we just finished a pricing study. Our goal at the time, our expectation at the time was because it's a much bigger patient population, that you weren't losing your kidney as you are in JELMYTO, that our expectation was the price would be somewhat lower than JELMYTO, but still, I would say, argue at the time, between $50,000-$75,000 per patient for six courses. I do also believe that this data, it's about value pricing, right? I do believe this data allows us to look at pricing, particularly, you know, given the compelling responses in recurrent patients and the high unmet need, we will be reevaluating that. I think it's safe to say that, you know, we'll be value pricing. It will be significantly more, frankly, than most of the analysts have in their models. We've been, you know, talking to everybody about that. This will demand, you know, a price, an innovative price. It's an innovative drug. We will, you know, look to price it innovatively. Hi, Liz. Just a quick one on IP. I think the Orange Book for JELMYTO goes to 2031. Can you maybe just remind us if for UGN-102, there's any different IP involved here and just what your base case assumption is for exclusivity here in the U.S. for UGN-102? Thank you. Yeah, I think it's a great question. I'll say a couple of things. One, the 2031 also applies to UGN-102, we also have. You know, when we received this data, we looked, you know, comprehensively across any potential IP to be able to extend the IP. We're continuing to look for ways to extend the IP on UGN-102, as well as JELMYTO. We will continue to do that. I have also mentioned in the past our next generation and next-generation formulation, we believe that there is a real opportunity with the next, our next generation, that we will get extended IP to 2035 minimally, potentially to 2041. The last thing I'm going to say is that this drug is very difficult to manufacture. The good news is that the feedback we've gotten from the FDA on the things that we have to do tell us that if anyone were to come in, even at 2031, they're not going to be able to. There's not gonna be an AB-rated generic. They're gonna have to do a clinical study. We think that, you know, we're working comprehensively across the board to extend our own IP, but also to ensure that, you know, the strategy will be that anyone trying to come in will have to do some clinical work. I think we have, we feel good about our runway as far as IP is concerned. To date, UroGen has been a U.S. commercial enterprise. You know, the strength of the data and the market opportunity, any thoughts about ex-U.S. opportunities, whether, you know, potentially with a partner or, or not? Yeah, when we come up for air, you know, with all of this data and the financing that we just did, we will look at that. I will tell you that we remain challenged outside of the US, not with getting approval. That has actually never been the challenge. The challenge is getting reimbursement at a decent rate. Because what happens, but now that we've demonstrated superiority to TURBT, may be a different situation, but what happens in, you know, every country in Europe, is they want to compare it, right? They have a basket. So we will still have that challenges, but we will revisit that as we go forward now. What, you know, what other data might we need to generate, you know, to get a decent reimbursement there? Hi, Matt. Yeah. I guess, given the strong results in low-grade intermediate-risk and the panel discussion around the potential outside of that, what are your plans to, I guess, develop it outside of low-grade intermediate-risk and facilitate the label expansion, potentially in the future, and utility and uptake? Yeah, sure. A couple things, and Arie actually mentioned it when he talked about UGN-301 and, you know, the zalifrelimab. One area would be to combine UGN-102 with zalifrelimab in high-grade disease, so that's one opportunity. Another opportunity is, and what I've always been very passionate about, is the unwilling and unable. You heard a lot on the panel today about patients who should not be going through surgery. They should not be going, you know, because of, you know, comorbidities. That actually opens up... We have, you know, the intermediate risk is 20% of the population of low-grade disease. That other 80%, you know, our study shows that 25% of those patients should not be going through surgery. I think an unwilling and unable study with UGN-102 allows that. Those are a couple of the initial thoughts. I don't know, Mark, if you had anything else, but. We have a lot of opportunities. A lot of ideas. We have a lot of ideas. Anything else? Well, look, I just want to take the opportunity to thank everybody for being here. We really appreciate your interest. We're excited about this data. It is game-changing for us as a company. I also just want to take the opportunity to thank our partners at RA Capital, Great Point, and Acorn, as well as, you know, Monograph and Horton for helping us fund our future. We're really, really happy, not only to be presenting the wonderful data that we have. You know, and as I said, you know, it's a, it's a great time in our company, and we look forward to continue to work with you guys. We'll keep you posted. Thank you.